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.
How GlycanAge Biological Age Testing Works - An Interview with Glycan Expert Gordan Lauc
Glycans Can Be Used to Estimate Biological Age
In our most recent post, we explored the basics behind biological age testing with glycans.
Working up from the basics (what are glycans?) through to how glycans interact with inflammation in the body, and ultimately are a signal of the aging process itself.
We also heard from Nikolina Lauc, CEO at GlycanAge, a longevity technology company based in the United Kingdom, whose mission is to “bring glycoscience into the hands of both clinicians and consumers to inform, guide and preserve your future health”.
GlycanAge has recently made it possible to purchase a direct to consumer kit to assess your ‘glycome’, which as we will learn in this follow-up post, is a powerful indicator of your future health and longevity.
Today, we’re publishing an exclusive interview with glycan expert and GlycanAge Director Gordan Lauc.
Gordan is not just a glycan expert, he is THE global authority on all things glycans.
As a Professor of Biochemistry and Molecular Biology at the University of Zagreb, he kicked off the Human Glycome Project in 2017 and has built the world’s largest human glycome database.
Through this effort, he has built an entire research team who have pioneered the glycomic analysis technology required to inspect glycans quickly and efficiently.
It is this technology which has made consumer testing of biological age and personal health status through glycans possible.
Our interview subject, and global glycan leader, Professor Gordan Lauc.
While an impressive figure of great reputation, Gordan is also a great conversationalist, amateur gardener and all around collaborative and friendly bloke who is passionate about helping people lead healthier lives.
Through collaboration with GlycanAge, we sat down with Gordan for a 1-on-1 interview, diving into the details behind how the human glycome works, and how to use it to assess biological age.
We even documented Gordan’s input on how you can run your own self-experiment with GlycanAge, to improve your health and overall longevity.
Let’s get into it!
GlycanAge Discount Code!
As a part of our mission, we are working to make your longevity budget stretch further!
Through our collaboration with GlycanAge, we have a 15% off coupon code, which you can use on their biological age test kits.
Use the code “longevityblog” to save 15% on GlycanAge
This interview was conducted on 20 May 2021, over Zoom and is an audio transcript with minor edits for clarity, brevity and correctness.
Screen capture from Gordan’s YouTube video where he briefly tours his state of the art glycan laboratory.
How does the GlycanAge test work?
Longevity Blog (LB): Gordan. We recently checked out a video that is uploaded to YouTube. It was from an Instagram Live video with longevity doctor. Dr Joseph Raffaele.
In this video, you briefly toured your glycan laboratory. We found that absolutely fascinating.
You had a few generations of machines that were in place, and it made us naturally quite curious.
Could you explain what happens when a GlycanAge sample comes into your lab?
Tell us about the process of going from blood sample to glycan analysis!
Gordan Lauc (GL): Glycans are very complicated molecules. You cannot just read the letters in the way you read DNA or protein, they're branched. They're chemically very similar, but in the same way very diverse. Analyzing glycans is a challenge. This is why we need so many fancy machines.
When we do the GlycanAge test, it focuses on the glycan immunoglobulins. First, we have to fish out immunoglobulins (IGG) from the blood sample (a dried blood stain collected by fingerprick),
We have a special technology to get just IGG out of all other proteins in the sample. From the IGG, we remove the glycans, using a special enzyme which acts like a pair of scissors. It removes the one group of glycans called N glycans from the IGG.
After this, we have to dye them to make them visible in our machines. These machines use capillary electrophoresis, or chromatography, which separates glycans based on their chemical structure. Then we quantify the amount of each of them.
For the GlycanAge, we focus on glycans which change with age.
LB: There's around 2,000 to 3,000 types of glycans, is that right?
GL: When we talk about the total 'glycome', there are approximately 2000 different glycan blocks. For IGG, there are 24 major structures, so this “fishing out” process of the immunoglobulin reduces the number of glycans significantly. Using these individual structures we calculate the changes which happen with age.
Biological Aging and Glycan Immunoglobulins
Pictured: A 3D model of an human immunoglobulin
LB: In this biological age analysis, there is a close link between the IGG N glycans you're analysing as age markers and inflammation.
Can you can you explain that connection between these immunoglobulins and inflammation in the body.
GL: Immunoglobulins are the main weapons of our immune system. They are made to recognize any foreign object (bacteria, virus food, any foreign molecules) which comes into the body. They do this by a relatively complex genetic process to make a hypervariable domain to bind to this foreign object.
LB: A complex process certainly - give us the simplified explanation.
GL: When antibodies are developed, they do not know whether a given foreign object will be an enemy, like a bacteria or a virus, or if it is friendly, such as food or a dust or something else they should ignore.
After the antibody binds to this foreign object, what happens next is determined by glycans. This very complicated process (glycosylation) is regulated by least 40 different genes. These glycans decide whether antibody will kill a target cell (activate inflammation) or will it suppress inflammation.
Inflammation and Glycans
LB: And it is this increasing level of inflammation across the body which is tied to aging. What does a youthful version of this process look like?
GL: What we see in young people is that the majority of immunoglobulins have these anti inflammatory glycans. But when there is an attack by a foreign invader, like a bacteria or virus, then you need inflammation.
The problem is that as we live longer. We are genetically not made to live over 40. Once you stop making children, your genes don't work for you anymore, they work against you!
As we're getting older, this process gets disturbed, and immunoglobulins become more and more pro inflammatory. And actually, what we are measuring in the GlycaAge test are these molecules which regulate inflammation.
GlycanAge Biological Age Estimate
LB: This is how you can produce a biological age estimate, right? If you know what the glycome of an old person would look like versus a young one, you can make a prediction. Talk about how you create a biological age assessment using this information?
Pictured: A GlycanAge biological age testing kit. We discussed some of the basics on these kits in a recent post.
GL: Initially when we developed the DNA typing, we noticed that glycans correlate with age. At the time, we were thinking to use this information to determine the age of a person who left a blood stain at a crime scene.
This is relevant information for police investigation, whether this was a young guy or experienced criminal.
We tried to correlate the glycans with chronological age, and this was reasonably successful.
When we did this, approximately a decade ago, this was one of the most accurate ways to determine the chronological age of a person. Subsequently methylation test was developed, which was way more accurate in predicting chronological age.
LB: But there is still unique value in the GlycanAge test, particularly in assessing lifestyle factors?
GL: What we have learned is that our test deviates from the chronological age, approximately nine years. But not in a random way! But in a way which associates with lifestyle.
On our GlycanAge test, people living healthy lifestyle will always be younger, while people living an unhealthy lifestyle will be older. Also, people with different diseases will generally look older too.
What is Biological Age?
GL: We realized that the GlycanAge is not a good test of chronological age, so we can't use it in forensics, but it is very informative about something we call biological age. Although biological age is a very tricky word, because there is no golden standard.
Learn more about assessing your biological age in our interview with Chronomics CSO Dani
There is no universal unit of measure of biological age. And so someone can give you any kind of number and you cannot say whether it's right or wrong.
LB: Let us ask you about that, Gordan. What do you think about this term biological age? Is “age” the right term? Or is it more of a “biological score” or a “health score”?
Why do you think the industry has chosen the term “biological age”? It sounds nice. But we’re hearing from you that that term is a bit squishy.
What Health Information Does GlycanAge Provide?
An example of the ‘indices’ for the G0 (top) and G2 (bottom) IGG glycans. A GlycanAge test gives you access to this information as well as your biological age.
GL: When we do research, we report 24 directly measured glycans and maybe additional 50 different scores.
But the problem is that this is too complicated for people to understand. So then we made two levels of simplification.
One level is that we have three key indexes or scores, which is G0, G2, and GS.
G0 are glycans without galactose, which are the most proinflammatory.
G2 are glycans with two galactoses, which are suppressing inflammation.
GS are glycans with sialic acid, which also suppress inflammation.
LB: These three indices are reported to users when they complete the GlycanAge test.
This ‘first level’ of simplification provides direct insight into the levels of inflammation driven by or suppressed by each group.
How are these indices useful for the user?
GL: These three indexes are something which one can use to quantify three different aspects of regulation of inflammation. These three indices are exactly measured from the blood sample. This means, anybody in the world who has the right equipment can take the same blood sample and they should get the similar number.
LB: From there, biological age is the next level of simplification?
GL: The ultimate simplification is the biological age, but that's just the name, you can also call it a score. This is the model number. It is not a number which has an absolute meaning.
Screenshot from one of Gordan’s presentations on the GlycanAge biological age clock. Source: YouTube and also this pubmed article.
However, we know that the higher biological age number means more inflammatory glycans, and that means more low grade chronic inflammation.
This chronic inflammation is something which happens with aging and with disease. A smaller number of the GlycanAge means more immune suppressive glycans, less low grade chronic inflammation.
This is a number which is modeled. We use 1000s of people (over 150k) to build a model and compare an individual to this model to determine their GlycanAge.
Of course, it's not absolutely “accurate”, because there is no golden standard of accuracy. But what makes GlycanAge different from other indexes of biological age, which are being used is that we know that glycans which we measure are functional effectors of inflammation. They're molecules which do the damage.
Improving Your GlycanAge Biological Age
LB: Gordan - let's talk about improving our biological age. In other interviews, we've heard you talk about four key factors: sleep, diet, exercise, and managing stress. Making postiive changes in these lifestyle can help change the glycan based biological age estimate.
Can you can you explain why that's the case? Why are those four factors driving the GlycanAge?
GL: These four factors are the key factors of healthy life. Now, we all know, we need enough sleep, we need healthy diet, we need a moderate amount of exercise, and we don't need too much stress. There is no magic in that.
The problem is that this is extremely difficult. We cannot do it all. It simply is not possible in a modern society.
Could GlycanAge testing help identify the most optimal diet for YOU?
The other important thing is that we are all very different. The more research we do, we are learning this.
For example, we did recently cohort of 1000 people on five different diets. And each diet is good for somebody and bad for somebody else, so there is no universal diet, which will help everybody.
LB: Fascinating! Could you share what some of those diets were?
GL: This is still unpublished. I cannot go into details. This was a large European project. But these diets were generally high and low protein and high and low glycemic index and different combinations.
High glycemic index is not bad for some people. It is bad for perhaps most people, but some people cope with glucose better than others.
What we are hoping that the GlycanAge can do is help people to focus on one of the four aspects which is dominant in them.
Gordan is actively collaborating with Dr Joseph Raffaele to explore using GlycanAge on his patients at his longevity clinic in New York. Image Source: LinkedIn
For example, for some people, it could be only a few extra hours of sleep, and then they don't have to spend an hour day in a gym.
For other people, it could be just less carbohydrates. And then maybe they don't have to sleep that much.
GlycanAge is a kind of objective tool to evaluate what works and what does not work for us.
You earlier mentioned this Instagram Live video Dr Raffaele and I did. He has an anti aging clinic in New York where they are testing these ideas.
GlycanAge and Hormone Optimisation
LB: Let's talk about that. Dr Raffaele specifically talks about hormone optimisation.
We know that there's a real strong relationship between hormone balance in women, for example, and menopause and perimenopause.
Research with GlycanAge is finding a close link in aging and hormone levels. You also just mentioned diet.
So here’s our next question: How do we create understanding on what an individual needs in terms of their own personalised approach to improving their GlycanAge?
GL: This is exactly what we're trying to do at the moment. We started to work with Joseph to test his patients, and they all turned out younger. His average patient is 20 years younger, for male and I think 15 for a female patient, which is unbelievable.
Estrogen levels change significantly over the course of a woman’s life. GlycanAge is closely correlated with these changes.
I asked him - what are you doing to your patients? What are you giving to them? He's giving them more or less everything one can do.
We decided to dissect what works in which patient, and are now trying to do proper, placebo controlled randomized trials to see which of the approaches work.
What we know is that estrogen is a very dominant factor in woman.
We had, we got samples from one very interesting study where menopause was chemically induced in young women. In a half of the group, the estrogen was returned with estrogen patch, and the other half of the woman received a placebo.
Estrogen supplementation completely prevented the change in the IGG glycome while the woman who were on placebo aged nine years in a few months on average. Some women going through menopause age as much as 20 - 30 years within a year (on average, this number is only 7-9 years)
This loss of estrogen is extremely strong regulator of IGG glycosylation. The problem is when these women lose their good glycans, its promoting low grade chronic inflammation.
We know for example, from animal models that this is causative of hypertension. The increased risk of cardiovascular diseases known to occur with menopause could be partly caused by the wrong balance in IGG glycans.
LB: Clearly the estrogen balance and associated with changes that occur in menopause are very important for aging in women.
What about hormone levels in men? Is it a drop in testosterone which drives the changes?
GL: Interestingly in men it is also estrogen which regulates IGG glycosylation. In the same study, they also had a group of men where the gonadal hormones were blocked. When the testosterone was returned, it saved the glycome from changing.
Pictured: Testosterone, which plays a secondary role in GlycanAge. It is the change in conversion of testosterone into estrogen, which is altered in ageing in men.
But if the testosterone was added back in combination with another drug which is blocking conversion of testosterone to estrogen, this (the glycome remaining stable) the protective effect did not happen.
So in men, it's not testosterone which regulates IGG glycosylation - it's estrogen.
Hormones are very important regulators. But it's not only hormones, and it does not work to the same extent, in everybody.
So we definitely need to do more research to understand it.
Self-Experimenting with GlycanAge
LB: Hormone optimisation is clearly a really interesting topic area. Here, you've highlighted how it works for women, how it could work for men in the estrogen sense, which is fascinating.
Let’s talk about isolating specific changes one could make using GlycanAge test results. On Longevity Blog, we focus on helping our readers conduct self experiments to find out what works for them.
Want to see an example of using GlycanAge to try to improve your biological age? Our Founder Nick is kicking off his own self-experiment, and wants to take you along for the journey. Subscribe to content notifications to learn how to do this yourself!
For GlycanAge, what does this process look like? Could you point to a successful model for testing and improving your GlycanAge in a way that you can say, I know what did improved it, it was _____ ?
GL: One good example is weight loss. Losing extra weight helps the vast majority of people, because obesity is a big driver of inflammation.
However, when trying to lose weight, people often make a mistake. I personally did the same mistake when I realised my GlycanAge was not ideal. I decided to sweat it out. I was hiking in mountains, three, four hours a day, for the whole summer.
While some aspects of my health did improve, my GlycanAge did not improve much. This is because overtraining is also causing inflammation. Usually people think more is better, but for physical activity, it is not!
What is a “Good” GlycanAge Result?
LB: How can users of the GlycanAge test use that information to strike the right balance?
GL: There is no magic coach who will tell you what to do. Even the best coach can only know what is good for an average person. But there is no average person in the world! We're all different.
Pictured: Our Founder Nick’s GlycanAge from April 2021. This is a ‘good’ age for him, as it is 5 years younger than his chronological age.
He will of course be trying to get it even lower!
What people have seen with our tests, and this is what makes me happy, is that, often they get a poor GlycanAge result.
At first, they're angry, they claim the test is not good. This is why we also offer a free consultation with some of our nutrition and lifestyle experts to help them identify the problem.
Soon, they find the problem.
Maybe I'm overworked. Maybe I'm not sleeping enough. Maybe it is too much stress, I have family issues.
But when people resolve these problems, GlycanAge improves! This is a fantastic motivator.
You know you did something right when you turn out now 5-10 years younger on the scale.
Elevated GlycanAge and Disease Risk
LB: And as you mentioned before, that reduced GlycanAge comes with reduced disease risk and many other health benefits.
“This is the process I like to see - when people get the bad result, improve and get a better result”
GL: Pro-inflammatory markers usually change up to decade before people become ill. Disease onset is usually like this - you work normally, live your life and at one point you feel pain.
Because of that pain, you go to the hospital, and then you do all the checkups. Then the doctor says - you have inflammation in your guts, this is Crohn's disease, or you have inflammation in your joints, this is arthritis.
