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.
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.
NMN Transporter Slc12a8 and the future of NMN clinical trials with Dr Alessia Grozio
The need for NMN Clinical trials
In a recent post, we discussed a key barrier in our knowledge of NMN supplementation in humans - namely the very limited clinical trial data.
However, this barrier is soon to be removed, thanks to high profile research + business collaborations which a directly confronting this lack of information.
Dr Alessia Grozio is Chief Scientist at Elevant and a researcher at the Buck Institute, ‘insanely’ interested in all things NMN and longevity.
With their execution and success, we will soon have a clear understanding of the benefits of NMN supplementation in human subjects (well beyond simpler experimental results, such as how NMN improved our Founder Nick’s biological age by 3.5 years).
Collaborations on NMN Clinical Research
One such collaboration we recently highlighted was the the work between aging research leader the Buck Institute, Elevant, and its parent company Seneque.
Together they have developed a healthy pipeline of NMN clinical trials in humans, which will focus on muscle recovery after exercise, potential benefits to skin health and much more (details in our interview).
Today, we host Elevant’s Chief Scientist and Buck Institute Researcher Dr. Alessia Grozio (PhD) for an exclusive interview on the future clinical trial outlook for NMN.
Interview with NMN researcher and expert Dr Alessia Grozio
Longevity Blog contacted Dr. Grozio with a number of important questions on the topic of NMN supplementation in humans.
Seneque’s mission is to increase healthspan by 20% in the next decade.
One key topic area we addressed was Dr Grozio’s co-discovery of a transporter that delivers NMN directly into cells called slc12a8.
This discovery was the first time that a pathway for NMN to enter cells directly had been discovered. A key development which well renowned NMN expert Dr. David Sinclair was very quick to highlight in Nature Metabolism (read it here) .
This discovery has not been without controversy, as NAD biologist and researcher Dr. Charles Brenner was quick to criticise the study. This has led to a bit of a schism in the research community on whether or not slc12a8 does what Dr Grozio says it does.
So we wanted to hear it from the expert directly, asking Dr. Grozio to help us better understand the significance of slc12a8, particularly around how NMN enters the cell (which is critical for it to fulfil its NAD boosting function).
As always, we also ask her about her personal longevity strategy.
Without further delay - onwards!
This interview was conducted in written format over email correspondence during May 2021
Longevity Blog (LB): Dr Grozio, thanks for joining us here on Longevity Blog.
To kick us off - you work diligently at both a research organisation and a commercial venture. Surely its hard work! Tell us - what drives you? What brings you into work each day?
Alessia Grozio (AG): Thanks for inviting me. The passion for my work and an “insane” curiosity for anything related to aging/longevity and NAD+ biology that brings me to work every day.
After earning my PhD in biochemistry, I started working on the enzymes (sirtuins, NAMPT, CD38/CD73 ecto-enzymes) involved in NAD+ metabolism.
NAD biology is quite complex. This is an area Dr. Grozio finds quite fascinating. We do too!
In a previous post with Dr Grozio’s college, Dr. Eric Verdin, we discuss this topics in further detail.
I have always been fascinated by the pivotal role that NAD+ plays in maintaining homeostasis in our body and the plethora of cellular processes in which it is involved.
Therefore, investigating the effects of NMN (nicotinamide mononucleotide), a critical endogenous compound for NAD+ biosynthesis, in different physio-pathological conditions where NAD+ levels are impaired, was a natural prosecution of my scientific interests.
More than “hard”, I would say that my job, as for many other scientists, is never boring!
What is NMN-C
LB: Thank you for sharing those personal insights. One of the reasons we’re speaking with you today is to help introduce ‘Elevant’, and your efforts to make ‘NMN-C’ available to a broad audience.
Please introduce us to NMN-C. How does this formulation differ from other forms of NMN that our readership may already be taking?
“What makes our NMN-C special is the extremely high level of safety and development that has gone into it. ”
AG: What makes our NMN-C special is the extremely high level of safety and development that has gone into it. We think what is most important is providing consumers with NMN-based products that have the highest levels of safety and quality possible.
NMN-C is exclusively available through Elevant in their “Prime” product (pictured)
What’s critical is, once NMN has been synthetized, to characterize the impurities, filter them as much as possible to reduce them to the minimum, and make sure that the few impurities remaining are safe.
In our NMN-C the level of impurities is very low, complying with the pharmaceutical grade guidelines.
Our product is then tested at high dosage, pre-clinically and in human, to confirm it’s safe to use.
Is NMN Safe for Humans?
LB: There was a recent study specifically looking into the ‘safe’ level of NMN supplementation, could you share some information on this work?
“NMN-C at doses up to 1500 mg/kg/d appears to be safe”
AG: Our NMN-C acquired self-affirmed GRAS (Generally Recognized as Safe) status in accordance with US FDA regulatory guidelines, performed by an independent panel of toxicology and nutrition experts.
Moreover, we have recently published the first OECD 408 toxicology study performed on NMN. This study analyses the No Observable Adverse Effect Level (NOAEL) of our NMN-C and demonstrated that repeated oral administration of NMN-C at doses up to 1500 mg/kg/d appears to be safe and did not promote adverse effects in rats up to 90 days.
Diagram showing the role of Slc12a8 and how it enables NMN to enter the cell. Source: Nature Metabolism
Does NMN enter the cell intact?
LB: You made some waves in the research community with your published results on a NMN ‘transporter’ slc12a8.
This was a particularly exciting discovery, as the ‘doorway’ for NMN to enter the cell was previously unknown.
Could you briefly explain why this discovery is significant for the prospects of NMN supplementation?
AG: The identification of a novel NMN transporter, Slc12a8, further advances our knowledge regarding NAD+ metabolism by providing a new mechanistic insight through which the absorption and distribution of NMN is regulated to fuel the NAD+ biosynthesis in different tissue.
In the manuscript published in 2019 in Nature Metabolism, we employed several biochemical and in vivo (testing done in a whole organism) analyses to demonstrate that the Slc12a8 gene encodes a selective NMN transporter that facilitates the direct uptake of NMN into cells and intestinal tissue of mice.
We found that Slc12a8 is regulated by NAD+, specifically, Slc12a8 expression is increased when intracellular NAD+ levels are declined, as a compensatory mechanism, in order to maintain the cellular NAD+ homeostasis.
The Debate Around Slc12a8
LB: Proponents of alternative NAD precursors (NAD biologist Dr. Charles Brenner amongst them) such a Nicotinamide Riboside have contested that slc12a8 is an ‘intestinal cation-calcium transporter’ and not an NMN transporter.
The NMN proponents predicted that NMN would still work as NMN in cells that don't have NR kinase but we and others showed that when NR kinase is knocked out, NMN can only raise NAD+ by acting as nicotinamide. That's because NMN works by conversion to NR and needs NR kinase /14
— Charles Brenner, PhD (@CharlesMBrenner) January 13, 2020
Surely the ‘devil in the details’, but what is your reply to such claims?
How can we trust that NMN is making it ‘into the cell’ intact, rather than only through the Nicotinamide Riboside Kinase pathway as NR?
AG: Slc12a8 is an orphan member of the SLC12 family of the electroneutral cation–chloride co-transporters, this means that so far, its function as cation–chloride co-transporter has not been demonstrated.
Indeed, Slc12a8 shares low level of similarity with its family members for what concerns amino acid sequence and predicted membrane topology.
As described in our Nature Metabolism paper, we have conducted isotopic tracing experiments using side by side isotopic NMN and nicotinamide riboside in Slc12a8-OE NIH3T3 cells (the cell line overexpressing Slc12a8 protein) and primary hepatocytes from Slc12a8 knockout mice (mice completely lacking the Slc12a8 protein).
Both experimental conditions demonstrate direct NMN uptake without any previous conversion of NMN to nicotinamide riboside outside of cells.
LB: Thanks for answering that very important question.
NMN as a Topical Cream for Skin Health
LB: Moving on from transporters, and onto Elevant’s impressive research efforts, you are engaging with some very significant topic areas - namely beauty and sports performance, which are very significant consumer markets.
Could you share with us the future of NMN based ‘creams’ for topical use? Is this a future development area for beauty products? And do we know if NMN can enter skin cells through a topical? (We are very interested in measuring & preserving aesthetic age)
AG: Yes, previous research has shown that NAD+ appears to play an enormous potential role in skin health.
Research has shown that NAD+ energizes aging skin cells to function more like young cells, counters transepidermal water loss and improves the moisture content of the outer layer of the skin, along with several other actions that support healthy skin.
