AKG supplementation improved my biological age in these three ways
IS AKG ANTI-AGING? AKG Supplement improves bio age
AKG supplementation improved three measures of biological age, and has now been permanently added to my longevity hacking stack.
AKG supplementation (also called “Alpha Keto Glutarate") caused a notable stir in the longevity community after a 2021 study in the journal Aging found it improved the biological age of 40 of 42 participants in a small study.
We recently discussed the outcomes of this study with TruMe Labs Co-Founder Yelena Budovskaya, who have now made the biological age measurement from this study available to the general public (via their “TruMe Age Explorer” test).
Naturally, this peaked my own curiosity - could I replicate these results in my own biological age?
After a bit of investigation, it became quite clear that I could. In fact, any one of you reading this could do the same. This post will show you how.
This type of self-experiment is quite straightforward. All you need is a before and after biological age test, a supply of AKG supplement (read our review here) and a scientific approach.
This is, after all, what we love to do here at Longevity Blog - guide our readers to develop their own longevity strategy through self-experimentation.
We have already posted on the reported benefits, basic science, best choice of supply for AKG supplementation in a previous post, so we will get straight into the self-experiment framework and results.
Alpha Keto Glutarate: Experimental framework
Score a 10% discount of high quality, third party tested Alpha Ketoglutarate from DoNotAge with the discount code “longevityblog”.
Dosing of Ca-AKG commenced in November 2022 at 4x capsules of DoNotAge Ca-AKG at 400mg each, for a total of 1.2 grams of Ca-AKG. This was taken with my morning supplement stack, after breakfast.
This dose amount continued for the first 3 months, before increasing the dose to 6x capsules to bring the dose to 2 grams per day.
Dosing remained at 2g/day for the remainder of the experimental period for a total 9 months.
In the 2021 Ca-AKG study from the Journal Aging, dosing was 1g/day for 7 months.
Biological Age Measurements
I measured my before and after biological age with Longevity Blog’s 3x favourite biological age tests (we tested nearly a dozen of them!):
TruDiagnostic’s TruAge (save 15% with code ‘longevityblog’)
TruMe’s TruAge Explorer (save 12% with code ‘longevityblog’)
GlycanAge (save 15% with the code ‘longevityblog’)
Biological age measurements were taken in July 2022 and July 2023, which is my regular annual biological age testing window.
This did mean that 12 months passed between biological age measurements, with only 9 months of AKG supplementation. As you’ll soon see, results were still quite clear.
Blood Measurements
Self-ordered blood tests were ordered through Australian supplier i-screen, who allow you to order and review your own bloods without visiting a doctor.
Blood tests were selected to be very comprehensive. Allowing for the review of immune, liver, kidney function, hormone balance, lipids and more. I carefully chose these tests to have all of the required parameters for the “Phenotypic Age” biological age estimate, providing a fourth type of biological age to test.
Blood tests were closely aligned with AKG supplementation start and ending dates.
A note for your own self-experimenting, you don’t need exact matching between supplement start/end and blood testing. Focus on what’s doable for you - the main thing is that you don’t change any other lifestyle or supplement factors until you’ve completed your follow-up testing.
AKG Self-experiment results
There was a clear improvement in biological age by multiple measures, we’ll work through them sequentially, and then come back for a discussion about interpreting the results.
Make it stand out
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The TruAge Explorer test kit. From only $90USD using the discount code ‘longevityblog’.
RESULT: TruMe Age
In July 2022, my TruMe biological age was 38.9 years, or 2.3 years older than my chronological age.
After 9 months of Ca-AKG supplementation, my TruMe biological age dropped to 37.9 years (-1.0 years), however during this period I aged +1 year. This result is 0.4 years older than my chronological age.
Overall, my biological age result improved by 1 year as compared to my chronological age, with an overall improvement of 2 years.
RESULT: Trudiagnostic extrinsic age
TruDiagnostic’s TruAge Complete biological age test kits provide significantly more comprehensive results than any other biological age test.
This includes estimates of both extrinsic and intrinsic biological age, and an estimate of your telomere length biological age.
You can learn more about the differences between extrinsic and intrinsic age in our interview series with Co-Founder of TruDiagnostic Ryan Smith - part 1 and part 2.
AKG supplementation did not have a significant impact on my intrinsic age, however, there was a notable change in extrinsic biological age. Which dropped from 27.56 years (-9 years from chronological age) to 25.10 years (-12 years from chronological age).
I’ve also supplemented with Nicotinamide Mononucleotide and measured biological age before and after using the Phenotypic Age method. Curious? So were we… read the post!
Again, while one year passed, my biological age actually became younger. This time, 3 years of total improvement.
This result is particularly interesting, given AKG’s known role in improving immune system health, but we’ll save that for the discussion.
RESULT: GLYCANAGE
Unfortunately our GlycanAge biological age test was lost in transit and we do not have the after results from this test.
RESULT: Phenotypic Age
In one of our first posts on biological age, we introduced three free ways to estimate your biological age.
Tabulated results across the three tests. Don’t forget that I aged one chronological year over the course of the experiment!
One of these estimates is called Phenotypic Age", and I have now been tracking mine for the past three years, and have been able to find blood tests reaching back all the way back to 2015 to re-calculate (age 30).
After 9 months of AKG supplementation, my Phenotypic Age improved from 30 years old to 27 years old (-3 years). Given that I also aged +1 year chronologically, this is a net result of -4 years.
This biological age estimate is much more sensitive to changes in diet, lifestyle and day to day ups and downs, so we need to consider this result conservatively.
Only once before have I seen a similar improvement (-3.5 years) in my biological age, which was after I self-experimented with NAD boosting supplement Nicotinamide Mononucleotide.
Selected blood results
In the following, I share all blood results that had a significant change over the experimental period, did not have other confounding factors and for which there was scientific research on AKG supplementation that supports a causal link.
All test data presented here is through self-ordered blood test provider i-screen (Australia).
Liver Function
Nov 2022 to Aug 2023 liver markers showed statistically significant improvement. Note that my liver markers are at time elevated because I am an endurance athlete.
Inflammation
Nov 2022 to Aug 2023 high sensitivity CRP, a key marker of inflammation, reached the lowest levels of all time. Even below the levels had 10+ years ago.
LDL-C
Nov 2022 to Aug 2023 saw a 10%+ drop in LDL-C, which, which is significant as it is now at the lowest level I have ever measured. Noteworthy after the March 2021 test, I eliminated dairy from my diet and LDL-C plummeted!
DHEA
Dehydroepiandrosterone sulfate (DHEA) levels are closely linked with cellular energy production, and many important bodily systems are downstream. My levels appeared to climb by 25% post AGK supplementation.
akg supplementation: DISCUSSION
You don’t have to use supplements to improve your biological age. Nick did it by adding more plants to his diet, read about it here.
Interpreting the results of a self-experiment is a very important step. It is very tempting to see rdata in results form and try to form a conclusion straight away. To bring in tools from science, we must discuss the results first!
If you’ve ready any of my previous self-experiments, you’ll know that how the self-experiment was controlled is pivotal. In essence, this means limiting as much as possible, any external factors which could ‘confuse’ the results.
When you come to complete you own self-experiments, you need to balance several factors.
First, you need to try the intervention long enough for it to have effect on the variables you are measuring.
In this example, we are looking at biological age changes, which in the case of epigenetic tests like TruMe Labs or TruDiagnostic, take around 3-6 months for effects to be observable.
AKG supplementation has an immediate on cellular energy production, but the flow on effects to the epigenome need significant time (months). In the case of the research study on Ca-AKG and biological age, the results were measured at 7 months of supplementation on average.
My selected period of 9 months allows for enough time for the AKG supplement to imprint on my epigenome and brought it into alignment with my annual biological age testing regimine.
Second, to effectively determine how long the self-experiment will run for, you need also consider controlling other variables which might effect the result.
You’ll want to run the self-experiment for long enough to impact the measurement variables you’re after, but not so long that you cannot control other variables that might impact the result.
Hear from our Founder Nick on biological age testing and how you can change diet, sleep, exercise and stress to improve yours! Read more
In the case of biological age tests, the most influential factors to control are:
diet
sleep
stress
exercise
pollution/smoking
supplements
COVID-19
Well Controlled
In my own case, I have a very regimented lifestyle. I keep to my triathlon and strength training with daily walks (exercise). I sleep a solid 7-8 hours a night, with a consistent bedtime. I live in a rural area with very low levels of air pollution and have not moved in the experimentation window.
No major changes to my exercise, sleep or environmental pollutants were observed.
My diet is a dairy-free, mediterranean-esque diet focused on plant diversity and high protein intake (meat, fish, poultry, eggs, whey protein isolate). I know that this diet works well for me based on my blood tests and biological age data, and I’ve not made any significiant changes to it.
These factors therefore can be considered to be well-controlled, for the purposes of impacting the epigenome.
Not Well Controlled
Stress however, was an unavoidable confounder.
I went through several major life changes over the self-experimentation period, and stress was at times at very high levels, often for weeks at a time. I do believe this negatively impacted by biological age results.
I also contracted COVID-19 in May 2023, which likely also negatively impacted my biological age result, with both experts - Ryan at Tru Diagnostic and Yelena at TruMe Labs suggesting I leave at least two months after my recovery before re-testing. I followed these instructions.
Conclusion: Ca-AKG positively impacted by biological age
Given that the not well controlled self-experiment results would raise by biological age, but that I measured improvements to biological age across three different tests, as well as in several important longevity blood measurements (LDL-C, DHEA, ALT/AST, hsCRP) - I believe there is a solid and clear conclusion.
Ca-AKG supplementation at 1-2g/day positively impacted by biological age.
Note that I do not say ‘reversed’ my biological age, as I do not believe that these tests are able to substantiate that claim.
However, given there was a 3.1 year mean improvement in biological age between these three tests, I can conclude that Ca-AKG will become a permanent addition to my longevity supplement stack.
And through this example, you are now empowered to run the same experiment. This is incredibly important, as if you run the math - taking 1-2g of Ca-AKG per day (using your 10% discount code ‘longevityblog’ at DoNotAge), it will cost you $630 to $1200 USD per year.
This is not a small investment - you want to know the supplement is working for you.
The method and example laid out here can help you answer that question! It did for me!
PARTNER Discount Code!
A part of our mission is to make your longevity budget stretch further.
Through our collaboration with TruMe Labs, we have a negotiated an industry leading 15% off coupon code for our readers.
Use the code “LONGVITYBLOG” at CHECKOUT TO SAVE 15%!
And through continued collaboration with DoNotAge, we are offering a 10% off discount for their Calcium Alpha-Keto Glurate supplement as well!
Use the code “Longevityblog” at checkout to save 10% on AKG
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Can Tru Diagnostic Finally Answer: Why am I aging so fast? An interview with Ryan Smith
Why am I aging? Why am I aging so fast?
Why do I feel older than I am? Why am I aging suddenly?
Sometimes aging can catch up with us very quickly, leading us to ask questions like these ones.
The years add up, and we don’t feel the vigour and vitality we are used to. Most of us assume, there isn’t much we can do about it. Aging is inevitable, after all?
You may be new to the longevity technology scene, most people are. Or you may be a longevity hacking legend, who thinks they know everything about how to slow the aging process.
It doesn’t matter which side of the spectrum you find yourself on, there is an exciting new development in the field of biological age testing which can help you answer the all important question…
Why am I aging?
In this post, we are going to review recent updates to TruDiagnostic’s biological age test, which help to answer:
Why am I aging?
If you’re new to biological age testing, there a few deep dive posts you can read on Longevity Blog, perhaps start here or here.
To summarise them in one sentence, it has become possible to measure how old you are biologically over the past few years and there are now dozens of tests for doing so.
But to date, none of them could give you concrete details on the why behind your biological age score.
You might be biologically older or younger than your chronological age (connected to your birthday, the number you celebrate each year).
And beyond ‘exercise more, eat better, sleep more, stress less, don’t smoke, avoid pollution’ - there really hasn’t been much you can do about the aging process.
Until Now….
Tru Diagnostic: Getting to the “Why” behind “why AM I AGING?” (and what to do about it)
Aging is ridiculously complex. Our approach with the OMIC Age clock has been to consolidate information from the entire system and taking a more complete look at the full picture of biological aging…
One of the big things that we have shown with this new aging clock is that it is really the most predictive of every type of age related outcome.
This quote is from our interview below with Ryan Smith, Co-Founder at Tru Diagnostic. We’ve previously introduced Ryan and interviewed him in a two part review series, which you can find here - Part 1 and Part 2.
Our role here at Longevity Blog is to dive into the why and how behind such claims. We aim to dig deep and find the real answers behind the marketing slogans.
We interview founders and lead scientists at longevity tech companies and present you the raw, unfiltered conversations that get straight into the answers.
Today, we’re going to explore some of the key updates to the TruDiagnostic test kit, including the powerful new research efforts behind its development.
What just become possible is truly impressive, and may even be groundbreaking into a new era of biological age testing (namely finally answering - why am I aging so fast?).
Let’s do just that.
PARTNER Discount Code!
A part of our mission is to make your longevity budget stretch further.
Through our collaboration with Tru Diagnostic, we have a negotiated an industry leading 12% off coupon code for our readers.
Use the code ‘longevityblog’ at checkout!
This interview was conducted in October 2023 over Zoom and is an audio transcript with minor edits for clarity, brevity and correctness.
Tru Diagnostic “OMICmAge” Update
Longevity Blog (LB):
Ryan, thanks so much for coming back to join us again on Longevity Blog, we are really excited to talk to you about some updates that Tru Diagnostic has to their biological age estimates.
The new algorithm is called “OMICmAge” which you are pronouncing as “OMIC Age”. This algorithm is multi “omic” in nature and has demonstrated some very impressive results particularly in predictive capability for mortality and health outcomes.
We are going to break it down - let's start first with what does it mean to be “multi-omic”? And what is an “omic”?
Ryan Smith (RS):
Generally, we would call these “omics” different levels of measurement that are trying to replicate what happens naturally in our body from a stepwise process.
This starts with things like genomics, everyone's familiar with the genome. That would go to the epigenome into things like transcriptomics, metabolomics, and proteomics. These are different ways to measure physical things which are happening in the body.
Bringing together data from all of your “omes” provides a more comprehensive picture of your biological age and why you are aging.
The reason that this is important for aging, is because aging is ridiculously complex. Our approach with the OMIC clock has been to consolidate information from the entire system and taking a more complete look at the full picture of biological aging.
LB: Just to make sure we get this really clear, you mentioned a few different types of “omes”. First genome and epigenome, our audience is pretty familiar with those.
You probably start to lose some readers when you mentioned proteome or metabolome. Why don't you briefly explain what either of those are just as examples?
Tru Diagnostics New Aging Clock Tests More of Your Individual Biology
RS: In the molecular biology world, we have being transcribed by the ribosome, which then create the proteins or peptides that make up the infrastructure of the body. That's what we call proteomics.
Metabolomics is the study of all the small molecules or metabolites within the body. One example of important metabolites are our hormones or neurotransmitters.
Even if you might not be familiar with proteomics and metabolomics, you are certainly familiar with the spectrum of biomarkers that influence disease progression or performance.
LB: This involvement of these different “omes”/”omics” provides a lot more information about what's happening in the body as it is aging. Including this additional information produces a great result - the predictive capability for both mortality and health outcomes.
Can you explain the significance of this development?
OMICmAge Can Predict Health Outcomes, Not Just Mortality
RS: One of the big things that we have shown with this new aging clock is that it is really the most predictive of every type of age related outcome.
More generally, if you are accelerated with this biological clock (biological age > chronological age), you are going to be at more risk of all negative health outcomes than you would be if you were accelerated with the same amount (e.g. +1 year) than any other clock (i.e. any other biological age test).
Pulling together so many sources of information, allows the new OMICmAge algorithm to be incredibly predictive of both mortality (death) and disease outcomes (what age related illnesses you are most likely to get).
LB: The last few sentences that you described are really exciting, and something we will converge in on after a few more questions here. One thing we want to go back to, in addition to this “omic” part of the clock name - we also have an “m” in there, which stands for methylation.
This part of the background development on the new clock comes from a broader collaboration, that is actually really impressive. You have pulled in some of the best researchers on this topic in the world.
We would like to just briefly hear from you about that collaboration.
Tru Diagnostic Partnered With Harvard to Bring in the Leading Science
RS: Proving outcomes about longevity and disease requires following up patients for 40 or 50 years to see what is happening to them. Are they developing disease? Are they dying? When are they dying and what are they dying of?
All that information is incredibly important, but also incredibly difficult to get because really, you had to start a lot of these studies or these data collections a long time ago. In order to do that type of analysis, which we know we needed, we had to work with a biobank.
TruDiagnostic’s dramatic leap ahead of the competition on biological age analyses has been made possible by collaboration with world class researchers and datasets.
Dr Jessica Lasky-Su ticks both of these boxes - an Associate Professor at Harvard Medical School with access to the incredible biobank data at Brigham’s Womens Hospital.
We chose to work with Brigham Women's Hospital and researchers at Harvard. Dr. Jessica Lasky , was our main collaborator on this, along with her postdoctoral student (Dr. Ching Win).
We were able to get samples that had been taken 50 to 40 years ago, and then do our analysis on those samples.
LB: An important part of which was methylation data, the “m” in the OMICmAge clock?
RS: To your point about methylation data, it actually saves greatly on costs. Biological aging is very complex and to measure all of those different “omes” in individual aging it is prohibitively expensive.
Of the 5000 patients in our cohort, costs for testing were $9,000 to $10,000 (USD), to quantify all of those different things at every single level. It's way too expensive.
We knew we had to consolidate data from all those ‘omics’ into a single test which can be done at a much lower price and at scale.
With DNA methylation we can actually predict the “omic” data. Meaning we can quantify things that previously you could only do through advanced proteomics and metabolomics.
OMICMAGE Uses Methylation Data to Predict Biomarkers of Aging
Through measuring your DNA methylation (epigenome), TruDiagnostic can now reveal how different systems in your body are contributing to your biological age.
In short, the “why” behind why you as an individual are aging is starting to be revealed.
LB: Let us jump in there and just break down some really important parts of what you just said.
The omic data you were describing at the opening of the interview is a rich source of information from all different systems in the body. However, it is very expensive to measure those things directly, but they are very indicative of aging outcomes. So we want that information.
Now, what Tru Diagnostic and your research collaborators have made possible, is using the DNA methylation data to make estimates or predictions of omic information that is driving aging - this is a really big advancement.
RS: That is exactly it. We are starting to understand the why of biological aging by incorporating more detail about the things that are driving the process. In our study we used methylation to predict other values.
Right now we can use methylation to predict things you would get at a typical doctor's visit, things like your HbA1c for blood sugar management, your fasting insulin, fasting glucose, or even your creatinine.
Now we can use DNA methylation to output the things that previously were things you had to go get a blood draw at your physician's office to actually quantify.
See Why You are Aging So Fast (Or Not!)
An excerpt from a sample report from TruDiagnostic. Your DNA methylation data can now reveal the status of key blood markers and how they are contributing to your biological age.
LB: To that point, this ability to use the methylation data to predict different biomarkers and provide information about the “why” behind individual aging - there are new reports that are going to be accessible to Tru Diagnostic customers on the 12th of October (2023).
Moving ahead, OMICmAge is going to become your primary biological age clock and this information about these biomarkers will be in the TruDiagnostic reports made available to your customers.
You have offered to show us a sample report with some of this information. Let's pull that up now and walk through some specifics of what information we are able to predict about different OMIC areas of the body with his DNA methylation data.
RS: This is a very robust report, I won't take you through everything. We have about 10 clinical biomarkers, 12 different proteins and 12 different metabolites which we can connect to impacting your epigenetic age.
For instance, we might give you your haemoglobin or your creatinine results, much like you might see on a blood based lab. The real important part here is that we can also tell you how it is contributing to either helping or hurting your biological aging process.
For instance, probably the most protective factor in this particular individual (see image) is serum albumin. Serum albumin is a protein which can bind a lot of other things in your body and for people who are very interested in aging, this is one of those factors, which tends to decrease in decline with age.
We also know that red cell distribution width (RDW) and HbA1c are probably the factors in this particular patient, which are driving their aging process the most.
Another excerpt from a TruDiagnostic OMIC Age test report. Key blood markers which are contributing to an individual’s aging. Here, low blood Albumin is a key target for intervention. Low levels are making this individual biologically older than the would otherwise be. Red cell distribution width (RDW) on the other hand, is looking healthy.
Why I am Aging? Then, What do I do about it?
LB: This seems to be directly related to the term precision aging - we have heard it in a few other places.
That concept is broadly representing what you just said - namely personalised outcomes and understanding aging for the individual.
Carotenediol also goes into the name Lutein, which people already often take as a supplement.
Through the work on the OMICmAge clock, its importance in aging has been even further emphasised. It is a key metabolite for biological age.
You have shown some examples there. Let's talk in a little bit more detail about what this means for an individual's longevity strategy for their own effort to stay helpful and youthful for longer.
You mentioned that we can use that report to find targeted opportunities for improving biological age. Could you give an example from this report that reveals a marker that is very important for that individual and what action would they take to improve their biological age?
RS: I think that one great example is a metabolite. These are really good examples because a lot of the metabolites in your body are based off of things you eat or supplement. Carotenediol also goes into the name Lutein, which people already often take as a supplement. People might be familiar with it for some of its eye health benefits, which is probably most common for.
Lutein and other Carotenoids are a pillar of longevity. With the OMIC Age test from TruDiagnostic, you can understand how your diet (and supplement) strategy are working (or aren’t working) to improve your biological age.
We included Lutein in our OMIC Age prediction through algorithmic selection. We find that if we wanted to predict death accurately, that Lutein (carotenediol) was one of those metabolites which was highly influential in terms of predicting longevity as an outcome.
This is a really good case example because we also know that if you supplement with carotenoids, you start eating more things like leafy green vegetables like spinach, or kale or, or carrots or yellow peppers, you can actually increase that carotenediol level within your plasma.
And that will actually change our biological age prediction through changes in DNA methylation. That will then take your overall biological age down.
OMIC Age and Self-Experimentation
LB: What is the sensitivity in or I should say, responsiveness of the algorithm to change that you just mentioned? How long do you think a user would have to run that self experiment? They are going to measure with a Tru Diagnostic test, they are going to make a dietary or supplement change, maybe both and test again. What does that testing protocol look like?
RS: That is a really good question, and to be honest with you, we are not quite sure yet.
I think quite frankly, it might be different for many of those different predictors. For instance, your HbA1c is a really good example, because it behaves a little bit like methylation biomarkers behave, which is sort of a three month running average.
Traditionally, we only recommend testing every six months. But we've seen even some of these epigenetic biomarkers change effectively, in as little as eight weeks.
LB: So we are still looking at six months as the approximate timeline for self experimentation, that could change because there is a lot here that is new and unknown.
Just come back to that example, if somebody wanted to make a dietary shift or dietary change, or supplementation change, and then measure before and after, we are going to still go with the guidance of approximately six months at this time for measuring before and after. Do you agree with that summarization?
RS: I think on a casual basis that is what I would recommend. In shorter periods of time, you might have some transient changes that don't reflect the true biological aging changes and so the longer period of time that you are doing intervention, the more confident we can be that the result is correct, and that you are moving in the right direction.
DISCOVERING NEW FACTORS DRIVING AGING
Before you go! Why not dive deeper on biological age testing with TruDiagnostic? Our two part interview with Ryan Smith covers many important basics.
LB: One other thing I wanted to explore before we close off, Ryan - You have actually been discovering new influential factors in aging through this research that were not previously known - please give us an example?
RS: As our ability to predict other things with epigenetic methylation become even more powerful we are going to have even more insights. The metabolite ribitol is one of those examples.
This is a metabolite that is influential in creating the baseline molecules we use to regulate DNA, RNA, or even some of those sugar based pathways.
If you look this up in the literature, you find only two examples about this in PubMed. Although there were very few references to it, we are seeing that it seems to be a very good predictor of mortality.
LB: That's really fascinating Ryan, and we have walked through a great update of what is coming out with this new clock. Soon, we are going to be able to look at some examples from our Founder Nick’s results after the OMIC Age clock comes out.
In closing, we just would like to say that this is really exciting and congratulations to TruDiagnostic and your collaborators for bringing such an advancement to the field!
RS: It is always a pleasure to talk with Longevity Blog. We always have some elevated conversations, which probably yield a lot of questions. If anyone has any questions, feel free to reach out to us directly at TruDiagnostic.
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
AKG supplement benefits your biological age? An Interview with Dr. Yelena Budovskaya of TruMe Labs
AKG Supplement benefits - A Younger YOU?
The AKG supplement has many benefits. However, the most powerful of them might just be making you biologically younger!
The AKG supplement “Alpha Keto Glutarate" has a wide array of benefits:
It improves muscle growth and athletic recovery
Delays fatigue in sport performance
Reduces muscle breakdown during exercise
Improves the health of skin by increasing collagen production
May improve bone density
Appears to improve immune function
Scavenges excess blood nitrogen and ammonia, improving detoxification
But perhaps most excitingly, recent evidence shows that it just might make you younger.
For many, this is a startling claim, so let us explain it in more detail.
First, as we will explore in our expert interview today, we can now measure biological age - meaning how old your body is, biologically (rather than just chronologically) - at home for only $100.
And second, in both animal models and in humans, AKG supplementation has been found to:
Improve the biological age of 40 humans by a median of 8+ years (clinical trial)
Change gene expression (epigenetics) to a younger state
Alter cellular signalling to be more youthful
Possibly be reducing wrinkles
May be reversing or delaying hair greying (in mice evidence is strong, in humans, anectdotal)
This is nothing short of groundbreaking information for wellness enthusiasts and longevity hackers everywhere.
If we’ve managed to catch your attention, please keep reading!
Alpha Keto Glutarate Supplement Benefits - The Why and How
Alpha Keto Glutarate is a pivotal molecule for your energy metabolism (interacts with the Krebs cycle).
The TruAge Explorer test kit. From only $100USD using the discount code ‘longevityblog’.
It is produced in your skeletal muscle and is involved in the balance of many key processes that regulate levels of carbon, ammonia and nitrogen across the body.
The reason that the AKG supplement seems to be involved with regulating aging is that the levels of Alpha Keto Glutarate decrease with age. This means that many cellular functions do not perform optimally, with many knock-on effects.
By supplementing with AKG, we may be delaying these effects significantly.
We’ve recently composed a more thorough review of AKG supplementation which you can read here.
As we move ahead, we are going to focus on the technology you can use to test whether or not AKG improves your own biological age and understand in a bit more detail why AKG supplementation might be one of the most powerful longevity interventions you can try at home.
AKG Supplementation and Biological Age - From Expert Dr Yelena Budovskaya
“AKG is actually balancing a basic metabolic process within your body, specifically the Krebs cycle...
What we see with alpha ketoglutarate is it influencing not just the methylation process, but also the methylation of certain sites associated with younger age.
Another example are the molecules called integrins that are key parts of our skin health... People do report less wrinkles and much better quality of skin.”
At Longevity Blog, we are fascinated by all things related to longevity technology. We define this sector as anything tech that is helping you stay healthier for longer.
In our post today, we are focusing on the intersection between two such technologies.
Calcium Alpha-Ketoglutarate - a longevity supplement, which we source from DoNotAge.
And, biological age testing, specifically the most affordable high quality offering on the market - the TruAge Explorer from TruMe Labs.
The unique nature and power of this combination cannot be understated. Here we have two technologies which together have been shown in clinical research, to improve the youthfulness of 40 (out of 42) human subjects.
The question is then of course - could it do the same for you?
The fantastic news is that both of these technologies are available to you in the safety and comfort of your own home.
With a bit of careful forethought, you can run your own self-experiment to see if AKG can improve your biological age for only a few hundred dollars (with our unique discount codes).
To understand how this all works in more detail, we reached out to CEO and Co-Founder of TrueMe Labs, Dr Yelena Budovskaya to learn about how biological age testing works and why Alpha Keto Glutarate appears to be so powerful for maintaining your health as you age.
Let’s hear what she has to say…
NOVEMBER 2023 UPDATE:
Nick has now completed his 9 month self-experiment with Ca-AKG. Read the results here!
PARTNER Discount Code!
A part of our mission is to make your longevity budget stretch further.
Through our collaboration with TruMe Labs, we have a negotiated an industry leading 15% off coupon code for our readers.
Use the code “LONGVITYBLOG” at CHECKOUT TO SAVE 15%!
And through continued collaboration with DoNotAge, we are offering a 10% off discount for their Calcium Alpha-Keto Glurate supplement as well!
Use the code “Longevityblog” at checkout to save 10% on AKG
This interview was conducted in November 2022 over Zoom and is an audio transcript with minor edits for clarity, brevity and correctness.
Alpha Keto-Glutarte, biological age & More
Longevity Blog (LB):
Yelena, thank you so much for joining us today, we're really excited to talk with you about biological age testing. You've co-founded TruMe Labs and you offer the TruAge Explorer test kit.
We might hear about biological age testing all of the time, but it's still a new concept to most people. And it's fundamental for the rest of this discussion.
An important important place to start: how do we determine biological age?
Yelena Budovskaya (YB): Biological age is the age an individual would be if they lived a perfectly healthy life, and did not take any anti aging supplements. His physiology will be representative of that generic age group. Your biological age is the physiological state of your body, not the years by calendar.
Interview excerpt: Biological age testing - how it works, what it means (in three minutes)
Biological age - How young you are on the inside
“Your true biological age... might be a little bit behind... or it might be faster than your chronological age. But in any case, it is more representative of your health...”
LB: In that way, we're looking at an age that tells you what you “look like” biologically, not necessarily what the clock says. But instead, comparing you to other people than other populations saying, do you look older or younger at a cellular level?
What would you add to that?
YB: We look at how your cells and in particular how your DNA looks after all you put it through over the years. How that information is written on your DNA is reflecting your physiological state.
This physiological state is your true biological age. So it might be a little bit behind your chronological age. It might be faster than your chronological age. But in any case, it's more representative of your health rather than your calendar years.
Biological Age Reveals How Old You Really Are - for ONLY $100USD
Nick with an AKG supplement from DoNotAge
LB: So ‘biological age’ is comparing your biology with other healthy individuals in your age group to see how you stack up in terms of biological years accumulated or not accumulated.