This is the end stage, when all the compensatory mechanisms have failed. All the ways your body tried to fix the problem have failed, then you have pain, and then you get the disease.
The problem with most of these chronic diseases, they are irreversible. This is why we call them chronic, you get some medicine, you feel better, you don't have the pain anymore, but you are stuck to these medicines for the rest of your life or the disease returns.
But if you identity and fix inflammation early, often simple lifestyle changes or an early pharmacological intervention can prevent disease.
This is the process I like to see - when people get the bad result, improve and get a better result.
“Approximately half of the GlycanAge is determined by your genes, you cannot fix it. ”
Something which is not so satisfactory for the user is when they are already good. Because then they ask - “what should I do now?” I say nothing, you're good. Just come in a year or two and do it again to see whether you're still good.
LB: What is “good” Gordan? Is it 5 years younger? 10 years younger? Exactly your age?
How does somebody know that they're doing “good”? What says - keep going, stay the course, this lifestyle approach is working for you?
GL: Anything which is younger than your chronological age, I would say it's good. It’s also important to not worry about the absolute number, because the absolute number is also strongly affected by genetics. Approximately 30-50% of the GlycanAge is determined by your genes, you cannot fix it.
It is the relative number, the pace of changes in biological age which are important. If your GlycanAge is increasing more slowly than your chronological age, then that’s good.
I recommend starting to do this relatively early, maybe even at 20 to 30 years old, initially once every few years. Maybe if you make a change in lifestyle, then you do it every few months to see whether something works or not. This is the most informative.
How Often Should You Test Your GlycanAge?
LB: Talk about that part. If one of our readers takes a GlycanAge test, and runs a self-experiment, they’ll be thinking about how to control the experiment. Here, the shorter the time-period, the more likely they are to keep it well controlled.
What is the timescale on which our GlycanAge is changing? Is it 3 months? 6 months? Does it depend on what one is changing? Give us a sense for how often we could retest if we wanted to say test, reducing our stress, for example, or changing our diet.
GL: Glycans change relatively slowly. The half life of IGG is approximately three weeks. I think the shortest period to see something would be maybe a month. But this is for a really radical change. If you start taking a drug, or really changed lifestyle factors a lot, such as completely changing diet, starting to exercise much more.
Normally, we see things changing after three or four months. If you slightly change your diet today, it first takes some some time to manifest in the glycans. Normally, we recommend people when they change a lifestyle, re-test after three months and then six months again. If what you are doing is working, you will see the result.
LB: That's a very clear answer. Thank you. We didn't find a good answer for this out there, and our readers are quite curious!
GlycanAge and the future of longevity?
LB: We are going to move toward the close here.
What do you think the role of testing glycans and GlycanAge is going to be as we transition into a future where more of these interventions are possible to slow, halt or possibly reverse our biological age? Where is the GlycanAge test going to fit in the next five to 10 years?
GL: I think the GlycanAge will be one of the tools to evaluate different types of therapies and interventions. It will also not be the only one. GlycanAge is primarily measuring the pro and anti inflammatory arms of the immune system, and there are many other aspects of aging.
If you’re interested in biohacking your biological age - so are we. We recently published results on using NAD booster NMN for improving you biological age
For example, cellular aging is something completely different. Something that happens within a cell, like telomeres or energy metabolism (NAD boosters) and so on.
GlycanAge is looking at the organism as a whole. I think this will be a very good tool for people to just monitor the way they are consuming their body.
In a reasonable timeframe, this will become a regular medical test, like testing the HbA1c for diabetes. We will soon be testing the IGG glycans for a low grade chronic inflammation as part of inflammaging.
Gordan’s Personal Longevity Journey with GlycanAge
LB: In your own personal longevity journey, you you've openly shared that you've tested you GlycanAge fairly frequently. You’ve learned that you go through phases, right?
For example, stress increases when there is extra work to be done, you start enjoying food a bit more and it worsens. However, then you get on to a new training regime or new diet, and your GlycanAge improves.
“Even now I’m losing weight again, and my GlycanAge is going down again. It’s a marathon. It’s not a sprint”
Is regular GlycanAge testing almost encouraging you to lead a more healthy lifestyle for your personally? Is that accurate to say?
GL: Definitely it's an indicator, which helped me to identify some of the problems I had. I don't have a magic solution for myself, my GlycanAge is still not ideal. But I have learned that my key problem is food. I like to eat too much, I should eat less.
So yes, when it GlycanAge gets too high, then I am motivated to fix it. For example, even now I'm losing weight again, and my GlycanAge is going down again. It's a marathon. It's not a sprint.
How Can You Use GlycanAge Testing?
LB: And what would you say as a closing statement for others who are out there in that same up and down? Those who are really trying to make a health lifestyle change and curious to test their GlycanAge?
What is the takeaway from your personal journey that you’d take the chance to share with them?
GL: I think the most important value in the GlycanAge test is it gives us opportunity to focus on the changes which are effective for us, because there is no standard human. For me, I have that I can occasionally have that extra cake. The cakes are not that bad for me. It's more the fruit which is not so good for me.
GlycanAge can help you customise your longevity strategy. Should you walk more? Sleep more? Eat less?
Not everything which is considered to be “healthy”, is healthy for you. So the key thing we can get from the GlycanAge test, is information about ourselves.
It's revealing the hidden secrets of our body, which we can modify, which we can change.
This allows you to see what works and what does not work for you. So whether we are going to live 50, 70, 90, 120 or 150, it doesn't really matter.
What matters is that for longest we live, we should be healthy and enjoy our lives and not suffering from different type of pain or diseases.
LB: That's a lovely place to close that off Gordan, and thank you so much for chatting with Longevity Blog today.
GL: My pleasure! Thank you for your time.
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Biological Age Testing with Glycans - Glycan Age
Should you try a Glycan Age Test?
The GlycanAge test kits - a clean, elegant design with fascinating technology under the hood.
This trend is in its early stages, but is set to continue, as gathering detailed information about your body to assess how quickly it is ageing hits the mainstream.
Today, we are introducing you to a new way to assess your biological age.
Whereas previous methods we have reviewed use age-related blood markers or your epigenome for this assessment - today’s technology from GlycanAge uses your glycans.
What are Glycans? Glycans and Biological Age
To start things off, we should probably address your first likely question - what the heck are glycans?
Clearly we need to understand this a bit first, before we can understand how they can be used as a biological age measurement.
Glycans is not a term that most people are familiar with, but they actually refer to a fairly simple concept.
First, we start with monosaccharides, which include more commonly known ‘sugars’ including fructose, glucose, and galactose.
Most of us are familiar with these monosaccharides - they are the simple carbohydrates common in our diet. More broadly, they can be thought of as the ‘fuel’ for our cells, as well as the energy source for most biological organisms!
use the code “LONGEVITYBLOG” at checkout to save 15% on GlycanAge tests
Glucose Molecule (Monosaccharide)
Fructose (Another Monosaccharide)
Combining Monosaccharides to Create Glycans
In practice, monosaccharides can actually be linked together in a very wide variety of long chain-like formations. This how you create a glycan.
A very well known glycan (also known as a polysaccharide) is cellulose, take a look at how it is built out of the monosaccharides above, just in a much more complex arrangement.
Cellulose - a combination of glucose molecules to form a glycan
Glycans and information
Glycans are influential in many processes occurring within your body. One way to think of their involvement is carriers of information.
As complex arrangements, there are many unique arrangements of glycans in the body which often represent very important signals regarding your health and wellbeing.
A healthy cell, with healthy glycans at the cellular membrane (the multi-coloured squares, circles and lines). Credit: Gly-tech
The valuable ‘signal’ that these complex sugar structures can offer has resulted in the field of ‘glycoscience’, which studies wealth of information glycans have to offer.
This information includes critical details about your overall wellbeing, with the presence (or absence) of certain glycans can be indicative of many conditions in the body, including many diseases, as well as - you guessed it - the processes behind ageing itself.
Glycans, Inflammation and Ageing
An unhealthy cell, with unhealthy glycans at the cellular membrane. Credit: Gly-tech
Glycans are intimately involved with your immune system, where they are used to ‘tag’ invading pathogens, signalling the immune system to attack and remove them.
Furthermore, the wrong glycans in the wrong place can generate an immune response, which then drives inflammation.
If you’ve learned about the basics of aging, and many of you have, you’ll be quite aware of the importance of tracking and managing inflammation to stay healthy for as long as possible.
The link between inflammation and ageing is known as ‘inflammaging’.
Dive deeper? Read more about inflammaging straight from the source in this very important 2014 paper which established the concept.
High level overview: Inflammaging is the process whereby increasing levels of inflammation add continual age-related stress and damage to the body, including more inflammation - and thus a feedback cycle develops making you age even faster.
Sounds like a great thing to keep in-check, no?
The links between inflammation, aging, and glycans are what make glycans great choice for monitoring your biological age.
GlycanAge as a Biological Age test
While glycoscience still has much to learn about glycans and their role in aging, metabolism, disease and immune function, there are many decades of research and enough large datasets available to support the creation of a biological clock based on glycans.
We’ll be covering the specifics on how this works in upcoming posts, but the key takeaway is: tracking the characteristics of the glycans in your body can provide an accurate and valuable assessment of your biological age.
And in the case of GlycanAge, your biological age will be primarily influenced by four lifestyle factors:
Stress levels
Exercise load (both too little and too much)
Dietary choices (including food allergies)
Sleep (what’s the right amount for you?)
Each of these factors are known to be very influential in how you are ageing.
As such, you can use a GlycanAge test to create a baseline, before making controlled changes/improvements in these factors, and then re-testing to see if they worked (i.e. did you reduce your biological age?).
This is central to what Longevity Blog is all about - self-experimenting and customising your own longevity strategy to make the best gains in your healthspan.
Given the nature of these lifestyle factors (stress, diet, exercise), self experimenting with GlycanAge is a very accessible way to start working to improve your own biological age.
Regularly testing GlycanAge can therefore be used to monitor and improve your health over time, with each of those small changes adding up to positively impact your longevity significantly over time.
GlycanAge and Its Mission
Don’t miss it!
We’ll be interviewing glycan expert Gordon Lauc on how you can used GlycanAge to improve your own health & longevity. Subscribe to get notified when we do!
The concept of using glycans to track and positively impact your healthspan has only been made possible through the vision and ambition of GlycanAge’s CEO and Founder Nikolina Lauc
Founded in 2016, the company is built upon the foundational work carried out by expert in all things glycans Professor (and Nikolina’s father) Gordan Lauc.
But don’t take it from us - hear it straight from Nikolina herself:
GlycanAge Founder and CEO Nikolina Lauc
Describe your motivations for founding GlycanAge - what opportunity did you see?
Nikolina Lauc (NL): GlycanAge originally came out of pure scientific curiosity.
My father is a glycobiologist who's worked in the glycan research field for 30+ years, they saw that glycans change with age and were curious as to how and why they change, as well as what we can do to influence it.
Hence the term GlycanAge, actually “GlycanBioAge” originally, was coined.
Glycans are one of the key regulators of our immune system, they contribute to ageing through a process called inflammageing.
Inflammation is a key driver of almost all chronic conditions and glycans are known to change before onset of symptoms and even a decade before onset of disease, giving us an opportunity to do true prevention and extend one's healthspan.
“Glycans are known to change before onset of symptoms and even a decade before onset of disease”
How would you describe GlycanAge’s mission - what drives your team? What have you set out to achieve?
NL: We want to keep you and your loved ones around for longer through precision health.
Our mission is to bring glycoscience into the hands of both clinicians and consumers to inform, guide and preserve your future health.
Glycans have a large influence on your unique biology, they play an intermediary role between your genetic potential and end phenotype, their true value lies in uncovering which intervention or lifestyle works for you particularly as an individual.
How has regularly testing your own GlycanAge improved your wellness?
“Glycans true value lies in uncovering which intervention or lifestyle works for you particularly as an individual.”
NL: Although my GlycanAge has always been favourable, regular testing helps me measure the damage (for example - COVID lockdowns and weight gain), and get back on track through sustainable change.
Beyond me, I've probably tested the majority of my extended family!
Coming Up:
(1) An interview with GLYCAN expert Gordon Lauc (read that here!)
(2) How our Founder Nick is using GlycanAge to run his own self-experiment (read it here)
Follow our Founder Nick on Twitter for the latest #Longevity news!
-
RT @rebeccavziegler: The cryonics payoff matrix. Choose wisely my friends. https://t.co/l1rzsmOC2w -
My rate of aging: 0.79 It’s the new street cred What you got? https://t.co/aHzWHAfCnD https://t.co/L3rZC4QFN2
-
It’s official - I’m co-producing and hosting a new #longevity docuseries, and will begin shooting in a few months… https://t.co/wLGqRrBfbp
-
“The #longevity segment opened my eyes to the groundbreaking advances in biotechnology, health, and wellness. The i… https://t.co/F8YB7PAeMW
-
I’m completely mindblown by what AI has done over the past 3-6 months, and it continues to accelerate… https://t.co/hh0JslucRg
-
Longevity legends take on many shapes and sizes https://t.co/X9vGa7gvOe
-
RT @BradStanfieldMD: Avoid These Popular Supplements (shout out to Professor Matt Kaeberlein @mkaeberlein & Professor Brian Kennedy… https://t.co/cy9CXldgUS
-
Who are influential persons in #longevity who are of Asian, African American or other “minority” group in the US?
Nick also posts related #Longevity content to Instagram as well, follow him at @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
NMN Nicotinamide Mononucleotide Before and After
NMN Before and After with Biological Age
In mid 2020, I set out on a self-experiment with NMN. The purpose of this experiment was three-fold
First - my primary intention was to lay out some suggestions for how you could structure your own self-experiments, and not just for NMN
Second - I of course was quite curious what my own results would be, and wanted to have a well-controlled self-experiment to answer the question: should I continue to invest in NMN as part of my longevity supplement stack?
Third - to raise awareness of NMN, biological age testing and encourage more of you to join in on being a biohacker!
Designing a self-experiment with NMN in mid 2020 was a unique challenge, as at the time, there was no direct way to test intracellular NAD levels.
That has however changed, and in upcoming posts, I am going to show you how to test your NAD levels directly. If that sounds interesting, be sure to subscribe below!
Takeaway: Over 6 months, a combination of 500mg NMN, 500mg TMG and 500mg resveratrol improved my biological age by 3.5 years. Read on to learn more!
Use the code ‘longevityblog’ to save 10%.
Looking for an NMN supplier? I recommend DoNotAge, who:
offer a third party tested product
have a bulk supply option (100g)
offer further savings when you subscribe to regular shipments
plus I can get you a discount: Use the code ‘longevityblog’ to save 10%!
Self-Experimenting With NMN
It is not easy to run a self-experiment. To review, all self-experiments are:
Difficult to control
Often hard to measure directly
Prone to bias and placebo effect
Even when well-controlled, don’t necessarily provide clear insights
Let’s take a minute to address each of these, how this particular self-experiment addressed each over the course of the 6-months of NMN supplementation.
Control
Over the course of my 6-month experiment, I made several efforts to control the experiment:
My exercise ‘Load’ as per my Garmin Fenix 6 Pro, which I use to track all of my workouts. At top, near the start, at bottom, near the end of the 6 month period.
I did not change my exercise load or volume
I did not change my diet
I did not start taking any other supplements
I did not make any other major lifestyle changes
It is of course not possible to completely control your life! However this does not mean you should not try.
Of these items, I would suggest that consistency in diet and supplementation are of paramount importance.
You can find many “NMN before and after” testimonials on YouTube, for example, but each of these has many problems with control.
The most common issue is making too many changes, mostly around supplementation protocol, during the ‘before’ and ‘after’ period.
Your chief goal here is to decide: is taking NMN worth my hard earned cash?
You can’t make that call if you’re also introducing many other longevity supplements at the same time! You’d be surprised how often this is the case! Be patient and be consistent.