We have conducted clinical trials that have directly shown the beneficial effects of NMN on the skin.
The trials demonstrated improved skin moisturization, elasticity and brightness, and a reduction in skin roughness and visibility of wrinkles. The results are to be published soon and we will share them with you.
NMN for Exercise Recovery
Longevity Blog is very interested in how anti-aging compounds might improve athletic performance and the benefits of exercise.
Another longevity supplement “Urolithin A”, which is derived from pomegranates, also has benefits on improving physical recovery, through the mitophagy pathway. Read more!
LB: An ongoing clinical trial is now recruiting participants, which will analyse the benefits of NMN for ‘physical capacity and recovery’.
Looking forward, do you see a potential future role for NMN in human performance (i.e. sport)? If so, do you have any insights on how it might improve an athlete’s ability to compete in their sport of choice?
AG: We have preliminary results showing NMN is efficient on physical recovery, at any age. We will keep you informed, prior to the publication of our results.
Upcoming NMN Clinical Trials
LB: Beyond these two clinical trial areas, Seneque are also ‘preparing’ several more clinical trials covering many areas with NMN-C: impact on NAD+ levels, NMN vs NR, sleep, cognitive function, immunity - each is a significant undertaking (self-titled ‘the world largest pipeline’).
What timeline do you expect for the results on these projects? They will each go quite a long ways toward demonstrating the efficacy of NMN supplementation.
Seneque has a very impressive pipeline of NMN based clinical trials at various stages of maturity. Find the latest on their website.
AG: Two more studies started this month (May 2021), a tolerance and a pharmacokinetic study with 20 participants each and dosage of 400mg per day. Preliminary results to be announced next July (2022).
The first results of further trials will be published Q3 2021 and several publications will occur until July 2022. You can see our extensive clinical research pipeline here.
Some additional confidential studies are being conducted at the moment, so pending the timing and results of those we hope to start communicating about them at the end of this year.
We are confident it won’t be long until we can demonstrate the efficacy of NMN supplementation in several clinical trials.
We aim to be able to share results sometime between Q3 and Q4 2021.
Research Business Partnerships for Longevity Research
“We are confident it won’t be long until we can demonstrate the efficacy of NMN supplementation in several clinical trials”
LB: Some elements of these clinical trial efforts will occur in partnership with the Buck Institute, namely the pre-clinical studies and basic research efforts.
Could you describe the merits/value of private longevity technology companies collaborating with leading aging research institutions? What are the challenges for you personally, ‘wearing two hats, so to speak (as you’re also a scientist at the Buck Institute)?
AG: The main interest in collaborating with leading aging research institutions is to work and share knowledge with scientists coming from various backgrounds and expertise, foster new ideas and drive our research to constantly innovate.
This allows diverse new research leads and areas of study, all undertaken in line with scientific principles.
The powerful and high-end equipment and infrastructure at the Buck is of course a huge asset.
Finally, as you know, time is of the essence. These partnerships allow invaluable gains of time.
NMN-C is Manufactured to a High Standard
LB: Elevant is now manufacturing NMN-C in Europe, which differentiates from other suppliers of NMN, who rely on manufacturing in China. This undoubtedly introduces additional costs, but likely as a trade-off for many benefits.
Could you comment on what ‘Made in Europe’ means for consumers?
AG: We strictly control every element of our proprietary manufacturing process, which we undertake at cGMP-certified facilities in France. Consumers receive what we believe are pharmaceutical grade and the highest levels of quality and safety available in an NAD+ booster today.
Dr Grozio’s Longevity Strategy
LB: Dr Grozio, changing gears, as we close off the interview - could you share with our audience one or two items from your personal longevity strategy?
AG: I am Italian, therefore I am following a Mediterranean diet, rich in vegetables, legumes, fish and extra virgin olive oil.
Moreover, I am taking our NMN-C every morning to boost my physical and mental energy needed to go throughout the entire day.
LB: Dr. Grozio, thank you such much for taking the time to answer our equations today!
Want more NMN Focused Content? We got it!
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.
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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.
NMN-C, Elevant and the future of NAD boosters: An Interview with Dr Eric Verdin
NAD Precursor NMN-C - A New NMN Supplement
As we have discussed in recent posts on NAD boosters, clinical trial data for NMN in humans remains quite limited.
In fact, up until recently, it wasn’t even well established that NMN was safe to use as a supplement. Hence, why we’ve had to discuss this issue and how minimise any risks in involved should you choose to self-experiment with NMN.
One key outstanding question has been - is NMN safe to take as a supplement?
IS NMN SAFE?
Excitingly, this question has now been answered, thanks to innovative work by the company ‘Elevant’ (in collaboration with two other parties, more on this shortly), who recently published results from a toxicology study for NMN supplementation (read it here).
On the back of this successful study, Elevant is now offering this a novel form of NMN, matching that which was used in the research effort - the product is called ‘Prime’, and the specific NMN formulation is called NMN-C.
What is NMN-C?
NMN-C is differentiated by its quality and extremely high-level of safety where the processes for characterising and removing as many potential impurities has been standardised and follows pharmaceutical grade guidelines.
Elevant’s NMN-C product, “Prime”
There are not any changes to the molecular structure, rather NMN-C is the outcome of this highly rigorous processing approach.
This outcome of this method for producing NMN has then been tested at high dosages (i.e. the study we just mentioned) and also in pre-clinical testing in humans.
This has made NMN-C the only form of NMN to be categorised by the US Food and Drug Administration as “Generally Recognised as Safe” - so called GRAS status.
Elevant, Seneque and the Buck Institute
These recent efforts to create and study NMN-C are the fruits of an exciting trifecta of collaboration between Elevant, its parent company Seneque and the Buck Institute.
They have an exciting pipeline of future NMN related studies in humans, including skin health, muscle recovery and more. We’ll explore these topics in an upcoming post with Elevant’s Chief Scientist.
Together, these companies boast some very grand visions, which should get any longevity enthusiast (that’s you) quite excited.
The Buck Institute for Research on Aging is a global leader in the study of aging, and increasingly, interventions in age-related disease.
Seneque, the parent company of Elevant, is a Swiss life sciences company, founded by French entrepreneur Guillaume Bermond, who now leads the company on its mission to “increase healthspan by 20% in the next decade”.
Rounding out the three-way collaboration is the Buck Institute for Research on Aging, who are global leaders in the study of aging, whose missions is equally grand - “to end the threat of age-related disease for this and future generations”.
Interview with Longevity Pioneer Dr Eric Verdin
Playing a key cross-over role between these three entities, is Dr Eric Verdin, CEO and President of the Buck Institute, and more recently, Chair of the Scientific Advisory Board at both Seneque and Elevant.
Longevity Blog reached out to Dr. Verdin to discuss this new role as at Seneque, and in order to better gauge his view on the promise of NMN supplementation in humans.
We discuss the use of NMN in human subjects, the role of inflammation and CD38 in NAD biology, the future of NAD boosters and even his personal longevity strategy.
This interview was conducted in written format over email correspondence during May 2021
Does NMN actually work? Is NMN effective?
Longevity Blog (LB): Clinical trial data for NMN supplementation in humans is at a very early stage, and we’ve yet to see conclusive results. Yet, the new venture Seneque will deliver NMN based products. What gives you confidence in the efficacy of NMN supplementation in humans?
Dr. Eric Verdin (EV): That’s a great question. I think that one should know that not everything from mouse or from animal model experimentation will actually translate into humans, and so there is always some degree of uncertainty in terms of what will happen.
Most NMN research has been performed in rodents, what will this mean for humans? Image credit
However, there is now growing evidence that NMN supplementation in animal models really has profound effects in the biology of every organism on which we have tested it. Based on this, one can be reasonably optimistic that we’re going to be seeing the same thing in humans.
One key thing that we will have to consider is the dose at which we give the NMN. Right now, NMN is typically commercially available at lower concentrations than what we’ve given to animals, and eventually we will have to account for some of the potential differences.
“NMN supplementation in animal models really has profound effects in the biology of every organism on which we have tested it”
CD38 Inhibitors for NAD Boosting?
LB: One of the more recent discoveries related to NMN supplementation, is a need to pay attention to the role of the CD38 enzyme. The Buck Institute recently published a study on the role of inflammation and macrophages in CD38 regulation. Could you comment on the potential role of CD38 ‘inhibitors’ alongside NMN supplementation? What compounds might prove useful in this role?