In this space, we've had biological age testing for a few years now, but they've traditionally been quite expensive, costing $400-$500 US dollars per kit. One of the most attractive aspects of the TruAge Explorer biological age test kit is that it's very affordable.
Talk to us about the innovations that are occurring at TruMe Labs in terms of biological age testing. How can you offer a biological age kit for only $100 US dollars?
Speaking of supplements - Our Founder Nick tried the supplement Nicotinamide Mononucleotide and measured biological age before and after. Curious? So were we… read the post!
YB: Our journey actually started quite a while ago. I spent so many years studying the natural genetics of the aging process.
One of the things that I noticed is that we cannot stop human beings from aging. But nor can we stop them from trying to extend their lifespan - people are always going to be searching for the answer to their aging process.
With the expansion of internet and social media what's happened is more individuals are reading new innovative science in longevity and they think “Okay, I'm gonna start taking that supplement tomorrow. If it works on mice, it should work on me”.
When I first started in this field, it shocked me to see a lot of people who take a lot of supplements without really checking whether or not it's actually working for them.
self-experiments & biological age tests
LB: It is so refreshing to hear you say this. Part of our philosophy at Longevity Blog is to guide people to know the answer to what works for them! Go on.
“When I first started in this field, it shocked me to see a lot of people who take a lot of supplements without really checking whether or not it’s actually working for them. ”
YB: Then we start thinking - how can we measure if these interventions works? And of course that means we needed a biomarker of aging. Today, we know many companies are spending the time looking at biomarkers of aging.
I really liked what Steve Horvath, Hanham and other centers in genetics were doing, because it looks like that biomarker was actually very simple to adapt to home testing.
LB: This is referring directly to epigenetic biological age clocks, based on DNA methylation data.
YB: Yes, but DNA methylation is a very dynamic process. We started the development of our test kit with several basic requirements in mind.
Firstly, how can we make our test very accurate. So deviation from the number that we predict, should not be more than five years.
Second, it should be affordable - no more than $120. About the cost of three months worth of vitamins.
Feeling impatient and just want to learn about Alpha Keto-GluTArate and biological age? Just Scroll down a few sections!
Third, it should be fast, because the tests that we've previously done take 8 to 10 weeks to complete. We wanted to have a two week turnaround time. And no needles!
LB: That’s a great answer, we can see that affordability was actually just one part of your holistic thinking about how you might produce a quality and low cost kit.
Does the AKG supplement actually work? What about other longevity supplements?
We love the part of the story where you referred to how others were taking supplements without knowing if the are actually working for them. This is precisely one of the things we talk about on Longevity Blog, repeatedly.
In your answer you mentioned accuracy - we want to get into some of the details around the accuracy and precision of your test. But first, we’ve just introduced the concept of “epigenetic” age testing where the test is looking at the epigenome and particularly these sites called CpG islands.
These locations control turning the genetic code on or off in our bodies. Please briefly tell our audience a bit about that process of on/off in the epigenome.
If you want to go deeper on biological age clocks, epigenetic aging and what all of these terms mean, check out our interview with Ryan Lewis, Founder at TruDiagnostic.
YB: Even at birth, we already have some level of methylation happening in the body. And as you mentioned, this is the CpG sites on our genome. These CpG sites are located all throughout genome.
In some cases they are in the “promoter region” of the gene. Methylation at these locations prevents the cellular machinery from binding this region before the gene and expressing it.
In some way, epigenetics is a dynamic mechanism instructing the cell to turn on and off genes to fine tune how the genes are working together.
DNA Methylation and Biological Aging
LB: Why is this turning on/off of genes important for aging/longevity?
You don’t have to use supplements to improve your biological age. Nick did it by adding more plants to his diet, read about it here.
YB: DNA methylation is happening all the time. DNA is methylated and demethylated. Certain genes activate expression and other genes repress the expression.
This is how the body is fine tuning its function throughout life. It can be associated with the biomarkers for almost every single physiological process with the body.
LB: With aging, tracking this process is incredibly complex. Some of the other technologies we looked at for biological age testing might look at hundreds of thousands to millions of points in the epigenome.
However, your biological age test kit has actually boiled it down to looking at just nine locations in the epigenome. Clearly those are very closely related to aging.
Can you help our readers understand how there could be this reduction from millions of points in the epigenome in some of the fancier, more expensive test kits down to just nine points in your TruAge Explorer test?
Low Cost Biological Age Testing: How TruMe Labs Made it Happen
Test your biological age for $100USD with TruMe Labs and our discount code “longevityblog”
YB: When we first studied epigenetic connections to aging, we looked at the whole genome, because we didn't know much. We didn't know where this information was actually kept.
Any model that uses epigenetics to calculate biological age is a statistical mathematical model. It converts DNA methylation data into the number that corresponds to the biological age.
As we have studied this more we have realised that not all the biomarkers are the same. Some of them actually influence and can predict your biological age more. Most others have a miniscule influence on the equation.
We have identified the methylation markers that change with age, which are promoters of those genes. These markers should also be age regulated (changing its expression with age).
When we put these constraints over our algorithm development, we end up only with 30 CpG sites. But still, 30 was too many sites for the affordability and scalability of the process that we were developing.
So we distilled it to the best performers (9 of them). Afters some early testing and improvements, we validated it within a clinical trial setting and we saw that our deviation from the chronological age of the healthy individual was only 3.8 years, which met our accuracy target.
How does TruAge Explorer Compare to More Expensive Biological Age Tests?
LB: What an interesting story to follow. You've described this process of thinking about how to constrain a very complicated problem through the lens of affordability and the very dynamic relationship between gene expression and aging.
You’ve mentioned accuracy again, so let’s discuss this in more detail. You've done a comparison with your kit to the MyDNAge test. That test kit uses a much larger portion of the epigenome (approximately two thousand CpG data points). And yet there's a really strong correlation between the outputs from your algorithm and theirs.
Tell us what that reveals about these nine CpG sites and the way you've just constructed the test?
YB: Well, of course I think it tells you that we're probably found the CpG sites that are more dynamically changing with age and that methylation within those sites is clearly important for measuring a normal natural aging process.
The main reason our accuracy is comparable to another test in the market is because we are actually using different technology.
We don't use next generation sequencing (NGS), because we wanted to keep the cost down. NGS is quite expensive unless you sequence hundreds of patient samples at the same time.
We are instead using single sequencing, which allows us to sequence at a greater depth. In other words we sequence the same region many, many, many times over.
Low Cost Biological Age Test, the Makings Of
LB: Let's help our readers understand in a bit more detail. Just so it's nice and clear.
You've described Next Generation Sequencing, which enables many samples to be computed in parallel. However this is not the route that you've chosen, as you’ve pursued affordability. Explain to us again, what the difference in your single sequencing approach means for the consumer.
YB: What we do is sequence only one sample at a time. From this one sample, one fragment at a time.
Altering CpG sites in action. By sleeping better, Stacey improved her biological age from TruMe Labs. Read their female biohacking guide here!
Let's say we are sequencing nine fragments, the nine CpG sites. This means we sequence each of the CpG sites separately.
For each of the sites, we look separately at all the messages we get to calculate the percentage of methylation at that particular site.
This means we get thousands to tens of thousands of messages that we aggregate together to calculate the percentage over one CpG site.
As a result, we can use statistics over these many messages to see how clean the sample was.
There's one positive side and one negative side of this approach. The positive side is, because we sequence it so deeply, it means that we can actually capture miniscule changes of methylation, which can have acute effects on your biological age.
The negative part is that our test is much more sensitive to your lifestyle changes than tests using the NGS approach.
Is the TruMe Age Explorer Precise? Repeatable results are key for self-experimentation
LB: Both the price point and the sensitivity to lifestyle changes make the TruAge Explorer a very nice tool for self experimentation.
Read our interview with Ryan Smith at TruDiagnostic to understand the importance of accuracy and precision for biological age testing.
Let's talk a little bit about error and precision in the test kit. We recently discussed these concepts with Ryan Smith of TruDiagnostic. Talk about your test through the lens of accuracy and precision.
YB: Yeah, so we actually tested two aspects of precision and accuracy.
The first was precision. Let's say, I give you five tests today and you collect your saliva across five samples. So the sample is the same, right? It was put in the paper at the same time, and was sent to us in the same envelope. So what is the result is going to be?
We actually tested this quite a bit and the result is that we predict biological age from these five samples to within 3 to 4 months of each other.
Then a second aspect of this is actually a bit tricky but super important to understand. And I'm not sure very many people actually understand it.
LB: Our audience will! Give it to us.
YB: Every single biological age algorithm, including ours, uses the chronological age to standardize your biological age number. This presents an issue - why is the chronological age the standard?
Well, we don't have any other markers right now that reliably would predict that. So that's why we still use it. And this is why I keep bringing up this healthy individual who does not take any anti-aging therapies, who would live a healthy life and overall being healthy in perfect health today. What is their biological age?
We make the assumption that their biological age is equal to their current chronological age.
Then we took individuals between ages 40 to 75 that were absolutely healthy. No chronic diseases, no big problems. When measured the biological age of these individuals (150 of them) we realised that were within plus or minus 3.8 years of that person's chronological age.
This is why we know that even with multiple repeats of the same test, we can say that we can predict person chronological age plus minus 3.8 years.
“We get biological age as a starting point, do something to change the biological age and then compare follow-up results to your first biological age test.
The goal is to make that number smaller (“younger”).”
TruMe AGe Explorer: Precise to within 3 months, accurate to within 4 years
LB: This is a really fascinating point that you're making. We are going to try to say it back to you in different terms.
You're saying here is that to know how “accurate” a biological age test result, we have to find a compare that to a source of truth. When we consider “what is the right answer?” or what is the “true age” of a given person, TrueMe Labs construct this by looking at both the biological age and chronological age of many healthy individuals across different ages, statistically.
Here, you found an accuracy of plus or minus 3.8 years.
YB: Exactly. But I want to add to that.
If you personally are taking a biological age test, the most important thing is actually comparing your own results after an intervention. We get biological age as a starting point, do something to change the biological age and then compare follow-up results to your first biological age test.
The goal is to make that number smaller (“younger”).
AKG Supplement BenefitS Video: Reducing Biological Age
AKG supplement benefits for biological age with Dr Yelena Budovskaya of TruMe Labs.
LB: This is great, because you're coming back around to the concept of self experimentation.
We believe this is true value of biological age tests. They are giving you a reference point from which to improve.
This is why it's so important to pick a kit that you can afford that you have confidence in, and to keep using it. Because you get your baseline result and then try to improve and see what works for you.
We have a really great example in the literature of this - your company the TruMe Labs technology worked participated in a clinical study published in the journal Aging back in 2021.
November 2023 Update: Nick’s 9 month self-experiment with Ca-AKG results are in! See how much his biological age improved.
There were 42 participants self-experimenting with an alpha ketoglutarate supplement (AKG), which we've just recently written about on the blog. Your TruMe Explorer test kit had an important role in that study.
Can you tell us about this study?
YB: This study was done in collaboration with Ponce de Leon Health, who are producing the akg supplement. They wanted to give their clients the opportunity to be sure that their product works.
In this study, the result showed that so many of the participants actually decreased their biological age significantly. They also reported that they don’t have gray hair anymore and that their skin health improved.
We saw that on average there was 8.8 years of healthy lifespan reversal. Only two people actually did not improve their biological age.
AKG Supplement Benefits: Why it Works on Biological Age
LB: We love this. We think this is the longevity science of the future, particularly as longevity technologies move faster and faster.
This is why finding a kit that we can use for self experimentation is so important.
Score a 10% discount of high quality, third party tested Alpha Ketoglutarate from DoNotAge.
How do you think the alpha ketoglutarate supplement is working on these nine CPG sites in a way that improves biological age? What’s happening here?
YB: I think the AKG supplement is actually balancing a basic metabolic process within your body, specifically the Krebs cycle. AKG is also important for increasing the activity of demethylase, which is the enzyme that the methylate the genome.
What we see with alpha ketoglutarate is it influencing not just the methylation process, but also the methylation of certain sites associated with younger age.
Another example are the molecules called integrins that are key parts of our skin health. They are important for wound repair and skin elasticity. We observed that some of those markers actually methylated more with alpha ketoglutarate.
Maybe that's why there's such a great effect on skin. People do report less wrinkles and much better quality of skin.
The Future of Biological Age Testing
LB: Thank you for diving into that. Our audience loves looking after their skin health!
As we move to close the interview, can you share us your your vision for biological age testing? Where is it going over the next five years? What will become possible?
YB: We think that the most important thing right now is not actually making more precise biological age measurements.
Instead, we intend to expand our portfolio with genetic tests which give you information is how your DNA by drivers of aging. For example, how you are are affected by your diet taken or by the air you breathe, or your stress levels, or level of inflammation in your body. This could also included your hormone status.
We are going to be combining epigenetic and genetic tests together to deliver this information. So this is where we're heading next.
Dr Yelena Budovskaya’s Longevity Strategy
“I also finally tested alpha ketoglutarate on myself. It actually did work and I love it! ”
LB: That's an exciting vision. We love that you have this idea of combining different types of data in practical way for people to influence their longevity, at ho
We're going to wrap up the interview here. But before we go, we'd like to ask every guest to just share one or two things that they do to look out for their longevity each day.
Hear from our Founder Nick on biological age testing and how you can change diet, sleep, exercise and stress to improve yours! Read more
YB: Personally, I have always been fighting with weight loss. I was also guilty of taking too many supplements.
Now I practice intermittent fasting and am trying to get my feeding window to just six hours a day. It seems to work great for me. I like the effect this is having on my body.
I also finally tested alpha ketoglutarate on myself. It actually did work and I love it!
Everything else I am trying, I aim to be very thoughtful and self-experimenting with one intervention at a time.
LB: Thank you for your answer Yelena, and thank you again for joining us on Longevity Blog today. It was a pleasure.
YB: Thank you. I'm looking forward to see what result you get from your AKG self-experiment!
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Calcium AKG Alpha Keto Glutarate Supplement Review
What is Alpha Keto Glutarate?
Alpha Keto Glutarate supplementation appears to slow or even improve biological aging. But will it work for you? We dig into the details!
Alpha Keto Glutarate or “AKG” is an important molecule involved in energy metabolism, specifically the Krebs cycle. As its name suggests, it is related to the amino acid L-glutamine, which is produced in the skeletal muscle.
AKG is produced in your body and plays several important roles, including in nitrogen, carbon and ammonia balance.
One very important fact to note about Alpha Keto Glutarate levels in the human body is that they are known to decrease with age, and important cellular functions begin to decrease along with them.
Boosting AKG levels through supplementation may have very significant longevity benefits, but such evidence is in the very early stages of research in humans.
That said, some of that new research is quite exciting - read on.
AKG supplement benefits and safety
AKG supplement use has been around for quite a while and the molecule is very safe to use.
More traditional use of Alpha Keto Glutarate supplementation includes kidney support, intestinal repair, liver support and even the treatment of cataracts.
These uses of AKG are well documented in the scientific literature, with hundreds of studies available for reference.
Alpha Keto Glutarate Supplement Benefits
Boosts muscle growth and athletic recovery
Can help prevent breakdown of muscle during exercise
May delay the onset of fatigue in sport performance
It increases collagen production and may improve bone density
It appears to improve immune function
It collects excess nitrogen and ammonia from the blood, improving detoxification
More recently - it has been linked to specific longevity benefits, such as improving biological age (more on this shortly)
Its role in gene expression (epigenetic) and cell signalling is in the early stages of research, but it is clear that AKG helps preserve youthful cellular function
Alpha Keto Glurarate Safety
Is Alpha Keto Glutarate safe? Are there side effects?
Yes, very much so. In fact, we were able to find no known adverse effects from AKG supplementation for doses up to 2g per kilo of bodyweight (that’s much more than you’ll need to take!).
How much AKG supplement should I take?
This entirely depends on your reason for taking an AKG supplement in the first place.
Here are three examples!
You are an athlete looking to improve sports performance or recovery. You’ll supplement anywhere from 1 to 15 grams per day. You can take it before exercise to limit muscle breakdown during the activity. Or you can take it afterwards to improve recovery.
As a bodybuilder, your goals are to increase muscle mass. You’ll likely be taking Arginine Alpha Ketoglutarate (AAKG) and doses will vary from 3 to 10g prior to your hypertrophy workouts.
Nick has now completed his own self-experiment with Ca-AKG, dosing at 2g/day. Read about how to replicate this yourself and see his results in detail here!
As longevity enthusiast and wellness biohacker (that’s us!), you most likely want to see if you can improve your biological age with Calcium AKG supplementation. At this stage, we have limited evidence of the dosing protocols, with one study using 1g/day (with impressive effects on biological age!).
The remainder of this post will focus through the lens of the longevity biohacker. However, our chosen supplier of Calcium AKG + our 10% discount may still be valuable to you as an athlete or bodybuilder, so scroll on ahead anyway!
Calcium Alpha Keto Glutarate for Longevity
To understand the applications for Calcium AKG for ‘anti-aging’ / longevity benefits, there are three key milestones to review
50% improvement in lifespan in C. elegans after AKG supplementation. Source: Nature
AKG supplement and Longevity in Worms
The first is a foundational research study in 2014 which grabbed a lot of attention, as AKG supplementation increased the lifespan of C. elegant (nematodes, a type of ‘worm’) by nearly 50%.
The primary mechanism for doing so was believed to be the inhibition of ATP synthase and TOR (the worm version of the mTOR pathway).
AKG supplement and Longevity in Mice
Secondly, a follow-up study in 2020 looked into the Calcium Alpha Ketoglutarate form of AKG in mice. In this study, middle aged mice received an AKG supplement, as as result male mice lived 10% longer and females 20% longer.
Observed benefits of Calcium Alpha Keto Glutarate supplementation in mice, who lived up to 20% longer. Source: Cellular Metabolism
The mice had fewer grey hairs and remained stronger and less frail than their peers. A key mechanism of action was believed to be a widespread reduction in inflammation (“inflammaging“ is one of the primary ways in which humans lose function and resilience with age).
AKG supplement and Longevity in Humans
Third, and most importantly, a 2021 study in the journal "Aging" made a startling discovery.
Across a cohort of human trial lists taking 1g/day of a Calcium AKG supplement for approximately 7 months - there was a median improvement in biological age of 8.5 years.
This is a very significant change/result! To put this in perspective, our Founder Nick has only been able to improve his biological age by 3 (read here) to 6 years (see here) and to date he has not been successful in improving his epigenetic biological age at all.
By the way….
The biological age test used in this Ca-AKG supplement study is the TruMe Age Explorer test.
This epigenetic biological age test kit is available to try at home for only $103USD when you use our discount code ‘longevityblog’ to save 15%.
If you order two kits (essential for doing before & after self-experimentation…) the cost per kit with our discount drops to $88USD.
When you consider that alternative epigenetic age tests costs $300-$500USD, this offer looks pretty appealing!
We’ll be interviewing Co-Founder Dr. Yelena Budovskaya in an upcoming post to discuss how this test works in more detail!
It’s the most affordable test on the market and is very fast and easy to complete.
AKG Supplement Review
AKG chemical structure before bonding with either L-Arginine or Calcium. Image Source: Pubchem
Given this encouraging result, a natural follow-up question from the longevity enthusiast is of course ‘where can I get myself some AKG??”.
We were of course curious ourselves.
There are two primary forms of Alpha Keto Glutarate supplements.
The first is Arginine Alpha Ketoglutarate (AAKG). In this formulation, AKG is bound to the amino acid L-arginine. L-Arginine is a good choice as it is involved in nitric oxide regulation and dilates blood vessels. This delivers more nutrition to the skeletal muscle and can increase insulin by up to 10-15%, meaning more muscle growth.
Research studies on Alpha Keto Glutarate over time
The second formulation is Calcium Alpha-Ketoglutarate. And if you’ve been reading closely, you’ll realise that this is the form of AKG supplement which has shown longevity benefits in both rodents and humans. By using calcium, the absorption of AKG in the small intestine is improved.
This is important as only 20% of oral AKG supplement intake makes it to the liver and then into the bloodstream, where its beneficial effects can take effect.
Given the improved absorption and the direct connection to the biological age improvement, we think that it will be pretty clear to you that a Ca-AKG supplement makes more sense for the longevity enthusiast.
What is the best AKG supplement?
By narrowing the search to a Calcium Alpha Keto Glutamate supplement, the list of options for supplying yourself with Ca-AKG for your own self-experiment narrows considerably.
As with any self-experiment, you’ll want to only add a Ca-AKG supplement to your stack and watch changes over time. One notable exception is taking a B6 vitamin (or B-complex) supplement along with it to increase absorption.
Reviewing the available Ca-AKG supplement options then narrows further, as we are only considering a pure formulation. Longevity Blog was able to identify approximately 3-4x options with global shipping and sufficient reputation for quality assurance.
Nick is preparing a video series on Ca AKG supplementation and his self-experiment to reduce his epigenetic biological age.
Our recommendation: Alpha Keto Glutarate Supplement - DoNotAge
Our recommendation (which is not entirely unbiased - read more here) is to purchase from DoNotAge.
This is partially based on our intimate knowledge of the manufacturing process, including products quality and purity.
It also based on our ability to reduce your costs (part of our goal at Longevity Blog is to help stretch your longevity budget further!).
Working the math, if you select the bulk 366 capsule option, which qualifies for free shipping in the United States, DoNotAge’s Ca-AKG costs $1.92/USD for a 1200mg dose (three capsules).
This drops to $1.72USD per 1200mg dose with 10% discount code ‘longevityblog’.
PARTNER Discount Code!
A part of our mission is to make your longevity budget stretch further.
Through our collaboration with DoNotAge, we are pleased to offer a 10% off coupon code for our readers. This applies to all DoNotAge products, not just Ca-AKG.
Use the code longevityblog at checkout to save!
CAN CALCIUM ALPHA KETO GLUTARATE REVERSE BIOLOGICAL AGE?
We’re not huge fans of calling it ‘reversing’ biological age, but this is the most common search term used by people looking for this answer.
Instead, we want you to think of biological age as a subjective number that you can improve.
After all, our Founder Nick has improved his biological age many times, using different biological age tests and approaches (read here and here, for example).
Here we are yet again - wanting to know, can a longevity supplement improv your biological age?
There is only one way to find out - it’s self-experiment time!
Soon, we’ll reveal the dosing strategy and before and after testing approach required to put Ca-AKG’s claims to the test!
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
How Fast are You Aging? A Biological Age Test for Rate of Ageing with Ryan Smith of Trudiagnostic (Part 2)
How Fast are You Aging?
Are you considering taking a biological age test?
If so, you probably are interested to know - how old am I really?
When investing in a biological age test kit, you’ll want to choose the product which has the best accuracy and precision. What does this mean? We’ll discuss this in detail in today’s interview.
This is of course a tempting data point for those interested in their longevity. But any given biological age test is really only a snapshot in time.
We often argue that the real value in biological age tests is in their ability to test, undertake a longevity self-experiment and re-test to see if your bio age improves. See this example or this example to see what we mean in more detail.
Using test kits in this way mean you really have to purchase at least two biological age tests. Even with the lowest cost kits, this means spending at least $300-$400USD.
However, recent developments in this space mean you can now see your rate of aging in a single test. This arguably saves you on cost twice - as the rate of aging biological age test kit is about half the price of the full test and you only need to purchase one kit.
TrueAGE PACE TEST KIT REVIEW
The capability to directly measure rate of aging has been developed by Longevity Blog partner TruDiagnostic. To our knowledge it is the only biological age test kit with this capability (at the time of writing).
This test (TruAge PACE) analyses short-term changes in epigenetic methylation and is a sort of “speedometer for aging”. Those looking out for their longevity want this speedometer value to be as low as possible!
This kit has very high precision and is very responsive to interventions, whereas most epigenetic test kits giving you a biological age are slow to respond. The TruAge Pace test kit is arguably quite ideal to see which longevity technologies are working for you.
Of course, we’ll be working to prove that hypothesis (be sure to subscribe to monthly updates to hear the answer!)
It is worth noting that the full cost kit from TruDiagnostic - TruAge Complete includes the rate of aging result (as well as extrinsic age, immune age and telomere age + more).
How Does Rate of Aging Testing Work?
To get into the details behind how the TruAge Pace test kit works, we continue our interview series with Ryan Smith the Co-Founder and VP of Business Development at TruDiagnostic.
We recently interviewed Ryan, and in the first part of this series, we had him walk us through the recent developments in biological age test kit technology.
One of the most important take-aways is that you want to be choosing a third generation biological age clock to get the most accurate and precise result. Be sure to review it for more details!
Today, we’re exploring this concept of the rate of aging and looking into Ryan’s view of the longevity technology roadmap - where will biological age test kits go next?
PARTNER Discount Code!
A part of our mission is to make your longevity budget stretch further.
Through our collaboration with TruDiagnostic, we have a negotiated a 12% off coupon code for our readers.
Use the code longevityblog at checkout to save!
This interview was conducted in August 2022 over Zoom and is an audio transcript with edits for clarity, brevity and correctness.
How fast are you aging?
Ryan Smith, Vice President of Business Development at TruDiagnostic is an expert in the latest developments in biological age testing.
Longevity Blog (LB):
TruDiagnostic are also providing an estimate of how fast you are aging. This is unique, and part of the reason this is possible is due to the DunedinPACE algorithm being a third generation clock.
Can you give us a brief history of why the city of Dunedin has become important in building a unique biological age algorithm?
Ryan Smith (RS):
This data comes from a study started in 1972, with a group of right around 1037 New Zealand children all at the age of three. They started this cohort by tracking them all the way across their aging process.
Now we're here, we are in 2022, and these individuals are approximately 50 years of age with 900 or so of those patients providing us information and blood biomarkers showing us how they're aging throughout their life.
Dunedin is located on the South Island of New Zealand. The Dunedin Study has followed the lives of 1037 babies born in 1972/73 since birth.
The study is now in its fifth decade and has produced a considerable amount of data that shapes what we know about the rate at which humans age.
This is a very, very unique cohort that really doesn't have replication anywhere else in the world.
LB: Do we have epigenetic measurements from these folks?
RS: Thankfully, they have saved some of that blood, but unfortunately, we haven't had epigenetic measurements across the entire lifespan.
It would be great if we did, but we have taken a lot of other lab measurements across their lifetime. And those 19 blood related biomarkers are what we have used to train an algorithm to estimate the pace of aging.
Following Individuals Aging over Time = Rate of Aging Algorithm
LB: So there's the connection from the blood based biomarkers to the rate of aging and methylation data. And all gathered longitudinally, again, which is what makes the third generation clock so powerful.
Let’s come back around to DunedinPACE’s (the algorithm behind the TruAge PACE test kit) ability to estimate the rate of aging. Explain how this works.
Source: TruDiagnostic ‘Pace of Aging’ report document.
RS: In order to look at the rate of aging, you have to have some context for the change over time.
What we do is look at all those 19 blood related biomarkers and giving them a composite score. Then looking at how that score changes as these individuals age from the time they were 3 years old to now, we can see what is optimal.
We really get to see what is happening on average to most people as they age chronologically with very little intervention. This gives us a standard to see - what is the average pace of aging?
We can show our customers how they individually compare to that, where we can get an instantaneous point in time measurement of what their aging rate is at this moment.
I think this is very exciting because most other clocks are encompassing the entire body's aging process over the course of a long period of time. But these instantaneous markers are showing how you are aging right at this moment.
This can be very helpful in terms of finding out what lifestyle changes or interventions are working on an individualised basis.
How to Improve Your Biological Age Rate
“We also know TruPace has probably the most accurate or most predictive of all clocks... this rate of aging estimate is responsive instantaneously”
LB: That last part that you just mentioned, in terms of determining what works on an individualised basis, is right at the heart of what we like to do at Longevity Blog.
One thing we find really fascinating about the TruDiagnostic TruAge test kit is this rate of aging algorithm.
We suspect it will actually be more responsive to interventions and helping our readers self-experiment and see how the rate of aging is changing.
The extrinsic age is a pretty sticky number. It's harder to change and takes longer. Do you agree with our thinking? That the rate of aging estimate lends itself better to the everyday longevity enthusiast or biohacker?
RS: I certainly think it does, and I think that we've already talked about some of the reasons why.
One is precision. This clock is extremely precise. That means as you're measuring biological age more frequently, you want an even more precise clock.
We also know it's probably the most accurate or most predictive of all clocks. Ultimately, this (rate of aging estimate) is responsive and responsive instantaneously.
Sometimes it can be very hard to improve or to fix damage. We know this to be true when dealing with classical aging, where it's harder to reverse disease than it is to prevent it. With some of these biological age clocks, what you're measuring is the whole history of a person being alive.
“With some of these biological age clocks, what you’re measuring is the whole history of a person being alive”
With the rate of aging estimated, you're getting a more intermediate effect. And that intermediate effect is absolutely correlated to health outcomes.
So as someone who is trying any type of intervention, whether it be diet, nutrition and exercise, they can look at their rate of aging and then find out what is the most optimal strategy for them by comparing markers even within three months.
LB: That's really valuable for the self experimenter.
TruDiagnostic Biological Age Test Kit Includes Telomere Age
Extract of the TruAge Complete telomere based biological age estimate.
LB: So far we’ve discussed three biological age values. Extrinsic, intrinsic and rate of aging. We won't talk about today, but we’d like to also mention that there's also a telomere based estimate that TruDiagnostic offers through the TruAge Complete test kit.
A theme has been building through this conversation about third generation biological age clocks. One innovative area of development for such clocks is a new and very powerful capability to be predictive of specific disease outcomes.
Tell us briefly about how TruDiagnostic test kitsare starting to connect the dots to certain disease risks.
Biological Age and Age Related Disease Risk
RS: We're lucky enough to have biobanks that have taken samples from 30 years ago. This enables us to look at how their epigenetic methylation correlated to the health outcomes that they faced.
A good example is our validation with the Framingham Heart Study cohort. We found that those people who are aging anywhere below one year per year generally would have a 50 to 50% less chance of dying over the next seven years. They also have a 54% decrease risk of a chronic disease over the next seven years.
But those people with an aging rate above one year per year, so called ‘fast agers’ were overall 65% more likely to die. That's obviously just talking about mortality.
