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.
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!
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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.
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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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.