EV: Yes. What this paper actually showed is that, as we age, the activity of this enzyme called CD38 increases. CD38 is an NAD hydrolase, and so it is able to take NAD and to cleave it into its byproducts – ADP-ribose and nicotinamide – and we think that it is one of the major pathways that leads the progressive degradation of NAD that occurs during aging.
Longevity Blog did a deep dive on CD38’s role in NAD biology with Nuchido Founder Dr. Nichola Conlon - be sure to check it out!
So, on this basis, one hypothesis would be that to restore or maintain NAD levels in aging, we have to inhibit CD38, but you also have to replenish depleted NAD levels.
This is where NMN could come in. One thing to also consider is that CD38 also cleaves NMN, so this makes it even more of an important potential synergy between providing inhibitors of CD38 and providing NMN.
I think this is one way to move forward into the future – to have specific CD38 inhibitors and also to provide NMN to restore NAD levels.
“one hypothesis would be that to restore or maintain NAD levels in aging, we have to inhibit CD38”
Chronic Inflammation: CD38 and Senescent Cells
LB: As a follow-up, given the role of chronic inflammation and senescent cell activity (SASP) to create pressure on NAD levels in the cell, does this suggest that senolytic compounds (e.g. fisetin, quercetin, etc) may be a natural partner in boosting cellular NAD levels in addition to NMN?
EV: That’s a very good question. In the paper you discussed just before, which we published last December in Nature Metabolism, we identified the mechanism for the progressive increase in CD38 during aging, and one of the mechanisms was the progressive accumulation of senescent cells.
As a part of the ageing process, CD38 and Senescent cell activity both increase, lowering NAD+ levels. Image credit: Buck Institute
The senescent cells secrete a series of pro-inflammatory cytokines, the so-called SASP, which means ‘senescence associated secretory phenotype’.
What we showed is that the SASP is one of the mechanisms by which CD38 increases during aging.
Based on this, one could predict that if we were able to eliminate a senescent cell, we would eliminate the SASP and then we would eliminate the induction of the CD38 expression.
One thing to remember is that the SASP is not the only mechanism that was responsible for the induction of CD38. There were other substrates including bacterial products such as LPS (lipopolysaccharide), and other series’ of factors that we will also have to control.
So I believe that fighting the induction of CD38 is going to be harder than inhibiting CD38 expression or providing NMN as an exogenous substrate.
“if we were able to eliminate a senescent cell, we would eliminate the SASP and then we would eliminate the induction of the CD38”
NAD Boosting Supplements: More Options on the Horizon?
LB: With a forward looking approach on NAD boosting, NAD precursors and their role in alleviating some of the pressures of aging, do you believe we are likely to see a wider variety of NAD boosting supplements emerge over the next 5-10 years?
If so, what form might these (strategies) take? The recent discoveries around the reduced form of NMN (NMNH) is one such example.
EV: This is a very good point, and one I think is exciting. Clearly, what the data shows is the interconnectedness between multiple processes is something that we had actually not fully appreciated.
One is NAD degradation, that’s the role of CD38. The role of senescence. The role of what we call the PAMPs (pathogen associated molecular phenotypes) such as LPS and others.
So, if you think about fighting aging and its manifestations, I would predict that in the future, we will likely have a combination of these approaches to really maintain NAD levels, to eliminate senescent cells, and to restore NAD levels, using a variety of precursors.
“I can predict, based on what has been published and what we know, that there will be other [NAD boosting] molecules.”
Right now, the field is focusing on NR (nicotinamide riboside) and NMN (mononucleotide nicotinamide). Both of those have shown remarkable activities, which is why there is so much excitement in this field.
But I can predict, based on what has been published and what we know, that there will be other molecules.
One thing that is really important to realize is that to be truly demonstrated as efficacious, I think it will be important for these molecules – whatever they are, whether they are CD38 inhibitors or NAD precursors – we need to conduct clinical trials to make sure that whatever we’re giving to patients is not only given at the right dose, but is safe and actually has the intended safety profile and the intended benefit.
I think this is the way that truly evidence-based medicine has been progressing over the last 100 years and I hope that our field of aging research will abide by this principle and demonstrate the efficacy of what we’re providing to patients.
Wearing Two Hats: Bridging the Gap Between Ageing Research and Deploying Interventions
LB: Dr. Verdin, could you comment on the importance of translational roles, such as your role as Chair of the Seneque Scientific Advisory Board, in bridging the gap between ageing research and making relevant treatments available to the general public?
While keeping a foot in both the ‘research’ and ‘commercial’ camps can be difficult to navigate, surely they are likely to become more common as this field matures?
EV: I am very excited by the ongoing opportunity and ability to not only conduct basic research and make discoveries – that’s been my whole life’s work.
But as I’m getting older I have been increasingly interested in taking things one step further and really pushing the envelope to make these discoveries closer to translation in humans.
This is certainly the approach we’re taking at the Buck Institute. We’re starting companies, we’re collaborating with established pharmaceutical companies, we’re collaborating with biotech companies such as Seneque.
I very much view my role not only as Director of a basic research institute, but as an advocate for pushing these discoveries into the clinics. And I really think the science is there in terms of the promise.
“I hope that in 20 years from now, we’ll look back at the Buck and say that this was an institute that really took the bull by the horns and really tried to change the way we age”
The deep questioning and the hard work start now. Which is to say really bring this into humans. We know from data in the pharma industry that it is much harder to translate into humans, especially given the diversity of the human population both in terms of genetics and lifestyle and so on.
One of the reasons we work closely with Seneque is the value they place on proper clinical research. They have a significant program of clinical trials in play which will drive the understanding of the effects of NMN in humans for all of us.
Seneque’s mission is to increase healthspan by 20% in the next decade.
In the future we will hopefully see that in some way the Buck successfully redefined what the basic research institute is doing.
In this case we are aggressively building a translational infrastructure – by collaborating with pharma and biotech and also by starting our own company.
I hope that in 20 years from now, we’ll look back at the Buck and say that this was an institute that really took the bull by the horns and really tried to change the way we age, not only in animal models but in humans. I think this is a little different from what most places do, but I find it very exciting.
“As I’m getting older I have been increasingly interested in taking things one step further and really pushing the envelope to make these discoveries closer to translation in humans.”
Dr. Verdin’s Personal Approach to Longevity. Does Dr. Eric Verdin take NMN? What supplements does Dr Verdin Take?
LB: Dr Verdin, changing gears, as we close off the interview - could you share with our audience one or two of your personal longevity strategies?
EV: I have to be careful here, because these are not ‘recommendations’, this is strictly what I do as a person. I believe in lifestyle effect being very critical in determining longevity, so I really focus on five different aspects.
Nutrition & Fasting
One is nutrition, with a focus on intermittent fasting. Every three months, I do a week of fasting. I do time-restricted feeding, which means I eat for about eight hours of the day and do not eat for the remaining 16. So that’s pillar number one – nutrition.
Exercise
Pillar number two is exercise. I try to fit in between one and two hours of exercise every day. I think it is the best and safest anti-aging medicine that we have today, and it will remain so for a little while longer, until we discover better medicine.
“I used to be an every-day-one-glass-of-wine drinker. I have seen how much this alters the quality of my sleep and I would now define myself as an occasional rare drinker.”
Sleep
The third pillar is sleep. I think we live in a society that is chronically sleep-deprived. I try to sleep a good amount every day and try to make sure it’s good quality by mitigating all the factors that I’ve discovered actually interfere with my sleep.
I use an Oura ring and the Whoop, which are two wearable devices that allow you to closely monitor your sleep and which have allowed me to determine what the factors are that affect the quality of my sleep.
One of the ones that actually surprised me was the effect of alcohol. I used to be an every-day-one-glass-of-wine drinker. I have seen how much this alters the quality of my sleep and I would now define myself as an occasional rare drinker.
Stress Management
The last thing is stress. I really believe that stress is a significant contributor to aging, so I try to mitigate my stress by doing yoga, by meditating when I have the time and really try to mitigate the factors that stress me. For me, exercise is probably the best anti-stressor.
Supplement Routine
In terms of supplements, I believe in measuring whatever can be measured in your blood.
There are number of companies that provide this type of services and in correcting what seems to be off-balance. So I take a number of supplements, simple ones like vitamin D and vitamin B12.
I also take NMN every day. Having taken it myself at significant doses, I really see the effects, so I’m encouraged to continue.
I take metformin for two reasons. First, it’s been shown to have many properties as an anti-aging medicine. But also my fasting blood sugar was borderline and I thought that, given my age, there were little risks in taking metformin.