“People who are aging anywhere below one year per year generally would have a 50 to 50% less chance of dying over the next seven years”
We have also found that the rate of aging marker is predictive of things like grip strength and muscle mass, as well as IQ and mental processing speeds, and even facial aging.
We have some really great composite images of how people age in our cohort, grouped according to their rate of aging, and even at age 45, the 10 slowest aging members of the cohort look to be maybe 20 years younger than the same individuals at 45 with a fast aging.
The Future of Biological Age Testing
LB: We love to talk about tools for disease risk on Longevity Blog. We believe there is significant value in thinking ahead about your personal risk, and that by analyzing that risk profile you can get 10 to 20 years ahead of the age-related problems you're going to develop.
As your team looks forward, what is going to become possible for TrueDiagnostic in the near future? Your company is actually very fast moving - you're putting out new reports every few months - tell us one or two new and exciting capabilities that are coming in the next year.
RS: There are a couple of things that I'm really excited about.
TruDiagnostic can analyse your epigenome to reveal much more than just your biological age. They are adding new reports regularly, including a recent ‘weight loss’ report to better understand how your body might respond to calorie restriction, for example.
One of which is a project we've been working on for a long time - what we consider a fourth generation algorithm. In order to do this, we want to include what we call multiple levels of the “multi-ome”.
This is a very complex process. We already have talked about how challenging working with longitudinal data can be, and how it is really important to remove confounding factors. But if we can also add to that longitudinal score more depth on those physiologic measurements or those molecular measurements, then we can get an even clearer composite image.
We are in collaboration with Harvard and have been working on a multi-omic clock for probably two years, now. It will include genetic data and will include some micro RNA data, as well as epigenetic, proteomic data (peptides and proteins in the blood), and then lastly, metabolomic data (metabolites in the blood). We will also expand it to to include 75 blood related biomarkers (up from 19 in the current version).
Measurement will take place over four different time points, which should allow for a biological age clock that is hopefully unparalleled, in terms of its accuracy and precision. So we're really excited about that.
LB: I think it is a very exciting version of the future capability of biological age clocks.
Ryan Smith Co-Founder at TruDiagnostic’s Longevity Strategy
Wrapping up our interview, one thing we always ask our guests is this - knowing all the developments upcoming in longevity technology, what are you doing everyday to look out for your own health and longevity? Tell us part of your longevity strategy.
RS: One thing I'm ashamed to admit now is that previously, I was, I would say, a big skeptic of the importance of meditation and mindfulness. I used to think, you know, am I doing this right? Is this really meditation? Is this even working?
Stress has a “Major Impact” on Biological Aging
The impact of stress and emotional regulation on aging and the aging process is incredibly strong. It is way stronger than I would have ever anticipated. It still baffles me that someone's emotional regulation can have such a major impact on their biological aging process.
Stress, sleep, diet, exercise - these all impact biological age results. Want to learn more? Check out our interview with Dr Robert Lufkin on YouTube here.
We're still not really sure how this is mitigated. I think a lot of people might say it's regulated by cortisol or some of these other stress hormones. But I can tell you that it has a major impact. And so one of the things I really try and do is to spend some time on mental health. I was never that way previously. But you know, seeing the results I've seen and the correlations I've seen, I've definitely done a 180.
In addition to that, from an interventional approach, I tend to be a very big fan of rapamycin and mTOR inhibitors. In all the aging interventions that we know about now, this one is probably one of the most exciting for wide scale application.
Lastly, even though I am probably not the best at actually implementing this into my own life, I think periods of fasting, fasting and caloric restriction are also some great strategies which have very little downside and have the potential to have really good longevity benefits.
LB: As that's fantastic, Ryan, we're going end the interview there. Thanks so much today. We really appreciate your time.
RS: Thanks for having me as guest on Longevity Blog!
Trudiagnostic Discount Code!
A part of our mission is to make your longevity budget stretch further.
You can save 12% off TruAge Complete or TruAge PACE biological age test kits.
se the code longevityblog at checkout and save!
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
What is the Most Accurate Biological Age Test? An Interview with Ryan Smith of Trudiagnostic (Part 1)
Trudiagnostic review: Most accurate Biological Age TEst
How accurate is the biological age test you are currently considering?
Great question, but you also need to ask - how precise is the biological age test?
What do we mean by this? If the difference between these two terms isn’t 100% clear to you, you’re definitely not alone.
The fact of the matter is, choosing the best biological age kit for you is not a straightforward decision, and with more test kits arriving on the market each month - you’ll be glad to know that Longevity Blog is here to help!
In this post, we cover the basics of ‘accuracy’ vs ‘precision’ and in our TruDiagnostic review, reveal why their kit is the best biological age test currently available (plus we score you a discount to purchase one!).
Biological age test technology is moving fast
When investing in a biological age test kit, you’ll want to choose the product which has the best accuracy and precision. What does this mean? We’ll discuss this in detail in today’s interview.
Just like most of the longevity technology sector, biological age testing is advancing quickly.
And while we’ve previously reviewed some biological age testing companies, it is very important to keep you informed of the latest developments.
We have two very important updates for you.
Firstly, did you know that we’ve now moved into the third generation of biological age clocks?
What does that mean? These are algorithms which use longitudinal data collected from the same individuals to see determine how aging occurs over time.
Secondly, many of the first and second generation biological age clocks may have good accuracy, but they are not necessarily great at precision.
To illustrate what this means, if you were to send off three of the same saliva or blood samples to your biological age testing facility of choice, a highly precise laboratory would provide you the same biological age estimate each time. But if they don’t have great precision, you could get three different results.
A graphical representation of accuracy and precision (credit: TruDiagnostic).
For example, if your age is 35 and you get a biological age of 33, 35 and 37, that test kits only has a precision of around 2 years.
So, which results do you believe?
You might be surprised to know that many of the offerings on the market offer precision within 2-3 years.
What does that mean? It means that if you measure your biological age, test an intervention through a self-experiment, and then test again (which is how we recommend you use these kits) - your actual results could get lost in the ‘noise’ with low precision kits.
If this concerns you (and it should!), then you’ll be very interested to hear what our latest interview guest has to say…
TruDiagnostic review video: Hear it straight from the expert, Founder Ryan Smith.
latest developments in Bioaging with trudiagnostic CO-FOUNDER RYAN SMITH
Ryan Smith the Co-Founder and VP of Business Development at TruDiagnostic.
But don’t let his ‘business’ title fool you - he is exceptionally knowledgeable on the science behind epigenetic testing.
Ryan is a biochemist who founded Tailor Made Compounding, which became the 4th fastest growing company in healthcare in the US at the time.
In late 2019, he saw tremendous potential in epigenetic testing and analysis and co-founded TruDiagnostic, who now offer once of the most accurate and precise biological age test kits on the market.
Today, we ask him to walk us through these important developments in biological age test kit technology. Strap in and put your thinking caps on!
PARTNER Discount Code!
A part of our mission is to make your longevity budget stretch further.
Through our collaboration with TruDiagnostic, we have a negotiated a 12% off coupon code for our readers.
Use the code longevityblog at checkout and save!
This interview was conducted in August 2022 over Zoom and is an audio transcript with edits for clarity, brevity and correctness.
How do you estimate biological age?
Ryan Smith, Vice President of Business Development at TruDiagnostic is a wealth of knowledge on the latest developments in biological age testing. In this interview, we first explore the development of biological age ‘clocks’ and what it means for these clocks to be accurate and precise.
Longevity Blog (LB):
Ryan, thanks so much for joining us today. We have a very common question that we'd like to ask you to kick things off. And it's an important one, lots of people ask it:
How do you determine your biological age? Could you give us a general answer?
Ryan Smith (RS): Certainly! I think that the answer has changed throughout time. The search for biological age has always been important because of something called phenotypic variation - there's a lot of difference between how people in the same chronological age group age differently.
This definition of biological aging, searching for how the body is aging was very crude initially. Things like the number of your chronological age plus the number of packs per year you smoke, as a biological age. But as we've gotten more sophisticated they’ve culminated in epigenetic clocks, which are probably the most sophisticated methods to determine biological age.
Even these have a little bit of a history where they've continued to improve. Right now, what we're essentially doing is creating algorithms to predict someone's biological age. And we do that by having a cohort that we train these algorithms and then a separate group as a validation cohort. That's what we've done with epigenetic clocks, and it's why they're generally the most predictive of negative age related outcomes and why they're so powerful.
What is an Epigenetic Age Clock?
Epigenetics instructs your DNA on how to be expressed. All cells contain all of your DNA, but how do they know to be a liver cell, or a brain cell or a skin cell? Epigenetics is where this information is stored.
LB: You've mentioned “epigenetic clocks”, briefly remind our audience what these are.
RS: Epigenetic clocks are essentially a biomarker measurement. Age clocks can be created using any type of data set, but here the data that we're measuring is an epigenetic methylation.
For those of you who aren't familiar with epigenetics, it essentially is the regulation of your DNA.
Every single cell on your body has the same DNA sequence, it's what makes it individual to you. But how that DNA is expressed is different from cell to cell. It's why your skin can behave like skin cells and your heart can behave like heart cells. This is determined by what genes are expressed or turned on.
What we're measuring is DNA methylation, which is the off switch, generally, for most of those DNA expressions. We have a lot of DNA methylation in our cells, with over 29 million spots in each cell, which can be methylated. And every cell is different. So it's a lot of data.
Epigenetic clocks have been created by seeing the differences in aging at these different locations across individuals. And then creating a predictive algorithm to see if we can predict that change with age and see how close we can get to variables, like someone's chronological age, for instance.
How Do You Determine Biological Age?
Methylation of the DNA is the on or off switch for DNA expression. There are over 29 million ‘CpG’ sites in your genome where methylation occurs. The patterns of methylation change with aging, and therefore they make an excellent predictor of how old you are biologically.
LB: Biological age clocks have been around for about a decade, and they’ve advanced very quickly over the last few years.
Can you introduce us to this concept of the “generations” of epigenetic clocks that have emerged and an approximate timeline?
RS; The first ever biological age clocks came out in 2011, with the first really widely applicable clocks created by Dr. Steve Horvath at UCLA in 2013.
I will go on record by saying I think he might be nominated for a Nobel Prize for this work. It is really groundbreaking, because, for the first time, we're able to read with a very high accuracy: the age of someone's body.
The clock was originally created by looking at those epigenetic methylation changes across a few thousand patients and looking at what markers were most significantly changed with age. Some locations might have no methylation at young adulthood, but as as we get older, significantly more methylation or vice versa.
That's how he was able to create this predictive algorithm. But it was trained to predict someone's chronological age. Originally, it was used for really interesting applications, but not necessarily health applications.
One example is collecting DNA at a crime scene to see how old a criminal might. In the case of the refugee crisis with Syria, it was used to see if people were adults or minors, and therefore eligible for asylum.
How Does Biological Age Testing Work?
Our Founder Nick has tested the TruDiagnostic product, and was very impressed with the wealth of knowledge TruDiagnostic provided through just a few drops of blood!
LB: But the new applications in health began to emerge, as ‘older’ individuals were connected to poorer health outcomes. Tell us about this transition.
RS: The research field started to notice a pattern, which is that those people who were older with this test than their chronological age, were at significantly increased risk for negative health outcomes.
While those people who were younger than their chronological age, were protected against those same outcomes.
They discovered, for example, that being seven years younger biologically than chronologically reduced the risk of morbidity and mortality by 50%. So that was the first generation of age clocks.
Generations of Biological Age Test “Clocks”
LB: That's a little bit of a complicated concept that you're introducing here, so let’s make sure we make this very clear for the reader.
First generation clocks weren’t developed to predict risk of poor health outcomes, but in their application were discovered to be capable of doing this.
Now, with this realization, we begin to see the development of ‘second generation’ clocks which are designed to be predictive of age related health outcomes. Is this correct?
RS: Exactly. An important concept here is “hazard ratios” for disease. This is essentially the likelihood of developing a particular outcome. You can have hazard ratios for anything. You know, that hazard ratio for it raining, for instance.
For disease, the higher the hazard ratio, the higher your likelihood. Ideally, the bigger the change in the biological age, the bigger the change in hazard ratio. That's exactly what we're seeing as these biological age clocks get better. “Second Generation” clocks are now being trained not on chronological age, but on biological signals.
LB: Have the inputs to second generation clocks changed? Are there new variables which are being considered in the training datasets with second generation clocks?
“the key characteristic of the third generation of biological age clocks is using ‘longitudinal’ data sets, which follow the same person over time”
RS: In the second generation clocks, we have started to measure things like your blood based biomarkers that we know change with age.
For example, your red cell distribution width, your immune cell types and distribution, or your serum albumin. These are all things that change as we get older.
Then, for third generation clocks, which is really where we're at now, they did the exact same thing, but they did so longitudinally. So instead of looking at a lot of different patients over a lot of different time points, they looked at the exact same patients over a long time period.
By analyzing data longitudinally, we are able to get rid of other confounding factors, things like environmental exposures. For example, if we get these from a biobank, the amount of antibiotics that someone was exposed to 40 years ago might have been a lot less than what we're exposed to now. And vice versa. Another example is leaded gasoline instead of unleaded gasoline.
By looking longitudinally, you can sort of factor those things out, because you can sort of assume that the population you're looking across time has had similar exposures, especially if they're living in a similar area. And so what we're starting to do is to now get rid of all of these confounding factors which might be taking away sensitivity and specificity from the biological signals of aging.
A graphical representation of the concept of generations of biological age clocks. For more information, you can read this scientific study.
LB: So the key characteristic of the third generation of biological age clocks is using ‘longitudinal’ data sets, which follow the same person over time, and understanding how that biological age is changing over time based on environmental factors and tracking blood based parameters? Second generation clocks are missing this ‘longitudinal’ data.
RS: Correct. There is really only one third generation algorithm that currently exists, DunedinPACE. This clock uses 19 blood related biomarkers from a longitudinal study, where they tracked gum health, for instance, and leukocyte telomere length, which has classically been a very popular marker for biological age.
Biological Age Tests: Accurate or precise?
“Precision is very, very important, especially on a personalized medicine aspect. If you have a wide degree of technical variation, you’re just not sure if the change you’re seeing is real biologic change, or if it’s just noise.”
LB: TrueDiagnostic have differentiated their biological age test from other providers by offering the market’s only third generation clock.
Tell us why this algorithm is better for biological age predictions in very simple terms.
One of the things you shared at pre-interview is the ability of this clock to consistently make the same predictions off the same sample data. Maybe start there.
RS: We've already talked a little bit about how to judge an aging clock’s accuracy, right? Which is generally more predictive of negative health outcomes? The other thing we want to always talk about is precision of the algorithm. We want it to be both accurate and precise.
This has been a very big problem, actually, for these epigenetic clocks to date. One of the reasons I think early adopters have been a little bit disillusioned with these second generation tests is because they've had wide variability.
For instance, even with Dr. Horvath’s original algorithm he created in 2013, if you took the exact same sample and tested it twice, you could have up to 3.9 years of variation from even the same sample. That's a huge problem, because if you're looking to use this for reliable information to judge things like interventions, you wouldn't be able to test within a period of 3.9 years in order to get a statistically significant outcome.
Precision is very, very important, especially on a personalized medicine aspect. If you have a wide degree of technical variation, you're just not sure if the change you're seeing is real biologic change, or if it's just noise.
What is the Most Accurate Biological Age Test?
The ICC (intraclass correlation coefficients) score represents precision. How consistent is a given biological age clock at reproducing a biological age prediction off of the same sample? At far right is the algorithm used by TruDiagnostic, showing how precise the algorithm is compared to other methods.
LB: Okay, so there's some complicated concepts you're talking about there, we're discussing the difference between precision and accuracy.
You've gone into some detail about some of the limitations of second generation clocks, and where this newer third generation has a bit more precision.
Generally, when people are trying to make a decision about a biological age test, they'll ask a question that's a bit more simple, or perhaps even naive of some of these details between terminology for precision versus accuracy. They're going to ask, “Which biological age kit is most accurate?”
If you're talking to that layperson, what do you tell them?
RS: Whenever you get the results of any biological age test - you want it to be informative about why you think they asked the question in the first place. I think for most people it would be - Why do you want to quantify aging in the first place? The answer is that biological age is the biggest risk factor for most chronic diseases and death.
So if you want to quantify a risk factor, usually, it's because you want to change it right? And so in order to measure that, you really want it to be predictive of outcomes. So the most accurate clocks are going to be the ones that get higher when you're going to have worse outcomes for all age related markers. And as they get lower, you're gonna have more positive outcomes for all age related markers.
And the way that we measure that is called a hazard ratio. What is your likelihood of getting a particular disease if you're aging at a rate of one versus if you're aging at a rate of 1.1? And in General, the higher the hazard ratio, the more predictive and so I would measure accuracy by its ability to be associated with health outcomes.
There are Different Types of Biological Age: Extrinsic vs Intrinsic
An example of an intrinsic biological age test kit is GlycanAge, which tracks inflammation in your body by analysing your glycans. What are glycans? How can you use intrinsic age to self-experiment, why not read about it here?
LB: Often, biological age is discussed as if it's one number. But one of the things that we've learned through engaging with your testing kit and platform is that there's two big categories of biological age.
Extrinsic biological age and intrinsic biological age. So far, we've been talking about extrinsic biological age.
Tell us about intrinsic biological age.
RS: At the cellular level, biological age measurement is different in every cell. Your skin cells are going to be very different than your heart cells, in terms of what genes are turned on, and turned off. So ideally, if we were to do this test, we would do it on a single tissue type and that would be the most precise and accurate way to develop an algorithm.
But the problem is that for most of our body, we have a whole combination of different tissues making up any given organ. In our skin, we might have keratinocytes, cells, as well as fibroblast cells. In our blood, the majority of the DNA is from our immune cells. These include things like CD8 T cells and CD4 T cells, your monocytes, your basophils - you know, all of these different cell type markers.
TruDiagnostic’s Immune Age ReporT: An Intrinsic Biological Age
LB: So in simple terms, intrinsic biological age can be based on different cell types representing a given organ or systems in the body.
In your TruDiagnostic report, you've focused on the immune system for the extrinsic biological age.
There's this important concept in biological aging known as immunosenescence, which is the decline of immune system age. Talk to us about this process and how looking at an intrinsic age can help us understand how we are aging biologically.
From a TruDiagnostic ‘Immune Age’ report, a graphical representation of immunosenescence.
RS: As we get older, one of our most important immune organs, the thymus, starts to degenerate. We lose thymic volume and as a result that changes the amount of immune cells which are circulating in our blood.
This means the immune system generally becomes worse at doing its job, and isn’t clearing things that are not supposed to be in the body. Being able to quantify immune cell changes allows us to quantify the aging process in a different way.
We can gain a bit of insight into how the immune system is aging. One important measure is the ratio of CD4 to CD8 T cells. We would usually see this decrease as we get older - so the decrease in this ratio can be used as a snapshot of your immune system’s aging.
LB: Would it be accurate to say that extrinsic biological age is more responsive on a short term basis to interventions?
RS: Yeah, certainly. I think that the answer is we definitely see more variation on a day to day basis. These changes that are happening in your blood are happening at a very large scale and new changes are some things that we can detect. This biomarker can be trained for a wide variety of things.
LB: Thank you, Ryan.
TruDiagnostic are also providing an estimate of how fast you are aging….
Read Part Two of the Interview Here
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Longevity: Fasting, Diet, Sleep, Stress - How to Personalise Your Approach
Longevity: Fasting, Diet, Sleep and Stress
Nick and Dr. Robert Lufkin MD dig into the ‘secrets’ of longevity. You can find the full video here.
Understanding how to positively influence your longevity is complicated and at times overwhelming!
Demystifying longevity and simplifying the steps you can take to make improvements to your healthspan (and someday soon, perhaps lifespan) is what Longevity Blog is all about!
Today, we hit upon three major topics in longevity - fasting, diet, sleep & stress in our with Dr Robert Lufkin, MD of Health Longevity Secrets.
How to Fast for Longevity
Fasting is one of the more recent major health trends. And like many health fads, it comes in hot and with plenty of miracle claims on how it cures all forms of ailments.
Analysing the benefits of fasting for your longevity and how you might approach fasting for longevity purposes is a challenging topic area with no ‘straight answer’.
Calorie Restriction and Longevity
Here’s what we know. Calorie restriction (eating slightly fewer calories than your body requires) over a lifetime improves healthspan and lifespan in many animal models, including rodents and even primates (who are closely related to humans).
However, there are no longitudinal studies on fasting which can demonstrate this is the case in humans.
Long-term strict calorie restriction has its advocates in the longevity health space. And quite a spritely bunch they are!
But to date, they are placing their bets on a very challenging type of fasting, which when done inappropriately can actually lead to early death (the opposite of what you want!) in some cases, and which has little to no robust scientific data specific to human longevity or lifespan.
Weight Management and Longevity
We love the fasting app Zero! It’s a great way to track your fasts and join a community of others looking out for their best health interests. Plus its totally free!
One thing that we do know for certain, is that eating too many calories (more than your activity level requires) over a long period of time is associated with many chronic health conditions.
Why? Because it leads to being overweight, even obese, and increases systemic inflammation.
It even increases your biological age.
If you want to improve your health outcomes, you should maintain a healthy weight.
Through the lens of longevity, this makes fasting is a valuable tool. One that can you can use to reduce your weight to a more optimal level & reduce age-related disease risk.
For some insights on the types of fasting you can use to accomplish this, checkout Nick’s discussion with Dr. Lufkin at ~33:40 (or the transcript below) in our YouTube interview!
Does sleep increase lifespan? How many years does lack of sleep take off your life?
Getting quality sleep is essential for your health and longevity. How much does sleep affect your healthspan? Well that depends!
It is well established that getting too little quality sleep is very bad for your health, while getting enough quality sleep helps your body heal/recover more effectively.
From a first principles standpoint - we can predict that getting enough quality sleep is certainly very important for your longevity.
How much sleep do you need?
However, the details behind this statement are difficult to pin down. Your personal needs cannot be explained to you in a generalised blog post.
You have to take this matter very much into your own hands, and become an expert in understanding how you sleep best.
Getting ‘enough good sleep’ breaks down into three major components:
Sleep duration (how much you are sleeping)
Sleep quality (how well you are sleeping)
Sleep schedule (how regular your bedtime/waking time are).
Improve your sleep by tracking sleep duration (how much you are sleeping), sleep quality (resting heart-rate, movement) and sleep schedule.
Once you have a baseline (4-6 weeks of data), start experimenting to see what can improve your numbers in these three categories.
How much sleep (duration) you need is very much an individual statistic. And your personal sleep requirements will change according to the demands of your day.
For example, athletes tend to need more sleep so their bodies can recover from their training. If they were to discontinue their intense training, they would need less sleep overall.
Meanwhile, shift workers who have irregular sleep schedules (e.g. nightshift work a few days/week) are known to have much higher age-related disease risks (e.g. cancer, cardiovascular disease).
How to Measure and Improve Your Sleep
Sleep quality has recently become more measurable, which allows you to monitor it over time and get a baseline for what ‘normal sleep’ looks like for you.
Jump ahead in our video interview to ~39:50 (or the transcript below) to hear from our Founder Nick on some tricks for using everyday wearables to establish your sleep quality and how to analyse what helps you sleep better (or worse!).
How Does Stress Affect Longevity / Life Expectancy?
We hear a lot about how damaging stress is to our health and longevity. So much so, it might even be stressing you out!
“Stress” however, is far too generic a term. For example, stress can be good, so long as it does not overwhelm the biological system. Nature has developed robust responses to stress to recover and then become more resilient against a specific stress.
You can self-experiment with stress, just by observing your emotions, feelings & thoughts. To do so, try mindfulness meditation to practice observing your mental state.
Once you build some basic skills, you’ll be able to better notice how the events of your day impact your mental health.
We’ll be bringing you some examples on how to track stress/anxiety and run a self-experiment in future posts.
What you should concern yourself more with is being able to 1) observe your mental health state and 2) identify what triggers poor mental health for you. From there, you experiment with positive changes to your lifestyle, supplement stack and mental adaptation strategies.
Starting with observing your mental health status, our Founder Nick recommends using mindfulness meditation.
Learning to sit with your thoughts, emotions and feelings creates an ability to observe them. Without practicing this, you’ll lack the all important skillset required to know what is stressing you out.
By building an ability to understand and observe your mental health state, you then become enabled do something about what brings on poor mental health and do something about it.
Using a mindful mind, you’ll be able to the self-reflection and self-observation required to become aware of what specific life events are causing you to feel stressed.
Nick is currently running a self-experiment to improve his anxiety levels, as informed by his personalised genetics report from Self-Decode.
From there, you can develop strategies specific to these triggers.
We’re in the progress of using Nick’s personal results from Self-Decode to explore our personalised stress and anxiety supplement recommendations from their platform, to demonstrate how you can do this effectively!
Tune into the YouTube interview to hear more from Nick on this topic, at ~43:40 (or read the transcript below!).
This is part two of our transcription of an October 2020 interview between Dr. Lufkin and our Founder Nick.
It is in excerpt format, to highlight key points of the discussion with basic edits made for purposes of clarity and correctness. Timestamps are approximate.
Is fasting good for longevity?
Robert Lufkin (RL) at 33:40
What about diet? Fasting, we hear so much stuff about that, and longevity, what's your what's your take on on that as as far as influencing longevity?
Nick Engerer (NE) at 34:02
Look, this is this is a fascinating discussion. And once again, when we start talking about diet, we start talking about fasting. We're really getting onto this question of what will work for you and you need to be able to measure before and after…
Fasting refers to many different types of restricting your diet, it might be calorie restriction, eating a fewer number of calories overall, it might be dietary restriction, removing a certain part of your diet. For example, keto diet, the ketogenic diet, it's an extreme example.
It might also be something where you change the times that you're eating, you might only eat in the evening, you might only for a few hours a day or maybe an eight hour window.
And then there's of course the true fast where you go for a few days at a time, with just some water and electrolytes, maybe a multivitamin
I've experimented with all of them. And so I've had to go through that self-experiment and learn for myself what works best for my biology, and do that through testing my bloods, looking at how I feel, what are my energy levels, what is my skin look like?
What Type of Fasting is Right for Your Longevity?
… Coming back to the point, somebody who is extremely overweight, maybe morbidly obese, and really needs to lose some weight - fasting is a powerful tool for that person, they should absolutely consider it … they might be able to go for extended periods of time and not eat and lose incredible amounts of weight
There might be just the average person who needs to lose 20 pounds, and they so they decide they're going to skip breakfast, eat in a smaller window, and make sure they're not overcompensating for missing breakfast by eating more calories at lunch and dinner.
Why Nick Doesn’t (Currently) Fast
… I mentioned earlier that I'm now a triathlete. So I wake up and eat and then I eat again and then I eat again, and then I eat again. And it's because I'm working out two times a day, to adapt my body to be more of an athletic one. I'm convinced that over a decadal timescale, the most important thing that my biology can have is better mitochondria, stronger muscles and adapted body with great angiogenesis and fresh blood vessels, circulating nutrients and clearing waste throughout my body.
There's all these benefits that I cite for why I'm doing this. Now, that means I'm not necessarily getting the benefits of restricting my calories, which we know does provide longevity benefits. Calorie restriction is one of the most powerful tools for actually improving lifespan outcome in primates. And we think that that applies to humans.
But that's not the only knob you can turn to improve your longevity. There's several - so you have to try to pick a longevity strategy and implement what you think's going to work best for you and your biology over the long-term, and put your cards on the table after you place your bets.
I'm going down the exercise route, I'll probably eat less as I get older overall, but now I'm finding that the eating small meals throughout the day is powering exercise, which is making my body stronger, my heart stronger, and leaving me feeling pretty fantastic.
RL at 38:11
What are the other knobs for longevity? We touched on exercise and diet. What other knobs can we turn there?
Using Blood Testing to Choose a Longevity Diet
NE at 38:25
When it comes down to thinking about your biological age there are four important things you can change, diet, exercise, stress and sleep.
We've just talked a bit about diet (fasting) - let me give a further example on how it can be personalised.
Nick’s blood lipids over time, with 3x different diets highlighted.
When I did the ketogenic diet for a year, my cholesterol levels were out of whack. My LDL-C was too high. My particle count for the lipoproteins was too high.
I looked at that data and said - “Look ketogenic diets, not the right thing for me”.
Instead I've come around to eating low amounts of saturated fat, pretty much eliminating dairy, and still eating red meats, fish, chickened balancing that out with eating a lot more plants
That diet has improved my inflammation levels and reduced my LDL-C and my ApoB number (representing the lipoprotein particles counts and their sizes). So that diet is a healthier thing for me.
But that's not necessarily the thing that will be right for everyone. So you have to back that up with blood testing, how you feel and your overall goals.
Eating a diversity of plants is one diet change Nick can back up with a self-experiment. Checkout the details here! You might find GlycanAge biological age tests to be valuable in your own diet optimisation! Use the code ‘longevityblog’ to save 15%!
Sleep and Longevity - What Nick is Tracking
Let’s talk about sleep next. And also, you've done some great experiments on NMN and some other things. If you want to talk about those that that would be interesting as well.
NE at 40:50
Okay, let me tell you what I think about sleep. Sleep is again, highly personalised, like all this stuff is. Some people will hit the hit the hay and just knock right out and sleep through the night. Good on them. I wish I was one of them. I'm not.
In fact, through analysing my own genome, I am in the the 98th percentile for insomnia! So I'm a bit of a thrasher!
I have to really think about my sleep and get on my A game. I've just pretty much eliminated alcohol altogether in my life. But more importantly, if I'm going to have a drink, it's going to be a day drink.
If I have a single beer or wine for dinner, I can already see resting heart rate increases my heart rate variability drops, and as a result I don't sleep as well for the first part of the night till my body clears that out of its system.
Same thing for eating meal too large of a meal late at night, I'll see elevated heart rate for a few hours before it finally comes down.
That increased heart-rate is reducing the amount of recovery that I get from my sleep.
It's fairly in vogue to do sleep tracking, I get a lot of data from the Oura ring. It's has its limitations. I wouldn't say I trust its sleep stage data very much.
But what it does tell me is it tells me how much I'm moving around. It tells me what my heart rate is and measures my heart rate variability, my body temperature.
Just looking at those metrics alone makes it possible to collect data and infer outcomes.