Measurement
In the absence of a direct NAD test, the decided measurements before & after were set according to the 2x clinical NMN trials which were ongoing at the time, as well as adding biological age:
Lipid profile
Blood pressure
Biological age
Epigenetic age (Saliva Test via Chronomics)
Phenotypic age (Blood Test)
Bias & Placebo
I put serious thought into how to conduct a double-blind experiment, but ultimately elected not to.
Given the objective measurements we could draw from the above, and the ‘n of one’ experimental design, this was not practical to implement.
It also reduced the likelihood that everyday folks like yourself would be able to repeat the experiment effectively.
In the effort to minimise placebo effect, I made it my mindful intention to not overhype my personal attitude toward the experiment.
To be quite honest - I adopted quite a sceptical attitude.
Personally, I was unconvinced that NMN would make much of a difference in my day-to-day experience, as there was relatively little science in human subjects & most of these ‘hot trends’ turn out to be over-hyped!
NMN
NMN Self-experimentation Protocol
The supplement protocol for this self-experiment was designed to match the widely used combination of NMN, Resveratrol and TMG:
NMN at 250mg/day (first two months), 500mg (following four months)
For risk management, 1:1 dosage of Tri-Methyl Glycine (TMG)
Resveratrol at 500mg/day, taken with a high fat meal
Note: this was not a change for me, I’d been taking it for 2+ years, and therefore did not interfere with the need for supplemental control
NMN Before & After: Our Hypothesis
This experiment was undertaken to test the following hypothesis (all self-experiments should have one!):
NMN supplementation will boost intracellular NAD+ levels
Boosting NAD+ levels with NMN will measurably improve select characteristics of youthfulness
Combining boosted NAD+ with a sirtuin activator (resveratrol) will enhance DNA repair
Combined, these effects are hypothesised to be likely to:
change blood lipid profile (as per clinical trial designs)
change blood pressure (as per clinical trial designs)
slow or reverse biological age (Longevity Blog hypothesis)
NMN Before & After: Results
The self-experiment was run from 1 August 2020 for 6 months until 31 January 2021.
What follows are the results, including both hard data points and anecdotal observations.
Blood Lipid Profile:
Blood lipids refer to the commonly assessed HDL, LDL and Total Cholesterol measurements. These are also joined by Triglycerides to form the ‘Blood Lipid Panel’ of tests.
As you can see in the provided image, there was no significant change in any of these parameters over the course of my NMN self-experiment.
Blood Pressure
Blood pressure measurements at the start of the experiment were ~125/85.
At the end of the experiment, 126/84.
There was no significant change in blood pressure from the NMN self-experiment.
Biological Age: Phenotypic Age
Phenotypic age is calculated using 9 blood based biomarkers, to calculate a biological age.
This is based on work led by Yale researcher and longevity thought-leader Dr. Morgan Levine (whom we hope to interview on the blog in the future!).
We’ve previously reviewed this test, including providing information on how you can use it yourself here (its free!).
Blood markers in this test include:
White Blood Cell Count (WBC)
Red Cell Distribution Width (RDW)
Mean Corpuscular Volume (MCV)
Fasting Blood Glucose
Lymphocyte %
Creatinine
Albumin
Alkaline Phosphatase (ALP)
C-reactive protein (CRP)
If you’d like to learn more about any of these blood markers, checkout Lab Tests Online.
Pictured: My Phenotypic Age (Biological Age measure #1) over time.
At the start of the self-experiment, my Phenotypic Age was 28 (Chronological Age 34).
At the end of the self-experiment, my Phenotypic Age was 25 (Chronological Age 35).
Given that 6 months passed, this equates to a total change of -3.5 years of Biological Age.
Did I reverse my biological age with NMN?
Now - the key question is, was this change significant? Was it due to the NMN based protocol?
This comes back around to one of my initial opening points about self-experiments: “Even when well-controlled, they don’t necessarily provide clear insights”
For our analysis, we should extrapolate from the baseline measurements a bit further.
Over the preceding 3 years, my Phenotypic Age was an average of 25.7 years old. It was as high as 28 and as low as 23.
More importantly, we need to consider the difference between biological age and chronological age.
My average difference between biological age and chronological age over the preceding 3 years was -7.7 years. This was as high a -10 years and as low as -5 years.
At the start of the NMN self-experiment, this difference was -7 years (below the average), whereas at the end, it was -10 years (at the previous extreme).
There is a degree of subjective interpretation which must occur here, as the data volume does not lend itself to statistical analysis.
Based on the data and trends, there is sufficient evidence to suggest that this NMN based protocol reversed my biological age.
It is however is not conclusive evidence, and as a scientist, I choose to approach that statement conservatively.
There is a bit more to explore however, to let’s continue.
Biological Age: Epigenetic Age
This one was a real bummer. My follow-up test with Chronomics failed their quality control step, meaning the biological age result was not valid.
This was a crushing blow, as it was the chief data point, in my opinion.
However, I have re-tested it, but it was not in-line within the 6-month period self-experimentation period.
Due to my choice to begin another 6-month self-experiment immediately following this one, the next biological age result will not be valid for this experiment.
I’ve since dramatically increased my exercise routine (I’m now training for triathlons), made major dietary changes and increased my NMN supplementation to 1000mg/day in a separate 6-month self-experiment aimed a direct feedback from Chronomics on how to reverse my biological age.
I will update this post with those results, when they are returned, however they will not be well-controlled for NMN experimental purposes.
I know - major bummer! 😔
Such is self-experimenting life!
NMN Before and After: Anecdotal Observations
SF-36 Questionnaire
My results from the SF-36 questionnaire before & after did show a slight change in a few key areas.
While I did not experience any changes in general health, physical health problems or limitation of activities, I did have interesting results in the energy & emotions section.
Excerpt from my SF-36 questionnaire, before and after the NMN self-experiment.
At the start of the self-experiment, I think I was feeling many of the things that folks in their mid-30s start to feel. Notably less energy than in their 20s, less upbeat and more likely to feel worn out at the end of a long day.
Over the course of the self-experiment, this changed in notable ways, in a sustained way that continues to today.
You can see for yourself the meaningful parts of the questionnaire that changed for me in the following image.
I have to add - it is completely possible that these results are placebo based. I was taking NMN, most folks who supplement with NMN boast ‘increased energy levels’.
But of course, since NMN is hypothesised to impact intracellular energy, this is what we expect to happen.
When it comes to ‘energy levels’, NMN is a prime placebo influence candidate.
Nicotinamide Mononucleotide Before and After Conclusions
To summarise, I was able to run a well-controlled self-experiment with NMN supplementation at 500mg/day.
I recorded before and after blood tests, blood pressure and detailed subjective experience related data.
Initial results do indicate improvement in my Biological Age (as per the Phenotypic Age) by approximately 3.5 years.
Subjective data (qualitative data) support this quantitative data, and therefore the conclusion is: NMN left me both feeling younger and perhaps biologically younger.
However, this cannot be placebo controlled, and warrants further testing. In particular, direct testing of NAD levels is now available, and that is what I will be testing next!
Also, we have not been able to test the much more robust and accurate epigenetic age via Chronomics, which was unable to be measured. Ultimately, this was the most powerful data point, and though disappointing - we will revisit it.
Coming soon, I will review the results from testing intracellular NAD levels directly, before and after 1000mg of NMN.
Follow NICK on Twitter for the latest #Longevity news!
-
RT @rebeccavziegler: The cryonics payoff matrix. Choose wisely my friends. https://t.co/l1rzsmOC2w
-
My rate of aging: 0.79 It’s the new street cred What you got? https://t.co/aHzWHAfCnD https://t.co/L3rZC4QFN2
-
It’s official - I’m co-producing and hosting a new #longevity docuseries, and will begin shooting in a few months… https://t.co/wLGqRrBfbp
-
“The #longevity segment opened my eyes to the groundbreaking advances in biotechnology, health, and wellness. The i… https://t.co/F8YB7PAeMW
-
I’m completely mindblown by what AI has done over the past 3-6 months, and it continues to accelerate… https://t.co/hh0JslucRg
-
Longevity legends take on many shapes and sizes https://t.co/X9vGa7gvOe
-
RT @BradStanfieldMD: Avoid These Popular Supplements (shout out to Professor Matt Kaeberlein @mkaeberlein & Professor Brian Kennedy… https://t.co/cy9CXldgUS
-
Who are influential persons in #longevity who are of Asian, African American or other “minority” group in the US?
NICK posts related #Longevity content to Instagram as well, follow HIM @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
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.
Mole check technology for skin cancer screening: An Interview with MoleMap’s Chief Customer officer
In our previous post, our Founder Nick shared his personal experience with a detailed skin cancer check with the Australian based company Mole Map.
Mole Map is an innovative organisation who have more than 25 years of experience in skin cancer screening, and have pioneered new technology for imaging skin lesions (aka your moles) as well as a ‘surveillance’ system for tracking your skin continually over time.
Today, we’re following up on that content with an in-depth and exclusive interview with MoleMap’s Chief Customer Officer Vlad Mehakovic.
In this interview, we discuss the basics on how the service works, as well as Vlad’s own motivations for joining the company nearly two years ago.
With the basics covered, we dive into the details on how their ‘surveillance’ approach is enabling customers to manage their unique skin cancer longevity risk, and why the business model has been such a success.
Also, we ask Vlad a series of questions on where skin cancer surveillance is headed in the future.
This has some exciting answers, including emerging opportunities for the application of artificial intelligence to the skin cancer detection challenge, as well as a future where more of us are empowered to self-monitor our own skin using apps (some of which are freely available from Mole Map already).
There’s even a cool AI start-up company in the mix! There is plenty to learn about in this post, so without further delay, let’s chat with Vlad from MoleMap.
This interview was conducted on 20 May 2021, over Zoom and is an audio transcript with minor edits for clarity, brevity and correctness.
Our guest - Vlad Mehakovic, Chief Customer Office at MoleMap
Longevity Blog (LB):Vlad, thanks so much for joining us today. To kick things off - could you give us a brief history of MoleMap and its mission?
Vlad Mehakovic (VM): Thanks for having me!
MoleMap was started about 25 years ago by a group of medical entrepreneurs. Their key innovation was creating a system for better skin cancer diagnosis. Not only a set of hardware and software technologies, but also a system that took the dermatologist away from having to do the screening process themselves.
We see ourselves as pioneers within telehealth. What we've been doing is taking specialised photography and sending them to a remote dermatologist for review - and we’ve been doing that for 25 years.
How does skin cancer screening work?
LB: Those early medical entrepreneurs, they saw a specific ‘gap’ in the diagnostic capability. Could you comment on that gap? What was it?
VM: It comes down to standardisation. We've got a standardised way to map at your entire body, at a macro level. We then go micro and do diagnosis when there are lesions (medical term for all types of moles) of risk. These risky lesions are identified by a trained registered nurse (melanographer), they will take macro images of your skin followed by a micro, very close up, image of your skin. This is completed with a specialized camera (Molecam). [See the process yourself in Nick’s post about his MoleMap visit]
This camera can see under the first few layers of your skin. Those images are then passed on to a dermatologist who reviews them remotely. We've built one of the best dermatologist teams in Australia and New Zealand, some real leaders in dermatology.
A ‘melanographer’ use a ‘Molecam’ to image a mole on Nick’s foot!
This team-up between the melanographers and dermatologists with high quality images, allows people to track their body over time. This is the ‘surveillance system’ in action. It's not a one time solution, it's something that you repeat over time. This is important because skin lesions can change very quickly.
LB: MoleMap has clearly built a talented team, and have creatively structured the business so you can pull in the best dermatologists to review the images, leaving the technical side of assessing the skin and taking images to the melanographer. It’s a great model.
Speaking of talented people coming into the company, you're the Chief Customer Officer and have been in that role for going on two years now. Talk us through what drew you to MoleMap?
VM: I came onboard as a consultant initially and I saw lots of opportunities for growth. After a few months a new CEO (Tanya Houghton) came on board. Everything was working well, and I really liked the company. I was really honored when she asked me to keep on working with business.
LB: We like how you're talking about a team who is continuing to pioneer technology for skin cancer surveillance. It is quite a remarkable success story of applying a technology to cancer detection.
Does Skin Cancer Screening Save Lives?
LB: Can you tell us in the instance of skin cancer, why does early screening, save lives?
MoleMap provide extensive literature and supporting information about the many types of skin lesions, and the ones you need to watch out for
VM: It’s a pretty simple equation - the less cancerous tissue there is to remove, the less likely that cancer is getting into the bloodstream. The earlier you remove them, the higher the rate of survival. It's really that simple.
Again, it's not necessarily just the technology, it's the system that we offer, that really offers the step-change. There are a lot of different medical professionals, even with good technology, good dermascopes, but they don't necessarily get their education updated after attending med school. It is the application and the surveillance system that allows us to detect skin cancer systematically and comprehensively.
LB: In our Founder Nick’s personal experience with MoleMap, he reviewed the very technical way you map the entire body. It first calls out areas of interest, but then, of course, requires the user to come back.
It seems that this surveillance system has been remarkably successful. MoleMap have seen over 300,000 patients, mapped over 5 million moles. Can you take that a step further? What is the likelihood that this surveillance approach will save somebody's life?
VM: On average, we’ll see a bit more than 50,000 people a year, and that grows every year. About 30% will have some sort of recommended action. Most often, that is to continue monitoring a lesion closely.
We've started providing an increasing number of free tools for our patients & non-patients alike, to help support them. One of these is a web application that allows you to track your own lesions over time. This web app can also integrate that with the professionally taken photographs from our clinic.
So of those 30% where we advise continual monitoring, around 3% of people need urgent attention. We call them straight away and advise to see a dermatologist immediately.
If Skin Cancer Screening Reveals an Issue, What Next?
LB: In the case of a finding that is immediately actionable, talk us through what happens next for a patient.
VM: If there is a lesion requiring urgent attention, we'll call that patient to find out if they've got an existing dermatologist or GP whom we can send them a copy of our detailed report. If the patient gives permission, we send off the report and then the practitioner will understand what needs to be done and can act swiftly.
LB: In the case where there's an immediate finding we could argue the MoleMap visit has been a life saving intervention.
Should I Get a Skin Cancer Check?
LB: Coming back to those 50,000 or so people that come every year, nearly 40% of Australians have never had a skin cancer check, and many more of them fail to do it regularly. Why do you think it is such a difficult thing for people to manage? Why don’t more people complete regular skin cancer screenings?
VM: Compliance is a difficult thing, full stop. The number one barrier we talk about is apathy, as in, it won't happen to me. The main driver we see that finally gets people to act is when someone close to them - a loved one, a close friend - is diagnosed with skin cancer or dies from it. In the case of males, it's usually a spouse that drives them in to get screened. To be honest, guys don't tend to come in of their own accord.
LB: This is where we wanted to pivot to next - these objections: apathy, time, budget, nerves - what are some elements of the MoleMap service that help people get past those barriers and into a regular screening program?
VM: Our core service is going to cost what it's going to cost. So really, when people talk about cost, they're talking about value. What we're trying to do is support people in and around the visit, even before the visit.
Software management tools are a great example. First, risk assessment - we've got an online risk assessment. We also provide a free service where you can talk to one of our melanographers for 15 minutes to assess your risk and find the right service fit for your needs. We have a free online body map tracker, which allows you to actually track your own moles for a period of time.
“The number one barrier we talk about is apathy, as in, it won’t happen to me.”
Skin Cancer Screening with your GP?
LB: We understand there is currently an effort to get your technology directly into the GP room. In this model, GPs are provided the same system you offer and you train their nurse staff to complete the assessment. Tell us about the maturity of this strategy - Is it a pilot project? Or is this something you're in the process of going more widely?
VM: The pilot is well and truly done, and we've validated that it makes sense. It's got a lot of interest. We've rolled it out successfully in a number of practices across Australia, and we're beginning to roll that out in in New Zealand as well. It's going extremely well
LB: Is this something Australian’s should be asking their GP about - saying “Hey, have you heard about the MoleMap technology? I'm interested”.