So there you are – the pillars of my health or longevity program at this point.
LB: Dr. Verdin, thank you so much for taking the time to answer our questions. It is a true privilege to hear from one of the aging’s sectors most notable and well respected leaders.
Looking for more NMN based content? Look no further
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.
Urolithin A, Endurance, Muscle Strength and the Longevity Future - An Interview with Amazentis CMO Federico Luna (Pt 2)
You can now score 5% off Mitopure with our exclusive discount code!
Use the code ‘longevityblog’ save 5% after adding an item to your cart & creating an account
Urolithin A Supplement Benefits: Endurance and Muscle Strength
Studying the effectiveness and safety of Urolithin A in human subjects has led to some exciting results in muscular endurance, strength and power.
To date, the research efforts into these benefits have been led by Swiss bioscience company Amazentis, who now sell a Urolithin A supplement under their “Timeline” nutrition brand.
This product “Mitopure” is a high purity form of Urolithin A, which as we discussed in the previous post, has been shown to have excellent bioavailability a in clinical trial setting.
Amazentis has run three clinical trials (in humans) on Mitopure as of this interview (Q1 2021).
Timeline’s Mitopure
Perhaps the most notable findings in their clinical trials so far have been the impressive benefits in skeletal muscle.
These results are notable because they are potentially important one with respect to your longevity.
Aging is known to be associated with loss of muscle mass and power, which is driven by a multitude of factors - including confusion in important signalling pathways within the skeletal muscle due to dysfunctional mitochondria.
Urolithin A acts upon the dysfunctional mitochondria in skeletal muscle by triggering mitophagy - which is the process by which these dysfunctional mitochondria die off, and are replaced by new, healthy mitochondria.
For more on this, we’ll let Federico add to the details. Without further delay, we continue our interview with Amazentis CMO Federico Luna.
[If you’ve not read part one of this interview, you can find it here]
This interview was conducted on 30 March 2021, over Zoom and is an audio transcript with minor edits for clarity, brevity and correctness.
This is part two of a two part interview. Part one of this interview is available here.
Urolithin A and Muscular Endurance
Longevity Blog (LB):
On the topic of mitophagy and muscle tissue, let’s come back around to this 40%+ improvement in running endurance in mice, as compared to untreated peers of the same age.
It naturally starts a conversation around whether Mitopure could improve athletic performance. Clearly. you haven't studied that yet, but surely you've been asked about it?
Federico Luna:
We're getting a lot of interest from the elite athlete population, as you can imagine. The fact that this is a natural molecule, the fact that it's safe, the fact that there's a growing body of scientific and clinical evidence - that's very exciting. Sports is an area that we're very interested in for sure.
Could Urolithin A be a sport performance supplement? Early results are promising - Longevity Blog will be sure to keep you up to date. Be sure to subscribe for updates!
Today we don't have any clinical studies in this specific population, but we do have some very interesting pre-clinical data in younger mice and also anecdotal feedback from athletes who have been taking Mitopure.
That's purely anecdotal at this stage. But we're very excited about the sports nutrition opportunity and athlete population, for sure.
LB: That really piqued our interest. 40%+ a quite a large improvement in endurance running from a supplement alone.
Thank you for commenting on that. We understand it's anecdotal at this stage, but it could make for some excellent self experimentation in athletes who are curious about the product.
On the topic of performance, let’s discuss the second clinical trial in more detaily. This trial looked at some very specific exercise tolerance metrics - cycling ergometer, handgrip strength, gait speed, lower body muscle strength - to name a few.
Urolithin A Benefits in Leg Muscle
What were the outcomes here? On the website that you refer specifically to hamstring strength as one area of improvement. Patrick Aebischer also mentioned there were some improvements in walking speed on the LLAMA podcast. Could you comment anymore on the outcomes for that clinical trial? How comprehensive were the improvements?
FL: I can only give you a ‘top line overview’. We’re seeing remarkable results on leg muscle strength, the hamstring, as you mentioned. We're seeing significant improvements, both vs baseline and also versus placebo. So, yeah, more to come on that study once it's published.
Leg muscle strength and power are crucial for maintaining independence in aged cohorts. Urolithin A benefits to leg strength are notable to longevity enthusiasts for this very reason.
LB: We'll plan to follow up with your team once that publication comes out. In a follow-up blog entry, so we can explore the details. Let’s talk about that third clinical trial you discussed. What is it exploring?
FL: You know, one of the big questions we often get from people as they start looking into reading about Urolithin A is - where do I get Urolithin A? How many pomegranates do I need to eat?
Up until the launch of Mitopure, there was no consumer product that offered people a pure form of the active.
Urolithin A Pomegranate Power
Sure, you could buy products containing pre-cursors like ellagic acid, pomegranate extract, or even pomegranate juice but you’ll never know how much Urolithin A you’re actually going to get.
What's remarkable about Urolithin A, is that it is an unusual molecule, it’s a metabolite, which means its not in the foods we eat but is produced by our gut after eating certain foods.
When you eat a pomegranate, it has a precursor compound, a family of compounds known as ellagitannins. After you eat the pomegranate, if you've got the right gut microflora , that bacteria then helps metabolize and create the bioactive Urolithin A.
The challenge, unfortunately, is that a lot of people don't have the right gut bacteria. And even if you do have the right bacteria, it's guesswork to figure out how much Urolithin A and whether you’re getting the right dose to reap the health benefits.
“if you’ve got the right gut microflora , that bacteria then helps metabolize and create the bioactive Urolithin A.
The challenge, unfortunately, is that a lot of people don’t have the right gut bacteria. ”
That's where Mitopure is really a breakthrough. There's a decade of work that's behind this - we've found a way to create and bypass the complexity of diet and the microbiome, by providing you a precise dose of the active.
LB: A decade of work but still easier than opening a pomegranate [joking]
FL: [Laughs]. Yeah. We've got a few tips we can share on how to open pomegranates, we've done a fair amount of pomegranate opening over the years.
Mitopure vs Pomegranate Juice for Urolithin A
Pomegranate juice can provide the building blocks of Urolithin A, but the correct gut bacteria are necessary to produce Urolithin A.
LB: The first clinical trial and publication had some excellent graphics exploring various Mitopure dosing strategies, and the resultant blood serum levels.
Have you explored Mitopure versus pomegranate juice in individuals with the correct gut bacteria?
FL: In our next [third] clinical study that we're going to be publishing, it really dives deep into the microbiome and that side-by-side comparison.
It compares the pure form of Urolithin A that Mitopure delivers into the bloodstream versus natural dietary sources, in this case a glass of pomegranate juice.
We took 100% pomegranate juice and did a crossover study with 100 people in Chicago. We compared over a 24 hour period the area under the curve to see total exposure to Urolithin A from natural dietary sources versus Mitopure. The comparison is remarkable.
There's really interesting data coming out in terms of how many people at baseline have Urolithin A in their system, as you can imagine, that's very low. The second data point is - how many people can actually naturally produce Urolithin A from pomegranate juice? That's also low.
The last question is, okay, even of those who can produce Urolithin A, what is the difference? How much do you get from Mitopure, versus how much do you get from a glass of pomegranate juice. We see a six fold higher levels of Urolithin A with Mitopure over a 24 hour period versus pomegranate juice.
LB: So this third clinical trial - it sounds like you're in the data analysis stage, it is completed and you're preparing results?
FL: Correct. We're preparing to publish them.
LB: Do you have an indication on when the preprints for those publications might be showing up? Is that something we could expect in 2021?
FL: Hopefully. The target is to get these published in 2021.
Is Urolithin A from Mitopure Too Expensive?
LB: Great, we’ll be sure to follow up on that. Let’s talk about the Mitopure product. One of the most common objections we’ve read, in our background research for this interview is cost.
People often balk at the price. That is understandable, as it's a relatively expensive supplement at $100 a month. Help us understand that price point.
There's 10 years of work that have gone into this. Amazentis has pioneered this work, but let’s go a bit further into why that number is something that's defensible. Why should a reader invest their budget in Mitopure?
FL: Coming back to the comparison I gave you around pomegranate juice - you know, one glass of pomegranate juice, [Mitopure] is not priced anywhere near to 6x the price of a pomegranate juice. In fact, we're very reasonably priced, if you make that comparison.
Comparing Mitopure vs Pomegranate Juice Cost
We did the comparison, based on Australian prices. $4 for a pomegranate or $6 for 1L of 100% pomegranate juice (from concentrate).