What about Sleep Supplements? Do they work?
I've also then been able to self-experiment with sleep stack supplements.
For example, I was just trying out valerian root. I thought I felt like I was sleeping better, but when I went back and looked at my data, I couldn't see any evidence of that. So I did not add it to my stack.
I've experimented with other sleep related supplements like magnesium L threonate, or Magtein, but that turned my brain on too much. One of the only things I found that works for me was magnesium glycinate. I'll take around 300-400mg as that seems to relax me a bit.
How to Interpret Your Sleep Data for Optimisation
… So for your own personalization, get a format for collecting data, the most important thing in my view, is being able to see movement and heart rate. Your heart rate should drop off fairly quickly and lower out into a nice plateau and then pick up when you wake up.
If you don't see that, if you see the heart rate staying up and you see it spiking throughout the night along with movement - these are signs that you're not sleeping as well as you could.
You can gather that information from a smartwatch. You can gather that stuff from a ring or a whoop band or any other mechanism you want. But being able to then take it and inform your personal longevity strategy is the most important part.
In my office rocking’ these blue light blocking glasses from DoNotAge. 10% off when you use the code ‘longevityblog’.
That means changing one thing at a time, collecting some data and deciding very objectively - did trying that thing improve my sleep yes or no? Do that over and over again until you know what works for you. That's how I would approach sleep.
One last thing - blue light blocking works for me in terms of sleep onset.
Particularly if you got a screen at night or you're in a bright environment. Light control is huge.
So I take all the blue light out of my environment I turn I got LEDs that light up my home and I turned them down to a warm tone and that turned them down to a red light as we're reading go to sleep in the house.
Controlling the lights is really, really important for sleep.
Stress and Longevity
How about stress then? Same type of thing?
NE at 45:05
Stress - we have a proclivity to it in modern society… I actually intentionally live out what we call in “the bush” in Australia - meaning I live in a rural area. Every time I go to the Big Smoke (Sydney), where my company is based and visit with my team, I'm amazed at just how many cars are trying to kill me, the noise that is in my ears, the pollution I'm breathing in, the light that's coming at me all times of the day…
Learning to understand that your body has having stress response to everyday activities… these things have impact on your subconscious and raise your stress level. Being able to notice what increases your stress level and what is causing you to have a stress response… is important to figure out in your in your own subjective awareness.
Meditation and Longevity - Become Aware of What is Stressing You
The most powerful tool for being able to notice this is mindfulness meditation. I've done a lot of meditating in my life. I've done a lot of self reflection, and meditation retreats - all that good stuff. Meditation has become a powerful tool, much like fasting, that I know when I need to use, and has also given me a baseline awareness to be able to see in my own mind, what I'm experiencing, what I'm thinking, what I'm feeling.
That's what you need to do in order to understand stress, because until you can take that step back and observe the things that are making you feel stressed, you won't know what to eliminate.
Once you can see that, then you need to eliminate and control. I'm actually doing a self-experiment with some of my personal results from Self-Decode, exploring the stress and anxiety supplements that have been recommended to me by my genetic reports
Self-experimenting with these supplements is important because the same thing won't work for everyone. A great example - CBD oil makes me feel anxious. I feel good for the first hour and then I feel anxious for the three hours after that. That's not the experience that most people have.
Developing the skills to figure that out for yourself by self experimenting, adding one thing at a time, keeping a journal … That's the way to approach managing stress.
So first - mindfulness to gain perspective, and then (second) try taking things away or adding things in (supplements) to control that stress more effectively.
RL at 47:38
I'm hearing the theme of personalization and being aware of your own body and what works for each of us. It's such an important important message.
What about supplements,? You mentioned a couple like resveratrol or NMN. Anything there you recommend?
…
This interview continues, covering Nick’s multiple self-experiments and his role as an Advisor to DoNotAge.
If you’d like to hear more, you You can watch the rest of this video interview between Dr. Robert Lufkin, MD and our Founder Nick here.
Follow usr for the latest #Ler for the latest #Longevity news!
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Calcium AKG Alpha Keto Glutarate Supplement Review https://t.co/K7keDM3Lyn
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Mitopure Review - Does this Urolithin A supplement actually work? https://t.co/0Y6Bx4yA7h
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How Fast are You Aging? A Biological Age Test for Rate of Ageing with Ryan Smith of Trudiagnostic (Part 2) https://t.co/5SZW3Or6JJ
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What is the Most Accurate Biological Age Test? An Interview with Ryan Smith of Trudiagnostic (Part 1) https://t.co/wdIxtTVeq0
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One Skin Review - Self-Experiment Before and After Results with OS-01 https://t.co/3hqzLtfVa3
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Nick posts plenty of #Longevity content to Instagram as well, follow him @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
How to use biological age testing kits and build a personalised longevity strategy
What is my biological age?
Nick and Dr. Robert Lufkin MD dig into the ‘secrets’ of longevity. You can find the full video here.
Your biological age can be estimated through a number of different methods. We’ll discuss those in some detail in this post.
What this biological age value is attempting to answer is - how old are you really? Meaning, how old is your body at the cellular level?
Answering this question has only recently become possible.
But one of the challenges is - there are many ways to ‘measure’ it, and not all of them will give you the same answer!
More to the point - can these tests enhance my longevity strategy?
How Do You Measure Biological Age?
Biological age can be ‘measured’ by a blood test or a saliva sample.
Using these samples, certain aspects of the sample are analysed, depending on the test type:
Telomere length (looking at your chromosomes)
Phenotypic age (comparing a compilation of blood tests to your peers)
Epigenetic age (looking how your DNA is expressed by the epigenome)
GlycanAge (reviewing the signalling molecules for inflammation in the body)
How to Calculate Biological Age
This question brings us nicely to our interview subject matter today.
Calculating biological age from the above samples is based on the following process, with widely varying degrees of simplification:
Researchers gathering many thousands to hundreds of thousands of the above samples
Building a model based on the chronological age of the donors + the markers measured
Choosing the risk target of the model (e.g. all cause mortality is most common)
Using the model to review your sample to tell you how hold you ‘look’ compared to your peers, biologically
There are many commercial offerings for doing this, several of which we have reviewed in detail on Longevity Blog (read on for more!).
What Does A Biological Age Value Tell You?
Biological age and longevity is a complicated topic, and it is not easy to sort through marketing hype and make a clear decision on how you want to engage with this relatively new technology.
Thankfully, our friend and colleague Dr Robert Lufkin is looking to make sense of these messages and find the ‘secrets’ often buried in the details.
In his recently launched Health Longevity Secrets show, he’s delivering a new episode/podcast each week interviewing topic areas experts.
On episode 18, he interviewed our Founder Nick, covering a wide range of topics with a distinct focus on biological age (the focus of this post) and also fasting, sleep, stress and diet (the focus of part two of this interview).
We’re bringing you the highlights (hosted on YouTube) of the discussion in excerpt form, where the tables have turned and Longevity Blog the interview subject for a change!
This is a transcription of an October 2020 interview between Dr. Lufkin and our Founder Nick. It is in excerpt format, to highlight key points of the discussion with basic edits made for purposes of clarity and correctness. Timestamps are approximate.
Biological age testing and the Personalised longevity strategy
Robert Lufkin (RL) 1:18
Maybe just to start off - when did you know you wanted to focus on longevity? I mean, you're not that old right now. So what happened?
Nick Engerer (NE) 3:08
I'm 35, but I've always been interested in health as a hobby.. That came through for me in powerful way in my late 20s when I had three important people in my life get cancer in the same year, all in their late 20s.
One of those was my wife - diagnosed with appendix cancer 30 minutes after my son was born through Caesarean section.
Those encounters with mortality really got me thinking at a young age around what can we do to engage with this ever present risk that we have in the background … there's a lot of technologies around to enable proactive screening for health conditions of all types. There's a big trend going on now with proactive healthcare technologies being able to pick up diseases earlier and earlier.
The costs and barriers of those coming down further and further.. those two trends really caught my interest.
building a personalised longevity strategy to simplify complexity
RL at 5:34
We’re all about ‘Sticking Around’, and self-experimenting with the many ways of doing so. Like this self-experiment with NAD booster NMN!
The Longevity Blog, which I love! … I love the motto for it: “Stick around”. That’s good… I look forward to reading and every time
Stepping back, how do you view longevity? What is your concept of longevity?
NE at 6:05
I'm a scientist ... I come to this thinking with a scientific view. I find it really interesting that we have an increasing availability of ways to test and gather data on our own body, and then form a view of how we interact with our health and specifically our longevity with that information.
When I think about longevity as a problem space… there's simply so much that one can do. There's so many pathways… it's simply overwhelming to try to engage with all of them. It's not possible.
How do we really simplify that? I like to think about it in terms of developing a personalised strategy. We’re working to pull together content on Longevity Blog…
I'll give you a specific example about how to think about this…. We can do a number of different exercises to actually personalise your risk profile.
The most simple example is doing a family health questionnaire; what did your grandfather and your grandmother on both sides of your family - what age related diseases did they experience? What about your parents, aunts and uncles?
This is totally free… you can take your doctor and start a discussion. See ahead of time - there's early heart disease in my family, what am I going to do about that? Or there's early onset Alzheimer's in my family. What am I going to do about that?
This simplifies the problem space down to some first actions that you can start to take in targeted ways to engage…
Personalised Longevity Strategy - where to start?
RL at 9:14
That's such a good point Nick. It's one thing to talk about longevity and and do the rapamycin and the resveratrol but we all need to first look at our risk factors because we can boost our longevity …
Giving blood at NextHealth Los Angeles for a Micronutrient Test. Finding critically low micronutrients in his blood was a key part of informing Nick’s personalised longevity supplement regime.
You mentioned screening and labs … could you talk about how someone would put together that screening profile for themselves?
NE at 10:10
That’s part of my obsession - trying to figure this out. There's simply so many tools at our disposal that we need to start with that simplifying lens that brings the scope down.
I've played around with many different technologies, some of which are a few thousands of dollars, some of which are less than 100 bucks. I’m continually working to pull together examples of how to use these different tests, or different blood screens or biological age estimates to really formulate a way of creating self experiments that show what works for you.
But even that's a bit advanced. So how do we really bring this back to the basics? Moving beyond that family health questionnaire, the place that I'm increasingly looking to is genetics.
How Do Genetics Influence Longevity?
There's been a big spike in recent developments and the capability of analysing the genome… what's happening is that computational resources and machine learning and data science are coming together with genetic information that's being studied... coming together in a way where we can not just look at single parts of the genome, but look at hundreds of thousands to millions of parts of the genome and pull together a picture with that, using machine learning and data science approaches.
Self-Decode, a comprehensive genetic testing kit for less than $100USD. Use it to customise your longevity strategy by targeting your stack-building and lifestyle changes toward future age-related disease risk.
We just interviewed Joe Cohen (Founder at SelfDecode) on Longevity Blog… 60+ scientists and data machine learning data science folks who are really moving the needle on the capability of genetic analysis.
What they've been able to do with the advances in the science is personalise analysis and suggestions … now we can look at an individual and say… here are the specific diseases we can connect your risk to, for cardiovascular disease, or for neurodegenerative disease, or for metabolic disease. And these are the age related diseases.
Again, use it as a simplifying lens in the overwhelming space of all the things we can do… to work toward avoiding age related disease. And to start doing that 10 to 20 years ahead of time… you can start being proactive in changing your lifestyle in a specific way
Epigenetic Testing for Longevity (including Biological age)
RL at 15:04
Are you aware of any other companies that are looking at the epigenome for doing machine learning of the same thing with, you know, methylation clocks?
NE at 15:49
Yes. This is where things are going now. Epigenetic understanding in science has really accelerated over the last five years, again, because of the ability to sequence and be able to do that types of real in depth analysis to pull the data out of the epigenome which is changing over time, which is responding to the environment.
...That space is a bit behind, you could say it's 10 years behind genome sequencing, and that we're still connecting what's happening in the genome to outcomes.
I've spoken with the CSO of Chronomics Dani Martin-Herranz, which is one of the leading companies in epigenetic analysis … we get a biological age number, but how do we know.. what we should do to improve that biological age?
Order your own epigenetic biological age test from DoNotAge. This kit includes customised insights into gut, vision and cardiac health. Use the code “longevityblog” to save 10%
The fact is that the data is not there yet, the science isn't there yet to say this is what the epigenome is showing us.
This is what you need to change to be more youthful or to solve a given problem…it's a even thornier problem than simple genetic analysis, but it will increasingly inform us on our health journey, particularly our longevity journey, as it's becoming central to understanding some of the ageing process itself.
what can biological age tell us about longevity?
RL at 18:36
Dr. Morgan Levine and some of the others from Yale and other places - they're finding that depending on what you train it on, the clock is going to be biassed towards cardiovascular risk or dementia risk or other risks like that.
NE at 20:15
I can add a few things there - Dr. Levine… I've watched several of her lectures, they've done some great collaboration with National University of Singapore talking about biological age clocks… what's happening biological age clocks is trying to express risks in the mortality space over time [to] represent your risk for a disease outcome.
That [biological age] number at the end is nice for a consumer because it's an easy story. But what's more interesting to me and where I think we're going to future is increasing dissection of those results to give useful information.
[Checkout 3x FREE ways to estimate your biological age!]
You mentioned Gordan Lauc from GlycanAge - we’ve interviewed him on Longevity Blog .. I actually just successfully improved my GlycanAge, it was our I'm 35, it was 30, I got it to be 24. I did this by eating a diversity of plants in my diet...
Nick improved his biological age by 6 years through a change in diet. How? By eating 30+ different plants per week. Checkout the details here!
Being able to use these tools to improve a biological age result does seem to suggest an improved health outcome.
But what's really interesting about the GlycanAge product is they actually break it down into three indices… you can actually look at these indices and see where you improved by trying an intervention.
… When you start to break down that result beyond just an age, you start to see, okay, I've increased my performance by reducing the number of inflammatory glycans in my body, which are causing chronic inflammation, and increasing the number of good glycans in my body, what you're saying to the rest of the body is systemically toned down inflammation… that's better for your longevity.
Reversing Aging versus Improving Biological Age
RL at 24:07
The question is if we reverse DNA methylation, have we reversed our risk of ageing?
NE at 24:47
This is important to get this out there for the consumer. There's a lot of different biological age tests. They will give you a result that comes out of a model that is trained that has some value.
If you get a number that says you're 40 years old, and you're 50, you're biologically younger on that metric, which is probably better than your peer who is 50, but gets a biological age of 60. There's some merit to the absolute value here.
But what's more interesting to me, and I've talked to Professor Lauc at GlycanAge about this, is that changing our biological age, the relative value… [getting a] lower value is indicative of making a positive health change wherever that model is trained.
Want to go deep on biological age models? Checkout our technical interview with Deep Longevity CLO Alex Zhavoronkov.
For glycans, the overall inflammation in your body. We're not talking about a single marker like C reactive protein, homocysteine… we're talking about 24 different glycans that track and tag the individual molecules in the body to tell the immune system what to do, before any of those blood markers go up.
The consumer needs to know what they’re trying to change based on which biological age test they’re using and what it represents. Then the should try to implement a positive change to that number, and testing again, some months later.
They also need to know how long that marker takes to change. With GlycanAge, you can change in just three months. With an epigenetic age test, it might take 6 to 12 months. So understanding the science and tech behind the biological age tool that you're going to use is part of what we demonstrate on Longevity Blog.
… One other thing I'll add - don't get caught up in calling it “reversing” ageing … No, you have improved your mortality risk because that age has gone lower. That's a great thing. But we're not at a point where we can “reverse” true biological age, in terms of turning that number down with interventions.
… The point is we have a couple new metrics that we can use to run self experiments and improve the longevity outcomes for our body, which is fantastic.
Biological Age in Athletes: Exercise and Longevity
RL at 28:31
One promising longevity molecule Urolithin A is making a big impact in the athelete work. Supplement “Mitopure” is demonstrating improvement in endurance performance through enhancing mitophagy (the death of defective mitochondria). Read more in our interview with Amazentis CMO Federico Luna.
That's a great point... I wanted to get what's your take on biological clocks measured in extreme athletes, they've noticed shortening of their age (increased biological age). Have you encountered that at all?
NE at 29:12
Yes. In fact, GlycanAge is a great example of this.... I am convinced far and away the best, the most powerful longevity drug you can take right now is exercise.
Now, exercise is an interesting drug, in that its doses are widely varying, and they're highly personalised. I recently did a deep dive on exercise and its profound benefits for longevity, and I decided that I wanted to really up my fitness game, and I actually became a triathlete.
So now I'm training for triathlons. And it's been a huge change for my body. I've seen so many positive things that have resulted from that. But I know that ... there's a so called J shaped curve, which is well known in the sports medicine industry. Once you exercise too much, you start increasing your risk, particularly for health conditions like atrial fibrillation
...There's risks that athletes face because when it comes down to a real true athlete, these individuals are pushing their body so hard day after day after day… exercise produces a profound amount of damage and inflammation in the body that the body that needs to recover to become stronger.
Over time, continuing to push your body really, really hard, like a professional athlete does, isn't actually probably good for longevity… I don't know where the bottom of that curve is, but it somewhere around 450 intensity minutes of exercise a week, according to big cohort studies.
So there's, you can do a lot of exercise. And you should, because it's a really good drug and it keeps improving your health outcomes. But professional athletes are on the far end of that. And this is why we see, you know, decreased benefit to high levels of really intense exercise, it's just simply too hard on the body for it to recover all the way.
RL at 33:19
Well, now that we're talking about some lifestyle things like exercising.. What about diet? Fasting, we hear so much stuff about that and longevity. What's your take on fasting influencing longevity?
Longevity Strategies for Fasting, Diet, Sleep and Stress - Read More in Part 2!
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RT @BradStanfieldMD: Avoid These Popular Supplements (shout out to Professor Matt Kaeberlein @mkaeberlein & Professor Brian Kennedy… https://t.co/cy9CXldgUS
-
Who are influential persons in #longevity who are of Asian, African American or other “minority” group in the US?
I also posts related #Longevity content to Instagram as well, follow me @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Increasing Plant Diversity Improves GlycanAge Significantly - A Self-Experiment
First things first - we have a 15% discount code available for the GlycanAge test - ‘LONGEVITYBLOG’.
Now go run your own self-experiment!
Glycan Age Test Self-experiment Results
In a series of recent posts, Longevity Blog has been investigating glycans and their many important roles in the body.
There is much to learn, but the key takeaway is that they play an informative role to the immune system by ‘tagging’ which of the many foreign molecules in the both are friend and which are foe.
We’ve some ideas on how you might improve your GlycanAge - by eating more types of plants! Read on for more!
If you’re across the basics of how the immune system works, you’ll be aware that inflammation is a sign that the immune systems is activated.
And while this can be highly valuable for enacting repair of specific areas of the body (e.g. damaged tissue), it is also a destructive process (e.g. tear down and rebuild that tissue).
As we age, levels of chronic inflammation rise, both as a result of and a cause of the aging process.
In your quest to maintain your ‘youthfulness’ and achieve longevity, monitoring and improving levels of inflammation in your body is highly important!
However this has not always been easy. There are many ways to measure inflammation in the body - which to choose? How to improve it?
It turns out, there is a simpler answer - don’t track the result of inflammation, instead track the molecules which signal - should inflammation be ‘on’ or ‘off’?
That line of thinking brings us to glycans and specifically the GlycanAge biological age testing kit.
In this post, we’ll review the results from our Founder Nick’s GlycanAge self-experiment. For the nitty-gritty details on the how & why the experiment was conducted, including the hypothesis and scientific framework, be sure to read that post first!
Read on for a few basics, and then a deep dive into the results.
Self-experimenting with diet to inform the immune system
Hey everyone, Nick here! I’m excited to share with you that I was able to improve my GlycanAge by 6 years in just 3 months, with a specific dietary change.
That change? Eating at least 30 different plants per week.
This self-experiment was completed in effort to improve a GlycanAge that was already quite favourable (30 yrs for a 35 yr old) in an individual who was already ‘doing all of the right things’ with diet, exercise, sleep and stress.
From my perspective, -5 years just wasn’t quite good enough. I was convinced I could improve further, as I’d achieved much younger biological age by other measures, and I like a good challenge!
To complete this self-experiment I dutifully designed and tested a specific hypothesis, which was:
“By programming the immune system with a diversity of plant information (local & organic where possible), chronic inflammation will be reduced as the immune system learns more about what is friend and what is foe, leading to an improvement in the Glycan Age”
Let’s briefly talk about why adding more plants to the diet could be reasonably expected to improve GlycanAge and then take a look at the evidence which shows it worked.
Why would 30 plants per week improve glycanAge? The basics
Of course I suggest you read the introductory post, which will offer you much more detail, but here is the main line of reasoning why eating a diversity of plants is likely to improve your GlycanAge.
Delicious veggies from our local farmers market. Full of environmental information just waiting to program your immune system. Eat me!
The immune system is constantly monitoring what you eat - deciding what should and should not be allowed into the bloodstream.
This surveillance occurs in the small intestine at your “intestinal epithelial cells” (IECs) which act as a filter, whereby nutrients, electrolytes, water and beneficial bacteria are allowed into the bloodstream (while the ‘baddies’ are not)
The immune system that is supporting the IECs with this ‘filtering' step is learning what is good and what is bad through the diet you eat
This effectively means that your diet is information about your environment
The diet is then responsible for telling the body, through a diversity of food and organisms, what is ‘friend’ and what is ‘foe’ - and it does this through partnership with glycans
Thus the hypothesis:
When you don’t eat a diverse diet your immune system receives less information = more inflammation (and higher GlycanAge)
However, the opposite is also hypothesised to be true: more information = less inflammation (and lower GlycanAge)
Did it work? Experimental results
The results from this self experiment are provided through the GlycanAge online dashboard, which delivers a biological age result, but more importantly, a breakdown of the three most important glycan indices.
These indices summarise the 24 glycan types which regulate inflammation in the body, and are broken down in GlycanAge test results as follows:
G0 are glycans without galactose, which are the most proinflammatory. These are represented by the Mature Index.
G2 are glycans with two galactoses, which are suppressing inflammation. These are represented by the Health Index.
GS are glycans with sialic acid, which also suppress inflammation. These are represented by the Youth Index.
Result: GlycanAge improves by 6 years
I am presently 35 years old. My GlycanAge at the start of the self-experiment was 30, an encouraging result. After eating 30+ plants per week for 3 months, my GlycanAge further improved by 6 years, to a value of 24.
If you’re interested to understand a bit more about how this biological age estimate works, you can read our interview with glycan expert Prof. Gordan Lauc.
One very important question that we asked Prof. Lauc was about the importance of the absolute value of biological age versus the relative changes that occur over time.
“It’s also important to not worry about the absolute number, because the absolute number is also strongly affected by genetics. Approximately 30-50% of the GlycanAge is determined by your genes, you cannot fix it.
It is the relative number, the pace of changes in biological age which are important. If your GlycanAge is increasing more slowly than your chronological age, then that’s good. ”
My GlycanAge at the start of the self-experiment.
My GlycanAge at the end of the 3 month experiment.
Result: glycan indices improve across the board
One aspect of the GlycanAge test kit that I really like is that they give me direct access to raw data, a summary PDF report and insightful indices which breakdown the biological age estimate further.
Not many biological age test kits will offer you this level of detail, and it provides an important layer of additional insight into why a given self-experiment worked/didn’t work for improving biological age.
Intriguingly, the self-experiment resulted in across the board improvements in these indices. The changes in the % relative to my peers (percentiles) reveal this in a straightforward way.
For example, the ‘Health - G2’ index improved by 0.11. What does that mean? My result is now better than 60% of others in my age group, whereas before it was only 49% (a below average result).
The three major glycan indices at the start of the self-experiment.
The three major glycan indices at the end of the self-experiment.
Improving GlycanAge with diet: Discussion
Interpreting the results of a self-experiment is very important. We cannot simply look at the data in results form and make a conclusion. In the spirit of science, we must discuss them!
The most important aspect to discuss here, is how the self-experiment was controlled. In essence, this means limiting as much as possible, any external factors which could ‘confuse’ the results.
Importantly, we need to examine any changes in the four main drivers of GlycanAge results. As Professor Lauc outlined for us in his in-depth Longevity Blog interview, these are: stress, sleep, exercise and diet.
Let’s briefly review each.
Controlling Diet
I kept a simple list organising plants I ate into groups of 10 for each week of the self-experiment. This was done in the ‘notes’ app on my iPhone and was very easy to manage.
In our experiment we turned the ‘diet knob’ in a very specific way. By introducing the primary experimental change of eating 30+ plants per week.
First of all - compliance. I can confidently report that I was fully compliant over the 12 week period of experimentation.
In no week did I eat less than 30 different plants. I ate as many as 40 different plants and as few as 31 different plants.
I did not change my dietary protein, carbohydrate or fat ratios or overall intake of calories.
Inevitably, I did eat more soluble fibre due to increased plant diversity, however, I was already eating many organic vegetables and select fruits to begin with.
I just was not eating many different types, instead favouring about 10-15 different plants which I ate repeatedly.
It was as a fun challenge to find new plant foods to try! It resulted in my whole family eating more plants as well - an added bonus.
Controlling Sleep
As any good longevity focussed biohacker, I’m quite religious with my sleep schedule.
During the experiment, I did not change my bedtime or my wake-up time. There was no significant changes in sleep duration or quality. I also did not change any sleep-related supplements.
As monitored by Oura Ring, sleep time was between 7.5 - 8 hours per day with a sleep score of 80 on average.
The below is a gallery of images you can click through (4 in total) showing the sleep score and total sleep from early and late in the self-experiment.
Controlling Exercise
As set out in the opening post for this self-experiment, I maintained a consistent exercise load to within 10% on average (in a given month) as measured by my Garmin smartwatch and heart-rate monitor.
No significant changes were made to total time exercising, exercise intensity or the type of exercise I was completing.
I kept up my routine of 4 weeks of triathlon training with a one week de-load. Average load over the period was unchanged at around ~750-800.
Controlling Stress
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This aspect of the self-experiment was more interesting! I’d originally set out to complete this experiment over 6 months with two GlycanAge tests. However I cut it off at 3 months. Why?
Australia went into a sudden COVID lockdown, upending my life routine and introducing significant additional stress (homeschooling in and of itself would confound the results, haha!).
I simply could not continue the self-experiment for the additional 3 months and maintain good control over the experiment.
Thankfully, I was able to complete the 3 month self-experiment with no significant lifestyle or stress related changes. So this was well-controlled overall.
Conclusion: Eating a diversity of plants significantly improved my GlycanAge
To design this self-experiment, I used Dr Jenna Macciochi’s suggestion to eat 30+ plants per week to boost the immune system.
Immunity: The Science of Staying Well is one of the most up to date, accessible and helpful books out there on building a healthy immune system. Check it out! (Amazon Affiliate link)
We are fortunate to have a pretty clear cut result in this self-experiment.
It was well-controlled and occurred over a short-time frame, with very limited opportunity for external factors to confuse the result.
Moreover, the magnitude of the change in GlycanAge was significant. A 6 year improvement is well outside the measurement error.
Had my GlycanAge improved by only 1-2 years, we would not be able to make such a strong conclusion.
In addition to the size of the change in GlycanAge, there was significant improvement in all three of the glycan indices, where I improved by ~10% in age group relative terms.
This firmly suggests hypothesis looks to have been ‘proven’, with the expressly limited scope of this being an ‘n of one’’ dataset.
Conclusion: Eating more plants improves GlycanAge (for me, and maybe you as well!)
Practically, what does this mean?
For one, I know that I should most definitely keep eating 30+ plants/week! I now consider this part of my longevity strategy.
This is in addition to other tactics like supplementing with NMN, which I also determined to improve my biological age through a seperate self-experiment.
This is precisely how we should use these types of tests. In an intentional and controlled way to test a change and see if it helps you in your longevity journey.
While the ‘conclusion’ is only applicable to myself, this design of this self-experiment provides the opportunity for other wellness and longevity enthusiasts (that’s you!) to use this approach to improve their biological age.
However, if you do not already have healthy diet, exercise, sleep or stress habits - start with those first! Don’t forget that losing weight is the surest path to reducing inflammation and improving your GlycanAge (we asked Gordan!)
If you plan to give it a try, be sure to reach out on Twitter or Instagram and let me know!
You can check out GlycanAge test kits here, and don’t forget to use the code “LONGEVITYBLOG” to save 15% on your order!
Follow me on Twitter for the latest #Longevity news!
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RT @rebeccavziegler: The cryonics payoff matrix. Choose wisely my friends. https://t.co/l1rzsmOC2w
-
My rate of aging: 0.79 It’s the new street cred What you got? https://t.co/aHzWHAfCnD https://t.co/L3rZC4QFN2
-
It’s official - I’m co-producing and hosting a new #longevity docuseries, and will begin shooting in a few months… https://t.co/wLGqRrBfbp
-
“The #longevity segment opened my eyes to the groundbreaking advances in biotechnology, health, and wellness. The i… https://t.co/F8YB7PAeMW
-
I’m completely mindblown by what AI has done over the past 3-6 months, and it continues to accelerate… https://t.co/hh0JslucRg
-
Longevity legends take on many shapes and sizes https://t.co/X9vGa7gvOe
-
RT @BradStanfieldMD: Avoid These Popular Supplements (shout out to Professor Matt Kaeberlein @mkaeberlein & Professor Brian Kennedy… https://t.co/cy9CXldgUS
-
Who are influential persons in #longevity who are of Asian, African American or other “minority” group in the US?
I also posts related #Longevity content to Instagram as well, follow me @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Self-experimenting with GlycanAge - Before and After Diet Changes
We’re glad you’re here! How about a 15% discount code available for the GlycanAge test?
Simply use the code “LONGEVITYBLOG” at checkout
Glycan Age Test review & Self-experiment
As we’ve learnt over the past few posts, glycans are incredible molecules with many important roles in the body.
Perhaps the most important of which is providing information to our immune system about what foreign molecules (i.e. diet, dust particles, bacteria, etc!) are friend and which are foe.
My GlycanAge biological age test kit - just a few drops of blood, drop it in the envelope & it’s ready to go!
As such, they strongly regulate inflammation in to the body, and as we’ve learnt - they are impressively capable of predicting age-related disease onset.