VM: Look, that would be lovely. A significant number of GP visits are already skin related, and GPs are increasingly, in the last decade becoming increasingly educated around skin diagnosis. It's an already growing aspect of general practice. We're coming in with a holistic solution that hopefully, increases the patient outcome while decreasing the workload on the practice.
Artificial Intelligence for Skin Cancer Screening
LB: Continuing down the technology angle, looking into the future, MoleMap have created a very large database of skin lesions. Upon each visit, there is an opportunity for patients to opt in to allow their moles to be part of R&D.
Let's talk about MoleMaps R&D a bit, specifically where skin cancer detection technology is going in the future. As a starting point - explain what happens when one of your patients opts-in to allows their anonymous mole/lesion images to be sent off to improve the detection technology? What's happening there? What is their contribution, so to speak?
VM: Our vision is a world where all skin cancers get diagnosed and treated. That means we need to have a variety of options and solutions. The more lesion images that we can capture and categorise, the better that we can achieve that outcome. So that means we've got to look a lot further than just our own clinics.
MoleMap operates the biggest database of high resolution skin lesion images in the world. Perfect for training Artificial Intelligence algorithms. Picture: one of Nick’s moles that he needs to track!
We're starting to do that by offering that service to GPs and we are in the talks with a couple of big pharmacies. We have a workplace program where we come into your office.
About three years ago, we kicked off a process with IBM, because we have the biggest database in the world of high quality dermatologist diagnosed and categorized skin lesions approved to be used for research and development.
“Our vision is a world where all skin cancers get diagnosed and treated”
LB: That is a highly valuable and unique asset. So, what are your plans for this database?
VM: For the last three years, we've been using that imagery to train an artificial intelligence algorithm. Specifically, a convolutional neural network. And we’re continuing to optimise its ability to categorise skin cancers correctly.
We’ve also been working with Monash University, which has progressed to the stage where we've been comfortable enough to really want to invest in the commercialization of that technology. About six months ago, we formed a start-up company. It’s a stellar team of both technical business people, but also scientists within AI that have applied AI commercially in medical imaging in the past.
The team is now in the process of regulatory approval, which means, number one, being able to use that AI as a medical device. Secondly, the team needs to figure out how it makes sense to take it to market.
LB: Is this company currently in stealth mode, or can we know its name?
VM: Oh, it's called. It's called kāhu, named after a large hawk known for its sharp vision. The only thing that’s really stealth is what exactly the product is going to be. We've got some tight time pressures on that team and are expecting to get it to market quickly.
How Might AI Change The Skin Cancer Screening Process?
LB: When it does come to market, what is the vision for how that might change diagnosis or the surveillance process for catching potentially cancerous lesions?
AI will assist dermatologists by reducing the time they need to spend assessing each skin lesion.
VM: Well, again, if we go back to our global vision of the business, we're trying to get more images diagnosed. So this potentially helps that happen. It's unlikely that it's going to be the case where there is no human intervention. If you look at a lot of the best applications of AI, it's assisting an existing professional in the decision making rather than taking over the decision making process.
The AI technology would most likely be running alongside an already trained healthcare professional. It’s main potential is to deliver a higher level outcome to a wider audience - in other words, deliver the same level of diagnosis and categorization and patient outcomes, without having to have as much specialist contribution for every single lesion.
The Future of Skin Cancer Screening is Based on enabling patients to self-manage risk
LB: That's a great answer. Just as an aside to that, it was actually announced just today that Google had launched an AI health tool for skin conditions, including skin cancer. So that is another signal that artificial intelligence and good data sets in skin health is part of the future.
Pulling from your insights and some of the things you just talked about, what is your vision for how skin cancer diagnosis and treatment is going to change in the next 5 to 10 years?
VM: I think the key thing is, we've got to think about how to enable the patient to better manage risk themselves. There's a couple of levels of triage that happen. A patient goes to see a doctor, when they've got an issue, usually it is their family GP. They go and see that person for advice.
MOBILE APPS FOR SKIN CANCER?
Longevity Blog will soon be reviewing a selection of DIY options for skin cancer screening, be sure to subscribe below to get notified when that new content arrives!
Now, the nature of that is changing somewhat. There are now a number of mobile applications that are claiming various things that you can do by taking a photo of your skin with your phone and performing self-tracking. But the truth is the quality of those images and the ability of those people to really do the same job as a trained professional - there's quite a gap.
What we need to be able to do is get the best system and solution in as many doorways where patients are already visiting, as possible. The intent for us is really Australia and New Zealand as a testbed, before we begin to export globally. But we want to prove the case, really solidly here first, before we start to look at those options.
Bulk Billed Skin Cancer Checks
LB: Your answer actually flows on really nicely to an Australian specific question - when can we expect ‘bulk billed’ skin cancer checks to become available? It’s a legitimate question, given the prevalence of the disease in Aussies.
Is there a future for bulk-billed skin cancer checks in Australia? Not anytime soon, unfortunately
VM: We haven't heard any plans, even of it being reviewed. We don't go out and lobby or do anything like that. For us it's a step by step approach. We know that Medicare coverage for these checks would be hugely powerful. It would be good for Australians, it would be good for skin cancer diagnosis.
The first step that we can take, and we’re making some headway with, is working with major private insurance providers. More than one of the major private insurance companies in Australia are interested, and we're talking things through. We’re hoping to launch some partnerships very soon. That would be a really good first first step.
LB: At least there's some hope in the future with private health cover!
VLAD’s Personal Approach to Longevity
LB: We're gonna wrap this interview up now, Vlad, but before you go we always like to ask interviewees a little bit about what they do for their own longevity and health. To start, do you use the MoleMap technology yourself?
VM: Yeah, of course! I believe in proactive health management. I have an annual week of bloods, gut, dentistry, skin health that I personally go through. It's almost that via negativa process of ruling out the worst conditions. I totally believe in proactive health management to increase longevity and quality of life.
LB: Great to hear that! What have you learned from that week of focus that could be valuable to our readers in terms of putting together their own longevity strategy?
Establishing a good working with your personal doctor is a key longevity tip from Vlad. (GP = general practitioner, the same as Primary Care Physician in the US).
VM: I've got a great holistic GP, and I've started educating myself around the importance of gut health, more so than anything else. I know that skin cancer is bad, of course, and I need to be monitoring it. I know that heart attacks and strokes are bad, and I should be monitoring them. Putting it all together makes sense.
LB: So a good relationship with a high quality doctor has been one of the most important parts of that journey for you, as well as taking initiative to educate yourself on longevity risks.
VM: Yeah, totally!
LB: Thank you so much for contributing today, Vlad. We really appreciate it!
VM: Thanks mate!
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
How Does Skin Cancer Screening Work
Skin Cancer Screening Saves Lives
“Don’t worry, be happy”
Getting a Skin Cancer Check “Mole Map”
“What are your plans for the day?” the tall brunette asked, as she rung up my Lulu Lemon shopping spree (I needed some new running shorts! They didn’t disappoint).
“I’m actually headed around the corner for a ‘mole mapping’, have you heard of that technology?”, I offered, excited to hear her reply.
Anxiously, she replied “Yes, you must be nervous! I’d be so scared of what they might find!”
I chuckled, “Well, actually I’m a bit used to it by now”, pointing to my Health Nucleus jacket and explaining this wasn’t my first cancer screening experience, quite the opposite in fact!
“Well, I’m sure you’ll be fine”, she offered.
“Actually, that’s what the appointment is for”, my somewhat cheeky reply.
In her polite laugh, I could see the point had landed.
“The clinic is just around the corner, you should check it out sometime”, my closing remark, as I headed off to a comprehensive skin cancer screening service, in search of that ‘sure you’ll be fine’ level of certainty - but not on a whim, instead, at the guiding hand of longevity technology.
Skin Cancer Spreads and Kills
Bob Marley - legendary musician, skin cancer victim
When Bob Marley, one of the most influential musicians of his time, collapsed during a run around Central Park, his first thought was not likely to fault skin cancer for the scare.
But further analysis revealed that a known cancerous growth in the skin under his big toenail had metastasised, spreading to his brain, liver and lung. He was dead only a few months later at age 36.
His death shook the world in a way not unlike that of Chadwick Bosemen, who died a similarly tragic death at the age of 43 from colorectal cancer last year, raising awareness of the disease, which has unfortunately continued to reek havoc on the lives of millions of people each year.
In my home country of Australia, skin cancer is particularly rife. 2 out of every 3 Australians will get some form of skin cancer by age 70. On average, an Australian dies every 5 hours from melanoma, the most aggressive and dangerous form of skin cancer.
However, it is not just older folks who are affected. Skin cancer is one of the most common cancer diagnoses for younger people in the ages of 25-44.
And while the 1970s did not offer the types of advanced skin cancer screening technologies that could have saved Bob Marley’s life - 2021 proves much different.
You don’t have to leave your skin cancer risk up to chance. You can manage the risk.
Let’s look at how.
Skin Cancer Screening Saves Lives
As I explain in the above video, my visit to a MoleMap clinic in the Sydney CBD was to provide a comprehensive skin cancer screening, leveraging imaging technology to make a ‘map’ of my skin, forming a baseline for future tracking.
The MoleMap clinic utilised a few key pieces of technology to complete this screening.
An example of one of the 26 high resolution images taken of my body.
Step 1: Full Body Images
The first was a series of high resolution photos, where, stripped ‘down to me undies’ (said in the lovely Irish accent of my melanographer Kathy).
In a series of coordinated movements, using a reference chart on the floor for my foot positions, I posed for more than 25 images.
These were taken with a Nikon DSLR, set for maximum focus on the skin of the body.
Each image was then mapped onto a virtual avatar in a specialised computer system.
Unfortunately the avatar was much more ripped than I, perhaps I will equal his masculinity next visit?
Step 2: Head to Toe Examination
After the full body images were taken, the melanographer (who was a registered nurse, specially trained by the Australiasian College of Dermatologists) reviewed my body from head to toe.
Side Note: I wasn’t asked to take off the underwear, unless I had a mole or skin issue I wanted them to track. Ladies - bra is optional, but recommend that you go without! Your female melanographer will be sure to make you comfortable and there is a robe you can use to cover up.
The dermatoscope in action. This tool is used after a mole has been marked by visual inspection, to further screen its shape, colour and size.
In this head to to review, Kathy would look at each of my moles using a Dermatoscope
This handy gadget uses a LED lighting and a magnifying lens to assess the surface features of a mole (more broadly referred to as ‘lesions’).
It allows up to 2.5x magnification and allows for the colour, shape and size to be reviewed in more detail.
Any more that ticks the boxes of being at increased risk (more on that in a moment), would have its location ‘tagged’ on my virtual avatar.
Kathy reviewed me thoroughly, including within my hairline, in a highly professional and considerate way.
Step 3: Enter the MoleCam
For any mole displaying any of the characteristics of skin cancer (basal cell carcinoma, squamous cell carcinoma or melanoma), further imagery was take using specialised device aptly named the “MoleCam”.
The dermatoscope identifies a mole with asymmetry and irregular border on my leg.
To be clear - this is not to say these moles are likely to be cancerous.
Instead, they match known characteristics of skin cancer risk are best remembered by the “ABCDs”:
Asymmetry (irregular shape)
Border (ragged or uneven)
Colour (more than two shades)
Diameter (greater than 6mm)
For each at risk mole, the MoleCam was used to capture two images.
The first, at a set distance and focal length - you can see the ‘slide’ extended from the device.
Second, with a ‘contact’ dermascopic image, where a dab of alcohol is placed on the lens, and the MoleCam is placed directly against the skin.
In the below 3x images, from left to right, we can observe the process.
The first image at extended focal length. The second ‘contact’ image. And finally, the contact image of the mole on my left foot is displayed on the device - you can see that Kathy rightly spotted its irregular shape, border and colour.
Step 4: Teledermatologist Review
In total, I had 26 moles of interest tagged and submitted for further review.
This is above average, and does suggest that my longevity is at elevated risk for skin cancer.
In general the moles were present all over my body, including the back, chest, abdomen, legs, arms and feet.
In some areas, sun exposure did appear to play a role, but in others, my naturally ‘mole-y’ complexion likely drove their prevalence.
Each of the detailed images that were taken by the MoleCam will now head off for a review by a ‘teledermatologist’, which is pretty much a fancy way of saying that a skin cancer expert will review each of the moles.
After this review, there will effectively be a ‘ranking’ of the risk each of the moles represents.
I will then receive customised advice on the MoleMap online patient platform, about 7 days or so after the appointment.
In most cases, the actionable information will be - watch & wait.
This is because the 5th aspect of the ABCDs of skin cancer is actually an E, standing for Evolution, or changes over time.
Cancerous moles, due to unregulated growth driven by DNA damage, generally have an inability to heal and fast cell turnover.
Whereas normal skin/moles will be steady-state, skin cancers will be changing. This is why your first MoleMap visit is so important - you form a baseline by which to assess the Evolution of your unique mole makeup.
This brings us to Step 5!
Step 5: Monitoring for Skin Cancer
The brilliant aspect of this mole mapping longevity technology is the ability to track changes in your moles over time.
New moles, quick changing moles or any areas of the skin which begin to react to excessive sun damage, need to be re-assessed over time.
Your MoleMap appointment will provide you with valuable reference material for self-assessment and tracking at home.
Depending on your individual risk factors (age, sun exposure, existing moles, genetics), MoleMap will provide you with guidance on how often you should re-assess with a follow-up appointment.
By the way - you can check your personal risk with this handy tool on the MoleMap website.
This of course also depends on your budget, and is one reason why you should form a personalised longevity strategy, and include skin cancer screening as a part of your approach to life a long and healthy life.
For me, this will be an annual visit (every 12 months), supplemented by a self-exam every 3 months.
Since I now know where each of my moles on interest are, and have been provided with some handy tools by the MoleMap team.
This includes a thorough information sheet, which I’ve uploaded here (see image).
However, one interesting fact to keep in mind - you can only ‘see’ about 40% of your skin - so be prepared to ask for some help!
Skin Cancer Screening - the Future
Coming up in our next post, Longevity Blog will interview MoleMap’s Chief Customer Officer Vlad Mehakovic.
We’ll dive deeper into how you can use skin cancer screening technology to manage your longevity risk, as well as chat about where this longevity technology will go in the future!
Be sure to subscribe below, so you won’t miss 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.
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.
Boosting NAD by down-regulating CD38 and improving the salvage pathway: Nuchido Time+
Looking to save 10% on Nuchido Time+?
Order here & use the code “LONGEVITYBLOG” for 10% off your first order!
Building an NAD boosting supplement stack with Nuchido Time+
In our previous post, Longevity Blog interviewed Nuchido founder and NAD systems expert Dr. Nichola Conlon, on the topic of NAD systems biology and its relative complexity.
Engaging with the challenges one faces when supplementing with an NAD precursor such as NMN or NR alone.
Aging cells see increased activity in an enzyme called CD38 which consumes NAD at an exorbitant rate, as well as a breakdown in the salvage/recycling pathway for the NAD+/NADH redox reaction.
These issues must be solved in order to restore our cells to their youthful state, and while the science in this arena is at quite an early stage - Dr Conlon and her company Nuchido are leading the pack, and have tackled these issues head-on with their Time+ product.
Nuchido Time+ Supplement Review and Discount Code
Longevity Blog used this second part of our Nuchido interview to explore the ingredients included in their Time+ product. For each, we discuss with Dr Conlon a specific ingredient, and its role in solving aging related degradation in the NAD system.
If you’ve not yet read Part 1 - you may find it helpful to review the NAD systems diagram where we focus on each of the major causes for the age-related decline in NAD.
If you’d like to save 10% on Nuchido Time+ use our supplement discount code “LONGEVITYBLOG”!
Lastly, we also briefly discuss the ongoing Time+ supplement clinical trials, which should provide further evidence of the efficacy of this product later this year.