One pomegranate will yield about 150ml of juice. That's 6.6 pomegranates for a 1L at a price of $26.
$26 for 1L of juice is a significant premium ($20) on buying a ‘from concentrate’ source, but likely to be more potent, and is what the ‘6x more effective’ figure is based on, so we need to use ‘fresh’ for a like-for-like comparison.
Our base unit is the 500mg dose of of Urolithin A (the standard Mitopure dosage) versus drinking 8 ounces of pomegranate juice (225ml).
225ml of fresh pomegranate juice would cost $5.85AUD. Multiply that by 6 for a whopping $35 worth of fresh pomegranate juice, not to mention the 1.3L you’d have to drink to get the same Urolithin A benefits (with the right gut flora, of course).
Even with the discount on the ‘'from concentrate’ option at 1.3L, you’d still be paying $7.80AUD.
Mitopure 500mg sachet works out to be $4.30AUD without the subscription discounts.
The takeaway: Federico is right on the maths. if you’re after Urolithin A benefits, Mitopure is a good deal and you’ll have fewer trips to the restroom each day ;)
Is Mitopure too expensive? Not according to the math
FL (cont.): The $100, for some people, we can understand that that's a sticker shock. On the other hand, if you break it down per dose, you're looking at a price of $3.33[USD] per dose. We do actually offer an [annual] plan, which is selling extremely well, where people get a discount - a per dose price of $2.87[USD].
Make the math even better - use the code ‘longevityblog’ to save 5%!
When compared to your alternative, which is, I would say at best a blind gamble with pomegranate juice - here you have a product that can deliver six times more at a relatively small premium.
Obviously, we're hoping over time, as more and more people start benefiting from Mitopure, that as our volumes increase - we'll be able to reduce cost and offer people an even better price.
LB: We will do that calculation to pomegranate juice, for the benefit of the readers just check that out.
One of the things that is often valuable in this case, are customer testimonials. You earlier mentioned you're getting some positive feedback. How does someone know that their investment in Mitopure is working for them? What feedback do you hear?
Urolithin A Benefits: What customers are saying about Mitopure
FL: I can't share details just yet what those testimonials are. What I can tell you is - we're getting great feedback. Biology is very personal, there is no average patient in a clinical study, as they say.
As you’d expect a few people are saying it's either too early to tell or some people don't necessarily feel a measurable difference. The majority however are giving us remarkable feedback.
We’re hearing from a variety of age groups - people as young as 30, all the way to people in their 80s talking about benefits in terms of energy and strength. Those are sort of the two primary areas where we're getting positive feedback.
We're working on taking all these great testimonials and making them available - because we do get that question a lot.
LB: Thanks for sharing that. We understand that individual biology is complicated. Everybody is their own self experiment. That's actually one of the things that Longevity Blog focuses on - helping people learn to take one thing at a time and measure meaningfully whether or not it's benefiting them.
Urolithin A and Mitopure: What’s Next?
Amazentis CMO Federico Luna - with a pomegranate, of course!
So energy and strength - that feedback matches with the research. There's also been other complimentary research on Urolithin A. Particularly around helping the gut barrier heal in cases of ulcerative colitis or irritable bowel syndrome.
Others have focused on neurodegenerative disease and also found a role for Urolithin A in triggering of autophagy. That work by Julie Anderson's group at the Buck Institute.
How do you feel the work of Amazentis has helped to ‘move the needle’, so to speak, in terms of the interest in Urolithin A more broadly?
Do you expect that the research in this area will be maturing quite quickly over the next few years?
Urolithin A science is moving quickly
FL: We've seen tremendous excitement from the scientific community. Again, if you look at PubMed as a source, typing ‘Urolithin A’ into PubMed - you'll see there's been an explosion of preclinical research over the past 10 years.
You mentioned the Buck. Its a remarkable research institution and Julie Anderson's lab is doing groundbreaking work on Urolithin A and Alzheimer's. There are a number of other leading researchers around the world pioneering new potential applications for Urolithin A. Interest is really growing.
The fact that Amazentis’ pioneered the first translation of the science into humans - I think that gives researchers the confidence. It’s been shown to do something in worms, it's something that's been shown to do something in mice.
Now there's very promising data in humans. We think that will catapult Urolithin A research over the next few years. We like to think of Urolithin A as sort of the ‘next omega 3’ and while there is a strong body of evidence already today, there’s much more to come.
LB: That's a fascinating answer. We're coming up on the end of our time here. So let's try to draw it to a close, by thinking about where this particular supplement (Mitopure) and the Timeline Nutrition brand are going to fit in the personal longevity strategies for people moving forward.
This particularly supplement seems to be filling a niche around loss of muscle mass and power as we age, as well a loss of energy as we age. Coming back to your company mission, your ‘science first’ approach, at Amazentis - where do you see Amazentis contributing to improving our healthspans over time?
The Amazentis & Timeline Mission
“It’s a really exciting time for longevity. It’s a really exciting time for muscle health. And we’re just at the beginning”
FL: Our mission is to optimize cellular health and help people live healthier lives for longer. As we talk to people, and take them through the science, particularly around muscle, people are surprised at how early our muscle health actually peaks.
There isn't an exact number, it varies from person to person, but we've seen studies that show muscle starts to peak in our 30s or 40s.
One of the big challenges in health is getting people to invest in prevention, because while we all like the sound of prevention, when it comes down to it - are you willing to invest in your health?
What's really exciting is we're seeing more and more people say - “Yes, I want to invest in my health, and I want to invest now”. So that I don't have to try to cure later on in life. That growing buy into prevention coupled with the data we have that shows that Mitopure can have in impact on your muscle health in 2-4 months is a great match.
It's a really exciting time for longevity. It's a really exciting time for muscle health. And we're just at the beginning. And, the fact that we've got the first and only clinically tested, pure form of Urolithin A, and we're offering that direct to consumers, through the Timeline brand and also through a great partnership with Nestle Health Science - arguably one of the leading global players in science driven nutrition is the perfect combo. We think this is just the beginning of a really exciting portfolio of products and innovations and things to come on Urolithin A.
LB: Fantastic. We look forward to staying in touch with you on that future vision, Federico. Particularly we look forward to those upcoming clinical trial results, as well as how you'll be expanding your partnerships and improving access to the forthcoming healthspan boosting technologies in the pipeline. It's exciting stuff. Thanks for speaking with us today.
FL: A pleasure! Thank you.
We negotiate the best discounts available for our readers.
Use the code ‘longevityblog’ to save 5% off Mitopure!
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.
Urolithin A Supplement - Benefits, Side Effects, Healthy Mitochondria
You can now score 5% off Mitopure with our exclusive discount code!
Use the code ‘longevityblog’ save 5% after adding an item to your cart & creating an account.
Urolithin A Supplement Benefits
In this post we’ll cover:
The top benefits of Urolithin A supplementation
What is Urolithin A and is it safe?
Urolithin A supplement Mitopure
Interview with topic expert Federico Luna of Amazentis, including
Urolithin A clinical trials
Mitophagy and improved mitochondrial function
Urolithin A in the Body
Urolithin A is certainly turning some heads in the longevity & wellness biohacking community, owing to an unusually wide array of purported benefits. Chief amongst them - improving mitochondrial health.
Urolithin A (UA) is a new longevity supplement with excellent results in placebo controlled human clinical trials. In this post, we’ll learn about what it is, its benefits, side effects and where to get it + save 5% off the best available option. we’ll also hear from an expert on the latest science.
Urolithin A Benefits
Urolithin A supplement benefits video with our Founder Nick.
UA and Gut Health
UA has shown remarkable benefits in the digestive track, with an apparent ability to heal the all-important and notably fragile, gut-barrier.
Currently being explored in non-human studies, Urolithin A appears to offer notable levels of improvement for irritable bowel syndrome and Crohn’s disease. These benefits also appear to extend to colon cancer.
Improvement to the gut microbiome and gut bacteria requires a strong gut-barrier and is linked to many positive health benefits. Therefore, it seems UA is clearly quite good for your gut!
Read the Nature Communications article on Urolithin A benefits in the gut here
UA Cleans Up Metabolism
Urolithin A (and B) appear to possess anti-glycative properties, meaning they can help prevent the accumulation of advanced glycation end-products or AGEs which leading to age-related complications such as the loss of flexibility in tissues with age.
Similar mechanisms may also link Urolithin A benefits to neurodegenerative disease, currently being researched in the (Julie) Anderson lab at the Buck Institute.