Also, their ‘youthfulness’ can maintained by paying attention to certain lifestyle factors - chiefly diet, exercise, stress and sleep - monitoring them can help us track how we’re doing as we biohack our way to long & healthy lives.
In this post we’ll cover:
The role of glycans in immunity
How glycans are involved in the digestive system
How to use diet to improve GlycanAge
Why food is information for the immune system
Setting up a self-experiment for improving GlycanAge
Plus - snippets from our interview with world expert on glycans - Professor Gordan Lauc
Glycans Regulate Immunity
It is the role of glycans in immunity and disease related processes which makes them so important with respect to the aging process.
Such is their potential impact, that any personalised longevity strategy should likely include an effort to maintain youthful glycan characteristics.
A tumour cell being tagged with 'bad guy’ glycans (represented by the squares, circles, diamonds on cell membrane). Image credit: Gly-tech
“Youthful” in this context essentially means ‘anti-inflammatory’, meaning:
the immune system is not overactive
chronic inflammation is not present (or in advanced age, well managed)
the ravages of inflammaging (the negative feedback cycle of inflammation creating more damage & inflammation) are avoided
How Glycans Impact the Immune System
As we learned in our exclusive interview with world expert in all things glycans, Professor Gordan Lauc, glycans keep track of foreign materials in the body, tagging them as ‘friend’ or ‘enemy’ so that our antibodies know whether to activate inflammation (attack) or suppress inflammation (don’t attack).
“When antibodies are developed, they do not know whether a given foreign object will be an enemy, like a bacteria or a virus, or if it is friendly, such as food or a dust or something else they should ignore.
After the antibody binds to this foreign object, what happens next is determined by glycans. This very complicated process (glycosylation) is regulated by least 40 different genes.
These glycans decide whether antibody will kill a target cell (activate inflammation) or will it suppress inflammation”
Glycans, Immunity and Digestion
A major role of this immune surveillance process is centred on digestion. This is because the process of taking what we eat, and turning it into our own cells or energy requires active decision making on what should be allowed into the bloodstream.
Ultimately, food is “a foreign object” (using Prof. Lauc’s words above) that has entered the body.
This is clearly done for the purposes of providing fuel and supplying important nutrients, such as vitamins and minerals. However, much more than simple nutrition comes along for the ride.
This includes a host of ‘commensal’ (friendly) bacteria, and sometimes, bad ones, along with the occasional plant compounds that may stress the body (such as glycoalkaloids in the ‘nightshade’ family of veggies).
Our immune system has an important role to play in screening which of these compounds should be permitted to pass through the wall of the small intestine and into the blood stream.
We’ll revisit this in detail later in the post!
Using Diet to Self-Experiment with GlycanAge
I (Nick here! Founder at Longevity Blog) am currently experimenting with improving my GlycanAge through a change in my diet, and in this post, I’ll explain what changes I am making, why and how to make this self-experiment an effective one.
Changing diet to improve my GlycanAge - can it be done? Certainly - the question is - for relatively health people, how?
This self-experiment will explore a hypothesis related to increasing the diversity of plants in my diet and potential improvement in my GlycanAge.
However, before we get into the specifics on how this experiment will work, let’s introduce some important background knowledge to support the approach.
Improving GlycanAge with Diet
Improving GlycanAge through changes in your diet can be either quite easy or mysteriously challenging.
If you’re someone who needs to lose some weight - you’re in luck. You can very likely improve you GlycanAge by simply losing weight. Look no further than our interview with Professor Lauc for the reasons why:
“Longevity Blog: Could you point to a successful model for testing and improving your GlycanAge in a way that you can say, I know what did improved it, it was _____ ?
Gordan Lauc: One good example is weight loss. Losing extra weight helps the vast majority of people, because obesity is a big driver of inflammation.”
However, if you’re already at healthy weight, how to use your diet to improve GlycanAge is not immediately obvious. In fact, clinical research with GlycanAge and diet has shown this to be quite challenging (see below tweet & follow me on Twitter for more!).
1000 people were divided into groups eating very different diets
— Nick Engerer (@nickengerer) July 16, 2021
The outcome? It was impossible to predict which diet was best for whom
However, by monitoring glycans, that became possible. Their role in inflammation signalling can reveal - what diet works best for you? pic.twitter.com/D7AyNlzVfp
Improving GlycanAge with Diet by Eating More Plants
Despite this challenge, I believer I have developed a solid hypothesis for testing how people at a healthy weight may be able to reliably improve their GlycanAge.
Through some serious homework, I also believe that this proposed change in diet that would also have relevance to other self-experimenters, and it could be replicated reliably.
This approach will leverage the sub-process of our immune system screening food particles and non-human organisms (i.e. bacteria) as they are processed in the duodenum (small intestine).
This critical step occurs before entering food materials and/or friendly bacteria are permitted to enter the bloodstream and intimately involves - you guessed it, glycans!
Food as Information for the Immune System
To continue down this line of reasoning, you need to adapt your thinking of the small intestine. Stop thinking of it as ‘inside’ your body, and start thinking of it as ‘outside’.
It is within the small intestine where a critical decisions is made - namely, what foreign materials from the diet are permitted to enter the blood stream.
Pictured: Intestinal villae, lines with intestinal epithelial cells (IECs) along with several other functional cells include macrophages (immune surveillance cells). Image Credit: Nature Reviews: Immunology
The small intestine is lined with “intestinal epithelial cells” or IECs for short. IECs are a single layer of cells with two key functions:
1) be a barrier to anything harmful - toxins, bad bacteria, viruses or antigens
2) act as a filter, whereby nutrients, electrolytes, water and beneficial bacteria are allowed into the bloodstream.
In this secondary function of ‘filtering’ where a detailed and highly important involvement of the immune surveillance system takes place.
The details are vastly complicated, but we can afford a useful simplification here.
Assuming you have tight junctions between the epithelial cells of the small intestine, only the foreign material ‘accepted’ by your immune system is permitted to pass through.
Anything else - and your immune system signals ‘attack’ - producing inflammatory signals.
IGG glycolisation (that’s science talk for how glycans are being used within the body - read more about this in the interview with Prof. Gordan Lauc) plays a critical roles in this screening process, and the ‘tagging’ of foreign material as friend or foe is at its peak level of activity at this epithelial junction.
Critically - this highly complex process includes many trillions of bacteria, which participate in the breakdown and processing of food materials by the body.
These so called ‘commensal’ bacteria are actually actively recruited and ‘pulled through’ the epithelial junctions by the immune system.
The commensal bacteria are pivotal to your broader bodily health, with your overall wellbeing depending on a vibrant and diverse population of these friendly bacteria in the gut.
Food as Information
Local organic root vegetables from our weekly farmers market. Covered in healthy soil based commensal bacteria - just waiting to program your immune system.
The activities of food screening and bacterial populations in the gut are tremendously influential on inflammation in the body.
To better illustrate this, we’ll adopt a basic framework - where our diet is information about our environment.
This is the case because the food we eat, the bacterial populations in that food, as well as ‘antigens’ (‘bad things for us’) effectively ‘program’ our immune system.
In prehistoric times, this information was often life-saving, as it was critical for our bodies to become well adapted to the organisms, toxins and food sources around us in order to survive.
In this way, we evolved for our diet to signal “this is what your environment is like and thus how you should adapt to prepare for it”.
Now consider the modern environment, where food is sterilised and our environment is kept much cleaner than ‘nature’ could ever be. Your immune surveillance system is now cut-off from this critical source of information!
Why does this matter? Well, because in a relatively sterile environment, your body lacks enough exposure to healthy bacteria and the wide variety of food it needs to know when or when not to attack.
What does that mean? A sterile diet effectively means your immune system’s default mode is ‘attack’. The immune system, out of interest in self-preservation, will work to eliminate a foreign material it is not comfortable with (used to seeing).
Add it all up and you get - you guessed, more inflammation.
Eating a Diversity of Plants Programs Immunity
In viewing food and organisms from the environment as information, we can begin to build up our glycan self-experiment in the following way.
If your body is not provided a diverse amount of information about the environment through a diversity of food and organisms through the diet, it will tend to react with ‘attack’ more often.
Through our framework: less information = more inflammation.
On the flip side the pathway to reconciling the overactive immune system is through providing ample information about the environment through the diet.
Dr Jenna Macciochi’s Immunity: The Science of Staying Well is one of the most up to date, accessible and helpful books out there on building a healthy immune system. (Amazon Affiliate link)
This will then support the immune system with a more comprehensive view of what foreign materials are ‘friendly’ and which are not.
This conceptual framework is precisely what Dr Jenna Macciochi lays out in her book Immunity: Science of Staying Well.
One of the key recommendations from this exceptionally insightful book is to eat a diversity of plants regularly, preferably local and organic ones.
The result will be a stronger immune system, which Dr Macciochi argues, is one of the only *real* ways to “boost your immunity”.
In her book, immunity expert Dr Macciochi says there is a valuable ‘rule of thumb’ for improving your immune system with diet.
What’s the rule? We’re glad you asked..
“A good rule of thumb for the biggest impact on health is to aim for over 30 different plants per week.
Whereas the opposite is also true. Eating 10 or few has a potentially damaging effect on the microbiota”
Why is this the case? It’s all about diversity of information about the environment.
And that information is programmed in the body via your glycans.
GlycanAge Self-experiment: A Diet with Diversity of Plants
My GlycanAge as of April 2021 is already ‘favourable’. But that’s not good enough for a longevity focussed biohacker now is it?
How low can we go?!
Coming full circle, this logic leads naturally to the experimental hypothesis:
“By programming the immune system with a diversity of plant information (local & organic where possible), chronic inflammation will be reduced as the immune system learns more about what is friend and what is foe, leading to an improvement in the Glycan Age”
The is precisely the hypothesis that this self-experiment will evaluate. So let’s get down to it!
My GlycanAge was first measured in April 2021.
My GlycanAge is 30, whereas my chronological age is 35.
According to Prof. Gordan Lauc, this is a great result.
“Longevity Blog: What is a “good” GlycanAge result Gordan?
Gordan Lauc: Anything which is younger than your chronological age, I would say it’s good.
It’s also important to not worry about the absolute number, because the absolute number is also strongly affected by genetics.
Approximately 30-50% of the GlycanAge is determined by your genes, you cannot fix it.””
Self-experiment: Starting Conditions & Control
This result does make sense. In the 6 months leading up to this test, I maintained optimal levels of physical activity (training for sprint triathlons), a healthy balanced diet (eating small meals across the day, mostly vegetarian but with animal protein 3-5x/week), sleeping fairly well (Oura ring sleep scores at 75-85 on average) and well managed stress levels.
So in each of the four levy lifestyle factors (diet, exercise, sleep, stress) for my GlycanAge, things were in tip-top shape.
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Subscribe to be notified when we announce the results from the GlycanAge before & after!
In this self-experiment, beginning from 1 May, I will eat 30+ plants per week.
Where possible, this will be from local and organic sources (of which we have plenty in the Byron Bay Area!).
Experimental Control
As discussed in my previous foray into self-experimentation with the NAD precursor NMN, it is challenging, but not impossible, to perform a well controlled self-experiment.
We approach this by keeping lifestyle factors as constant as we can, not changing any other key variables, and running the self-experiment for as short a time as possible.
For the GlycanAge self-experiment I will:
maintain a consistent exercise load to within 10% on average (as measured by my Garmin smartwatch and heart-rate monitor)
keep my same sleep schedule (7-8 hours a night)
not make any large lifestyle changes that might negatively impact my stress
not make any other changes to my diet (we’ll have to keep in mind that my diet will also have a reduction in non plant foods - to make room for all of the plants!)
Experimental Test Period
The experiment, according to advice from Prof Lauc will be run for a minimum of 3 months and maximum of 6 months.
This means I will re-test date on 1 August and again on 1 November.
I asked @GordanLauc - how often should we test @GlycanAge?
— Nick Engerer (@nickengerer) July 20, 2021
⁰⁰The half life of IGG glycolisation is ~3 weeks. 1 month would be the shortest period for re-testing
Lifestyle change effects take a bit longer. Modify diet, sleep, stress or exercise?
Recheck every 3 to 6 months pic.twitter.com/hjuVEdWIBo
Other Relevant Items
To keep track of my plant intake, and ensure that eat enough plants, I am keeping a weekly record of all of the plants that I eat.
I keep this pretty simple, recording them in the iOS notes app - presumably you could do this just about anyway that you please.
There is of course an important question - what is a ‘plant’? What counts as 1x plant?
I will only be counting whole food plant sources which equate to at least one serving of that food.
So for example, I would not count ‘bread’ to be a plant, although it comes from wheat flour at it is quite refined/processed (not a whole food). I would however count rolled oats as a 1x plant (limited processing, effectively a whole food item).
Follow our Founder Nick on Twitter for the latest #Longevity news!
-
RT @rebeccavziegler: The cryonics payoff matrix. Choose wisely my friends. https://t.co/l1rzsmOC2w
-
My rate of aging: 0.79 It’s the new street cred What you got? https://t.co/aHzWHAfCnD https://t.co/L3rZC4QFN2
-
It’s official - I’m co-producing and hosting a new #longevity docuseries, and will begin shooting in a few months… https://t.co/wLGqRrBfbp
-
“The #longevity segment opened my eyes to the groundbreaking advances in biotechnology, health, and wellness. The i… https://t.co/F8YB7PAeMW
-
I’m completely mindblown by what AI has done over the past 3-6 months, and it continues to accelerate… https://t.co/hh0JslucRg
-
Longevity legends take on many shapes and sizes https://t.co/X9vGa7gvOe
-
RT @BradStanfieldMD: Avoid These Popular Supplements (shout out to Professor Matt Kaeberlein @mkaeberlein & Professor Brian Kennedy… https://t.co/cy9CXldgUS
-
Who are influential persons in #longevity who are of Asian, African American or other “minority” group in the US?
Nick also posts related #Longevity content to Instagram as well, follow him at @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
How GlycanAge Biological Age Testing Works - An Interview with Glycan Expert Gordan Lauc
Glycans Can Be Used to Estimate Biological Age
In our most recent post, we explored the basics behind biological age testing with glycans.
Working up from the basics (what are glycans?) through to how glycans interact with inflammation in the body, and ultimately are a signal of the aging process itself.
We also heard from Nikolina Lauc, CEO at GlycanAge, a longevity technology company based in the United Kingdom, whose mission is to “bring glycoscience into the hands of both clinicians and consumers to inform, guide and preserve your future health”.
GlycanAge has recently made it possible to purchase a direct to consumer kit to assess your ‘glycome’, which as we will learn in this follow-up post, is a powerful indicator of your future health and longevity.
Today, we’re publishing an exclusive interview with glycan expert and GlycanAge Director Gordan Lauc.
Gordan is not just a glycan expert, he is THE global authority on all things glycans.
As a Professor of Biochemistry and Molecular Biology at the University of Zagreb, he kicked off the Human Glycome Project in 2017 and has built the world’s largest human glycome database.
Through this effort, he has built an entire research team who have pioneered the glycomic analysis technology required to inspect glycans quickly and efficiently.
It is this technology which has made consumer testing of biological age and personal health status through glycans possible.
Our interview subject, and global glycan leader, Professor Gordan Lauc.
While an impressive figure of great reputation, Gordan is also a great conversationalist, amateur gardener and all around collaborative and friendly bloke who is passionate about helping people lead healthier lives.
Through collaboration with GlycanAge, we sat down with Gordan for a 1-on-1 interview, diving into the details behind how the human glycome works, and how to use it to assess biological age.
We even documented Gordan’s input on how you can run your own self-experiment with GlycanAge, to improve your health and overall longevity.
Let’s get into it!
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Through our collaboration with GlycanAge, we have a 15% off coupon code, which you can use on their biological age test kits.
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This interview was conducted on 20 May 2021, over Zoom and is an audio transcript with minor edits for clarity, brevity and correctness.
Screen capture from Gordan’s YouTube video where he briefly tours his state of the art glycan laboratory.
How does the GlycanAge test work?
Longevity Blog (LB): Gordan. We recently checked out a video that is uploaded to YouTube. It was from an Instagram Live video with longevity doctor. Dr Joseph Raffaele.
In this video, you briefly toured your glycan laboratory. We found that absolutely fascinating.
You had a few generations of machines that were in place, and it made us naturally quite curious.
Could you explain what happens when a GlycanAge sample comes into your lab?
Tell us about the process of going from blood sample to glycan analysis!
Gordan Lauc (GL): Glycans are very complicated molecules. You cannot just read the letters in the way you read DNA or protein, they're branched. They're chemically very similar, but in the same way very diverse. Analyzing glycans is a challenge. This is why we need so many fancy machines.
When we do the GlycanAge test, it focuses on the glycan immunoglobulins. First, we have to fish out immunoglobulins (IGG) from the blood sample (a dried blood stain collected by fingerprick),
We have a special technology to get just IGG out of all other proteins in the sample. From the IGG, we remove the glycans, using a special enzyme which acts like a pair of scissors. It removes the one group of glycans called N glycans from the IGG.
After this, we have to dye them to make them visible in our machines. These machines use capillary electrophoresis, or chromatography, which separates glycans based on their chemical structure. Then we quantify the amount of each of them.
For the GlycanAge, we focus on glycans which change with age.
LB: There's around 2,000 to 3,000 types of glycans, is that right?
GL: When we talk about the total 'glycome', there are approximately 2000 different glycan blocks. For IGG, there are 24 major structures, so this “fishing out” process of the immunoglobulin reduces the number of glycans significantly. Using these individual structures we calculate the changes which happen with age.
Biological Aging and Glycan Immunoglobulins
Pictured: A 3D model of an human immunoglobulin
LB: In this biological age analysis, there is a close link between the IGG N glycans you're analysing as age markers and inflammation.
Can you can you explain that connection between these immunoglobulins and inflammation in the body.
GL: Immunoglobulins are the main weapons of our immune system. They are made to recognize any foreign object (bacteria, virus food, any foreign molecules) which comes into the body. They do this by a relatively complex genetic process to make a hypervariable domain to bind to this foreign object.
LB: A complex process certainly - give us the simplified explanation.
GL: When antibodies are developed, they do not know whether a given foreign object will be an enemy, like a bacteria or a virus, or if it is friendly, such as food or a dust or something else they should ignore.
After the antibody binds to this foreign object, what happens next is determined by glycans. This very complicated process (glycosylation) is regulated by least 40 different genes. These glycans decide whether antibody will kill a target cell (activate inflammation) or will it suppress inflammation.
Inflammation and Glycans
LB: And it is this increasing level of inflammation across the body which is tied to aging. What does a youthful version of this process look like?
GL: What we see in young people is that the majority of immunoglobulins have these anti inflammatory glycans. But when there is an attack by a foreign invader, like a bacteria or virus, then you need inflammation.
The problem is that as we live longer. We are genetically not made to live over 40. Once you stop making children, your genes don't work for you anymore, they work against you!
As we're getting older, this process gets disturbed, and immunoglobulins become more and more pro inflammatory. And actually, what we are measuring in the GlycaAge test are these molecules which regulate inflammation.
GlycanAge Biological Age Estimate
LB: This is how you can produce a biological age estimate, right? If you know what the glycome of an old person would look like versus a young one, you can make a prediction. Talk about how you create a biological age assessment using this information?
Pictured: A GlycanAge biological age testing kit. We discussed some of the basics on these kits in a recent post.
GL: Initially when we developed the DNA typing, we noticed that glycans correlate with age. At the time, we were thinking to use this information to determine the age of a person who left a blood stain at a crime scene.
This is relevant information for police investigation, whether this was a young guy or experienced criminal.
We tried to correlate the glycans with chronological age, and this was reasonably successful.
When we did this, approximately a decade ago, this was one of the most accurate ways to determine the chronological age of a person. Subsequently methylation test was developed, which was way more accurate in predicting chronological age.
LB: But there is still unique value in the GlycanAge test, particularly in assessing lifestyle factors?
GL: What we have learned is that our test deviates from the chronological age, approximately nine years. But not in a random way! But in a way which associates with lifestyle.
On our GlycanAge test, people living healthy lifestyle will always be younger, while people living an unhealthy lifestyle will be older. Also, people with different diseases will generally look older too.
What is Biological Age?
GL: We realized that the GlycanAge is not a good test of chronological age, so we can't use it in forensics, but it is very informative about something we call biological age. Although biological age is a very tricky word, because there is no golden standard.
Learn more about assessing your biological age in our interview with Chronomics CSO Dani
There is no universal unit of measure of biological age. And so someone can give you any kind of number and you cannot say whether it's right or wrong.
LB: Let us ask you about that, Gordan. What do you think about this term biological age? Is “age” the right term? Or is it more of a “biological score” or a “health score”?
Why do you think the industry has chosen the term “biological age”? It sounds nice. But we’re hearing from you that that term is a bit squishy.
What Health Information Does GlycanAge Provide?
An example of the ‘indices’ for the G0 (top) and G2 (bottom) IGG glycans. A GlycanAge test gives you access to this information as well as your biological age.
GL: When we do research, we report 24 directly measured glycans and maybe additional 50 different scores.
But the problem is that this is too complicated for people to understand. So then we made two levels of simplification.
One level is that we have three key indexes or scores, which is G0, G2, and GS.
G0 are glycans without galactose, which are the most proinflammatory.
G2 are glycans with two galactoses, which are suppressing inflammation.
GS are glycans with sialic acid, which also suppress inflammation.
LB: These three indices are reported to users when they complete the GlycanAge test.
This ‘first level’ of simplification provides direct insight into the levels of inflammation driven by or suppressed by each group.
How are these indices useful for the user?
GL: These three indexes are something which one can use to quantify three different aspects of regulation of inflammation. These three indices are exactly measured from the blood sample. This means, anybody in the world who has the right equipment can take the same blood sample and they should get the similar number.
LB: From there, biological age is the next level of simplification?
GL: The ultimate simplification is the biological age, but that's just the name, you can also call it a score. This is the model number. It is not a number which has an absolute meaning.
Screenshot from one of Gordan’s presentations on the GlycanAge biological age clock. Source: YouTube and also this pubmed article.
However, we know that the higher biological age number means more inflammatory glycans, and that means more low grade chronic inflammation.
This chronic inflammation is something which happens with aging and with disease. A smaller number of the GlycanAge means more immune suppressive glycans, less low grade chronic inflammation.
This is a number which is modeled. We use 1000s of people (over 150k) to build a model and compare an individual to this model to determine their GlycanAge.
Of course, it's not absolutely “accurate”, because there is no golden standard of accuracy. But what makes GlycanAge different from other indexes of biological age, which are being used is that we know that glycans which we measure are functional effectors of inflammation. They're molecules which do the damage.
Improving Your GlycanAge Biological Age
LB: Gordan - let's talk about improving our biological age. In other interviews, we've heard you talk about four key factors: sleep, diet, exercise, and managing stress. Making postiive changes in these lifestyle can help change the glycan based biological age estimate.
Can you can you explain why that's the case? Why are those four factors driving the GlycanAge?
GL: These four factors are the key factors of healthy life. Now, we all know, we need enough sleep, we need healthy diet, we need a moderate amount of exercise, and we don't need too much stress. There is no magic in that.
The problem is that this is extremely difficult. We cannot do it all. It simply is not possible in a modern society.
Could GlycanAge testing help identify the most optimal diet for YOU?
The other important thing is that we are all very different. The more research we do, we are learning this.
For example, we did recently cohort of 1000 people on five different diets. And each diet is good for somebody and bad for somebody else, so there is no universal diet, which will help everybody.
LB: Fascinating! Could you share what some of those diets were?
GL: This is still unpublished. I cannot go into details. This was a large European project. But these diets were generally high and low protein and high and low glycemic index and different combinations.
High glycemic index is not bad for some people. It is bad for perhaps most people, but some people cope with glucose better than others.
What we are hoping that the GlycanAge can do is help people to focus on one of the four aspects which is dominant in them.
Gordan is actively collaborating with Dr Joseph Raffaele to explore using GlycanAge on his patients at his longevity clinic in New York. Image Source: LinkedIn
For example, for some people, it could be only a few extra hours of sleep, and then they don't have to spend an hour day in a gym.
For other people, it could be just less carbohydrates. And then maybe they don't have to sleep that much.
GlycanAge is a kind of objective tool to evaluate what works and what does not work for us.
You earlier mentioned this Instagram Live video Dr Raffaele and I did. He has an anti aging clinic in New York where they are testing these ideas.
GlycanAge and Hormone Optimisation
LB: Let's talk about that. Dr Raffaele specifically talks about hormone optimisation.
We know that there's a real strong relationship between hormone balance in women, for example, and menopause and perimenopause.
Research with GlycanAge is finding a close link in aging and hormone levels. You also just mentioned diet.
So here’s our next question: How do we create understanding on what an individual needs in terms of their own personalised approach to improving their GlycanAge?
GL: This is exactly what we're trying to do at the moment. We started to work with Joseph to test his patients, and they all turned out younger. His average patient is 20 years younger, for male and I think 15 for a female patient, which is unbelievable.
Estrogen levels change significantly over the course of a woman’s life. GlycanAge is closely correlated with these changes.
I asked him - what are you doing to your patients? What are you giving to them? He's giving them more or less everything one can do.
We decided to dissect what works in which patient, and are now trying to do proper, placebo controlled randomized trials to see which of the approaches work.
What we know is that estrogen is a very dominant factor in woman.
We had, we got samples from one very interesting study where menopause was chemically induced in young women. In a half of the group, the estrogen was returned with estrogen patch, and the other half of the woman received a placebo.
Estrogen supplementation completely prevented the change in the IGG glycome while the woman who were on placebo aged nine years in a few months on average. Some women going through menopause age as much as 20 - 30 years within a year (on average, this number is only 7-9 years)
This loss of estrogen is extremely strong regulator of IGG glycosylation. The problem is when these women lose their good glycans, its promoting low grade chronic inflammation.
We know for example, from animal models that this is causative of hypertension. The increased risk of cardiovascular diseases known to occur with menopause could be partly caused by the wrong balance in IGG glycans.
LB: Clearly the estrogen balance and associated with changes that occur in menopause are very important for aging in women.
What about hormone levels in men? Is it a drop in testosterone which drives the changes?
GL: Interestingly in men it is also estrogen which regulates IGG glycosylation. In the same study, they also had a group of men where the gonadal hormones were blocked. When the testosterone was returned, it saved the glycome from changing.
Pictured: Testosterone, which plays a secondary role in GlycanAge. It is the change in conversion of testosterone into estrogen, which is altered in ageing in men.
But if the testosterone was added back in combination with another drug which is blocking conversion of testosterone to estrogen, this (the glycome remaining stable) the protective effect did not happen.
So in men, it's not testosterone which regulates IGG glycosylation - it's estrogen.
Hormones are very important regulators. But it's not only hormones, and it does not work to the same extent, in everybody.
So we definitely need to do more research to understand it.
Self-Experimenting with GlycanAge
LB: Hormone optimisation is clearly a really interesting topic area. Here, you've highlighted how it works for women, how it could work for men in the estrogen sense, which is fascinating.
Let’s talk about isolating specific changes one could make using GlycanAge test results. On Longevity Blog, we focus on helping our readers conduct self experiments to find out what works for them.
Want to see an example of using GlycanAge to try to improve your biological age? Our Founder Nick is kicking off his own self-experiment, and wants to take you along for the journey. Subscribe to content notifications to learn how to do this yourself!
For GlycanAge, what does this process look like? Could you point to a successful model for testing and improving your GlycanAge in a way that you can say, I know what did improved it, it was _____ ?
GL: One good example is weight loss. Losing extra weight helps the vast majority of people, because obesity is a big driver of inflammation.
However, when trying to lose weight, people often make a mistake. I personally did the same mistake when I realised my GlycanAge was not ideal. I decided to sweat it out. I was hiking in mountains, three, four hours a day, for the whole summer.
While some aspects of my health did improve, my GlycanAge did not improve much. This is because overtraining is also causing inflammation. Usually people think more is better, but for physical activity, it is not!
What is a “Good” GlycanAge Result?
LB: How can users of the GlycanAge test use that information to strike the right balance?
GL: There is no magic coach who will tell you what to do. Even the best coach can only know what is good for an average person. But there is no average person in the world! We're all different.
Pictured: Our Founder Nick’s GlycanAge from April 2021. This is a ‘good’ age for him, as it is 5 years younger than his chronological age.
He will of course be trying to get it even lower!
What people have seen with our tests, and this is what makes me happy, is that, often they get a poor GlycanAge result.
At first, they're angry, they claim the test is not good. This is why we also offer a free consultation with some of our nutrition and lifestyle experts to help them identify the problem.
Soon, they find the problem.
Maybe I'm overworked. Maybe I'm not sleeping enough. Maybe it is too much stress, I have family issues.
But when people resolve these problems, GlycanAge improves! This is a fantastic motivator.
You know you did something right when you turn out now 5-10 years younger on the scale.
Elevated GlycanAge and Disease Risk
LB: And as you mentioned before, that reduced GlycanAge comes with reduced disease risk and many other health benefits.
“This is the process I like to see - when people get the bad result, improve and get a better result”
GL: Pro-inflammatory markers usually change up to decade before people become ill. Disease onset is usually like this - you work normally, live your life and at one point you feel pain.
Because of that pain, you go to the hospital, and then you do all the checkups. Then the doctor says - you have inflammation in your guts, this is Crohn's disease, or you have inflammation in your joints, this is arthritis.
This is the end stage, when all the compensatory mechanisms have failed. All the ways your body tried to fix the problem have failed, then you have pain, and then you get the disease.
The problem with most of these chronic diseases, they are irreversible. This is why we call them chronic, you get some medicine, you feel better, you don't have the pain anymore, but you are stuck to these medicines for the rest of your life or the disease returns.
But if you identity and fix inflammation early, often simple lifestyle changes or an early pharmacological intervention can prevent disease.
This is the process I like to see - when people get the bad result, improve and get a better result.
“Approximately half of the GlycanAge is determined by your genes, you cannot fix it. ”
Something which is not so satisfactory for the user is when they are already good. Because then they ask - “what should I do now?” I say nothing, you're good. Just come in a year or two and do it again to see whether you're still good.
LB: What is “good” Gordan? Is it 5 years younger? 10 years younger? Exactly your age?