Longevity Blog (LB):
Nichola, let's start thinking about how to repair that NAD factory (reference part 1 of the interview). This is where I see an innovative approach out of Nuchido, which extends from some of your own research background. Tell us what approach you’re taking at Nuchido to restore the NAD ‘factory’ back to youthful levels.
Dr Nichola Conlon (NC):
As you mentioned at the start, we are focused on taking a ‘whole system’ approach. We didn’t want to just put more raw material in, we actually wanted to increase the cell's ability to make NAD by up-regulating those anabolic enzymes. We wanted to increase the cell's ability to recycle NAD, and also inhibit those processes that are breaking down and wasting NAD. From this angle, we knew we were going to have to go beyond simply providing a precursor ingredient.
Nuchido Time+ Ingredients
LB: And you’ve put together quite a unique mix of ingredients in your Nuchido TIME+ product. Could you walk us through these, one by one, and explain what each is doing in terms of the NAD system we’ve discussed?
Saphora Japonica flowers in bloom. Image credit
NC: First of all, I will start with Sophora Japonica. This is an extract from the flowers of a tree, which contain the really powerful flavonoids quercetin, rutin and troxrutin. These were selected based on evidence that they increase expression of the Nampt enzyme - critical for that recycling pathway.
A second ingredient is green tea extract. Everyone's heard of green tea, and how it is a really healthy beverage with lots of powerful actives. But there is one compound in particular that we're really interested in - epigallocatechin-3-gallate, abbreviated to EGCG. The reason that we're really interested in this compound is its ability to inhibit the methylation enzyme NNMT. By inhibiting the methylation process, we promote the recycling pathway for replenishing NAD.
The next ingredient is alpha lipoic acid (ALA), which works in two ways to boost cellular NAD. The first is activation of AMPK, which I'm pretty sure most of you readers will be familiar with. AMPK is a cellular energy sensor, which has another relatively unknown link to NAD. AMPK increases NAD levels in the cell by activating the Nampt enzyme. This is actually the same pathway that promotes the beneficial effects of exercise and fasting.
The second way that ALA works is that it acts on another pathway that promotes the conversion of NADH to NAD+. As a refresher, NAD+ is the oxidized form, and NADH is its reduced form. They are both part of the redox reaction of NAD. In aging cells, the ratio of NAD+ to NADH tends to drift towards NADH, which is unfavorable in terms of the energy status of the cell.
Lastly, an important thing I always like to point out when I talk about ALA, is be really careful what form of ALA you take if you take ALA supplements. There are two forms of ALA - the natural form R-ALA and the unnatural synthetic form S-ALA. Most ALA supplements use the synthetic version (S-ALA) or a 50:50 mix of the two, but there’s evidence to show that S-ALA doesn't work in the body, unlike the natural R-ALA form. So in Nuchido TIME+ we only use pure R-ALA.
LB: This is a great chance to interject with a common objection to the Nuchido TIME+ product: if I search around for many of these ingredients, and combine them all together, I can ‘re-create’ the product for myself, possibly at a lower price. However, what I am hearing from you, and S-ALA is a great example, is that it takes a lot of careful decision making and expertise to appropriately source these ingredients. Could you respond to those who think: “I’ll have a go at making my own?”
Dr Conlon is an expert on the bioavailability of molecules and supplements
NC: You know, obviously, we hear that conclusion quite a lot. My background is actually in bioavailability of molecules, drugs and supplements in the body. It’s what I did my PhD thesis on, so I was really passionate about making sure that each of the ingredients in Nuchido TIME+ were included at the optimal level so that it is able to be absorbed with good bioavailability and have maximum efficacy in the body. So the amounts and the ratio of the ingredients in our formulation have been very carefully optimised to give maximum benefit which took a lot of scientific consideration and testing to determine.
The other thing to note is that many people read about active ingredients in scientific papers and presume that they can just go and buy the ingredient in its raw form, and start taking it and it will have the same effect. But there are two things to consider here. The first is that many experiments are performed on isolated human cells and translating the dose of an active ingredient from what works on an isolated cell, to what will work when given orally to a whole human is actually very complex. Also you'll notice, with the green tea extract, parsley and sophora japonica in Nuchido TIME+ - that we don’t actually use the active molecules in their purest form, instead we use them in their raw form because this actually improves bioavailability in the body especially when taken orally.
LB: Thanks for sharing that philosophy and how your research background has informed it. The attention to detail on bioavailability is not to be underestimated. Now, let’s specifically address what I usually consider a salad ingredient, not part of my NAD boosting protocol - parsley.
NC: [Laughs], yes that sounds like a crazy one. But parsley contains very high levels of a molecule called apigenin. Apigenin is really important for inhibiting CD38, and has been shown to increase cellular NAD levels by 50%, just by inhibiting that one enzyme. Apigenin by itself doesn't have the best bioavailability, but you can get more of it into the system through its raw form, parsley.
Parsley is a really critical part of the mix, because CD38 breaks down so much NAD, I can't emphasize that enough. So it's in there (Nuchido TIME+) to provide the apigenin to actually inhibit CD38.
LB: I guess I’ll view parsley in a new light, beyond the salad bowl! Are there some other ingredients to address - zinc, vitamin C, nicotinamide and piperine are all in the mix as well?
Learn more about Nicotinamide and NAD precursor NMN in this Longevity Blog Post
NC: Nicotinamide is used as the raw material/precursor for NAD. We know the cell is very efficient at converting nicotinamide into NAD, as long as it's got all the other pathways working efficiently. Unlike stand-alone precursors like NMN or NR, Nuchido TIME+ not only supplies the cells with the raw material they need to make NAD+ but it also has all the other ingredients to make sure the root causes of NAD+ decline are addressed too.
Piperine is known to be very good at helping increase the uptake of nutrients from the small intestine. This means they can better enter the bloodstream and access the rest of the body. So it's included to help with absorption and bioavailability of the other ingredients.
Then we include vitamin C and zinc as further support ingredients. We did this, as we were conscious of the fact that many people like to have a regime that includes vitamin C and zinc for immunity and other benefits. We believe having it all wrapped up in one supplement is more convenient for the customer.
Nuchido Clinical Trials
LB: Thank you for that thorough walk through. I really appreciate the holistic approach that Nuchido is applying to this problem. I know that you've had some early results from a handful of people whom have tested Nuchido TIME+, and that you are working on a broader clinical trial. Could you comment on the observations you’ve gathered from test subjects to date?
NC: We know from our initial pilot studies, that we can expect around a 242% increase in NAD within two weeks of taking the product. This is quite a significant increase compared to some of the reported values for NAD precursors.
The clinical trial that we are running, should have been finished by now. But it's been delayed due to COVID. This is a 28 person, placebo controlled, double blind crossover study with participants aged from 20 to 80, taking the Nuchido TIME+ supplement. Not only are we looking at NAD levels, but also more deeply at the downstream effects of higher NAD.
This includes mitochondrial biogenesis and sirtuin pathway activation. We’ve collected many samples and are starting the analysis, but due to COVID this is not complete.
LB: So you were able to run the trial and collect multiple data points, but have effectively completed the clinical trial component. Now that you're in the analysis phase, can you comment on when you expect to be able to talk about your results?
Clinical trials are often a key step to proving efficacy
NC: Yeah, we're hoping within the next couple of months. The issue is that in the UK, we're again, back into lockdown. There are different policies between the labs we have to use, and when we thaw the samples, we need to be able to analyse them all at the same time. It's very important that when analysis starts we are confident that we can complete it all in one go, without any spot-start that could negatively impact results.
LB: We'd be very happy to share your results with our audience when it is completed. Pivoting, as we close out the interview - you've been very comprehensive in discussing the NAD system and ways to intervene with respect to aging. But I can’t let you go without asking you about your own personal longevity strategy. This is clearly something you're very knowledgeable on and passionate about. For starters, I noticed you're a competitive runner?
NC: Yes! I absolutely love running. I do a lot of running and a lot of running competitions. I really can't emphasize enough the importance of lifestyle choices that you can do for free. I'm really big on having a good diet and exercise routine. For me, that is a non negotiable. I get up every morning, and at 6am I go for a run or I go to the gym, or I do something physical every day, that's my routine. It boosts your energy levels, but is just good for your wellbeing in general.
I obviously take our supplement, and I take other supplements, but don't normally go into much detail about what I personally take - I'm a firm believer that everyone's an individual. You can't just copy what someone else does. You know, first of all, I'm a woman. So it's very different to what a man should be taken or doing.
LB: In personalising your own longevity strategy, what types of data to you collect?
NC: A key thing that I say to people is - get to know your own blood. Get your blood levels different markers analysed on a regular basis. That way you can keep track of any changes in your body early because what is normal for you might not be what is normal for the rest of the population. It is much better to understand your own body and know what's normal for you.
For example, I have mutations in particular genes that mean I don't absorb certain nutrients as well. So I supplement with things like folate, because my folate levels are always really low. I've seen that's really helped. Understanding if there's any parts of your biology that need a little bit of help by getting your blood drawn, or even analysing your genetics or epigenetics, can really help to track what works for you.
LB: One last thing I have to ask you - how would one describe your lovely accent?
NC: [Laughs] It’s called a Geordie accent. I grew up in the north of England, in a place called Newcastle. It is right up at the top near Scotland. We do have a very distinct accent, which also includes lots of words and phrases, which apparently the rest of the world doesn’t use or understand - but I didn’t actually realise this until I grew up and started travelling outside of Newcastle!
LB: That’s lovely, I’d like to learn some of those phrases over a pint sometime :)
We’ll close it there Nichola, thank you so much for your time on the Longevity Blog today.
NC: It’s been a pleasure, I’ve really enjoyed 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.
Do NAD precursors work? It may be the wrong question. Interview with Nuchido founder Dr Nichola Conlon
Looking to score a discount on Nuchido Time+ ?
Save 10% on your first order with the code “LONGEVITYBLOG”
Does Nicotinamide Mononucleotide Work in Humans?
Readers of the blog are well aware, and in rapt attention, as our Founder Nick personally delves into the self-experimentation required to answer this question - Does NMN work? In just under two weeks, he will re-test his biological age after a 6-month NMN led protocol, using the most advanced and detailed epigenetic aging clock available.
The aim - get to the bottom of what many thousands of you are asking - should I be taking a NAD precursor?
As Longevity Blog has continued to review the latest research on NAD boosting strategies for enhanced longevity, a number of important discoveries have emerged, which can broadly be grouped into two categories.
First, the absorption and effectiveness of Nicotinamide Mononucleotide in humans is still hotly contested.
If you cite the research from advocates of Nicotinamide Riboside (NR), you’ll note objections about the lack of clinical research for NMN and how NMN ultimately must first be converted into NR prior to entering into the cell.
Now most of these folks are financially involved in NR’s success (which is a patented molecule), so we must consider the potential role this will play in their personal biases.
Ultimately, we owe it to NMN to allow it to pass through the rigour of clinical trials, of which a growing number are now underway.
The list of NMN clinical trials continues to expand. Review them yourself on clinicaltrials.gov
Secondly, it is clear that the NAD precursor approach to NAD boosting in the cell is actually a bit myopic.
The NAD system, like all things in biology, is much more complex than our favourite supplement company’s marketing bullet points.
The layperson could be forgiven for overlooking this complexity, but we think it is incredibly important to explore it in an approachable form.
Enter NAD systems expert Dr Nichola Conlon
As Longevity Blog explored the complexities of NAD systems biology in greater detail, the expertise, charming accent and straight-forward explanations of Nuchido founder Dr Nichola Conlon emerged as a bright spot in the perhaps oversimplified NAD precursor debate (NMN vs. NR vs. Nicotinamide, etc).
One particularly valuable point of reference was Dr Conlon’s explanation of the ‘multi-targeted approach’ her company has developed (led by her own expert background) to the NAD boosting challenge, presented at Undoing Aging 2019:
To dive deeper into this complexity, including how a more nuanced understanding of NAD biology can help us enhance our approach to boosting it to more youthful levels, Longevity Blog conducted a zoom interview with Nichola in February 2021. Let’s dive into Part 1…
Interview with Dr Nichola Conlon of Nuchido: Part 1 - NAD Systems Biology
Longevity Blog (LB):
Readers of the Longevity Blog are familiar with NAD precursors, however, what may be new information is how taking precursors can be equated with a single targeted approach. You’ve previously spoken about this on many occasions, could you introduce the reader to this concept? What do you mean by a single targeted approach?
Dr Nichola Conlon (NC):
So first of all, biology is extremely complex and complicated. And nothing in biology ever exists alone, or in isolation. Everything that is going on within our bodies and in our cells, is actually very interconnected and intertwined. For example, there are multiple pathways that are running alongside each other performing the same job, and there are multiple pathways that are talking to each other. There are pathways, proteins and genes that are feeding information to each other all the time, and may be also activating or inhibiting each other and other processes.
Another very important concept for your readers to appreciate, is that, in order for scientists to understand and analyse biology, it is normal for them to pick these complex processes, for example, they might do experiments on a particular protein or a particular pathway, and then write a scientific paper on it. Overall, this is fine, because it helps us to understand that small piece of biology. But problems arise when you try to interpret those results in isolation without the wider context - you've got to appreciate that a single protein or pathway in the body is a very small part of a much bigger picture.
LB: What you are describing is precisely what science has done with NAD to date. What is in our mind is the classic chart of our NAD levels declining with with age - the natural conclusion becomes “We need to boost NAD levels”, and that's where much of the early research has focused. But what you’re very clearly pointing out is - it's not that simple.
NC: Yeah, that's it. All of the science says, ‘OK, NAD declines over age’, so the most obvious response is ‘how do we boost NAD?’. So at first sight, it would seem that taking a NAD precursor is a good idea.
These NAD precursors are basically the raw material that the cell needs to make NAD. But the problem is, it's now known that NAD doesn't decline because your cells have a shortage of the raw material to make NAD. Rather, it's actually declining because there are multiple other things going on in the cell causing its decline. For example, the cell is losing its ability to manufacture and recycle NAD.
Image credit: Nuchido
LB: You have kindly provided a really nice graphic (pictured) showing why NAD declines with age, within which this ability to make and recycle NAD is declining over time. Let’s focus on the major components in this graphic. Can we walk through each of those points and have you provide the reader with the basic concepts?
NC: The first point is that old cells use up more NAD. The reason for this is that they have more damage and inflammation, and so they need more repair. NAD is also a substrate for important repair pathways in the cell that are trying to fix this damage. What this means is that the enzymes and repair processes are turned right up, and whilst performing their function they’re consuming huge amounts of NAD.
LB: This consumption of NAD by repair processes is discussed broadly in the anti aging community, including compounds such as resveratrol, and its role in activating sirtuins. Could you elaborate on how aging impacts how these repair processes consume NAD?
NC: DNA repair enzymes use NAD as a substrate to drive their activity, and these activities start to increase as our cells get older - which means aging cells are actually consuming more NAD. In a young cell, this NAD consumption is not actually a problem, as young cells have a very good ability to make their own NAD via recycling. So when NAD is used up in young cells it is broken down into nicotinamide and they have the ability to recycle this straight back into fresh NAD again. This means the cells are simply recycling the same NAD time and time again.
LB: This recycling process, also commonly known as the ‘salvage pathway’, is #2 in the provided image. There are a few key inputs to this pathway, one of those is Nampt - walk us through it.
NC: Correct, this is the salvage pathway. And that's why it's called the salvage pathway - it is salvaging NAD. This pathway relies on an enzyme called Nampt, which is known as a ‘rate limiting enzyme’. This means that it is the bottleneck in the process. When the levels of this enzyme go down, it slows down the recycling of nicotinamide back into NAD.
What's been discovered recently, is that one of the main reasons that NAD is declining in cells as we get older, is because the Nampt enzyme declines with age. This means that older cells are less able to recycle NAD. And this is problematic because, as I have already mentioned, in older cells NAD is getting used up more quickly (#1, as discussed previously), because of increased activity of the damage repair systems. So large amounts of NAD is being used up and broken down in nicotinamide, which has the capacity to be recycled - but its not.