UA and Muscle Strength
Perhaps the most interesting benefits are observed in mitochondrial health and skeletal muscle, which have recently been discovered in randomized double blind placebo controlled clinical trials through research led by Amazentis (2019 to present).
In our upcoming interview, we’ll focusing specifically on the ability of Urolithin A to improve mitochondrial function and restore healthy mitochondria in the skeletal muscle.
But first, what is Urolithin A exactly?
What is Urolithin A?
Given Urolithin A is demonstrating extraordinary promise in a few key areas of age-related disease, it’s natural to be curious about what it is and where it comes from.
Urolithins are a by-product of the digestion of ellagitannins, which are found in certain foods, including raspberries, walnuts and pomegranate, which also include the polyphenol ellagic acid.
Before you jump toward filling up the shopping trolley with pomegranate juice, note that urolithins are only produced by certain types of gut flora, who participate in the digestion of ellagitannins.
Only 20-30% of people are thought to have the right gut microbiome to complete this conversion, and the ability to produce urolithins in the bloodstream. They naturally have UA levels several times higher than those who do not have these gut flora (who may have no UA in their bloodstream at all!).
We’ve completed a thorough Urolithin A supplement review, including a self-experiment guide to see if Urolithin A supplementation will work for you! Read it here.
Is Urolithin A safe? Urolithin A Side Effects?
The inability of most people to produce Urolithin A has given rise to the first Urolithin A supplementation options.
Notably, using Urolithin A as a dietary supplement has achieved GRAS status from the US FDA (2018), meaning it is ‘Generally Recognised as Safe’ for human consumption in the proscribed range of 250 mg to 1000mg per dose.
Urolithin A does not have any documented adverse side effects - provided you choose from a high quality provider. As per usual, many imposters exist on eBay and Amazon - buyer beware! (We write more about this issue here)
The Best Urolithin A supplement
‘Mitopure’ is a Urolithin A supplement, and the focus of our interview content in this post.
Studying the effectiveness and safety of Urolithin A in human subjects, is what leads us into our interview subject - Swiss bioscience company Amazentis and their recently launched (2019) “Timeline” nutrition brand.
Their mainstay product “Mitopure”, is a Urolithin A supplement, brought to market in the culmination of more than ten years of scientific work, including capstone clinical trials in human subjects.
The Timeline brand’s ‘Mitopure’ is a high purity form of Urolithin A with excellent bioavailability (proven in clinical trials which we will discuss shortly), demonstrated to show up in the blood supply after supplementation.
Urolithin A in Humans
Amazentis’ growing number of clinical trials in humans has demonstrated Urolithin A to function as a catalyst for mitophagy, which is the orderly death of dysfunctional mitochondria.
This has been demonstrated to be specifically helpful in skeletal muscle, which accumulates an increased number of dysfunctional mitochondria as we age.
These benefits look to be a welcome ally in the struggle against loss of muscle mass and power with age, and there is early evidence Urolithin A supplementation is particularly effective for this purpose in leg muscle.
To dive deeper into these fascinating and promising results we completed a detailed interview with Amazentis Chief Marketing Officer Federico Luna, to get into the nitty gritty details and enable our readers to make an informed decision on whether or not to self-experiment with Urolithin A.
This interview was conducted on 30 March 2021, over Zoom and is an audio transcript with minor edits for clarity, brevity and correctness.
Longevity Blog (LB):
Federico, thank you for joining us today. To start out, let’s discuss the central values of your venture. Timeline refers to itself as a “science-first nutrition brand”, explain what this means, and how it might differentiate you from other companies which sell dietary supplements?
Federico Luna (FL):
Our interview guest, Federico Luna, Chief Marketing Officer at Amazentis + our subject matter pomegranate!
Great question. There's a lot of brands out there that call themselves science driven. We thought hard about how we are different to that.
It's difficult in a world where perception is everything, and anyone can put a couple of words on a website, and consumers interpret that as sort of very high science.
‘Science first’ means a couple of very concrete things.
Unlike many nutrition companies, Amazentis was founded by leading scientists, doctors and entrepreneurs in the life sciences who wanted to create a new class of nutrition supported by the rigor of research you typically only find in biotechs that are developing drugs.
The company invested over a decade into research before commercializing its first product, Mitopure (the first clinically tested pure form of Urolithin A). Our primary focus for all these years has been to pioneer the pre-clinical and clinical trials with this novel molecule, Urolithin A.
We started with preclinical trials, using tiny little worms called C. elegans, and showed that these worms were living close to 40-45% longer after taking your Urolithin-A compared to placebo. We then took it into mice, and started learning more about the running endurance and muscle health potential benefits.
And now we’re translating this science into humans. In the last five years, we've run multiple human clinical trials. This approach is what we mean when we say ‘science first’. You do the rigorous science first, and only then go to market.
Amazentis - Pioneers and Experts on Urolithin A
LB: It sounds like what we are hearing from you, is that Amazentis has been leading in this research area, since the beginning. We might have to consider Amazentis to really be the authority on Urolithin A? Would you agree with that statement?
FL: Many researchers around the world are doing interesting studies with Urolithin A. And in the last 10 years alone, if you go to pubmed.org, you'll find over 100, preclinical studies, exploring the benefits of Urolithin A.
Not only for muscle, but also for brain and other very important organs. But Amazentis is the first and only company that has taken Urolithin A into the clinic with very rigorous double blind placebo controlled trials.
Urolithin A Clinical Trials
LB: To date there have been two clinical trials in humans, is that correct?
FL: There's actually been three. One with published results in Nature Metabolism.
The purpose of this first trial was a couple of things. First and foremost, was to establish safety. So that was the primary endpoint. But what was fascinating and remarkable is we also started looking at the impact of Urolithin A on mitochondrial function, and more specifically on gene expression.
LB: Let's talk a little bit about that first trial and follow-up publication. One of the most notable things about the study was the proof of the bioavailability of Mitopure. It demonstrated that Urolithin A is getting into the bloodstream and spreading throughout the rest of the body.
Help our readers understand - why is this such an important and significant finding? Can you walk us through what that means in terms of the downstream effects?
Mitopure supplementation at 250mg, 500mg and 1000mg in human subjects, with the concentrations of Urolithin A and its metabolites (UA glucuronide, UA sulphate) in the blood.
FL: One of the key outcomes of this study was a characterization of the pharmacokinetic profile of Urolithin A in humans. We wanted to understand the absorption, bioavailability, distribution and excretion of different doses of UA.
We found that UA was bioavailable in plasma at all doses tested, which is indicative of its potential to have a systemic impact and it also gave us insight into the right dosing to take into subsequent clinical trials.
If you think about mitochondria, these little energy factories inside of most of our cells – in the brain, in our muscle, our eyes, our liver, in a number of key organs - by looking at the bloodstream, we're gaining more insight on how Urolithin A could act on the mitochondria, across all these other potential organs.
“We found that Urolithin A was bioavailable in plasma at all doses (of Mitopure) tested, which is indicative of its potential to have a systemic impact”
The second thing we did is look at the muscle specifically. We wanted to understand if the molecule can actually make it into specific muscle tissues. That's very important for the molecule to have a local effect.
LB: One interesting aspect about that publication was in the concluding remarks, where the effects were described to ‘resemble a regular exercise regimen’. While we don't quite have that elusive ‘exercise in the pill’ solution yet, it does seem that Mitopure may be conveying many of the benefits of exercise.
How can your Urolithin A supplement benefit sedentary folks and folks who are perhaps a bit older and losing muscle strength and power?
Urolithin A restores healthy mitochondrial function
FL: If you think about the mechanism of action here, what we've shown is Urolithin A acts on the mitochondria. Even more specifically, it acts on the mitophagy pathway. In short, mitophagy is a natural cleansing and renewal process whereby damaged and inefficient mitochondria are identified and cleared away.
This makes room for new healthy mitochondria, a process known as [mitochondrial] biogenesis to kick in and help create and rejuvenate the mitochondria.
This mitophagy pathway is really a breakthrough scientific discovery. A lot of that work was led by Professor Johan Auwerx, here at [Laboratory for Integrated and Systems Physiology at École Polytechnique Fédérale].
Love podcasts? Live Long and Master Aging is one of the best in the longevity field. Listen to an interview about Urolithin A with Chairman of Amazentis’ Scientific Advisory Board Patrick Aebischer.
As you look at mitophagy and inducers of mitophagy, exercise is a one, another key one is caloric restriction.