How does somebody know that they're doing “good”? What says - keep going, stay the course, this lifestyle approach is working for you?
GL: Anything which is younger than your chronological age, I would say it's good. It’s also important to not worry about the absolute number, because the absolute number is also strongly affected by genetics. Approximately 30-50% of the GlycanAge is determined by your genes, you cannot fix it.
It is the relative number, the pace of changes in biological age which are important. If your GlycanAge is increasing more slowly than your chronological age, then that’s good.
I recommend starting to do this relatively early, maybe even at 20 to 30 years old, initially once every few years. Maybe if you make a change in lifestyle, then you do it every few months to see whether something works or not. This is the most informative.
How Often Should You Test Your GlycanAge?
LB: Talk about that part. If one of our readers takes a GlycanAge test, and runs a self-experiment, they’ll be thinking about how to control the experiment. Here, the shorter the time-period, the more likely they are to keep it well controlled.
What is the timescale on which our GlycanAge is changing? Is it 3 months? 6 months? Does it depend on what one is changing? Give us a sense for how often we could retest if we wanted to say test, reducing our stress, for example, or changing our diet.
GL: Glycans change relatively slowly. The half life of IGG is approximately three weeks. I think the shortest period to see something would be maybe a month. But this is for a really radical change. If you start taking a drug, or really changed lifestyle factors a lot, such as completely changing diet, starting to exercise much more.
Normally, we see things changing after three or four months. If you slightly change your diet today, it first takes some some time to manifest in the glycans. Normally, we recommend people when they change a lifestyle, re-test after three months and then six months again. If what you are doing is working, you will see the result.
LB: That's a very clear answer. Thank you. We didn't find a good answer for this out there, and our readers are quite curious!
GlycanAge and the future of longevity?
LB: We are going to move toward the close here.
What do you think the role of testing glycans and GlycanAge is going to be as we transition into a future where more of these interventions are possible to slow, halt or possibly reverse our biological age? Where is the GlycanAge test going to fit in the next five to 10 years?
GL: I think the GlycanAge will be one of the tools to evaluate different types of therapies and interventions. It will also not be the only one. GlycanAge is primarily measuring the pro and anti inflammatory arms of the immune system, and there are many other aspects of aging.
If you’re interested in biohacking your biological age - so are we. We recently published results on using NAD booster NMN for improving you biological age
For example, cellular aging is something completely different. Something that happens within a cell, like telomeres or energy metabolism (NAD boosters) and so on.
GlycanAge is looking at the organism as a whole. I think this will be a very good tool for people to just monitor the way they are consuming their body.
In a reasonable timeframe, this will become a regular medical test, like testing the HbA1c for diabetes. We will soon be testing the IGG glycans for a low grade chronic inflammation as part of inflammaging.
Gordan’s Personal Longevity Journey with GlycanAge
LB: In your own personal longevity journey, you you've openly shared that you've tested you GlycanAge fairly frequently. You’ve learned that you go through phases, right?
For example, stress increases when there is extra work to be done, you start enjoying food a bit more and it worsens. However, then you get on to a new training regime or new diet, and your GlycanAge improves.
“Even now I’m losing weight again, and my GlycanAge is going down again. It’s a marathon. It’s not a sprint”
Is regular GlycanAge testing almost encouraging you to lead a more healthy lifestyle for your personally? Is that accurate to say?
GL: Definitely it's an indicator, which helped me to identify some of the problems I had. I don't have a magic solution for myself, my GlycanAge is still not ideal. But I have learned that my key problem is food. I like to eat too much, I should eat less.
So yes, when it GlycanAge gets too high, then I am motivated to fix it. For example, even now I'm losing weight again, and my GlycanAge is going down again. It's a marathon. It's not a sprint.
How Can You Use GlycanAge Testing?
LB: And what would you say as a closing statement for others who are out there in that same up and down? Those who are really trying to make a health lifestyle change and curious to test their GlycanAge?
What is the takeaway from your personal journey that you’d take the chance to share with them?
GL: I think the most important value in the GlycanAge test is it gives us opportunity to focus on the changes which are effective for us, because there is no standard human. For me, I have that I can occasionally have that extra cake. The cakes are not that bad for me. It's more the fruit which is not so good for me.
GlycanAge can help you customise your longevity strategy. Should you walk more? Sleep more? Eat less?
Not everything which is considered to be “healthy”, is healthy for you. So the key thing we can get from the GlycanAge test, is information about ourselves.
It's revealing the hidden secrets of our body, which we can modify, which we can change.
This allows you to see what works and what does not work for you. So whether we are going to live 50, 70, 90, 120 or 150, it doesn't really matter.
What matters is that for longest we live, we should be healthy and enjoy our lives and not suffering from different type of pain or diseases.
LB: That's a lovely place to close that off Gordan, and thank you so much for chatting with Longevity Blog today.
GL: My pleasure! Thank you for your time.
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Biological Age Testing with Glycans - Glycan Age
Should you try a Glycan Age Test?
The GlycanAge test kits - a clean, elegant design with fascinating technology under the hood.
This trend is in its early stages, but is set to continue, as gathering detailed information about your body to assess how quickly it is ageing hits the mainstream.
Today, we are introducing you to a new way to assess your biological age.
Whereas previous methods we have reviewed use age-related blood markers or your epigenome for this assessment - today’s technology from GlycanAge uses your glycans.
What are Glycans? Glycans and Biological Age
To start things off, we should probably address your first likely question - what the heck are glycans?
Clearly we need to understand this a bit first, before we can understand how they can be used as a biological age measurement.
Glycans is not a term that most people are familiar with, but they actually refer to a fairly simple concept.
First, we start with monosaccharides, which include more commonly known ‘sugars’ including fructose, glucose, and galactose.
Most of us are familiar with these monosaccharides - they are the simple carbohydrates common in our diet. More broadly, they can be thought of as the ‘fuel’ for our cells, as well as the energy source for most biological organisms!
use the code “LONGEVITYBLOG” at checkout to save 15% on GlycanAge tests
Glucose Molecule (Monosaccharide)
Fructose (Another Monosaccharide)
Combining Monosaccharides to Create Glycans
In practice, monosaccharides can actually be linked together in a very wide variety of long chain-like formations. This how you create a glycan.
A very well known glycan (also known as a polysaccharide) is cellulose, take a look at how it is built out of the monosaccharides above, just in a much more complex arrangement.
Cellulose - a combination of glucose molecules to form a glycan
Glycans and information
Glycans are influential in many processes occurring within your body. One way to think of their involvement is carriers of information.
As complex arrangements, there are many unique arrangements of glycans in the body which often represent very important signals regarding your health and wellbeing.
A healthy cell, with healthy glycans at the cellular membrane (the multi-coloured squares, circles and lines). Credit: Gly-tech
The valuable ‘signal’ that these complex sugar structures can offer has resulted in the field of ‘glycoscience’, which studies wealth of information glycans have to offer.
This information includes critical details about your overall wellbeing, with the presence (or absence) of certain glycans can be indicative of many conditions in the body, including many diseases, as well as - you guessed it - the processes behind ageing itself.
Glycans, Inflammation and Ageing
An unhealthy cell, with unhealthy glycans at the cellular membrane. Credit: Gly-tech
Glycans are intimately involved with your immune system, where they are used to ‘tag’ invading pathogens, signalling the immune system to attack and remove them.
Furthermore, the wrong glycans in the wrong place can generate an immune response, which then drives inflammation.
If you’ve learned about the basics of aging, and many of you have, you’ll be quite aware of the importance of tracking and managing inflammation to stay healthy for as long as possible.
The link between inflammation and ageing is known as ‘inflammaging’.
Dive deeper? Read more about inflammaging straight from the source in this very important 2014 paper which established the concept.
High level overview: Inflammaging is the process whereby increasing levels of inflammation add continual age-related stress and damage to the body, including more inflammation - and thus a feedback cycle develops making you age even faster.
Sounds like a great thing to keep in-check, no?
The links between inflammation, aging, and glycans are what make glycans great choice for monitoring your biological age.
GlycanAge as a Biological Age test
While glycoscience still has much to learn about glycans and their role in aging, metabolism, disease and immune function, there are many decades of research and enough large datasets available to support the creation of a biological clock based on glycans.
We’ll be covering the specifics on how this works in upcoming posts, but the key takeaway is: tracking the characteristics of the glycans in your body can provide an accurate and valuable assessment of your biological age.
And in the case of GlycanAge, your biological age will be primarily influenced by four lifestyle factors:
Stress levels
Exercise load (both too little and too much)
Dietary choices (including food allergies)
Sleep (what’s the right amount for you?)
Each of these factors are known to be very influential in how you are ageing.
As such, you can use a GlycanAge test to create a baseline, before making controlled changes/improvements in these factors, and then re-testing to see if they worked (i.e. did you reduce your biological age?).
This is central to what Longevity Blog is all about - self-experimenting and customising your own longevity strategy to make the best gains in your healthspan.
Given the nature of these lifestyle factors (stress, diet, exercise), self experimenting with GlycanAge is a very accessible way to start working to improve your own biological age.
Regularly testing GlycanAge can therefore be used to monitor and improve your health over time, with each of those small changes adding up to positively impact your longevity significantly over time.
GlycanAge and Its Mission
Don’t miss it!
We’ll be interviewing glycan expert Gordon Lauc on how you can used GlycanAge to improve your own health & longevity. Subscribe to get notified when we do!
The concept of using glycans to track and positively impact your healthspan has only been made possible through the vision and ambition of GlycanAge’s CEO and Founder Nikolina Lauc
Founded in 2016, the company is built upon the foundational work carried out by expert in all things glycans Professor (and Nikolina’s father) Gordan Lauc.
But don’t take it from us - hear it straight from Nikolina herself:
GlycanAge Founder and CEO Nikolina Lauc
Describe your motivations for founding GlycanAge - what opportunity did you see?
Nikolina Lauc (NL): GlycanAge originally came out of pure scientific curiosity.
My father is a glycobiologist who's worked in the glycan research field for 30+ years, they saw that glycans change with age and were curious as to how and why they change, as well as what we can do to influence it.
Hence the term GlycanAge, actually “GlycanBioAge” originally, was coined.
Glycans are one of the key regulators of our immune system, they contribute to ageing through a process called inflammageing.
Inflammation is a key driver of almost all chronic conditions and glycans are known to change before onset of symptoms and even a decade before onset of disease, giving us an opportunity to do true prevention and extend one's healthspan.
“Glycans are known to change before onset of symptoms and even a decade before onset of disease”
How would you describe GlycanAge’s mission - what drives your team? What have you set out to achieve?
NL: We want to keep you and your loved ones around for longer through precision health.
Our mission is to bring glycoscience into the hands of both clinicians and consumers to inform, guide and preserve your future health.
Glycans have a large influence on your unique biology, they play an intermediary role between your genetic potential and end phenotype, their true value lies in uncovering which intervention or lifestyle works for you particularly as an individual.
How has regularly testing your own GlycanAge improved your wellness?
“Glycans true value lies in uncovering which intervention or lifestyle works for you particularly as an individual.”
NL: Although my GlycanAge has always been favourable, regular testing helps me measure the damage (for example - COVID lockdowns and weight gain), and get back on track through sustainable change.
Beyond me, I've probably tested the majority of my extended family!
Coming Up:
(1) An interview with GLYCAN expert Gordon Lauc (read that here!)
(2) How our Founder Nick is using GlycanAge to run his own self-experiment (read it here)
Follow our Founder Nick on Twitter for the latest #Longevity news!
-
RT @rebeccavziegler: The cryonics payoff matrix. Choose wisely my friends. https://t.co/l1rzsmOC2w
-
My rate of aging: 0.79 It’s the new street cred What you got? https://t.co/aHzWHAfCnD https://t.co/L3rZC4QFN2
-
It’s official - I’m co-producing and hosting a new #longevity docuseries, and will begin shooting in a few months… https://t.co/wLGqRrBfbp
-
“The #longevity segment opened my eyes to the groundbreaking advances in biotechnology, health, and wellness. The i… https://t.co/F8YB7PAeMW
-
I’m completely mindblown by what AI has done over the past 3-6 months, and it continues to accelerate… https://t.co/hh0JslucRg
-
Longevity legends take on many shapes and sizes https://t.co/X9vGa7gvOe
-
RT @BradStanfieldMD: Avoid These Popular Supplements (shout out to Professor Matt Kaeberlein @mkaeberlein & Professor Brian Kennedy… https://t.co/cy9CXldgUS
-
Who are influential persons in #longevity who are of Asian, African American or other “minority” group in the US?
Nick also posts related #Longevity content to Instagram as well, follow him at @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
NMN Nicotinamide Mononucleotide Before and After
NMN Before and After with Biological Age
In mid 2020, I set out on a self-experiment with NMN. The purpose of this experiment was three-fold
First - my primary intention was to lay out some suggestions for how you could structure your own self-experiments, and not just for NMN
Second - I of course was quite curious what my own results would be, and wanted to have a well-controlled self-experiment to answer the question: should I continue to invest in NMN as part of my longevity supplement stack?
Third - to raise awareness of NMN, biological age testing and encourage more of you to join in on being a biohacker!
Designing a self-experiment with NMN in mid 2020 was a unique challenge, as at the time, there was no direct way to test intracellular NAD levels.
That has however changed, and in upcoming posts, I am going to show you how to test your NAD levels directly. If that sounds interesting, be sure to subscribe below!
Takeaway: Over 6 months, a combination of 500mg NMN, 500mg TMG and 500mg resveratrol improved my biological age by 3.5 years. Read on to learn more!
Use the code ‘longevityblog’ to save 10%.
Looking for an NMN supplier? I recommend DoNotAge, who:
offer a third party tested product
have a bulk supply option (100g)
offer further savings when you subscribe to regular shipments
plus I can get you a discount: Use the code ‘longevityblog’ to save 10%!
Self-Experimenting With NMN
It is not easy to run a self-experiment. To review, all self-experiments are:
Difficult to control
Often hard to measure directly
Prone to bias and placebo effect
Even when well-controlled, don’t necessarily provide clear insights
Let’s take a minute to address each of these, how this particular self-experiment addressed each over the course of the 6-months of NMN supplementation.
Control
Over the course of my 6-month experiment, I made several efforts to control the experiment:
My exercise ‘Load’ as per my Garmin Fenix 6 Pro, which I use to track all of my workouts. At top, near the start, at bottom, near the end of the 6 month period.
I did not change my exercise load or volume
I did not change my diet
I did not start taking any other supplements
I did not make any other major lifestyle changes
It is of course not possible to completely control your life! However this does not mean you should not try.
Of these items, I would suggest that consistency in diet and supplementation are of paramount importance.
You can find many “NMN before and after” testimonials on YouTube, for example, but each of these has many problems with control.
The most common issue is making too many changes, mostly around supplementation protocol, during the ‘before’ and ‘after’ period.
Your chief goal here is to decide: is taking NMN worth my hard earned cash?
You can’t make that call if you’re also introducing many other longevity supplements at the same time! You’d be surprised how often this is the case! Be patient and be consistent.
Measurement
In the absence of a direct NAD test, the decided measurements before & after were set according to the 2x clinical NMN trials which were ongoing at the time, as well as adding biological age:
Lipid profile
Blood pressure
Biological age
Epigenetic age (Saliva Test via Chronomics)
Phenotypic age (Blood Test)
Bias & Placebo
I put serious thought into how to conduct a double-blind experiment, but ultimately elected not to.
Given the objective measurements we could draw from the above, and the ‘n of one’ experimental design, this was not practical to implement.
It also reduced the likelihood that everyday folks like yourself would be able to repeat the experiment effectively.
In the effort to minimise placebo effect, I made it my mindful intention to not overhype my personal attitude toward the experiment.
To be quite honest - I adopted quite a sceptical attitude.
Personally, I was unconvinced that NMN would make much of a difference in my day-to-day experience, as there was relatively little science in human subjects & most of these ‘hot trends’ turn out to be over-hyped!
NMN
NMN Self-experimentation Protocol
The supplement protocol for this self-experiment was designed to match the widely used combination of NMN, Resveratrol and TMG:
NMN at 250mg/day (first two months), 500mg (following four months)
For risk management, 1:1 dosage of Tri-Methyl Glycine (TMG)
Resveratrol at 500mg/day, taken with a high fat meal
Note: this was not a change for me, I’d been taking it for 2+ years, and therefore did not interfere with the need for supplemental control
NMN Before & After: Our Hypothesis
This experiment was undertaken to test the following hypothesis (all self-experiments should have one!):
NMN supplementation will boost intracellular NAD+ levels
Boosting NAD+ levels with NMN will measurably improve select characteristics of youthfulness
Combining boosted NAD+ with a sirtuin activator (resveratrol) will enhance DNA repair
Combined, these effects are hypothesised to be likely to:
change blood lipid profile (as per clinical trial designs)
change blood pressure (as per clinical trial designs)
slow or reverse biological age (Longevity Blog hypothesis)
NMN Before & After: Results
The self-experiment was run from 1 August 2020 for 6 months until 31 January 2021.
What follows are the results, including both hard data points and anecdotal observations.
Blood Lipid Profile:
Blood lipids refer to the commonly assessed HDL, LDL and Total Cholesterol measurements. These are also joined by Triglycerides to form the ‘Blood Lipid Panel’ of tests.
As you can see in the provided image, there was no significant change in any of these parameters over the course of my NMN self-experiment.
Blood Pressure
Blood pressure measurements at the start of the experiment were ~125/85.
At the end of the experiment, 126/84.
There was no significant change in blood pressure from the NMN self-experiment.
Biological Age: Phenotypic Age
Phenotypic age is calculated using 9 blood based biomarkers, to calculate a biological age.
This is based on work led by Yale researcher and longevity thought-leader Dr. Morgan Levine (whom we hope to interview on the blog in the future!).
We’ve previously reviewed this test, including providing information on how you can use it yourself here (its free!).
Blood markers in this test include:
White Blood Cell Count (WBC)
Red Cell Distribution Width (RDW)
Mean Corpuscular Volume (MCV)
Fasting Blood Glucose
Lymphocyte %
Creatinine
Albumin
Alkaline Phosphatase (ALP)
C-reactive protein (CRP)
If you’d like to learn more about any of these blood markers, checkout Lab Tests Online.
Pictured: My Phenotypic Age (Biological Age measure #1) over time.
At the start of the self-experiment, my Phenotypic Age was 28 (Chronological Age 34).
At the end of the self-experiment, my Phenotypic Age was 25 (Chronological Age 35).
Given that 6 months passed, this equates to a total change of -3.5 years of Biological Age.
Did I reverse my biological age with NMN?
Now - the key question is, was this change significant? Was it due to the NMN based protocol?
This comes back around to one of my initial opening points about self-experiments: “Even when well-controlled, they don’t necessarily provide clear insights”
For our analysis, we should extrapolate from the baseline measurements a bit further.
Over the preceding 3 years, my Phenotypic Age was an average of 25.7 years old. It was as high as 28 and as low as 23.
More importantly, we need to consider the difference between biological age and chronological age.
My average difference between biological age and chronological age over the preceding 3 years was -7.7 years. This was as high a -10 years and as low as -5 years.
At the start of the NMN self-experiment, this difference was -7 years (below the average), whereas at the end, it was -10 years (at the previous extreme).
There is a degree of subjective interpretation which must occur here, as the data volume does not lend itself to statistical analysis.
Based on the data and trends, there is sufficient evidence to suggest that this NMN based protocol reversed my biological age.
It is however is not conclusive evidence, and as a scientist, I choose to approach that statement conservatively.
There is a bit more to explore however, to let’s continue.
Biological Age: Epigenetic Age
This one was a real bummer. My follow-up test with Chronomics failed their quality control step, meaning the biological age result was not valid.
This was a crushing blow, as it was the chief data point, in my opinion.
However, I have re-tested it, but it was not in-line within the 6-month period self-experimentation period.
Due to my choice to begin another 6-month self-experiment immediately following this one, the next biological age result will not be valid for this experiment.
I’ve since dramatically increased my exercise routine (I’m now training for triathlons), made major dietary changes and increased my NMN supplementation to 1000mg/day in a separate 6-month self-experiment aimed a direct feedback from Chronomics on how to reverse my biological age.
I will update this post with those results, when they are returned, however they will not be well-controlled for NMN experimental purposes.
I know - major bummer! 😔
Such is self-experimenting life!
NMN Before and After: Anecdotal Observations
SF-36 Questionnaire
My results from the SF-36 questionnaire before & after did show a slight change in a few key areas.
While I did not experience any changes in general health, physical health problems or limitation of activities, I did have interesting results in the energy & emotions section.
Excerpt from my SF-36 questionnaire, before and after the NMN self-experiment.
At the start of the self-experiment, I think I was feeling many of the things that folks in their mid-30s start to feel. Notably less energy than in their 20s, less upbeat and more likely to feel worn out at the end of a long day.
Over the course of the self-experiment, this changed in notable ways, in a sustained way that continues to today.
You can see for yourself the meaningful parts of the questionnaire that changed for me in the following image.
I have to add - it is completely possible that these results are placebo based. I was taking NMN, most folks who supplement with NMN boast ‘increased energy levels’.
But of course, since NMN is hypothesised to impact intracellular energy, this is what we expect to happen.
When it comes to ‘energy levels’, NMN is a prime placebo influence candidate.
Nicotinamide Mononucleotide Before and After Conclusions
To summarise, I was able to run a well-controlled self-experiment with NMN supplementation at 500mg/day.
I recorded before and after blood tests, blood pressure and detailed subjective experience related data.
Initial results do indicate improvement in my Biological Age (as per the Phenotypic Age) by approximately 3.5 years.
Subjective data (qualitative data) support this quantitative data, and therefore the conclusion is: NMN left me both feeling younger and perhaps biologically younger.
However, this cannot be placebo controlled, and warrants further testing. In particular, direct testing of NAD levels is now available, and that is what I will be testing next!
Also, we have not been able to test the much more robust and accurate epigenetic age via Chronomics, which was unable to be measured. Ultimately, this was the most powerful data point, and though disappointing - we will revisit it.
Coming soon, I will review the results from testing intracellular NAD levels directly, before and after 1000mg of NMN.
Follow NICK on Twitter for the latest #Longevity news!
-
RT @rebeccavziegler: The cryonics payoff matrix. Choose wisely my friends. https://t.co/l1rzsmOC2w
-
My rate of aging: 0.79 It’s the new street cred What you got? https://t.co/aHzWHAfCnD https://t.co/L3rZC4QFN2
-
It’s official - I’m co-producing and hosting a new #longevity docuseries, and will begin shooting in a few months… https://t.co/wLGqRrBfbp
-
“The #longevity segment opened my eyes to the groundbreaking advances in biotechnology, health, and wellness. The i… https://t.co/F8YB7PAeMW
-
I’m completely mindblown by what AI has done over the past 3-6 months, and it continues to accelerate… https://t.co/hh0JslucRg
-
Longevity legends take on many shapes and sizes https://t.co/X9vGa7gvOe
-
RT @BradStanfieldMD: Avoid These Popular Supplements (shout out to Professor Matt Kaeberlein @mkaeberlein & Professor Brian Kennedy… https://t.co/cy9CXldgUS
-
Who are influential persons in #longevity who are of Asian, African American or other “minority” group in the US?
NICK posts related #Longevity content to Instagram as well, follow HIM @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Biological Age Estimates through Epigenetics: An interview with Chronomics CSO
Measuring your Biological Age
Measuring your biological age is quickly working its way into the mainstream.
Just 12 months ago, we compiled our first comprehensive list of all of the companies offering a biological age test, and since that time the list of offerings has more than quadrupled in size. (Did you see our post on 3 free ways to test your biological age?)
Longevity Blog believes the strong growth in offerings to be driven by our collective curiosity and drive for personal optimisation. But there are two key questions to be answered: 1) How should I use these test kits? and 2) Which test kit should I use?
Let’s answer those!
How To Use Biological Age Test Kits
Biological age is a very unique and comprehensive way to check in and see “how am I doing with my health?”, or for those of us seeking to extend our healthspan - checking in with “how old am I biologically?” or “how fast am I aging?”.
The prospect of measuring our biology in this way, let alone halting or even reversing that number, is tantalising.
Use biological age testing kits, like GlycanAge, to make a change to your lifestyle and see if it improves your biological age!
The thinking goes - If I can track my biological age over time, perhaps I can use the result to run self-experiments and to determine what things I can do to improve this number.
This could be through lifestyle changes (like a change in diet), longevity supplements (like NMN), or a variety of other interventions - each of which (with a bit of careful, but relaxed experimental design) can show each of us what works best for our individual biology.
This ‘test yourself and see what works’ messaging is certainly what those now offering biological age test kits want you to believe.
But is this just clever marketing, or does it actually work?
Our Founder Nick set out to investigate, and has now shown this can indeed be done - twice! Once with a longevity supplement protocol with NMN and also with a changing his diet to include more diversity of plants.
If you’d like to see an example of how to set-up a self-experiment and use a biological age test kit in a useful way, check-out either of those examples.
Choosing the Best Biological Age Test
Over to the second important question: “Which test kit should I use?” or “What is the best biological age test kit available?” (for your own self-experiment!).
It is not easy to draw a simple conclusion, as this question is multi-faceted. The answer to which kit is best? depends on what intervention you’d like to try. If your keen to change your exercise regimen, tweak your diet or improve your sleep over the course of a few months - you might want to choose the GlycanAge test kit.
Learn more about why in our interview with world glycan expert Gordan Lauc here. (Hint: it has to do with how quickly the biological age score can be changed)
But if you’re looking for the ‘best answer’, meaning the ‘most accurate’ result, and don’t plan to test before and after an intervention - which test kit you should use could be different.
Let’s discuss what this means in a bit more detail.
To answer ‘what is the best biological age test kit available?’ question, we will turn to an expert on these matters - using the framework provided to us by Deep Longevity CLO and Insilico Medicine CEO Alex Zhavoronokov.
Alex’s message: look to the test kit’s accuracy and representativeness.
So as our first checkpoint - any biological age estimation service should provide information on the accuracy of the model they have developed, including the size and representativeness of the population (data) it was trained and tested on.
Think of accuracy as: how often is the result correct when it tries to predict someone’s age based off their blood or saliva sample?
Think of representativeness through this lens: human biology is complicated and diverse, so does the dataset the biological age clock was constructed with represent me? (e.g. ethnicity, age, gender, etc).
THe BEST BIOLOGICAL AGE TEST KIT is Chronomics
We recently introduced UK based Chronomics, a company specialising in measuring, quantifying and interpreting the human epigenome.
As covered in our most recent post (Advances in DNA methylation based biological age clocks), using the epigenome has recently emerged as the most robust way to estimate biological age.
This is to say, it is the most comprehensive and accurate way to estimate biological age currently available at the time of writing.
While this could change with the emergence of new technologies and/or methods, we believe this will continue to be the case well into the future.
It will likely then come as no surprise to the reader that we have selected Chronomics as the ‘best’ option for estimating your biological age.
Chiefly, we can chalk this up to the fact that Chronomics has had about a five year head start on nearly all of their competition.
But more specifically, let’s look at the numbers - simply put, as of early 2021, they have the most accurate biological age clock (mean error less than 2 years), with the most diverse and representative sample set of user (10,000+).
Want to dive deeper? Keep reading to see our interview with Chief Scientific Officer Dani Martín-Herranz diving into the details of what this means, and how Chronomics created such an amazing biological test kit.
We ALSO RECommend
Longevity Blog recommends “GlycanAge”, which provides a detailed picture of the inflammation status of your body. Check out their kits here - and use the code “LONGEVITYBLOG” to save 15%.
You can also read about how our Founder Nick improved his GlycanAge by 6 years by eating more plants!
Longevity Blog also recommends trying out this updated kit from DoNotAge. We’ll be covering the technology powering this option soon.
Use “LONGEVITYBLOG” to save 10% on your order.
Chronomics Interview with DANI (CSO)
Despite Dani’s ‘hard look’ in this mug shot - he is an exceptionally friendly and approachable bloke ;-)
Longevity Blog (LB): Dani, thanks for speaking with Longevity Blog. Let’s start with my own curiosity - what happened to the generously sized vial of saliva our Founder Nick shipped across the world from Byron Bay to the UK? How does Chronomics turn his spit into valuable longevity data?
Dani Martín Herranz (DH): [Laughs], firstly, thanks for having me. We used Nick’s saliva to extract his DNA from the cells contained within it. We use a number of preparation steps to isolate your DNA, and then undertake a ‘library preparation’ step in order to make the DNA readable for our sequencing machines.
LB: This sounds like we’re now ready for the specialised ‘bisulfite sequencing’ method you employ in order to read the epigenome, is that correct?
DH: Yes! Once we have the DNA isolated, Chronomics can then prepare the methylated portion of the genome (a key part of the epigenome) to be analysed. To do this, we treat the sample with sodium bisulfite; which allows us to clearly identify the methylated points of the genome
It’s more saliva than it looks like! #generousvial
How Does Epigenetic Data Produce A Biological Age?
LB: So these must be the ‘cytosine’ letters of our DNA, which are the ‘CpG’ sites we often hear about from the scientists studying longevity and epigenetic aging. How many of these are there?
DH: That’s correct. There are over 28M CpG sites in the human genome. With the bisulfite sequencing approach, Chronomics can see if a CpG site is either methylated or not in a specific DNA strand.
LB: 28M CpG sites in a genome of 3 billion base pairs - how many of these sites contain valuable information for interpreting our biological age?
DH: Our technology looks at 5.6M cytosines at high depth, meaning we are reading and then re-reading each point up to 30 times.
LB: That’s impressive! Let’s move this conversation along to the main topic - How is DNA methylation used to predict biological age? Outline the process at a high level for us
DH: Since the work of Steve Horvath and others in 2013, we’ve known there are specific positions in the DNA (known as CpG sites, places where normally DNA methylation occurs in mammalian genomes) where DNA methylation levels change very consistently with age.
For example, there are CpG sites where we accumulate more DNA methylation in our cells and tissues, and there are CpG sites where we lose DNA methylation with age. These changes can be relatively big, in some places, and in others, smaller. These changes can be leveraged to train machine learning models that can measure biological age.
While biological age is generally conserved across cells and tissues, it was recently found that the heart is consistently ‘younger’ than other tissues - watch this space! (click on image for link to open access article)
Does a Saliva Sample Represent the Biological Age of the Rest of the Body?