This is because with Nampt enzyme levels declining, the recycling process can’t keep up. So the nicotinamide starts to build up and rather than being recycled back into fresh NAD. So right at a time when our cells need this recycling process to work really well, it's actually declined. This creates a deficit in NAD, and from there, quite an exponential drop in NAD levels.
LB: That’s a great segue into part #3, which relates to methylation. Methylation plays a collaborative role with the recycling pathway of NAD.
NC: The body wants to keep a very tight handle on the levels of anything the cell considers a waste product. In the cell, when NAD is used up and broken down, for example by PARPs, sirtuins, etc the output is nicotinamide. If the recycling pathway is working well, it can be recycled straight back into NAD. But when it doesn’t work well (i.e. in aging), nicotinamide can build up and the cell essentially says “Oh my goodness, and there’s a buildup of nicotinamide in the cell, we need to get rid of it!”
The cell does this by increasing expression of another enzyme called NNMT, which adds a methyl group to nicotinamide, creating methyl nicotinamide. This acts as a signal to tell the cell to excrete it, which helps the cell to get rid of this excess nicotinamide from the NAD breakdown.
So what you find is that in older cells, there is increased expression of the NNMT enzyme because the cell is actively trying to remove excess nicotinamide, because it is no longer being recycled. The consequence of this is that your cells end up using a lot of methyl groups to process it. Methyl groups are also very important in other areas of biology such as epigenetics, so this has a knock on effect and the result is methyl donor depletion, meaning that the cell doesn’t have available methyl groups for those other important processes.
This is a great example of how everything's really interlinked in biology, and you can't look at any of these processes in isolation.
LB: This complexity is one of the reasons why Longevity Blog was so interested to speak with you about the NAD system in more depth. One of the things that you had spoken about previously, was this idea of there being anabolic and catabolic elements of the NAD cycle. As a reminder for the reader, anabolic means building up, and catabolic means breaking down. How do these terms relate to this image that we're looking at now?
NC: The main anabolic enzyme is Nampt, because that is the main way that cells replenish their NAD - by recycling the breakdown product, which is nicotinamide. The main driver on the catabolic side, or breakdown of NAD, which we haven't spoken about yet is CD38. CD38 is another really important part of the puzzle.
LB: Discussion in the longevity community on CD38 is certainly picking up, with more compounds for inhibiting CD38 becoming available. Talk to us about CD38, our readers are quite curious to dive into this topic as well.
CD38 via Wikipedia
NC: CD38 is a membrane protein, which basically acts as an enzyme that uses NAD as a substrate to produce cADPR, which is a secondary messenger for the cell. CD38 expression is found to massively increase with age and the main problem with this is that CD38 uses a lot of NAD. To create just one molecule of its downstream messenger, it has to metabolize around 100 molecules of NAD. This means that even relatively small increases in the levels of CD38, result in a massive decrease in the amount of NAD available to the cell. Inhibiting CD38, can increase cellular NAD levels by 50%, which shows what a huge impact CD38 actually has.
LB: Now we're starting to really understand the difference between the ‘single targeted approach’ of adding more NAD precursor (e.g. NR, NMN) into the cellular system, and a ‘multi targeted approach’ which considers CD38 levels, as well as NNMT, Nampt, etc.
Clearly, we need to think about this in any NAD boosting strategy, as well as managing methylation. How do we engage with each of these components to raise cellular NAD to more youthful levels, as we grow older and the systems we discussed are starting to break down?
NC: Exactly, a multi targeted approach is what Nuchido is all about, because nothing in biology exists in isolation. I think just one thing just to point out, which will probably be interesting for your readers is just looking at it from the point of view of what happens if you are only taking a precursor?
LB: Let’s absolutely discuss this, Nichola, at the moment, Longevity Blog is running a self-experiment with the NAD precursor NMN. This includes a before and after biological age test with UK based Chronomics, and will conclude at the end of February 2021.
Longevity Blog’s self-experiment with NMN is powered by DoNotAge. Use the code ‘longevityblog’ to save 10% on any order.
The supplement stack I am testing is the popular NMN + Resveratrol + Tri-Methyl Glycine combo from David Sinclair's Lifespan book, which many folks around the world are now taking. This is why Longevity Blog is running this experiment - to see if it can impact biological age, as Dr. Sinclair seems to suggest.
NC: We'll use that exact protocol as an example. You are adding NMN into the system, which will be converted in the cell to NAD. This NAD will then be used up in the cell by processes that rely on NAD such as your DNA repair enzymes and also the sirtuins, which you're also activating with the resveratrol that you mentioned. It will also be consumed by CD38 (#1), and all of these processes cause the NAD to be broken down into nicotinamide.
This is where the problem begins, especially in older people, because the levels of the Nampt enzyme which would usually recycle this nicotinamide back into NAD (#2) have declined. So by taking an NAD precursor, you've put NAD into the system, but it only has the opportunity to be used once, when really the cell could keep recycling that precursor back into new NAD again, if it had an efficient salvage pathway, but in older cells, it doesn't.
NAD precursor supplementation can deplete the Methyl donor pool - learn more about this risk in our previous post on NMN safety and risk management.
The outcome of this failure to recycle results in a buildup of nicotinamide in the cell. Now we’re back to the methylation problem (#3) because the cell has all this new nicotinamide hanging around. It can't convert it back into NAD because Nampt isn't working as well as it should be so it needs to get rid of it, so it increases expression of the NNMT enzyme which methylates nicotinamide to help excrete it from the cell. And the resulting problem is a reduction in methyl groups in the cell. Which is exactly why you are taking tri-methyl glycine (TMG) alongside NMN. Because it's known that people taking precursors have a big problem with methyl donor depletion, and TMG contains three methyl groups and a glycine to try to replenish this.
The key point is that you're never addressing the root of the problem and instead by effectively trying to paper over the cracks you are creating other issues. And actually, if you just fixed the recycling problem, then you wouldn't have that issue with methylation because the levels of nicotinamide would never build up so big that they need to be methylated and excreted, it would just get recycled.
LB: Brilliant explanation Nichola. So would you say that with the precursor supplement approach that we're on the right track, but we're missing some components? Or is the precursor led approach fundamentally flawed?
NC: Precursors were the first solution that was available based on the best available information at the time. But the scientific understanding has developed since then. We now know the underlying reasons why NAD declines with age, and we know how we can fix them.
People who are experimenting should always keep re-evaluating what they're doing - asking themselves ‘is this still a sensible approach based on what the science is saying?’
As we age, the NAD factory is losing function
I often ask people who are taking NAD precursors to think of it in this way - imagine that your cells are little NAD factories, and and all of a sudden, the production of NAD in this factory declines. You find that the reason that NAD production has gone down is because the machines have become old and broken and the factory pipes are leaking, wasting material. In this scenario, do you think it would be a good idea to try and boost production in this factory, simply by ordering more raw material to be delivered to the factory gates?
Of course not! If you want to boost production again you are going to have to fix the factory first, otherwise the raw material will just pile up. But this is exactly what the precursor approach to boosting NAD does - it ignores that the cell’s NAD enzymes aren’t working like they used to and that proteins such as CD38 are wasting NAD and just piles more raw material into the cell. But if you want to have any real impact you need to address the root causes.
LB: It's a wonderful illustration. And I'm glad you shared that with us. In doing my background research for this interview, I’d heard you use it before, and I thought it was a very appropriate way to visualise the problem.
Nichola, let's start thinking about how to repair that factory. This is where I see an innovative approach out of Nuchido, which extends from some of your own research background. Tell us what approach you’re taking at Nuchido to restore the NAD ‘factory’ back to youthful levels…
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.
Adding Colon Cancer Screening to Your Longevity Strategy
Early Disease Detection is Essential for Longevity
As regular readers of the Longevity Blog will know - we stand on the precipice of incredible advances in the technologies available for measuring, halting and even reversing the aging process.
As the fusion of AI and computational power with healthcare and biological data marches forward, rapid improvements can be expected over the coming decades.
Therefore, if you’re keen on leveraging these advances, you’d better have a plan to stay healthy in the mean time!
[Timesaver Tip: If you’re not big into reading a blog post - you can skip the details and order your own at-home colon cancer test here! ]
Searches for ‘Colon Cancer Testing’ surged to a 5-year high after Chadwick Boseman’s death in August 2020. Source: Google Trends
Thankfully, modern medicine has become exceptionally proficient at treating life-threatening diseases - so long as they are caught early at the so-called ‘treatable stage’.
However, what is not entirely obvious is who is responsible for managing your access to the technologies ensuring early disease detection.
While, as we’ll discuss below, healthcare systems have begun to take on the role of providing some early screening services, you’d be quite naive to think leaving your health up to them is a bulletproof strategy.
Quite the opposite is true, in fact - ensuring your longevity requires a radical level of personal accountability and a proactive attitude.
This is to say, that longevity strategy is yours to lead, and while it should absolutely include your doctor and the broader healthcare system, it should not entirely depend upon them.
You need to know your risk factors, educate yourself on the many resources available and stay on top of the emerging technologies available for your personal risk management.
Thankfully, Longevity Blog is here to help. In this post, we carve out a segment of that risk management strategy - focusing in on colorectal cancer - and will present some newly available resources at your disposal.
Early Detection of Colon Cancer is a Lifesaver
Hear more about Aaron’s journey of colon cancer survivorship on the Pelatonia podcast “One Goal”. Pelatonia is an organisation who have raised over $218M for cancer research through the sport of cycling. Pictured: Aaron Conley
Colorectal cancer is both one of the most common and most deadly (in terms of total lives lost) forms of cancer in the developed world.
It also strikes a personal chord with the Longevity Blog.
While our Founder Nick’s wife was awaiting her surgery for the treatment of appendiceal cancer in late 2013, one his closest friends (Aaron, see image) was besieged by this disease at the young age of only 27 years old.
The shock of these diagnoses evoked strong motivations for exploring the ways we might contribute to the end of late stage disease diagnosis, once and for all.
And while that is a big dream, the ambition of reducing human suffering through the early detection of disease is very much at the core of the Longevity Blog mission.
We believe we already have most of the technologies required to ensure the long-term health of everyone who chooses to dedicate their resources to a comprehensive longevity strategy.
Colorectal cancer screening is one such resource. Let’s explore this topic - starting with, what is ‘screening’ exactly?
Cancer Screening - A Key Component of Your Longevity Strategy
The highly detailed, full body MRI available at the Health Nucleus is a key pillar of the ‘screening’ component of my personal longevity strategy - this is a very high tech form of cancer screening & where the Longevity Blog got started!
The concept of cancer screening is quite topical for the Longevity Blog. It forms one of the pillars of our shared longevity strategy - detect disease early, while it remains treatable.
Longevity Blog believes this can be accomplished through the *right* combination of medical technologies.
This of course includes detailed, full body MRI imaging as central to this objective.
However, full body MRI imaging has limitations with respect to its sensitivity to certain disease types - chiefly with respect to gastrointestinal cancers, and specifically esophageal and colorectal cancers.
Therefore, in order to comprehensively screen, one must turn to alternative strategies to minimise risk with respect to the diseases not sampled. Thankfully, colorectal cancer has several screening technologies at our disposal…
Colon Cancer Screening
Outside of advanced facilities like the Health Nucleus, cancer screening is most often disease specific. Australia’s most common cancer - breast cancer - can be screened via mammogram, for example.
And thankfully, the same is true for the 2nd most common cancer in Australia (and 4th most common in the United States) - colorectal cancer.
Colorectal cancer is the result of uncontrolled growth of abnormal colon or rectal cells, which grow to form a tumour.
However, most such cancers do not immediately begin in the tumour phase, originating instead as small abnormal tissue growths (called lesions) and/or polyps.
Source: Harvard Health
The process of forming a lesion and/or polyp, followed by possible malignancy, is often associated with the release of small amounts of blood into the stool, as well as low levels of tumour DNA material in more advanced cases/recurrence.
It is from this blood and/or DNA, that currently available cancer screening technologies can detect this potentially malignant activity. Let’s dive into how that works.
Colon Cancer Screening Technologies
Direct visual inspection of the colorectal (nether?) regions (e.g. colonoscopy) with biopsy (direct tissue sample) remains the gold standard for colon cancer screening.
However, over the past few years, test kits which can be completed at home have become widely available, as well as generally accepted by the broader medical community (For more, read this JAMA article).
These kits are so popular and effective, that governments in many countries have rolled out widespread test by mail kits.
Such a move has created strong market forces for driving the supply of these kits up, and the associated cost per unit downward - to the point where purchasing such kits out of pocket has become possible (we’ll come back to this point shortly!).
In the ‘test at home’ market offering, there are three primary technologies in use today. Two are tests which detect blood in the stool (known as a faecal occult blood tests [FOBT]), and the third tests for tumour DNA directly.
Review of Three ‘Test at Home’ Technologies
The current standard of care uses FOBT tests as ‘first-line screening’. These can be either the ‘guiac-based form (gFOBT)’’ or the ‘immunochemical form (FIT).”
gFOBT tests look for haemoglobin (an important oxygen carrying protein in the blood) in the stool, however it has been shown to be sensitive to diet and medications (e.g. red meat or high vitamin C intake). The requisite chemical reaction can however occur locally, meaning the test kits don’t have to be shipped back to a laboratory for the results. For example, one of these kits might involve dropping a tablet into your toilet and seeing if it turns a signalling colour.
FIT methods use an antibody reaction instead, which removes any complications from the diet (or medications), identifying human haemoglobin directly. These kits must be sent back to the lab for processing. FIT tests have become the ‘go to’ testing method for widespread use.
A third, emerging testing option is the ability to detect tumour DNA directly, with a high degree of accuracy (92%). These kits have not yet become directly available to consumer, and I won’t mention them again here.
For further reading, you can find a detailed list of pros/cons of the above three methods here
Who Should Get Tested for Colon Cancer?
The age at which the general population is recommended a colorectal cancer screening varies by who you ask. However, one trend is clear - the recommended screening age keeps getting younger.
For example, longstanding recommendations from the American College of Gastroenterology state “Men and women at average risk for colorectal cancer should be screened starting at age 50”, but go onto several caveats (45 for heavy smokers or African Americans), and even ≤ 40 years anyone with:
A first-degree relative who has had colorectal polyps or cancer
Crohn’s disease or ulcerative colitis
Lynch syndrome or familial adenomatous polyposis (FAP)
More recently, the general testing age was also dropped to 45 by two influential bodies in the US. The American Cancer Society changed its recommended screening guidelines in 2018, from 50 to 45 years citing “rising rates of bowel cancer in young and middle-aged populations.” Furthermore, the US Preventive Services Task Force also changed the age of screening to 45 quite recently (October 2020).
Should You Get Tested for Colon Cancer?
Depending on your age bracket, you may already qualify for free or subsidised colorectal cancer screenings. If this is the case - the answer is obvious, you should definitely test according to the recommended guidelines.
But what about folks under the standard age in their region of care? Should they get a test? Well, there a few factors to consider when answering this question - let’s address them.
#1 Colon Cancer Screening Tests are Inexpensive and Easily Available
With a bit of digging around online, you will likely be able to find commercially available test kits in your country. The price point on these kits is pretty outstanding, costing the user only a few bucks a month to test every year or so. Let’s take a look at four options, all available for under $70 (3x United States, 1x Australia):
Our Top Choice: LetsGetChecked
Let’s Get Checked at Home ($69 USD)
Technology: FIT
Second Generation FIT ($25)
Technology: FIT
[Alternative Link] (CVS)
EZ Detect ($12)
Technology: gFOBT
[Alternative Link] (Walgreens)
ColoVantage ($42AUD)
Technology: FIT
#2 The recommended screening age is falling
As was briefly discussed before, the recommended screening age has been on a downward trend over the past decade.
This is because colorectal cancer occurrence in young adults is on the rise, as a part of a global trend in developed countries (read more).