We don't see Mitopure as a substitute or replacement, but as complimentary to physical exercise and caloric restriction.
LB: Patrick Aebischer (Chairman of the Amazentis Scientific Advisory Board) said previously on a podcast in 2020, that Mitopure was the only known compound capable of simulating mitophagy. Do you still know if that's still believed to be the case?
Mitopure: The Best Urolithin A Supplement?
FL: This is a rapidly evolving space and there's a lot of ongoing scientific research. So I can't comment in absolute terms. What we do know is Mitopure is the only mitophagy inducer that has been taken into the clinic and has been shown to improve mitochondrial function and muscle strength in humans.
LB: On the topic of mitophagy and muscle tissue, let’s come back around to this 40%+ improvement in running endurance in mice, as compared to untreated peers of the same age.
It naturally starts a conversation around whether Mitopure could improve athletic performance…
Want to learn more? Read Part 2 of our Interview Here
You can also check-out our Urolithin A supplement review and self-experiment guide here
We’ve negotiated a discount on Timeline Nutrition’s Urolithin A supplement “Mitopure” for our readers.
Use the code ‘longevityblog’ at the Timeline Nutrition website to save 5% on any order
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.
Choosing an NMN Supplier for Self-Experimentation
What is the Best NMN Supplement?
Who should you choose for your NMN supplement?
Fast-take: 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%!
Want the details and the ‘why’ I make this recommendation? Do read on!
Today on Longevity Blog, I wrap up my three part series on self-experimenting with Nicotinamide Mononucleotide. Complete with NMN before and after testing.
As discussed in the first post of the series on NMN risk management, there are three key questions that Longevity Blog will engage with on the topic of NMN. These are:
What NMN supplement should I use?
In this third post of the three-part series, we’re going to zoom right in on the question - how do I choose a high quality NMN supplier?
Choosing the best NMN supplement: Potential Pitfalls
NMN is a supplement, meaning its production and distribution are largely unregulated. As such, this potentially exposes the self-experimenter to several potential pitfalls when purchasing.
The most important of which are:
Imposters (i.e. not actually NMN)
Contaminants (e.g. heavy metals)
Impurities (e.g. fillers, extras)
Unnecessarily high cost per dose (e.g. low potency)
Naturally this raises the question - How can we avoid these potential disruptors to our self-experimentation?
For those currently searching for their own NMN supplier, I personally understand where you are coming from.
First up - you are aiming to purchase a product with confidence in knowing it is NMN, but fake supplements are common and are lurking amongst in the available NMN suppliers on the web right now.
Even if you can become confident the product in question is NMN (not an imposter), you still must consider the risk of contaminants such as heavy metals showing up in your supply.
Furthermore, we don’t want to waste our money on a product that has low potency and/or uses fillers to push more product (impurities).
And then there is cost. Once satisfied on the above three - imposters, contaminants, impurities - we still need an NMN supply that fits our budget. This is complicated by varying levels of potency across the options:
what is a ‘dose’?
how much NMN per dose?
how many doses per container?
shipping costs?
The above long list of factors can make selecting an NMN supplier quite daunting, and perhaps overwhelming!
No one individual can take on the challenge of sorting through these points on their own. Thankfully, the NMN self-experimentation community is working together on this one…
NMN Supplement Review Useful Sources
One of my favourite aspects of the self-experimentation community, is the collective spirit of sharing knowledge and helping each other navigate the pitfalls of sourcing supplements.
Despite its relative novelty, NMN suppliers have been usefully reviewed in several formats - the most valuable of which, at this stage, are two YouTube videos.
In the first, we find that once again, my mate Dr. Brad Stanfield continues to be one of the top sources of information on NMN.
In his videos, he reviews several brands - and parallels my above selection criteria - analysing imposters, impurities, contaminants and cost per dose.
Dr. Stanfield’s endeavour to find 3rd party testing data reveals a key resource in our journey to select our NMN supplier.
The second YouTube video is from Vince and his channel “My NMN Experiment”.
Vince has several relevant videos for the NMN self-experimenter on the topic of NMN sourcing, self-experimentation and review of available third party testing.
Of particular use is his video on ‘Testing Heavy Metals” which you can view below:
Choosing the Best NMN Supplier
Use the code ‘longevityblog’ to save 10% on any order with DoNotAge
Amongst the growing number of choices for supplying NMN, is UK based company DoNotAge.
I recently became a strategic advisor to this company, owing to our shared interest in making longevity supplements like NMN widely available.
Simply put, if NMN can deliver even a fraction of the longevity benefits to humans that are observed in mice, then I firmly believe in the democratisation of access to the molecule.
By democratisation, I mean - making it widely available in both supply and cost. Quality is of course pre-requisite.
Before we move on, it is important to disclose that I stand to benefit from the sales of NMN by DoNotAge due to my advisory role.
However, this monetary benefit is modest and frankly, is not part of what motivates me to self-experiment with NMN, nor to recommend the company to you personally.
Instead, what my position as an advisor has allowed me to do is more clearly understand the NMN global supply chain and access certain confidential information about its production, proprietary competitor testing, distribution and profit margin.
Many NMN options are low quality
Through the clarity this position has provided me, I have a heightened level of concern on the practices of many of the other NMN suppliers.
The issues I am now privy to are numerous and commonplace. I am aware of products sold on Amazon, claiming to be NMN, which contain nicotinamide instead (imposters).
Suppliers who claim to be ‘manufactured in the USA’, source their products from China (lack of integrity) and package it in the United States in order to ‘cheat’ their way to this label.
Others have degradation of the product due to poor packaging and storage practices (potency), while many others provide no third party certification regarding heavy metals (contaminants).
Moreover, many sell NMN at low potency, including doses at 50 - 150mg, which are well below even the conservative doses being used in early clinical trials.
DoNotAge is a High Quality Supplier of NMN
In addition to the “insider scoop” on the NMN supply landscape, my advisory position has also provided me with a high degree of confidence on DoNotAge’s Pure NMN product.
I know with certainty it is NMN (not an imposter), is appropriately free of contaminants or impurities, and it is amongst the highest potency options available on the market (500g NMN per capsule).
This combination of factors given me the confidence to personally consume the DoNotAge product, using it in my current NMN self-experiment, selecting it from the ‘Wild West’ of NMN suppliers.
Despite the potential conflict of interest I hold in monetarily benefiting from the sales of this product, it is my hope that this vote of confidence may contribute to your own decision making process.
Simply put - in my longevity journey, I am very disciplined in choosing the supplements I consume! DoNotAge passes all my checkpoints.
Reviewing NMN for Self-experimentation Protocol:
Use the code ‘longevityblog’ to save 10% on any order with DoNotAge
Zooming out from the details of choosing the best NMN supplier, let’s come back to my NMN self-experiment.
I am presently wrapping up week 4 of the protocol, which will run for a total of 6 months.
The experiment will rely on several different data points, one of which is before & after biological age tests from Chronomics, and will wrap up at the end of February.
Unlike many of the other self-experimenters out there, I am holding constant my daily habits, diet and supplement routine, in the interest of generating the most robust scientific outcome.
When complete, I will finalise the results and protocol, in order to support the self-experimentation community.
The self-experimentation protocol is as follows:
NMN 500mg per day (updated)
TMG 500mg, every day (1:1 ratio to support methylation)
All of which is being supplied by DoNotAge.
You can find the relevant DoNotAge products in each of the above hyperlinks.
Use the discount code ‘longevityblog’ to save 5%!
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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.
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!
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RT @rebeccavziegler: The cryonics payoff matrix. Choose wisely my friends. https://t.co/l1rzsmOC2w
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My rate of aging: 0.79 It’s the new street cred What you got? https://t.co/aHzWHAfCnD https://t.co/L3rZC4QFN2
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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
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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
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Longevity legends take on many shapes and sizes https://t.co/X9vGa7gvOe
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RT @BradStanfieldMD: Avoid These Popular Supplements (shout out to Professor Matt Kaeberlein @mkaeberlein & Professor Brian Kennedy… https://t.co/cy9CXldgUS
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Who are influential persons in #longevity who are of Asian, African American or other “minority” group in the US?
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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.
NMN - Nicotinamide Mononucleotide Safety and Risk Management
NAD boosters are a HOT topic. NMN is the hottest 🔥
One of my favourite ways to analyse the latest health action in longevity technologies is to use Google’s keyword planner and trends tools. They form a great way to track the ‘pulse’ of human interest on healthspan. And as I planned my next upcoming series of blog posts on NAD boosting with NMN and diving deep into epigenetics and biological age, I certainly found plenty of evidence of our collective curiosity on the topic.