LB: You’ve just mentioned how these changes in DNA occur across ‘cells and tissues’. Many members of the Longevity Blog readership have asked - why that methylation changes in DNA in the saliva are representative of those occurring in a kidney or liver cell, for example?
DH: Most of the work on biological age and DNA methylation has actually been done in blood. If you look across the many epigenetic clocks and studies that have been developed, blood used to be considered the ‘gold standard’.
Epigenetic changes in blood have also been associated with a lot of clinical endpoints - many different diseases, effects of lifestyle, environmental factors, etc. However, blood is not such a pleasant tissue from a consumer point of view - many people don't want to complete a fingerprick or blood draw.
Chronomics wants to make the journey of accessing actionable biological insights as user friendly as possible. This also means considering logistics and sampling. From the very beginning, we pushed to have saliva as one of the tissues that we can process as part of our workflows for biological age.
What’s interesting about saliva, is that it is actually not that dissimilar from blood. Saliva, like blood, is made up mainly of immune cells that infiltrate from the immune system.
We’ve also come to understand from research of Steve Horvath and others, that many age-related changes in the epigenome are conserved across tissues. Meaning, what we observe in the saliva, may be representative of other tissues throughout the body.
We don’t yet know why this is the case, but this fact is tremendously useful for representing to a certain extent your whole body from a single tube of saliva.
How Accurate is Chronomics’ Biological Age Test Kit?
LB: In your company technology white paper, you report that the Chronomics epigenetic clock has a median absolute error (MAE) of 1.97 years.
This is quite impressive, and outperforms other widely-used epigenetic clocks (e.g. Horvath’s multi-tissue clock MAE=3.6 years) and even more recent models such as the Deep Longevity clock Longevity Blog covered in our previous post.
We have several questions on this topic - first, explain to us what you've done to establish that accuracy? For example, give us some details on the training and test group look like? What's the test group that you've done in terms of the volume and representativeness of the population?
DH: We have integrated many public datasets and combined that with data from our own users. Our main focus is on tissue samples which are relatively non invasive - blood and saliva. And we are also taking into account different technologies.
With epigenetics, we're not yet in the order of millions of samples, but we are on the order of 10,000. I think it is also important to keep in mind one thing that people normally miss - when it comes to biological age, you can overfit the models.
For example, if you work with many many samples, and if you become obsessed with reducing only the error that is associated with the prediction of chronological age.
Learn more about advances in DNA methylation based biological age clocks in this collaborative post with Deep Longevity.
There are papers that show that if you start to perfectly capture chronological age prediction, and you reduce that error a lot, you also lose the ‘biological age’ component of the prediction, which is the one associated with clinical outcomes.
So it's a bit of a complex problem where there are many definitions of biological age, but there is not yet a ‘goldstandard’ for which we're optimizing for (as seen by the different types of epigenetic clocks available).
Probably the most useful and actionable proxies are those that are mapped to specific age-related medical outcomes.
Why is Chronomics The Most Accurate Biological Age Test Kit?
LB: Following up, while respecting the complexity of the problem, why are you able to produce such an accurate biological age estimate?
DH: At Chronomics, we are also taking into account different technologies to build our models. So not only methylation arrays, which is what a lot of people out there have used, but also next generation sequencing data, which is what we mainly work with for our internal processes.
When you combine all of that, and a variety of different machine learning approaches, that is how we managed to get the median absolute error down to < 2 years, and that is an evolving number over time.
Part of that error will reflect true biological age variation in the population and part of it technical variation due to limitations in the technology.
LB: Could you elaborate further on how the biological age model works? You mentioned machine learning before.
DH: One challenge we have had to solve is that we have millions of epigenetic features (CpG sites) from a given sample with our sequencing platform. These are the measurements of the DNA methylation status across the genome.
If we use a methylation array, we’ll have hundreds of 1000s of data points. In other words, you have a problem of high dimensional data.
Essentially, we are trying to find the best features of the best places in the genome to predict biological age (or other biomarkers). This problem lends itself well to elastic net regression, for example,and there are now many groups trying different types of deep neural networks.
So what we've done is benchmark different approaches internally and completed a robust feature selection process using many different types of machine learning algorithms. From there, we have come up with our own machine learning pipeline to make the biological age estimate.
Does the Chronomics Test Kit Represent Me?
LB: Thanks Dani, let’s pivot away from accuracy and over to relevance.
In a previous Longevity Blog interview with Alex Zhavaronkov of Deep Longevity, he pointed out how we must question both the accuracy and the relevance of a given biological age model.
Which genetic backgrounds is the Chronomics biological age model relevant to?
DH: This is a huge issue across all the ‘omics’ and health data in general. Overall, the healthcare ecosystem has very biased data sets towards Caucasian populations in general, and epigenetics is unfortunately not an exception to that.
This is unacceptable and we need to do better if we don’t want health inequality to become even bigger.
At Chronomics we are very much aware of this issue, and proactively try to solve that problem. In the case of epigenetics, different genetic backgrounds can lead to slightly different predictions for epigenetic biomarkers.
When we build our biomarkers, we try to correct for this as much as we can, so we can maximize the chances that the biomarkers work across different populations.
One thing that benefits us with respect to this problem is that Chronomics is a global company. We collect data across many countries and genetic backgrounds, testing our predictions, across these different backgrounds.
But obviously, I'm sure we can do better at this, and we will keep improving.
LB: So in summary, would you agree it's fair to say there's a bias towards Caucasian populations, but that does not mean people from other ethnic backgrounds can’t trust the result. Is that fair to say?
DH: There is a bias towards Caucasian populations at the level of the dataset, but in terms of the epigenetic biomarkers that we have built, we've ensured that they work across populations so everyone can access them.
How Do You Use Biological Age TESTs to Improve Health?
LB: That’s a nice clear answer, thanks. Let’s move on to the ‘actionable’ insights a biological age estimate from Chronomics may inform.
Naturally, the reader who is considering accessing a Chronomics test kit wants to know, if I take this biological age test, what actionable information will I receive? What is a biological age estimate to teach me about myself?
DH: Many people read Longevity Blog, because they are interested in reducing the speed at which they are aging. The challenge is that aging is quite a complex phenotype to measure at the molecular level and without accurate biomarkers of aging there is no way to know if specific interventions are working or not to reduce aging rate.
A biological age result provides people with the tools to essentially to decide if the aggregate of all of what they’re doing seems to be working.
While we have long been good at quantifying a very specific aspect of health, for example - do I have high cholesterol or not - which is obviously a good proxy for cardiovascular disease, these measures may be missing other aspects of our health.
Biological age is a very good holistic measurement of your overall health status, and represents how well in general, you're doing with the aging process.
It represents how your entire lifestyle is interacting with your genetics to control your aging rate.
Biological age is also very valuable to track over time, and see whether the different interventions that you're trying are working or not.
This is why it is ‘actionable’, because we observe that depending on what people do, that value will change - better lifestyles lead to better biological ages.
There is no point in giving people access to biological data that they can not improve through positive behavioural change.
LB: This actually brings us to a repeat question that many Longevity Blog readers have. We've received emails upon emails about this - simply put, folks are scared to know their biological age. Mainly because they're afraid that they will receive a result 5-10 years older than their chronological age.
What do you say to people who are afraid of getting that number?
DH: I would say that, in order to have positive impact upon our health, we need to be courageous in that way. Everyone of us is scared to receive medical results we don’t like. It is much easier to just wait until something really bad happens.
But I think that anyone who is going through a difficult chronic disease wishes they would have detected and acted earlier. We need to become much more proactive towards our health and measure pre-disease states.
For some insights on genome sequencing and how genetic risk markers can be usefully applied, check out the Longevity Blog interview with the Health Nucleus’ Medical Director Keegan Duchicela
It is important to make a very strong distinction here between receiving certain types of genetic insights versus epigenetic insights.
Someone telling you that you have a specific genetic variant that is not ‘actionable’ (something that you cannot change or influence the outcome through lifestyle changes) and that gives you an increased risk to a specific disease is probably not very useful (and for some people may be even depressing).
The epigenetic biomarkers that we build, on the other hand, capture actionable aspects of our health.
What that means is that with epigenetic insights, you can always do something around it. It is a tool for positive behavioral changes.
It can be used to guide you through that journey of improvement, a different type of mindset where you can actually change those results.
“In order to have positive impact upon our health, we need to be courageous in that way. Everyone of us is scared to receive medical results we don’t like. It is much easier to just wait until something really bad happens”
LB: Dani, given what you’ve just discussed, is the directional nature of one’s biological age (going up or down) more important than the absolute value?
In other words, if we receive our first biological age result, it is actually the second one, following some intervention, which provides us the actionable information? (i.e. those lifestyle changes or given longevity protocol made a positive change, so keep it up)
I’m currently measuring my biological age every ~6-9 months, in between intervention protocols to see what ‘works’ for my biology.
DH: You are absolutely right when you say that we should not become so obsessed with the absolute value of our biological age.
It is more important to look at the directionality, how your biological age is changing over time and how your aging rate changes as a function of your lifestyle.
When you take your first biological age test you are de facto comparing yourself against a population of individuals.
When you take your second epigenetic test, we can start to compare you against yourself and build your digital twin (or N=1 experiment). And, as you probably would imagine, you are your best control.
How Often Should You Test Biological Age?
LB: How often should we measure biological age, Dani? Because if we're looking at a signal over time, is it something we should measure every six months, every 12 months? What does your experience suggest?
DH: We normally recommend people to measure every 6 to 12 months. Before that, it's difficult to see statistically significant changes.
This is mostly because the aging process is relatively slow and most anti-ageing interventions are not that powerful yet.
However, how quickly biological age can change varies a lot from person to person. There is a lot of variation between people and the types of interventions that they are making.
Also, someone with a very good biological age result (younger) will probably have a more difficult time further reducing their result.
LB: Did you just suggest that it is easier to change an accelerated age, as in someone who is biologically older than their chronological age, than it is to get biologically younger when your biological age is low?
DH: It's always dangerous to generalize in biology, but there is a trend. Think of it as this - the repertoire of basic things that someone can do to improve is broader for someone with a poor biological age result.
If someone is having a horrible diet, a horrible exercise routine - those people will likely have higher biological ages, and therefore they will have more opportunity to improve that biological age than someone that is already doing those things.
LB: Dani, as we close out this interview, help us understand your vision for the future of quantifying biological age. Where is this going to take us in the next five to 10 years?
For example, Alex Zhavoronokov of Deep Longevity spoke to the Longevity Blog about “Longevity as a Service”. What’s your take?
DH: I agree with Alex in those regards. Maybe at Chronomics, we wouldn't exclusively frame it as “Longevity as a service”, but more as “Biomarkers as a service” or “Actionable biological insights as a Service”.
We provide access to complex and actionable biological data that was previously hidden in the lab. Our goal is to bring it out and make it very easy to sample and access - making the entire journey of accessing that information as seamless as ordering a book online.
Bringing the tech and digital revolution also to biological data. And this needs to happen if we truly want to move to a preventative healthcare paradigm.
Epigenetic information plays a very key part in that mission and it is also very close to our hearts. But the name of the company, as you can see, is not “epi-something”.
It's ‘Chron-omics’, which means ‘large biological data over time’.
We're on a mission to offer people across the healthcare ecosystem, all sorts of actionable biological data. So not only epigenetics, but also for example, metabolites from blood or even COVID-19 testing.
That's really what we are passionate about - to make the unseen, actionable, and make it easier for everyone to access those insights and democratize them.
January 2022 Update: We’ve worked with Chronomics to make their biological age testing kits available to the public again! Price check these kits & place your order at the below link:
INterested in Other Biological Age Test Options?
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FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Advances in DNA methylation based biological age estimates
Biological Age Testing Technology
DNA methylation (DNAm) based Biological Age (BA) tests are unique, in that they supercede the more superficial BA tests which rely on blood data, white blood cell telomere length or surveys, by going deep into the aging signals expressed within your DNA.
Increased methylation (hypermethylation) or decreased methylation (hypomethylation) of the DNA in specific regions can now be tied directly to the aging process, thanks to the growing body of ‘Epigenome Wide Association Studies’.
Of the 28 million sites in your genome where methylation is known to occur, a ‘signal’ representing how old you are at the DNA level is present.
The Latest Biological Age Testing Technology
Recently, there have been significant advances in the technologies available for reading this signal, and interpreting the methylated state of these 28 million locations (called ‘CpG islands’, as they occur in linkages between your DNA at C-G pairs).
Longevity Blog has previously covered this concept in an introductory post on UK based Chronomics & will be hosting a follow-up interview with their CTO in short-order.
While Chronomics has certainly led the way from the outset, a wide array of other promising developments are occurring across this nascent industry.
This week, Deep Longevity released results utilising machine learning to interpret DNAm data to make BA estimates.
The outcome is their “DeepMAge” clock, which samples 1000 unique CpG sites fed through a neural network to estimate the biological age of an individual.
Published in the journal “Aging and Disease”, Deep Longevity (and parent company Insilico Medicine) report “the lowest error margin among other DNAm clocks published to date” with a Mean Absolute Error of 2.77 years. You can read more about this announcement here.
Side note: While not published in a peer-reviewed journal, the Chronomics kits I am using, offer accuracy of 2 years, so this result from Deep Longevity reflects that the capabilities in this field are rapidly maturing, and that is exciting.
What does this accuracy number mean for the consumer? - read on…
Biological Age - Accuracy and Relevance
To understand the importance of aging clock error rates, we can look back to Longevity Blog’s interview with Deep Longevity’s Alex Zhavoronokov, where Alex highlighted two key properties one needs to assess in order to interpret the BA estimate - accuracy and relevance.
In essence, if a BA estimated has an accuracy of 2 years, this would mean that a BA result of 40 years old, would be accurate to within + or - 2 year (38 - 42 years old).
This, as we’ll explore in upcoming posts, is important, in interpreting the impact of the intervention we are testing.
As an illustration, to say with confidence that in intervention has 'reversed’ BA in someone whose baseline BA estimate was 40 years old, it would have to lower the BA by more than 2 years (<38 years old).
Equally, a result of 42 years old would not mean that the individual became meaningfully biologically older.
As far as the relevance of the Deep Longevity DNAm based model, it surveyed 4,930 blood DNA methylation profiles from 17 studies, and from what we can tell, comprised a diverse ethnic background. This makes the model ‘relevant’ for a wide audience.
All of this of course begs the question - when will the longevity community be able to access this technology?
The Future of DNA Methylation based Biological Age Testing with DEEP LONGEVITY
Given these exciting results, and our shared curiosity, we reached out to Deep Longevity’s Fedor Galkin, lead author on this study, with a few questions about the future of DNAm BA tests at Deep Longevity
Q: Will Deep Longevity be offering a DNA methylation test kit in the future?
A: Yes. There are still some other more pressing models to be integrated in Young.AI. But once we are done with them, we are going to make DeepMAge available for institutions and individuals. Global logistics are always an issue, so we are planning to start with US. We will also release API access to DeepMAge, which will let people use it on their data .
Commentary: The development of an API for DeepMAge is in-line with previous efforts by Deep Longevity parent company Insilico, and fits well with the company strategy of making their suite of BA testing services widely available. The possible entry of this Deep Longevity BA test offering in to the US market is of course quite exciting for the longevity/biohacking community!
Q: How does/will this research benefit everyday users of DNA methylation based biological age testing services?
A: We are building a longevity ecosystem. DeepMAge will be integrated with other aging dimensions to enable a multimodal look at aging within one organism.
Ultimately, we aim to create a model that will be able to tell how methylation at a specific gene is associated with psychological traits, for example.
When integrated in Young.AI, DeepMAge will be accompanied with more detail than just age prediction. We are working on methylation reports to let our users see which features increase or decrease their biological age and how it can be changed.
Commentary: The reason the development of a DNAm based BA test from Deep Longevity is so significant, is that it will sit alongside many other BA tests that they operate, and will be one more item in their ‘suite’ of tools for their vision to provide ‘Longevity-as-a-Service’.
It is also important to respect the complexities of DNAm data; as there are many interactions between bodily systems which alter DNA expression. By commenting on ‘psychological traits’, we see that Deep Longevity is already thinking well ahead of the curve with respect to these challenges.
Q: You’ve mentioned your primary goal is to ‘find academic collaborators’ - is it your intention to share the collection of DNAm profiles with other researchers? If so - how best to request this access?
A: We share our data annotated data collection on OSF. We have uploaded the short annotation: GEO id of a sample, sex, chronological age, health. We have spent quite some time looking for DNAm data sets with age annotated, so this collection will be useful to other biogerontologist who want to work with DNAm.
We have not uploaded the methylation values per se, but since all data is publicly available at GEO, any researcher can easily download it given the accession IDs. https://osf.io/74zga/
Commentary: Sharing data and knowledge is highly important for the research community, and Deep Longevity has adopted the ethos of sharing their datasets and helping other research groups to avoid the hard work of compiling DNAm datasets on their own. Use the link above or contact Fedor directly to explore how to leverage their previous work on this topic.
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FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Deep Longevity, Biological Age and the future of Longevity as a Service - an Interview with Alex Zhavoronkov
How old am I? What a valuable question
Biological age testing is the start of a new longevity as a service industry, in this post we explore what that means, and evaluate the emerging ‘longevity economy.
In this post you’ll learn about:
The story behind ‘Deep Longevity’, an Insilico Medicine spin-out
Biological age clocks and the role of machine learning in creating them
Insight into what the launch of Deep Longevity means for the future of longevity medicine
Alex Zhavoronkov is perhaps best known for his role in founding Insilico Medicine in 2014 and as a prominent voice for longevity science globally.
And while Insilico has predominantly focused on drug discovery over the past six years, is has also generated valuable intellectual property in the ‘longevity’ sphere, including ‘AgingAI’, previously covered on the Longevity Blog.
In recent news, a new company - Deep Longevity - was announced, followed in the last few days with news of an acquisition of the spin-out by Regent Pacific.
Whatever your take on the new venture, it has clearly already signalled strong expectations in future revenue growth & impact through this acquisition.
The Longevity Blog approached Alex to inquire about an interview to dive ‘Deep’ into the details on this new venture, prior to the announcement of this acquisition - which will now see Alex move into the fitting role of ‘Chief Longevity Officer’.
In this post, The Longevity Blog (LB) sits down with Alex (AZ) to better understand his vision of the future of longevity, how it might benefit our community and what hard work remains to be done.
What is Deep Longevity?
LB: Let’s start with the new venture - Deep Longevity. It looks to have a very close relationship to Insilico Medicine. Could you provide us with a bit of background on this relationship?
Our zoom interview revealed Alex to be not only a friendly and charming individual - but also phenomenally knowledgeable on the subject of quantifying biological age.
AZ: Insilico Medicine started-up in 2014, at the dawn of the AI revolution. Our main focus area is, of course, target discovery. We discover novel molecular targets in a variety of diseases and also develop the capability to generate really good chemistry to validate those targets very quickly [via AI - Artificial Intelligence].
Many of the targets that we've discovered at Insilico are related to age related diseases. So, we are looking at age related diseases through a prism of longitudinal data and changes. [This includes] training AI to predict your biological age and to look for individual targets that might be implicated in disease.
LB: Insilico has always had a strong inclination toward longevity technology, I’m sure that reflects your own vision. What changes have recently occurred at Insilico to lead to this new venture?
AZ: After we raised our last [investment] round from [series] B, we realized that the work at Insilico on aging and longevity - specifically in the biomarkers - might be consuming too much of our time. We had to refocus the company efforts on drug discovery to servicing the pharmaceutical companies and also building our own internal software systems for target discovery and small molecule chemistry generation.
LB: It is very important for a new business to be laser focussed on the problems they are aiming to solve. So there was a growing mismatch between drug discovery and developing capabilities in longevity?
AZ: The aging research part was largely neglected over the past year … none of us wanted to happen because aging research is the most important cause out there to pursue. We decided to spin-out the aging research business inside a separate company.
Insilico will continue focusing on target discovery, generation of novel chemistry and prediction of clinical trials outcomes - servicing the pharmaceutical industry. That includes pursuing a pipeline of small molecules, therapeutic programs targeting cancer and fibrosis, but also age related diseases and senescence itself. Insilico will still have some assets that we are developing for aging.
LB: It sounds like Deep Longevity could best be described as a spin-out of Insilico?
AZ: The aging biomarkers business has been spun off into Deep Longevity - a company which predicts your biological age using pretty much every data type that is predictive of biological age. And not only biological age, we're looking at many other endpoints. It's a standalone company, and I'm the CEO of both companies. That's that's kind of, you know, pulling Elon Musk and longevity here [joking].
Note: At the time of publishing, Alex has now been named as the “Chief Longevity Officer” at Deep Longevity and is no longer CEO.
LB: I like your style
AZ: Yeah, as you can imagine, investors in both companies need to have a lot of clarity when that happens, right? You are running two separate businesses, you need to ensure that you spend adequate amount of time on both. You need to ensure that you prioritize your role within the two very distinct businesses... these are elite investors - elite biotech and elite AI investors.
LB: It’s not easy ‘wearing two hats’ so to speak. I’ve been there before myself.
AgingAI is one of the foremost longevity tools created by Insilico.
Help us understand the technology transfer here - will the AgingAI and YoungAI tools effectively become part of Deep Longevity’s technology, in practical terms?
AZ: AgingAI is transferred to Insilico. Young AI is also transferred. We are taking this body of knowledge, of published papers, and patents - some already granted - to form a new company. This also includes a substantial number of scientists who were doing the original work transferring from Insilico to Deep Longevity, or are joining Deep Longevity from the outside. It is definitely built on a lot of prior effort.
Partnership with Human Longevity Inc
LB: In addition to Insilico medicine, there is also a relationship between Deep Longevity and Human Longevity Inc, including investment. Tell us about that.
AZ: The partnership with Human Longevity Inc is a huge milestone for us. It is actually a milestone for the entire industry. To my knowledge this is the first partnership where an ‘aging clock’ company partners with a clinical organization. The Health Nucleus, Human Longevity Inc, those are the best doctors on the planet.
The Health Nucleus will make you say ‘wow’, read more in this four part interview with Dr. Keegan Duchicela.
LB: The blog has previously covered my own personal experience at the Health Nucleus, and interviewed their Medical Director Dr. Keegan Duchicela. There are some very high quality folks working there.
AZ: They are not only high quality folks, the people who come to Human Longevity Inc, they are doctors from Harvard, the Cleveland Clinic Mayo Clinic - and they have been exposed to very high end medicine before. But when they come to Human Longevity Inc - it still makes them go ‘wow!’”
These elite people, elite doctors at Human Longevity Inc - the way they analyze you is a depth of analysis which is much more granular, much deeper than even other elite clinics elsewhere.
LB: Explain to us why Deep Longevity and HLI coming into collaboration is so important
AZ: The fact that HLI has started working on aging clocks is extremely important, extremely impressive. It actually made history in a way - it turns aging clocks into a clinical support tool that allow you to detect changes that are taking the the patient into the wrong direction… that there is room to for a correction, for an intervention, I that is a very powerful utility that was not available before.
Longevity as a Service
LB: It sounds like you may now be describing longevity-as-a-service.
AZ: These are the first steps to longevity medicine and longevity as a service. Traditional medicine looks at you within within the reference range for your age group… if you are coming to a doctor and when you are 60 or 70 they will compare you to the other people within the same age group from you know 60 to 80 or 60 to 70.
With longevity as a service, you are viewed in the context of your optimal performance... how far away are you from [when you were] 20 to 30? … How are you doing in terms of the context of the overall lifespan performance? So, longevity is a service the objective of this paradigm. I think I coined that term
LB: So we’re paving new ground by even discussing it?
Read Alex’s thought-leadership piece on Medium.
AZ: I wrote a blog about this when we when we raised our first round of funding from Juvenescence, and my thinking on the concept evolved over time. Longevity medicine and longevity as a service is applying cutting edge technology to bring the person back to the reference range of optimal performance and optimal well-being.
LB: Optimal performance, optimal well-being. It sounds as if Longevity as a Service seems will have a close relationship with aging clocks?
AZ: So the idea is to reverse as many of those clocks as possible. Let's say 20 to 40 [years old], or that ideal range of 20 to 30, right? That's where humans are supposed to function at the best of their abilities. That's where evolution kind of wants us to ‘stop’… longevity as a service wants you to remain at that state for as long as possible - where you convert money into years of high performance life.
LB: This, again, seems to suggest that aging clocks are likely to be a key metric in the longevity-as-a-service paradigm?
AZ: We have seen a major acceleration in longevity as a service as a goal in the industry, primarily in the advent of aging clocks. Aging clocks are the major innovation, I think, over the past 10 years
Aging clocks are ticking at different rates, and are driven by different properties. The fact that we have started studying them, and there is an acceleration in this area - that’s extremely promising, and is the big step towards longevity medicine and longevity as a service.
Biological Aging Clocks
LB: This is the perfect opportunity to transition into some deeper discussion on aging clocks, as you are a certainly a global expert on this topic. Aging clocks are, most commonly referred to as ‘biological age tests’ are propagating very quickly, and becoming commercially available for the layperson.
If a layperson uses an aging clock to learn their biological age - what does that information actually mean?
AZ: It depends on the property or the specific clock and on how you design it. A given clock can tell you that you have a lower risk of dying for some specific cause or all causes.
LB: So, of course, the science is much more complicated than the marketing! Could you help user better understand ‘design’ of aging clocks in the world of AI?
The Longevity Blog is continually covering new ways to test biological age - just check out this post on Chronomics, a DNA methylation based aging clock company.
AZ: You have your training data set up in a way that that's very actionable and that it serves some purpose. So for example, if you're discovering novel targets, from data using AI, you want to ensure that the data you start with is target rich. So that's the philosophy we follow at Insilico.
LB: ‘Target rich’ data, explain this concept in context in a bit more detail.
AZ: [It is] data economics, right? Some data types are more valuable than the others, but for aging clocks it’s not obvious. Some data types are very predictive of age, but they're not actionable. And some data types are very relevant to certain diseases, but they are not actionable. And some data types are actually actionable but not very predictive. So you really need to understand the data type and the combination of multiple data types in terms of the value of the intervention for disease or mortality..
LB: We need predictive data on actionable insights related to aging - this is clearly quite challenging. How does Insilico/Deep Longevity find those valuable predictors?
AZ: We do a lot of work on feature engineering - [the data] that will go into the [AI] networks for training. You start with a certain number of parameters from a blood test, a transcriptome or a methylome, [which] can be mixed and matched because all of them are linked to age. Then you train your deep neural network to predict the age. Or, you can predict, for example, the age and the health status - the age and specific conditions.
LB: So the feature engineering process helps to identify useful predictors, complete AI training and then predict biological age and health condition. With different feature sets, it is possible to predict varying age and health condition outcomes. Could you give us a more specific example?
AZ: There are multiple properties of each aging clock that you need to evaluate and analyze and use. Not every clock has the same properties - one of these properties is disease relevance.
For example, if the aging clock is predictive of disease status, and [that clock] predicts you to be older than your chronological age, this is predictive of that disease.
A second property of aging clocks would be on relevance to mortality - the risk of death from certain cause or from all causes. If a clock is predictive of mortality, there is a higher chance of dying or for any cause or a specific cause if you’re ‘older’, and vice versa.
The Accuracy and Representativeness of Biological Age Clocks
LB: Thank you for unpacking that. These two properties are quite important.
The relevance of the clock to disease state is very important for readers to understand. An ‘age’ from a clock is relevant to the disease, phenotype or mortality risk it was built to represent.
Keeping that in mind, how can we conceptually understand the accuracy of age predictions provided by aging clocks?
AZ: Every aging clock has a specific error rate. Within a specific range [of age], the clock may be accurate and inaccurate. [As an example] say plus minus five years. If that clock predicts to be three or four years younger, it might not actually mean much.. the prediction is just within that [accuracy] range.
All of this depends on how you design the clock and how you validate the clock, because every time you design the clock, you need to test these properties. This is usually done by cross validation - testing the clock on completely unrelated data sets.
LB: So against the backdrop of the propagation of many different biological age tests - we need to carefully analyse an aging clock’s relevance and accuracy before applying the age prediction to an individual.
AZ: Exactly. So that's, that's, that's the exact point. And also, not it's not just the way it's built. It's also the way it's validated. Because very often when you build the clock, you don't have a clue where it's going to work.
LB: Aging clocks take on many forms, not just the AI based one we have discussed so far. What about methylation clocks, an epigenetic approach? Recent coverage by EndPoints suggested your view was that these had not proven very accurate. Could you clarify?
AZ: That was actually not what I said.
LB: Ok - consider this is an opportunity for you to set the record straight!
AZ: I must say on record that I consider Steve Horvath as a hero. He is really a pioneer. There is some kind of debate about who was the first to publish the methylation agent clock. But he did it as a single author. He published it in a perfect journal... He really goes into the annals of aging research as a mastermind of aging clocks... if you look at the stream of papers coming out of his lab, and also many labs over the world, all over the world - you can really clearly see that.
LB: Thanks for clarifying, and making it clear that methylation clocks may offer a valuable tool in the efforts to quantify aging. Could you give us some examples of where the Horvath methylation clock is being used in research?
AZ: Researchers are trying it everywhere. Can you predict menopause? Can you predict the stage of Alzheimer's? Can you predict severity of the disease? There are hundreds of different attempts and successes, some of them might be very credible, some of them might not be super credible.
Especially when people claim that there is substantial age reversal using certain interventions. I saw those claims - they need to be validated multiple times. We also need to understand why it's happening to understand the cause and effect.
LB: Pivoting back to aging clocks more generally, and the continual development of more of them - what can be done to ensure we have several, robust and useful clocks for quantifying aging?
AZ: When you're developing an aging clock, using any data type, it is of course important to think about the future - Where will it be applicable? How relevant is going to be? We really need to put the best practices into this.
Very often you're not gonna know where [the aging clock] is going to work. So you really need to validate on independent data sets. Ideally the best validation is always prospective and in the wild. So you really need to deploy those clocks in a clinical setting where people measure those clocks. They basically use those clocks over time, and then correlate those predictions to various outcomes.
Ageing Interventions
LB: Let’s again draw from your previous comments on Deep Longevity. In that same article - you said “you cannot intervene, if you cannot measure”.