Consider this startling statistic: People born in 1990 onwards have double the risk of colon cancer and quadruple the risk of rectal cancer compared with people born in 1950 (source).
Concerningly, when the disease is detected in young adults, it is often at a late stage. You need only scroll back up to the top of this blog post to read about 27 year old cycling enthusiast Aaron for an example.
In his case, a fairly late (stage III) diagnosis, following him experiencing extreme fatigue on his regular rides. Chadwick Boseman was only 43 years old when he passed away, after battling colon cancer for four years (age of stage III diagnosis ~38-39 yrs).
While its not yet settled why later diagnosis is common among young adults, it is surmised they are more likely to write off early warning signs, and are also less likely to have health insurance.
None of these details are particularly important to the point being made here - individual young adults are still at risk for developing colon cancer, even if the average risk of this population is low.
Source: Bowel Cancer Australia
#3 Colon cancer screening tests are accurate and highly effective
Test at home colon cancer screening technology is highly developed, and so effective, that is has become the standard of care for early screening.
So useful in fact, the biggest challenge healthcare systems have with colon cancer screening is increasing compliance (link). Imagine that - a healthcare service where increased demand is viewed positively!
Why? Because the tests are cheap, save lives and reduce downstream costs. That’s a rare win-win for healthcare!
#4 False positive downsides are small
Positive FIT tests are about 80% accurate for detecting cancer, and positive findings only occur in about 5-8% of people.
If your test comes back positive, your doctor will likely recommend you for a colonoscopy. Colonoscopies (as Aaron addresses in the podcast) are not as unpleasant as they might first sound.
Aside from the inconvenience of missing work, and the potential costs (check your insurance policy carefully), there is very little downside ‘false positive’ test result.
Furthermore, if there is blood in your stool, but no cancer or pre-cancerous legions/polyps, there may be other health related issues revealed in the process (e.g. hemorrhoids).
One could perhaps think of these tests more broadly as a ‘blood in the stool’ test, in that regard.
Colon Cancer Screening Conclusions
The Longevity Blog can’t make any healthcare recommendations to you, full stop. However, following the logic of the previous four points brings me to a fairly obvious, personal conclusion:
Colon cancer screening tests are accurate, effective, commercially available without a prescription at low cost, with very little downside to a false positive result (miss work, potential out of pocket costs, anxiety for some). Risk rates for adults below the screening age are not negligible. There are very high costs to late stage diagnoses.
Follow us on Twitter for more Longevity & Biohacking info
-
RT @nickengerer: Join a team, do a sport. Staying fit is easier with a clear purpose Bonus: you just might live longer Pic: Byro… https://t.co/L5yHxHJXas -
Calcium AKG Alpha Keto Glutarate Supplement Review https://t.co/K7keDM3Lyn
-
Mitopure Review - Does this Urolithin A supplement actually work? https://t.co/0Y6Bx4yA7h
-
How Fast are You Aging? A Biological Age Test for Rate of Ageing with Ryan Smith of Trudiagnostic (Part 2) https://t.co/5SZW3Or6JJ
-
What is the Most Accurate Biological Age Test? An Interview with Ryan Smith of Trudiagnostic (Part 1) https://t.co/wdIxtTVeq0
-
One Skin Review - Self-Experiment Before and After Results with OS-01 https://t.co/3hqzLtfVa3
-
Regrowing Knee Cartilage and Restoring Joint Health Naturally. An Interview with Reviiv Light CEO Forrest Smith - P… https://t.co/O671LROvzw
-
RT @nickengerer: 90 years old, what to do? A half Ironman, why not? Hiromu Inada now holds the record for the oldest ever competi… https://t.co/wv7NPhslUM
-
One Skin Before and After - Skin Aging in the Future: An interview with OneSkin CEO Dr Carolina Reis - Part 2 https://t.co/RlLlqRurT6
-
RT @Do_Not_Age: Our new ingredient, Spermidine, reduces amyloid plaques and inflammation of the brain in rodents Check our Science… https://t.co/RgehOqmVtf
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Biological Age Estimates through Epigenetics: An interview with Chronomics CSO
Measuring your Biological Age
Measuring your biological age is quickly working its way into the mainstream.
Just 12 months ago, we compiled our first comprehensive list of all of the companies offering a biological age test, and since that time the list of offerings has more than quadrupled in size. (Did you see our post on 3 free ways to test your biological age?)
Longevity Blog believes the strong growth in offerings to be driven by our collective curiosity and drive for personal optimisation. But there are two key questions to be answered: 1) How should I use these test kits? and 2) Which test kit should I use?
Let’s answer those!
How To Use Biological Age Test Kits
Biological age is a very unique and comprehensive way to check in and see “how am I doing with my health?”, or for those of us seeking to extend our healthspan - checking in with “how old am I biologically?” or “how fast am I aging?”.
The prospect of measuring our biology in this way, let alone halting or even reversing that number, is tantalising.
Use biological age testing kits, like GlycanAge, to make a change to your lifestyle and see if it improves your biological age!
The thinking goes - If I can track my biological age over time, perhaps I can use the result to run self-experiments and to determine what things I can do to improve this number.
This could be through lifestyle changes (like a change in diet), longevity supplements (like NMN), or a variety of other interventions - each of which (with a bit of careful, but relaxed experimental design) can show each of us what works best for our individual biology.
This ‘test yourself and see what works’ messaging is certainly what those now offering biological age test kits want you to believe.
But is this just clever marketing, or does it actually work?
Our Founder Nick set out to investigate, and has now shown this can indeed be done - twice! Once with a longevity supplement protocol with NMN and also with a changing his diet to include more diversity of plants.
If you’d like to see an example of how to set-up a self-experiment and use a biological age test kit in a useful way, check-out either of those examples.
Choosing the Best Biological Age Test
Over to the second important question: “Which test kit should I use?” or “What is the best biological age test kit available?” (for your own self-experiment!).
It is not easy to draw a simple conclusion, as this question is multi-faceted. The answer to which kit is best? depends on what intervention you’d like to try. If your keen to change your exercise regimen, tweak your diet or improve your sleep over the course of a few months - you might want to choose the GlycanAge test kit.
Learn more about why in our interview with world glycan expert Gordan Lauc here. (Hint: it has to do with how quickly the biological age score can be changed)
But if you’re looking for the ‘best answer’, meaning the ‘most accurate’ result, and don’t plan to test before and after an intervention - which test kit you should use could be different.
Let’s discuss what this means in a bit more detail.
To answer ‘what is the best biological age test kit available?’ question, we will turn to an expert on these matters - using the framework provided to us by Deep Longevity CLO and Insilico Medicine CEO Alex Zhavoronokov.
Alex’s message: look to the test kit’s accuracy and representativeness.
So as our first checkpoint - any biological age estimation service should provide information on the accuracy of the model they have developed, including the size and representativeness of the population (data) it was trained and tested on.
Think of accuracy as: how often is the result correct when it tries to predict someone’s age based off their blood or saliva sample?
Think of representativeness through this lens: human biology is complicated and diverse, so does the dataset the biological age clock was constructed with represent me? (e.g. ethnicity, age, gender, etc).
THe BEST BIOLOGICAL AGE TEST KIT is Chronomics
We recently introduced UK based Chronomics, a company specialising in measuring, quantifying and interpreting the human epigenome.
As covered in our most recent post (Advances in DNA methylation based biological age clocks), using the epigenome has recently emerged as the most robust way to estimate biological age.
This is to say, it is the most comprehensive and accurate way to estimate biological age currently available at the time of writing.
While this could change with the emergence of new technologies and/or methods, we believe this will continue to be the case well into the future.
It will likely then come as no surprise to the reader that we have selected Chronomics as the ‘best’ option for estimating your biological age.
Chiefly, we can chalk this up to the fact that Chronomics has had about a five year head start on nearly all of their competition.
But more specifically, let’s look at the numbers - simply put, as of early 2021, they have the most accurate biological age clock (mean error less than 2 years), with the most diverse and representative sample set of user (10,000+).
Want to dive deeper? Keep reading to see our interview with Chief Scientific Officer Dani Martín-Herranz diving into the details of what this means, and how Chronomics created such an amazing biological test kit.
We ALSO RECommend
Longevity Blog recommends “GlycanAge”, which provides a detailed picture of the inflammation status of your body. Check out their kits here - and use the code “LONGEVITYBLOG” to save 15%.
You can also read about how our Founder Nick improved his GlycanAge by 6 years by eating more plants!
Longevity Blog also recommends trying out this updated kit from DoNotAge. We’ll be covering the technology powering this option soon.
Use “LONGEVITYBLOG” to save 10% on your order.
Chronomics Interview with DANI (CSO)
Despite Dani’s ‘hard look’ in this mug shot - he is an exceptionally friendly and approachable bloke ;-)
Longevity Blog (LB): Dani, thanks for speaking with Longevity Blog. Let’s start with my own curiosity - what happened to the generously sized vial of saliva our Founder Nick shipped across the world from Byron Bay to the UK? How does Chronomics turn his spit into valuable longevity data?
Dani Martín Herranz (DH): [Laughs], firstly, thanks for having me. We used Nick’s saliva to extract his DNA from the cells contained within it. We use a number of preparation steps to isolate your DNA, and then undertake a ‘library preparation’ step in order to make the DNA readable for our sequencing machines.
LB: This sounds like we’re now ready for the specialised ‘bisulfite sequencing’ method you employ in order to read the epigenome, is that correct?
DH: Yes! Once we have the DNA isolated, Chronomics can then prepare the methylated portion of the genome (a key part of the epigenome) to be analysed. To do this, we treat the sample with sodium bisulfite; which allows us to clearly identify the methylated points of the genome
It’s more saliva than it looks like! #generousvial
How Does Epigenetic Data Produce A Biological Age?
LB: So these must be the ‘cytosine’ letters of our DNA, which are the ‘CpG’ sites we often hear about from the scientists studying longevity and epigenetic aging. How many of these are there?
DH: That’s correct. There are over 28M CpG sites in the human genome. With the bisulfite sequencing approach, Chronomics can see if a CpG site is either methylated or not in a specific DNA strand.
LB: 28M CpG sites in a genome of 3 billion base pairs - how many of these sites contain valuable information for interpreting our biological age?
DH: Our technology looks at 5.6M cytosines at high depth, meaning we are reading and then re-reading each point up to 30 times.
LB: That’s impressive! Let’s move this conversation along to the main topic - How is DNA methylation used to predict biological age? Outline the process at a high level for us
DH: Since the work of Steve Horvath and others in 2013, we’ve known there are specific positions in the DNA (known as CpG sites, places where normally DNA methylation occurs in mammalian genomes) where DNA methylation levels change very consistently with age.
For example, there are CpG sites where we accumulate more DNA methylation in our cells and tissues, and there are CpG sites where we lose DNA methylation with age. These changes can be relatively big, in some places, and in others, smaller. These changes can be leveraged to train machine learning models that can measure biological age.
While biological age is generally conserved across cells and tissues, it was recently found that the heart is consistently ‘younger’ than other tissues - watch this space! (click on image for link to open access article)
Does a Saliva Sample Represent the Biological Age of the Rest of the Body?
LB: You’ve just mentioned how these changes in DNA occur across ‘cells and tissues’. Many members of the Longevity Blog readership have asked - why that methylation changes in DNA in the saliva are representative of those occurring in a kidney or liver cell, for example?
DH: Most of the work on biological age and DNA methylation has actually been done in blood. If you look across the many epigenetic clocks and studies that have been developed, blood used to be considered the ‘gold standard’.
Epigenetic changes in blood have also been associated with a lot of clinical endpoints - many different diseases, effects of lifestyle, environmental factors, etc. However, blood is not such a pleasant tissue from a consumer point of view - many people don't want to complete a fingerprick or blood draw.
Chronomics wants to make the journey of accessing actionable biological insights as user friendly as possible. This also means considering logistics and sampling. From the very beginning, we pushed to have saliva as one of the tissues that we can process as part of our workflows for biological age.
What’s interesting about saliva, is that it is actually not that dissimilar from blood. Saliva, like blood, is made up mainly of immune cells that infiltrate from the immune system.
We’ve also come to understand from research of Steve Horvath and others, that many age-related changes in the epigenome are conserved across tissues. Meaning, what we observe in the saliva, may be representative of other tissues throughout the body.
We don’t yet know why this is the case, but this fact is tremendously useful for representing to a certain extent your whole body from a single tube of saliva.
How Accurate is Chronomics’ Biological Age Test Kit?
LB: In your company technology white paper, you report that the Chronomics epigenetic clock has a median absolute error (MAE) of 1.97 years.
This is quite impressive, and outperforms other widely-used epigenetic clocks (e.g. Horvath’s multi-tissue clock MAE=3.6 years) and even more recent models such as the Deep Longevity clock Longevity Blog covered in our previous post.
We have several questions on this topic - first, explain to us what you've done to establish that accuracy? For example, give us some details on the training and test group look like? What's the test group that you've done in terms of the volume and representativeness of the population?
DH: We have integrated many public datasets and combined that with data from our own users. Our main focus is on tissue samples which are relatively non invasive - blood and saliva. And we are also taking into account different technologies.
With epigenetics, we're not yet in the order of millions of samples, but we are on the order of 10,000. I think it is also important to keep in mind one thing that people normally miss - when it comes to biological age, you can overfit the models.
For example, if you work with many many samples, and if you become obsessed with reducing only the error that is associated with the prediction of chronological age.
Learn more about advances in DNA methylation based biological age clocks in this collaborative post with Deep Longevity.
There are papers that show that if you start to perfectly capture chronological age prediction, and you reduce that error a lot, you also lose the ‘biological age’ component of the prediction, which is the one associated with clinical outcomes.
So it's a bit of a complex problem where there are many definitions of biological age, but there is not yet a ‘goldstandard’ for which we're optimizing for (as seen by the different types of epigenetic clocks available).
Probably the most useful and actionable proxies are those that are mapped to specific age-related medical outcomes.
Why is Chronomics The Most Accurate Biological Age Test Kit?
LB: Following up, while respecting the complexity of the problem, why are you able to produce such an accurate biological age estimate?
DH: At Chronomics, we are also taking into account different technologies to build our models. So not only methylation arrays, which is what a lot of people out there have used, but also next generation sequencing data, which is what we mainly work with for our internal processes.
When you combine all of that, and a variety of different machine learning approaches, that is how we managed to get the median absolute error down to < 2 years, and that is an evolving number over time.
Part of that error will reflect true biological age variation in the population and part of it technical variation due to limitations in the technology.
LB: Could you elaborate further on how the biological age model works? You mentioned machine learning before.
DH: One challenge we have had to solve is that we have millions of epigenetic features (CpG sites) from a given sample with our sequencing platform. These are the measurements of the DNA methylation status across the genome.
If we use a methylation array, we’ll have hundreds of 1000s of data points. In other words, you have a problem of high dimensional data.
Essentially, we are trying to find the best features of the best places in the genome to predict biological age (or other biomarkers). This problem lends itself well to elastic net regression, for example,and there are now many groups trying different types of deep neural networks.
So what we've done is benchmark different approaches internally and completed a robust feature selection process using many different types of machine learning algorithms. From there, we have come up with our own machine learning pipeline to make the biological age estimate.
Does the Chronomics Test Kit Represent Me?
LB: Thanks Dani, let’s pivot away from accuracy and over to relevance.
In a previous Longevity Blog interview with Alex Zhavaronkov of Deep Longevity, he pointed out how we must question both the accuracy and the relevance of a given biological age model.
Which genetic backgrounds is the Chronomics biological age model relevant to?
DH: This is a huge issue across all the ‘omics’ and health data in general. Overall, the healthcare ecosystem has very biased data sets towards Caucasian populations in general, and epigenetics is unfortunately not an exception to that.
This is unacceptable and we need to do better if we don’t want health inequality to become even bigger.
At Chronomics we are very much aware of this issue, and proactively try to solve that problem. In the case of epigenetics, different genetic backgrounds can lead to slightly different predictions for epigenetic biomarkers.