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. And while the requisite clinical trials (those in humans which reveal their effectiveness) are still ongoing, it is clear from the data and trends I analysed that these molecules, particularly NMN, are moving into the mainstream. Heck, I’ve even run into many folks in the energy sector (where I run my day job - Solcast), taking NR and/or NMN!
Trends in NMN and NR over time
Here is a great illustration on how the search analysis for NR and NMN have changed over time. While NR got an early boost with the launch of Elysium Health and their product “Basis”, searches quickly returned to baseline within a matter of weeks.
NMN however, after an outstanding boost from David Sinclair’s appearance on the Joe Rogan Experience podcast, and likely supported by Dr. Sinclair’s impressively wide-reaching Lifespan book launch tour, has clearly achieved a wider and more sustained appeal. NMN is clearly the hottest topic in the world of NAD+ boosters, and this is supported further by the search results present in many English speaking countries, with thousands of searches for NMN and related topics each month (and growing steadily).
What is NMN? What are its benefits?
It is hardly my role to explain the basics of NMN and NAD+ boosting supplementation, as that is not the focus of the Longevity Blog (here we focus on decision making, actionable insights). Thankfully however, my mate from across the pond Dr Brad Stanfield (New Zealand) runs a fantastic and educational YouTube channel covering these topics. You should be able to find the resources you need to become more familiar with NAD+ boosting supplementation by watching his videos (be sure to SMASH that like button 😂).
NMN Supplementation: Safety, Strategy, Sourcing
There are however three key questions that Longevity Blog will engage with on the topic of NMN. These are:
Is NMN safe for self-experimentation?
How can we self-experiment to determine efficacy?
What NMN supplement should I use?
In this post, we’re looking into NMN safety and risk management. We’ll come back to #2 and #3 in future posts.
NMN Supplementation: Is it safe? (Key Question #1)
When exploring NMN supplementation safety, there are two important sub-questions to explore:
1) Has the molecule been found to be safe by reputable third-parties?
2) Are there known risks with supplementing the molecule?
NMN Safety
Perhaps the most compelling safety certifications a molecule can receive is the GRAS accreditation from the FDA. GRAS - Generally Regarded As Safe status has been awarded to NR, as well as other forms of Vitamin B3 such as Niacin and Nicotinamide. NMN however has not yet reached this hurdle as of mid 2020.
However, in my opinion, this is inevitable, will arrive soon, and there are currently no reasons other than timing and resourcing as to why this has not yet occurred. NMN supplements are just entering the market en masse (see the above analysis!), and the FDA will be certain to react to this. To be clear, I am not asserting its safety independently, this is the role of the FDA. What I am saying is that closely related molecules have received GRAS status, and the lack of GRAS status for NMN is related to its relative newness in the world of supplementation not due to any known risks.
In summary, NMN is likely to become Generally Recognized as Safe (GRAS), and the other members of the Nicotinamide family (NR, Niacin) have GRAS status. We presently have no reasons to doubt it is a safe molecule to ingest.
NMN Supplementation Risks
However, GRAS status doesn’t ensure it will yield us a positive longevity based outcome. It more or less means it won’t poison us. Safety in this context does not mean there are not risks.
Nicotinamide. Source: Wikipedia
I have spent many tens of hours studying scientific publications available on the topic of Vitamin B3 supplementation and other closely related molecules to NMN (NR, Nicotinamide). What I have found clearly suggests supplementation of Vitamin B3 and its related molecules at high doses. At the most fundamental level, NAD booster supplementation of any form, results in adding significantly higher amounts of B vitamins into the body than it is prepared to metabolise. This is what I would refer to as ‘high doses’ in this context - specifically, consuming 1, 2 or even 3 orders of magnitude greater than the RDA for the vitamin group.
NMN! Source: Wikipedia
Conversely, my research also cemented the claims behind high dose supplementation, as there are a wide array of purported benefits for NMN (limited to mouse studies at the time of writing) and even greater supporting evidence for the benefits of NR (which NMN is converted into prior to entering cells) including early studies in humans. I won’t delve into all of these benefits - if you’re reading this post, you’re likely already sold on the benefits!
In making a judgment call, one is left with a risk management scenario. The possible benefits are significant. However, there are risks associated with high doses of B vitamin intake. To gauge how we make a decision, we turn to the fundamentals of risk management. Understand the motivations for the activity, diagnose the risks of the activity, apply a risk management strategy, and make a decision based on the residual risk.
This means, we next need to understand the risk better, after which we look at the options to managing the risk.
From the abstract:
“However, possible adverse effects and their mechanisms are poorly understood. High-level NAM (Nicotinamide) administration can exert negative effects through multiple routes. For example, NAM by itself inhibits poly(ADP-ribose) polymerases (PARPs), which protect genome integrity. Elevation of the NAD+ pool alters cellular energy metabolism. Meanwhile, high-level NAM alters cellular methyl metabolism and affects methylation of DNA and proteins, leading to changes in cellular transcriptome and proteome. Also, methyl metabolites of NAM, namely methylnicotinamide, are predicted to play roles in certain diseases and conditions.”
NMN Supplementation Primary Risk - Depletion of Methyl Pool
In my review, the primary risk of NMN supplementation (or NR), is the depletion of the methyl group ‘pool’ on which many aspects of your metabolism interact and modulating your DNA expression depend.
A recent study in the journal Biomolecules shares the work of South Korean duo Eun Seong Hwang & Seon Beom Song, who approach this topic from the same place that we opened this blog post - Vitamin B supplementation is growing dramatically in all forms, what are the possible consequences?
Of the many possible negative effects of NMN supplementation, only one of these has been determined to be highly probable. In fact, based on the fundamentals of organic chemistry, it is nearly certain to occur.
Taking high doses of Vitamin B3 (NAM, NMN or NR) will increase the demand on your available methyl pool. This means there are reduced methyl groups available for the methylation of DNA (which, for example, operates in the epigenetic expression of DNA via histones). This could have the deleterious effect of altering your patterns of gene expression and thereby impacting the supply of proteins your cells need to encode for important processes such as cellular repair or replication.
I have adapted the below image from the Biomolecules paper in order to add a bit of clarifying sign-posting on the diagram. From left to right, we have the flow of potential consequences of elevated NAM intake. At far left, the methylation cycle is represented, and at the nexus of it and the NAM cycle, we can see the methylation of NAM (to metNAM) occur. This is what will need to occur in high doses of Vitamin B (NR, NMN or any other form of NAM).
NMN Supplementation Risk Management
Having understood the risk, analysis reveals a critical system (DNA expression, protein encoding) depends on the methyl groups which high doses of Vitamin B are likely to deplete.
So now the question is, can we employ a risk management strategy to minimise this risk?
I believe the answer is yes. Thankfully, it is possible to replenish the cellular methyl pool exogenously via supplementation. Allow me to explain a bit further.
At left in the above image, is an input to the methylation cycle via betaine. Betaine is a metabolite of choline (note how the methylation cycle flows from betaine to choline) and is one of the most important methyl ‘donors’ (another being folate). Betaine can also be called ‘Trimethylglycine’ (TMG). More broadly betaine actually refers to a class of molecules, but in the context of metabolism TMG and betaine are used interchangeably.
TMG is our risk management strategy when it comes to high dose NAM supplementation (including NR and NMN). This molecule is formed of an amino acid (glycine) that has three methyl groups attached to it. It is these three methyl groups that provide the extra inputs we need to support our ramped up methylation cycle when supplementing with NAM. It is possible that different forms of methyl groups, not provided by TMG, could also be required. This will be the subject of future research and updates to featured on the Longevity Blog.
nmn and nr Supplementation gets the green light
Based on the deep dive of research I have been completing on the topics of NAD+ boosters and epigenetics + biological age, I believe NMN supplementation to be risk-appropriate and a potentially effective tool in my longevity supplement stack.
I will soon be embarking upon my own NMN self-experimentation, and as I do so, I will be supplementing with Tri-methyl glycine (TMG) on a 1:1 basis with my NMN intake. In my view, the supplementation of TMG provides self-experimenters with an appropriate risk management strategy for long-term (i.e. more than 1-2 months) NMN (or NR) supplementation.
Need NMN?
DoNotAge offer the cheapest high-quality NMN available. Third-party tested. Fast international shipping. Use the code ‘longevityblog’ to save 10%
Snag yourself some TMG!
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.