We’ve discussed aging clocks in terms of their ability to ‘measure’, considering relevance, accuracy and how to engineer them. Let’s move onto ‘intervention’.
This concept clearly will resonate with many in the longevity community, where we’ve long talked about intervention, but have still been stuck in ‘exercise more, sleep well, eat less’. Could you give us an example of an intervention being tied to an aging clock?
AZ: Some clocks are very sensitive to interventions. So for example, using the composition of your gut flora we can guess your age. I was actually very surprised when this first worked. I think [Insilico] were the first ones to do that.
This clock is quite sensitive to intervention - you can see if any of the drugs that you're taking or any of the foods that you are eating are influencing the predicted age.
So for example, if you drink some alcohol and we know that alcohol kills bacteria - does it make you “younger” or does it make you “older”? This aging clock is very intervention relevant, because many interventions will affect the microbiome
Some aging clocks are sensitive to intervention, others are not sensitive to intervention at all. This makes understanding the intervention relevance extremely important. Sometimes the only way to test the intervention relevance is to really conduct a clinical study
LB: So, with the right, well-designed clock, we can measure the impacts of intervention. This is precisely what the longevity community is interested in. This brings us full circle with respect to longevity as a service and the new venture Deep Longevity.
Tell us - what milestone does the launch of Deep Longevity represent for longevity as a service becoming reality?
AZ: From one perspective, we see a major acceleration of longevity-as-a-service as an industry, through the advent of aging clocks. That’s the major innovation over the past ten years - thanks to Steve Horvath and many others.
Once again - you cannot intervene if you cannot measure - Steve Horvath established one dimensionality to measure, we came up with more than twenty different dimensionalities. We are also aging on many different dimensionalities that we have not even thought about yet - we need to measure it at every level… the fact that we have started studying this, and that there is an acceleration in this area is extremely promising
From a second perspective, we now have interventions that are available like NAD boosters for example...senolytics are a very promising area… there are rapalogues… metformin....
Looking into the Future of Longevity Technology
LB: So we can measure, we are increasingly able to intervene…. Where does the launch of Deep Longevity fit in the longevity technology future?
We are standing before the inflection point. If you think about the internet or personal computer or the iPhone or Facebook, these exponential technologies that took over the world - with respect to PCs we are currently in the 60s, if you compare us to the internet, you are probably in the late 80s…”
LB: You have the backing of some very smart investors, and a like-minded community who are in admiration of your work and supporting you from around the world.
Alex, we’ve used up all of your available time for today. Any closing thoughts?
AZ: Thanks so much. We have built a community of people who don’t prioritise anything else over longevity research. I recommend everyone do the same - this is the most important aspect of life to focus on - if we accelerate now, we will reap the benefits later.
LB: You’ve dedicated your life to this effort, and that is evident in the impact you’ve had to date Alex, thank you.
—- End —-
Did you enjoy this interview with Alex?
You can hear more from him by following him on Twitter, or if science is your thing - review his Google Scholar profile.
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“The #longevity segment opened my eyes to the groundbreaking advances in biotechnology, health, and wellness. The i… https://t.co/F8YB7PAeMW
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I’m completely mindblown by what AI has done over the past 3-6 months, and it continues to accelerate… https://t.co/hh0JslucRg
-
Longevity legends take on many shapes and sizes https://t.co/X9vGa7gvOe
I post related #Longevity content to Instagram as well, follow me @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Self Experimentation with NMN Nicotinamide Mononucleotide
NMN Before and After with Biological Age
Given the introduction of nicotinamide riboside (NR) and more recently nicotinamide mononucleotide (NMN) as supplements over the past four years, many in the longevity community are self-experimenting with these molecules which boost NAD+ levels.
Looking for an NMN supplier? I recommend DoNotAge, who offer a third party tested pure product, have a bulk supply option (100g) with further savings when you subscribe to regular shipments. Use the code ‘longevityblog’ to save a further 10%.
Get the details in Part 3 of this NMN self experiment series
As discussed in the previous post on NMN risk management, there are three key questions that Longevity Blog will engage with on the topic of NMN. These are:
NMN
How can we self-experiment to determine efficacy?
In this post, I’ll discuss how we can self-experiment to determine the efficacy of NMN supplementation. Let’s do it!
NMN Self-experimentation: A first draft “how to” guide
Let’s science this and see what happens
As with any good self-experiment, we should design a solid experimental framework based on the principles of the scientific method.
This has caveats however, owing to our inherent complexity as a biological system.
As you up your self-experimentation game (what a biohacker you are!), you’ll find out that self experiments are:
Difficult to control
Often hard to measure directly
Prone to bias and placebo effect
Important to make repeatable
Through this post and others that follow, we will do our best to continually consider these issues with self-experimentation (an example of this can type of thinking can be seen in previous posts).
In your endeavour to self-experiment with NMN, getting the experiment right is particularly important.
It should be our goal to provide insight to the broader self-experimentation community, and facilitate others to effectively self-experiment so we can benefit from collective knowledge sharing.
So let’s aim to get this right, in the name of science!
NMN Before and After, Our Hypothesis: What are we testing?
After thorough consideration, I believe our hypothesis for NMN supplementation can be summarised as follows:
NMN supplementation will boost intracellular NAD+ levels
Boosting NAD+ levels with NMN will measurably improve select characteristics of youthfulness
This hypothesis is formed upon on a large volume of work around NAD+ boosting supplements such as Nicotinamide, Nicotinamide Riboside (NR) and NMN (nicotinamide mononucleotide), which indicate 1) the importance of NAD+ levels on a plethora of cellular processes, 2) the known decline of NAD+ levels with age and 3) the apparently causal relationship in this drop in NAD+ levels with a wide array of age-related diseases.
It also formulated in such a way that we can test it, by gathering related data and analysing them to draw conclusions.
Does NMN Work in Humans? How We Can Test the Hypothesis:
In order to test our hypothesis, we need to determine:
An appropriate NMN dose for raising NAD+ levels
How we will measure the NAD+ levels
What controls we can apply, and adopt defensive positions against bias/placebo
How much NMN should you take?
In order to determine the appropriate dose for the experiment, I suggest we look to the two FDA approved clinical trials which are currently evaluating NMN safety and efficacy:
You can search for clinical trials on any topic you like at clinicaltrials.gov
Clinical Trial #1: Dosing for participants 40-65 years olds set at 300mg/day
Clinical Trial #2: Dosing for post-menopausal women set at 250mg/day
Anecdotes from elsewhere suggest this a good level for supplementation. Consider this 27 year old who was totally ‘buzzed’ on 500mg/day and this discussion thread for a 34 year old (same age as me at the time of writing) settling on ~250mg day.
Setting the NMN supplementation level should be done based on age and moderated based on one’s experience with the dose (e.g. insomnia, flushing, etc can be inferred to mean one should titrate downwards).
Measure: Data Collection for the NMN Self-Experimenter
From first principles, our goal here will be to measure related biometrics before NMN supplementation, and then again after sustained NMN supplementation. However, the details here are challenging. As, unfortunately sampling intracellular NAD+/NADH levels presents a few issues.
So for widespread, democratised access to NAD+/NADH testing, we face these two barriers:
First, direct testing of NAD+/NADH is limited to professional assay test kits (like this one)
This violates our goal to make the experiment repeatable for other self-experimenters.
Secondly, it turns out they are fairly ‘noisy’ data anyway, making interpretation difficult and making representativeness of the measurement problematic
NAD+/NADH levels change dramatically across the day with activity, eating, circadian rhythm (Interestingly, blood glucose exhibits these same characteristics; which is perhaps unsurprising as they are both part of our body’s ‘energy system’ );
even if we could test it directly, we would also need to sample it semi-continuously (many measurements)
However, given the widespread interest, research funding and commercial development of NAD+ boosters, measuring NAD+/NADH is likely to become more widely available in the near future. My research found at least two promising options,:
Liquid chromatography - “high-performance liquid chromatography (HPLC) to accurately measure the levels of NAD+ in cells and tissues”
A bioluminescent biosensor - “for the rapid quantification of NAD+ levels in biological samples, which can be used either in laboratories or at the point of care”
Establishing an NAD+ Proxy
In science, where we can’t measure something directly, we use a suitable proxy. In atmospheric science, to study the past climate, we can use bubbles captured in glacial ice cores to estimate past CO2 concentrations and global temperatures.
Climate researchers do this because they inconveniently didn’t have thermometers sampling the atmosphere 100,000 years ago. Here, our issue is we don't have the ‘thermometer’ for NAD+/NADH levels yet. So what’s our proxy?
I have spent many hours researching and considering this. It is my suggestion is that we leverage several different biomarkers that are representative of youthfulness as our proxies. The reasoning for this reaches back to the hypothesis and the purpose of boosting NAD+ : to restore youthfulness.
There are a few proxies we can draw from the clinical trials mentioned above, these are:
Walking speed tests
Blood pressure
Lipid profile
I suggest we eliminate the walking speed test, as it is really only valuable in advancing aging or for sedentary individuals. The latter three are widely accessible, so we’ll adopt them.
But I suggest we go a bit further in our assessment of expressing a youthful phenotype, and adopt measurements of biological aging. My reasoning for using biological age (BA) is the following:
BA is our target for longevity optimisation
BA measurement and calculation is accessible to others, therefore can be repeated
BA is a wide reaching measurement of overall bodily youthfulness (that is its purpose)
BA has multiple modes of testing available to us; so we can work with more than one
Epigenetic test kits for before and after the Longevity Blog NMN based planned biological age reversal experiment. Read about what I made this choice!
For the NMN self-experimenter, I suggest the following two biological age computation methods.
The first is the Phenotypic Age test, which I cover in this post.
The second is a biological age test based on measurement of DNA methylation (aka epigenetic age)
While the prior test is a blood test, the latter is direct measurement of methylation at CpG sites in the epigenome.
There is a fundamental connection here between NAD+ levels, which are the ‘fuel’ for the SIRT enzymes which repair DNA and regulate expression of the genome.
In theory, increasing NAD+ levels could improve our bodily ability to regulate the epigenome, so potential improvements could be realised in the epigenetic age.
Epigenetic age kits are also becoming widely accessible very quickly, and therefore are repeatable.
Analysis: How should the self-experimenter analyse their data?
At the most fundamental level, at the very least, one should statistically compare the before & after measurements of our proxy measurements.
An added benefit would be the inclusion of additional baseline measurements from before the experiment begins.
This inherently needs to include some basic corrections for the non-stationary nature of the data. In layperson terms - chronological time is passing over our measurement period.
So the ‘after’ measurements should be corrected in our analysis, considering the amount of time that has passed over the course of the experiment.
Lastly, and perhaps more importantly, we must employ purposeful management of potential confirmation bias.
Anyone who is running an NMN self-experiment and is looking after their longevity wants and likely expects the supplement to work.
Since we know the result we want, therefore we need to be defensive against our bias when we draw conclusions based on this result.
This is particularly relevant for bloggers and social media focussed folks - we inherently want the Ben Greenfield headline to draw clicks and eyeballs.
I refuse to do that to you, and will revisit these issues when we analyse the data and draw our conclusions.
NMN Self-experimentation: What’s Next for Longevity Blog?
We’ve nearly designed our experimental framework, but we’ve not yet discussed the dosing protocol. So here’s what I personally plan to do:
Baseline
Measurements of:
Blood lipids
Blood pressure
Estimation of:
Phenotypic Age (established here)
Epigenetic Age (via Chronomics)
Complete the SF-36 questionnaire
Post Protocol
Measurements of:
Blood lipids
Blood pressure
Estimation of:
Phenotypic Age (established here)
Epigenetic Age (via Chronomics)
Complete the SF-36 questionnaire
So, what will the exact dosing protocol be? It is still in draft form, as I am awaiting potential additional insights from first Chronomics test.
These may provide additional insights on what to add to the protocol to further improve my biological age.
This does step outside of the experimental design for NMN self-experimentation, but let’s delay that discussion until further posts.
NMN Self-experimentation Protocol (DRAFT):
NMN dose will be set at 250mg per day (based on clinical trial dosing levels)
Update: Two months into the protocol, I raised to 500mg per professional advice from a knowledgeable third-party
For risk management, we’ll include 1:1 TMG (as discussed in my last post)
Resveratrol at 500mg/day, taken with a high fat meal (I’ve been doing this for 2+ years)
Inclusion of Resveratrol is based on its role as a SIRTuin activator, which pairs well with NAD+ boosting and potential benefits to the ‘health’ of the epigenome
Will you experiment with NMN? You’ll need a trusted supplier - I recommend DoNotAge, who offer a third party tested pure product, have a bulk supply option (100g) with further savings when you subscribe to regular shipments.
Use the code ‘longevityblog’ to save a further 10%.
Get the details in Part 3 of this NMN self experiment series
Follow me on Twitter for the latest #Longevity news!
-
RT @rebeccavziegler: The cryonics payoff matrix. Choose wisely my friends. https://t.co/l1rzsmOC2w
-
My rate of aging: 0.79 It’s the new street cred What you got? https://t.co/aHzWHAfCnD https://t.co/L3rZC4QFN2
-
It’s official - I’m co-producing and hosting a new #longevity docuseries, and will begin shooting in a few months… https://t.co/wLGqRrBfbp
-
“The #longevity segment opened my eyes to the groundbreaking advances in biotechnology, health, and wellness. The i… https://t.co/F8YB7PAeMW
-
I’m completely mindblown by what AI has done over the past 3-6 months, and it continues to accelerate… https://t.co/hh0JslucRg
-
Longevity legends take on many shapes and sizes https://t.co/X9vGa7gvOe
-
RT @BradStanfieldMD: Avoid These Popular Supplements (shout out to Professor Matt Kaeberlein @mkaeberlein & Professor Brian Kennedy… https://t.co/cy9CXldgUS
-
Who are influential persons in #longevity who are of Asian, African American or other “minority” group in the US?
I post related #Longevity content to Instagram as well, follow me @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Chronomics - Biological Age, DNA Methylation, Methylation Clocks
Biological Age - DNA Methylation, Methylation Clocks
One for now… One for later! Testing my epigenetic age with Chronomics.
In my previous post on biological age, I introduced you to three free online tools for estimating your biological age.
And while these tools are quite useful, they hardly represent the state of the art in biological age assessment.
To really sample biological age directly, we need to leverage the advent of methylation clocks, which track changes in methyl groups in the epigenome.
The epigenome is the system that controls how our genome is expressed. It’s an incredibly intricate system that goes so far as to actually program your stem cells on what type of cell they should become (e.g. blood cell vs. skin cell).
And while the expression of the genome by the epigenome works excellently when we are young, it is known to change as we age in detrimental ways. This makes managing, delaying or even reversing this age-related process of methylation a key pillar of any longevity strategy.
Quantification of Biological Age
My biological age is 22 years old. I’m 34. How are you doing? Learn how to estimate your biological age with a simple blood test.
This naturally leads us to the nature of quantifying (ie measuring) the amount and intensity of age-related DNA methylation which has occurred in one’s body to date.
This process is occurring as an unfortunate byproduct of your metabolism continually, but is also strongly modulated by environmental factors.
Alcohol, smoking (cigarettes), toxin exposure, stress and environmental pollutants all play a role in DNA methylation, and the science of connecting the dots as to why a given methylation pattern exists in a particular area of the genome is emerging rapidly.
In my view, there are two important capabilities emerging in the biological age testing space which utilise DNA methylation to estimate one’s biological age.
Emerging Capability #1 - Test your Biological Age at Home
The first is the ability to leverage a consumer testing kit to measure your DNA methylation. At my last count, I found six reputable companies who are offering a test which will provide you a biological age estimate through the methylation clock (i.e. Horvath).
They have a wide range of price points, utilise different technologies (blood vs saliva), and fit into a company’s offering in different ways.
Longevity Blog will be covering as many of these test kits as it can… if we can keep up! This space is moving quite fast, and it will be our aim to help you make informed choices.
Emerging Capability #2 - Determine What Aged You
The second capability is harder to find, but in my view is far more valuable as I expect it to provide actionable insights (a key theme of this blog).
This is the newly emerging capability to not just quantify the biological age, but to qualify it. By this I mean, to analyse the biological age and make attributions as to why one has aged.
In my review of the technology in this space, there is only one company who can provide us with this level of detail to date - and that is UK based Chronomics.
In an upcoming post, I’ll be interviewing CSO Dani Martín Herranz to dive a bit deeper into the how and the why beyond their incredible capability in this space. For now, let’s play biohacker guinea pig…
Testing Chronomics Testing Me
Chronomics is not a direct to consumer testing service, and in most cases one has to work with their partnership network in order to access their testing kits.
However, after hearing CEO Tom Stubbs interviewed at the Biohacker Summit in 2019, I knew I had to reach out and find a way to work together. Through our collaboration, Longevity Blog purchased two testing kits from Chronomics.
We will be using these test kits to not only review the company, process and results (sharing them with you of course!), but also to run a unique type of biological age experiment on yours truly (more on this in an upcoming post - be sure to subscribe not to miss it).
The Chronomics testing process involves a saliva sample - very generous volume I might add, which is provided in a test tube with stabilisation medium so that the sample can survive the long trip back to the UK.
From this sample, we’ll be given access to an online dashboard of 35+ different health metrics of which biological age is only part of the ‘health picture’ which will be represented there.
It is my expectation that the specific insights I gain from this process will highlight areas of my DNA methylation that might be ‘reversed’ (a not so subtle hint on what I plan to do with the 2x kits 🤔?)
Chronomics and Biological Age: Some Basics
As a part of our collaboration, I completed a personalised walk-through of their dashboard, I was able to ask a number of preliminary questions about the process, the science and what to expect in my results. Here’s what I asked, and what I found:
LB: Alright, give me some numbers, how much of my genome are we going to analyse?
Chronomics: We’ll be analysing more than 20 million positions in your epigenome using next-generation sequencing, the most comprehensive epigenetic snapshot to date. We’ll also be able to run a community inter-comparison across 1000s of other samples (all anonymous of course).
LB: Rad. Now what will it tell me about my biological age - can I get a number?
Chronomics: Yes, we’ll use those over 20 million positions in your DNA to give you a biological age estimate. We’ll also give you some insights on your age trajectory versus a supercentarian
LB: Love it. But what value will that information provide me. Age is just a number, after all. I need actionable insights.
Chronomics: We’ll use this analysis, along with a detailed personal survey to identify what lifestyle changes you could make to have the biggest impact on your epigenetic age. These include metabolic status, alcohol consumption and cigarette smoking.
LB: Uh oh. I was the guy known for building a two-story beer bong in graduate school. Perhaps that will finally catch up with me. Tell me a bit more about how this works?
Chronomics: It is a cumulative exposure measure, and was built through our internal research team of data scientists, engineers and academic partners. There is actually a specific methylation signature that occurs in the epigenome from this exposure overtime.
LB: Did I also mention I once built a wizard staff of 21 beer cans? Let’s move on… What about cigarette smoking. I’ve enjoyed my fair share of ‘party cigarettes’ and smoky bars - what will your test reveal?
Chronomics: Cigarettes contain certain toxins and heavy metals which are now known to methylate the genome in unique ways. Repeat exposure to chemicals known to be contained in tobacco will damage your DNA and we’ll be able to measure that.
LB: * Chuckles nervously *
Chronomics and Longevity Blog - What’s Next?
In upcoming posts, I’ll interview the team at Chronomics in more detail, review my personalised results and discuss my plans for making the insights actionable.
Follow me on Twitter for the latest #Longevity news!
-
RT @rebeccavziegler: The cryonics payoff matrix. Choose wisely my friends. https://t.co/l1rzsmOC2w
-
My rate of aging: 0.79 It’s the new street cred What you got? https://t.co/aHzWHAfCnD https://t.co/L3rZC4QFN2
-
It’s official - I’m co-producing and hosting a new #longevity docuseries, and will begin shooting in a few months… https://t.co/wLGqRrBfbp
-
“The #longevity segment opened my eyes to the groundbreaking advances in biotechnology, health, and wellness. The i… https://t.co/F8YB7PAeMW
-
I’m completely mindblown by what AI has done over the past 3-6 months, and it continues to accelerate… https://t.co/hh0JslucRg
-
Longevity legends take on many shapes and sizes https://t.co/X9vGa7gvOe
-
RT @BradStanfieldMD: Avoid These Popular Supplements (shout out to Professor Matt Kaeberlein @mkaeberlein & Professor Brian Kennedy… https://t.co/cy9CXldgUS
-
Who are influential persons in #longevity who are of Asian, African American or other “minority” group in the US?
-
The AI powered future is here 🦾 Contrary to the narrative, you’re not going to be replaced in the workplace by AI… https://t.co/BojTzyfDzA
-
I built and exited my first company today A big moment in my entrepreneur journey What’s next? All in on… https://t.co/5oTo3IjSyN
-
I’m seeing tweets from accounts I follow that I have seldom seen over the past two years. Why? Locking your accou… https://t.co/dt21RnfRxT
-
It’s 2023 and I’m using ChatGPT to brainstorm brand names for my next company Welcome to the future 🦾🤖
-
93 year old Buzz Aldrin is a #longevity legend, and he’s at it again… The 2nd man to walk on the moon just married… https://t.co/IXZpfH2S3r
-
In 2021 @ChromaDex tested 22x brands claiming to be NMN The (perhaps not so) shocking outcome? Only 3x met label… https://t.co/PiqiQ581Ra
-
What #longevity books should I be reading in 2023?
I post related #Longevity content to Instagram as well, follow me @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
What's My Age Again? Quantifying Biological Age with Three Free Online Tools
“How old are you?”
It’s a common question, and one that we often use in early conversation with acquaintances of all sorts. I’ve noticed just how common a query it is, because I’ve turned it into a fun guessing game, where I reply - “Well, how old do you think I am?”. People will often take a few moments to look at my face, and spurt out their guess without much hesitation. I’ve been casually keeping track of the responses, and the median age is currently 27 (range 24 - 30, 15 responses) - not bad for a 34 year old.
This fun little guessing game starts to beg a deeper, biological question. The difference between how old we look (we might call this one’s aesthetic age) versus our actual chronological age, varies from person to person. Looking at my classmates from high school or college over the years has been quite remarkable in this regard - many of my male classmates are now balding or have grey hair, others seem to have many wrinkles or sagging facial features already, many are overweight or obese - but a select few are trim, fit, glowing and youthful in appearance. So onto that biological question - are there measurable differences between people of the same chronological age that may shed some light on the seemingly different rates of aging I observe across my peers?
For a great, layperson explanation of the epigenetic ageing process, and what to do about it - Grab yourself a copy of “Lifespan” by Dr. David Sinclair
Well, fairly recently, the answer to this question has become a very clear yes. Enter the concept of biological age - where measuring representative variables in human biology have yielded remarkably accurate answers to this tricky question. There are several methods of approach, but by far the most widely discussed and accepted in the scientists exploring this topic are methylation clocks, which track changes in methyl groups in the epigenome. The epigenome is the system that controls how our genome is expressed, and this is known to change as we age. Later this year, I have plans to test and review several different biological age tests, including methylation clocks and other tools for tracking the epigenome and telomere length.
Given this emerging field of science, and new technologies that are following it, I have spent much of my recent longevity research efforts exploring the tools that are available to biohackers and wellness enthusiasts like myself for quantifying biological age. Today, I’ll share three different online tools that you can leverage, and share my results with you.
Biological Age Tool #1 - Phenotypic Age
[EDIT: Alternative direct download for spreadsheet hosted at the above link]
“Phenotypic Age” was first discussed in two separate studies, which you can find here (study 1 and study 2 -< note that Steve Horvath is one of the authors, who has pioneered the methylation clock work mentioned above). Phenotypic Age is calculated based on 9 biomarkers and measured chronological age using a cohort of 11,432 adults (a range of 20-84 years old). I was first introduced to this tool by Dr. Michael Lustgarten, who also blogs on longevity related topics, and was recently able to test out this tool for myself, thanks to the 15 vials of blood I gave at NextHealth.
Using the results from my Total Baseline test, and the excel spreadsheet located here (EDIT: some readers have reported the spreadsheet link is not working, so here is an alternative direct download) , I was able to enter the following information to reveal my phenotypic age. This includes information about the shape and size of my red and white blood cells, inflammation (C-reactive protein), albumin (protein in blood plasma) and creatinine (a byproduct of muscles and measure of kidney performance).
My biological age: 22 years old. That’s 12 years younger than my chronological age of 34! Hey - I must be doing something right :)
Biological Age Tool #2 - AgingAI
Another group of researchers who have pioneered biological age tools are the team at Insilico Medicine, developers of the ‘AgingAI’ tool. In fact, I considered Alex Zhavoronkov (CTO of Insilico) one of the world’s leaders in advocacy for longevity technology research, and if you are interested in this space, he is someone you should certainly follow.
AgingAI uses an artificial intelligence approach to biological age estimation, which is significantly more complex and technical than the linear model used in the phenotypic age tool. This approach employs deep neural networks and was trained on more than 60k data points (read more about the details here). In my view, this tool is inherently more subjective in that due to the machine learning approach employed, it will be biased toward chronological age more strongly than the phenotypic age model (simply put - the neural networks are trained against chronological age as ‘the answer’).
Using the results from my NextHealth Total Baseline I was able to complete both the AgingAI 2.0 and AgingAI 3.0 Tests. For those of you interested in replicating this with your own Total Baseline test, here are a few tips:
be sure to select “US” for the sample metric at the top
you won’t have a value for “Lactate dehydrogenase”, so I recommend using the median value of the reference range
“Basophils” is “Basos %”, “Eosinophils” is “Eos %”, and “Lymphocytes” is “Lymphs %”
in your Total Baseline report
And my results? AgingAI 2.0 guesses I am 30 years old. AgingAI 3.0 guesses 32 years old. Pretty close on both counts! And I suppose it is good news it knows I am a male (LOL).
Biological Age Tool #3 - RealAge by ShareCare
Not everyone will have the blood test results on hand to use both of the above tools (but you can likely get them if you find the right medical doctor! Also, read-on below, as it appears you can order these online via “Walk-in Labs”). So I wanted to make sure I included an age test that did not require a blood test. This one is arguably not truly a biological age tool, but I’ll place it in that category based on the amount of biological data it ingests through its questionnaire style approach (it does collect cholesterol numbers for example). Co-created by “Dr. Oz” and Mike Roizen, this tool boasts that is has been completed more than 43M times.
An example question from the RealAge survey tool
I appreciated this test for its accessibility and its candour. What I mean by the latter point is that it asks many questions that clearly gauge youthfulness through emotional and psychological data points (really digging into whether or not you still have that quintessential ‘zest’ for life or not!). It also provides a wide array of follow-up tools that directly target your RealAge score, and can help you improve it, including a ‘dashboard’ tool that will let you track your behaviours and give you tailored advice (and I am sure it will use your data to make money somehow!).
This test reported a ‘Real Age’ (biological age) of 28 years old.
Should you complete a Biological Age test?
If you’re interested in maximising your longevity, it’s important to establish a baseline. This means, to establish where your overall health and wellness are at NOW, so that you can make changes to your diet, lifestyle, supplements and other input variables, and then re-test to determine how you’re faring with your own longevity strategy.
In my view, biological age tests are an ideal choice of baseline testing, as they are designed to comprise the overall impact of many different factors and are specifically dedicated to measuring aging. However, there is a rapidly growing list of options for testing, including checking your telomere length (of white blood cells), DNA methylation clocks (e.g. DNAge), and more broad spectrum epigenetic tests (check out Chronomics for example). So selecting which test to use comes down to a few key parameters, in my view:
Representativeness of the test to your overall health & wellbeing (Does the age test capture the most representative biomarkers of aging?)
Affordability (Are you able to routinely repeat the measurement based upon its cost?)
Accessibility (Do you need a doctor to work with you to get the test? Is it available in your country/region? Can you order it online?)
As a part of my commitment to the purpose of this blog (supporting you in generating your own longevity strategy), I am preparing a review of several of the biological age tests available on the market, for publication on this blog later this year. By working with the providers of these tests, I’ll share my results with you, and compare and contrast the (1) representativeness, (2) affordability and (3) accessibility of each approach. In this post, we got off to a solid start, so let’s close today by summarising these three factors for the above biological age tests in a succinct tabulated format. I will be sure to update this table as I evaluate additional options in the future!
![Costing estimates produced with “Walk-in Labs” [1], [2], [3]. My total baseline test cost $999USD.](https://images.squarespace-cdn.com/content/v1/534cff75e4b0ce1c16de5321/1578708035056-NQBT0PVSD7FSR14BJDYH/Aging+Tests+Matrix+v1+January+2020)
If you enjoyed this post, be sure to read my coverage on epigenetic age testing company Chronomics
Want to test & improve you biological age? Longevity Blog recommends GlycanAge
Our Founder Nick used these kits to improve his biological age by 6 years, just by changing his diet. Read more about that here.
If you’d like a more robust and accurate biological age test than the free options above, GlycanAge is a great place to start!
-
RT @rebeccavziegler: The cryonics payoff matrix. Choose wisely my friends. https://t.co/l1rzsmOC2w
-
My rate of aging: 0.79 It’s the new street cred What you got? https://t.co/aHzWHAfCnD https://t.co/L3rZC4QFN2
-
It’s official - I’m co-producing and hosting a new #longevity docuseries, and will begin shooting in a few months… https://t.co/wLGqRrBfbp
-
“The #longevity segment opened my eyes to the groundbreaking advances in biotechnology, health, and wellness. The i… https://t.co/F8YB7PAeMW
-
I’m completely mindblown by what AI has done over the past 3-6 months, and it continues to accelerate… https://t.co/hh0JslucRg
-
Longevity legends take on many shapes and sizes https://t.co/X9vGa7gvOe
-
RT @BradStanfieldMD: Avoid These Popular Supplements (shout out to Professor Matt Kaeberlein @mkaeberlein & Professor Brian Kennedy… https://t.co/cy9CXldgUS
-
Who are influential persons in #longevity who are of Asian, African American or other “minority” group in the US?
-
The AI powered future is here 🦾 Contrary to the narrative, you’re not going to be replaced in the workplace by AI… https://t.co/BojTzyfDzA
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I built and exited my first company today A big moment in my entrepreneur journey What’s next? All in on… https://t.co/5oTo3IjSyN