When we build our biomarkers, we try to correct for this as much as we can, so we can maximize the chances that the biomarkers work across different populations.
One thing that benefits us with respect to this problem is that Chronomics is a global company. We collect data across many countries and genetic backgrounds, testing our predictions, across these different backgrounds.
But obviously, I'm sure we can do better at this, and we will keep improving.
LB: So in summary, would you agree it's fair to say there's a bias towards Caucasian populations, but that does not mean people from other ethnic backgrounds can’t trust the result. Is that fair to say?
DH: There is a bias towards Caucasian populations at the level of the dataset, but in terms of the epigenetic biomarkers that we have built, we've ensured that they work across populations so everyone can access them.
How Do You Use Biological Age TESTs to Improve Health?
LB: That’s a nice clear answer, thanks. Let’s move on to the ‘actionable’ insights a biological age estimate from Chronomics may inform.
Naturally, the reader who is considering accessing a Chronomics test kit wants to know, if I take this biological age test, what actionable information will I receive? What is a biological age estimate to teach me about myself?
DH: Many people read Longevity Blog, because they are interested in reducing the speed at which they are aging. The challenge is that aging is quite a complex phenotype to measure at the molecular level and without accurate biomarkers of aging there is no way to know if specific interventions are working or not to reduce aging rate.
A biological age result provides people with the tools to essentially to decide if the aggregate of all of what they’re doing seems to be working.
While we have long been good at quantifying a very specific aspect of health, for example - do I have high cholesterol or not - which is obviously a good proxy for cardiovascular disease, these measures may be missing other aspects of our health.
Biological age is a very good holistic measurement of your overall health status, and represents how well in general, you're doing with the aging process.
It represents how your entire lifestyle is interacting with your genetics to control your aging rate.
Biological age is also very valuable to track over time, and see whether the different interventions that you're trying are working or not.
This is why it is ‘actionable’, because we observe that depending on what people do, that value will change - better lifestyles lead to better biological ages.
There is no point in giving people access to biological data that they can not improve through positive behavioural change.
LB: This actually brings us to a repeat question that many Longevity Blog readers have. We've received emails upon emails about this - simply put, folks are scared to know their biological age. Mainly because they're afraid that they will receive a result 5-10 years older than their chronological age.
What do you say to people who are afraid of getting that number?
DH: I would say that, in order to have positive impact upon our health, we need to be courageous in that way. Everyone of us is scared to receive medical results we don’t like. It is much easier to just wait until something really bad happens.
But I think that anyone who is going through a difficult chronic disease wishes they would have detected and acted earlier. We need to become much more proactive towards our health and measure pre-disease states.
For some insights on genome sequencing and how genetic risk markers can be usefully applied, check out the Longevity Blog interview with the Health Nucleus’ Medical Director Keegan Duchicela
It is important to make a very strong distinction here between receiving certain types of genetic insights versus epigenetic insights.
Someone telling you that you have a specific genetic variant that is not ‘actionable’ (something that you cannot change or influence the outcome through lifestyle changes) and that gives you an increased risk to a specific disease is probably not very useful (and for some people may be even depressing).
The epigenetic biomarkers that we build, on the other hand, capture actionable aspects of our health.
What that means is that with epigenetic insights, you can always do something around it. It is a tool for positive behavioral changes.
It can be used to guide you through that journey of improvement, a different type of mindset where you can actually change those results.
“In order to have positive impact upon our health, we need to be courageous in that way. Everyone of us is scared to receive medical results we don’t like. It is much easier to just wait until something really bad happens”
LB: Dani, given what you’ve just discussed, is the directional nature of one’s biological age (going up or down) more important than the absolute value?
In other words, if we receive our first biological age result, it is actually the second one, following some intervention, which provides us the actionable information? (i.e. those lifestyle changes or given longevity protocol made a positive change, so keep it up)
I’m currently measuring my biological age every ~6-9 months, in between intervention protocols to see what ‘works’ for my biology.
DH: You are absolutely right when you say that we should not become so obsessed with the absolute value of our biological age.
It is more important to look at the directionality, how your biological age is changing over time and how your aging rate changes as a function of your lifestyle.
When you take your first biological age test you are de facto comparing yourself against a population of individuals.
When you take your second epigenetic test, we can start to compare you against yourself and build your digital twin (or N=1 experiment). And, as you probably would imagine, you are your best control.
How Often Should You Test Biological Age?
LB: How often should we measure biological age, Dani? Because if we're looking at a signal over time, is it something we should measure every six months, every 12 months? What does your experience suggest?
DH: We normally recommend people to measure every 6 to 12 months. Before that, it's difficult to see statistically significant changes.
This is mostly because the aging process is relatively slow and most anti-ageing interventions are not that powerful yet.
However, how quickly biological age can change varies a lot from person to person. There is a lot of variation between people and the types of interventions that they are making.
Also, someone with a very good biological age result (younger) will probably have a more difficult time further reducing their result.
LB: Did you just suggest that it is easier to change an accelerated age, as in someone who is biologically older than their chronological age, than it is to get biologically younger when your biological age is low?
DH: It's always dangerous to generalize in biology, but there is a trend. Think of it as this - the repertoire of basic things that someone can do to improve is broader for someone with a poor biological age result.
If someone is having a horrible diet, a horrible exercise routine - those people will likely have higher biological ages, and therefore they will have more opportunity to improve that biological age than someone that is already doing those things.
LB: Dani, as we close out this interview, help us understand your vision for the future of quantifying biological age. Where is this going to take us in the next five to 10 years?
For example, Alex Zhavoronokov of Deep Longevity spoke to the Longevity Blog about “Longevity as a Service”. What’s your take?
DH: I agree with Alex in those regards. Maybe at Chronomics, we wouldn't exclusively frame it as “Longevity as a service”, but more as “Biomarkers as a service” or “Actionable biological insights as a Service”.
We provide access to complex and actionable biological data that was previously hidden in the lab. Our goal is to bring it out and make it very easy to sample and access - making the entire journey of accessing that information as seamless as ordering a book online.
Bringing the tech and digital revolution also to biological data. And this needs to happen if we truly want to move to a preventative healthcare paradigm.
Epigenetic information plays a very key part in that mission and it is also very close to our hearts. But the name of the company, as you can see, is not “epi-something”.
It's ‘Chron-omics’, which means ‘large biological data over time’.
We're on a mission to offer people across the healthcare ecosystem, all sorts of actionable biological data. So not only epigenetics, but also for example, metabolites from blood or even COVID-19 testing.
That's really what we are passionate about - to make the unseen, actionable, and make it easier for everyone to access those insights and democratize them.
January 2022 Update: We’ve worked with Chronomics to make their biological age testing kits available to the public again! Price check these kits & place your order at the below link:
INterested in Other Biological Age Test Options?
Follow me on Twitter for more Longevity & Biohacking info
-
RT @nickengerer: Join a team, do a sport. Staying fit is easier with a clear purpose Bonus: you just might live longer Pic: Byro… https://t.co/L5yHxHJXas
-
Calcium AKG Alpha Keto Glutarate Supplement Review https://t.co/K7keDM3Lyn
-
Mitopure Review - Does this Urolithin A supplement actually work? https://t.co/0Y6Bx4yA7h
-
How Fast are You Aging? A Biological Age Test for Rate of Ageing with Ryan Smith of Trudiagnostic (Part 2) https://t.co/5SZW3Or6JJ
-
What is the Most Accurate Biological Age Test? An Interview with Ryan Smith of Trudiagnostic (Part 1) https://t.co/wdIxtTVeq0
-
One Skin Review - Self-Experiment Before and After Results with OS-01 https://t.co/3hqzLtfVa3
-
Regrowing Knee Cartilage and Restoring Joint Health Naturally. An Interview with Reviiv Light CEO Forrest Smith - P… https://t.co/O671LROvzw
-
RT @nickengerer: 90 years old, what to do? A half Ironman, why not? Hiromu Inada now holds the record for the oldest ever competi… https://t.co/wv7NPhslUM
-
One Skin Before and After - Skin Aging in the Future: An interview with OneSkin CEO Dr Carolina Reis - Part 2 https://t.co/RlLlqRurT6
-
RT @Do_Not_Age: Our new ingredient, Spermidine, reduces amyloid plaques and inflammation of the brain in rodents Check our Science… https://t.co/RgehOqmVtf
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Advances in DNA methylation based biological age estimates
Biological Age Testing Technology
DNA methylation (DNAm) based Biological Age (BA) tests are unique, in that they supercede the more superficial BA tests which rely on blood data, white blood cell telomere length or surveys, by going deep into the aging signals expressed within your DNA.
Increased methylation (hypermethylation) or decreased methylation (hypomethylation) of the DNA in specific regions can now be tied directly to the aging process, thanks to the growing body of ‘Epigenome Wide Association Studies’.
Of the 28 million sites in your genome where methylation is known to occur, a ‘signal’ representing how old you are at the DNA level is present.
The Latest Biological Age Testing Technology
Recently, there have been significant advances in the technologies available for reading this signal, and interpreting the methylated state of these 28 million locations (called ‘CpG islands’, as they occur in linkages between your DNA at C-G pairs).
Longevity Blog has previously covered this concept in an introductory post on UK based Chronomics & will be hosting a follow-up interview with their CTO in short-order.
While Chronomics has certainly led the way from the outset, a wide array of other promising developments are occurring across this nascent industry.
This week, Deep Longevity released results utilising machine learning to interpret DNAm data to make BA estimates.
The outcome is their “DeepMAge” clock, which samples 1000 unique CpG sites fed through a neural network to estimate the biological age of an individual.
Published in the journal “Aging and Disease”, Deep Longevity (and parent company Insilico Medicine) report “the lowest error margin among other DNAm clocks published to date” with a Mean Absolute Error of 2.77 years. You can read more about this announcement here.
Side note: While not published in a peer-reviewed journal, the Chronomics kits I am using, offer accuracy of 2 years, so this result from Deep Longevity reflects that the capabilities in this field are rapidly maturing, and that is exciting.
What does this accuracy number mean for the consumer? - read on…
Biological Age - Accuracy and Relevance
To understand the importance of aging clock error rates, we can look back to Longevity Blog’s interview with Deep Longevity’s Alex Zhavoronokov, where Alex highlighted two key properties one needs to assess in order to interpret the BA estimate - accuracy and relevance.
In essence, if a BA estimated has an accuracy of 2 years, this would mean that a BA result of 40 years old, would be accurate to within + or - 2 year (38 - 42 years old).
This, as we’ll explore in upcoming posts, is important, in interpreting the impact of the intervention we are testing.
As an illustration, to say with confidence that in intervention has 'reversed’ BA in someone whose baseline BA estimate was 40 years old, it would have to lower the BA by more than 2 years (<38 years old).
Equally, a result of 42 years old would not mean that the individual became meaningfully biologically older.
As far as the relevance of the Deep Longevity DNAm based model, it surveyed 4,930 blood DNA methylation profiles from 17 studies, and from what we can tell, comprised a diverse ethnic background. This makes the model ‘relevant’ for a wide audience.
All of this of course begs the question - when will the longevity community be able to access this technology?
The Future of DNA Methylation based Biological Age Testing with DEEP LONGEVITY
Given these exciting results, and our shared curiosity, we reached out to Deep Longevity’s Fedor Galkin, lead author on this study, with a few questions about the future of DNAm BA tests at Deep Longevity
Q: Will Deep Longevity be offering a DNA methylation test kit in the future?
A: Yes. There are still some other more pressing models to be integrated in Young.AI. But once we are done with them, we are going to make DeepMAge available for institutions and individuals. Global logistics are always an issue, so we are planning to start with US. We will also release API access to DeepMAge, which will let people use it on their data .
Commentary: The development of an API for DeepMAge is in-line with previous efforts by Deep Longevity parent company Insilico, and fits well with the company strategy of making their suite of BA testing services widely available. The possible entry of this Deep Longevity BA test offering in to the US market is of course quite exciting for the longevity/biohacking community!
Q: How does/will this research benefit everyday users of DNA methylation based biological age testing services?
A: We are building a longevity ecosystem. DeepMAge will be integrated with other aging dimensions to enable a multimodal look at aging within one organism.
Ultimately, we aim to create a model that will be able to tell how methylation at a specific gene is associated with psychological traits, for example.
When integrated in Young.AI, DeepMAge will be accompanied with more detail than just age prediction. We are working on methylation reports to let our users see which features increase or decrease their biological age and how it can be changed.
Commentary: The reason the development of a DNAm based BA test from Deep Longevity is so significant, is that it will sit alongside many other BA tests that they operate, and will be one more item in their ‘suite’ of tools for their vision to provide ‘Longevity-as-a-Service’.
It is also important to respect the complexities of DNAm data; as there are many interactions between bodily systems which alter DNA expression. By commenting on ‘psychological traits’, we see that Deep Longevity is already thinking well ahead of the curve with respect to these challenges.
Q: You’ve mentioned your primary goal is to ‘find academic collaborators’ - is it your intention to share the collection of DNAm profiles with other researchers? If so - how best to request this access?
A: We share our data annotated data collection on OSF. We have uploaded the short annotation: GEO id of a sample, sex, chronological age, health. We have spent quite some time looking for DNAm data sets with age annotated, so this collection will be useful to other biogerontologist who want to work with DNAm.
We have not uploaded the methylation values per se, but since all data is publicly available at GEO, any researcher can easily download it given the accession IDs. https://osf.io/74zga/
Commentary: Sharing data and knowledge is highly important for the research community, and Deep Longevity has adopted the ethos of sharing their datasets and helping other research groups to avoid the hard work of compiling DNAm datasets on their own. Use the link above or contact Fedor directly to explore how to leverage their previous work on this topic.
use the code ‘longevityblog’ to save 5%!
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%!
Follow Longevity Blog on Twitter for the latest #Longevity news!
-
RT @nickengerer: Join a team, do a sport. Staying fit is easier with a clear purpose Bonus: you just might live longer Pic: Byro… https://t.co/L5yHxHJXas
-
Calcium AKG Alpha Keto Glutarate Supplement Review https://t.co/K7keDM3Lyn
-
Mitopure Review - Does this Urolithin A supplement actually work? https://t.co/0Y6Bx4yA7h
-
How Fast are You Aging? A Biological Age Test for Rate of Ageing with Ryan Smith of Trudiagnostic (Part 2) https://t.co/5SZW3Or6JJ
-
What is the Most Accurate Biological Age Test? An Interview with Ryan Smith of Trudiagnostic (Part 1) https://t.co/wdIxtTVeq0
-
One Skin Review - Self-Experiment Before and After Results with OS-01 https://t.co/3hqzLtfVa3
-
Regrowing Knee Cartilage and Restoring Joint Health Naturally. An Interview with Reviiv Light CEO Forrest Smith - P… https://t.co/O671LROvzw
-
RT @nickengerer: 90 years old, what to do? A half Ironman, why not? Hiromu Inada now holds the record for the oldest ever competi… https://t.co/wv7NPhslUM
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.
Deep Longevity, Biological Age and the future of Longevity as a Service - an Interview with Alex Zhavoronkov
How old am I? What a valuable question
Biological age testing is the start of a new longevity as a service industry, in this post we explore what that means, and evaluate the emerging ‘longevity economy.
In this post you’ll learn about:
The story behind ‘Deep Longevity’, an Insilico Medicine spin-out
Biological age clocks and the role of machine learning in creating them
Insight into what the launch of Deep Longevity means for the future of longevity medicine
Alex Zhavoronkov is perhaps best known for his role in founding Insilico Medicine in 2014 and as a prominent voice for longevity science globally.
And while Insilico has predominantly focused on drug discovery over the past six years, is has also generated valuable intellectual property in the ‘longevity’ sphere, including ‘AgingAI’, previously covered on the Longevity Blog.
In recent news, a new company - Deep Longevity - was announced, followed in the last few days with news of an acquisition of the spin-out by Regent Pacific.
Whatever your take on the new venture, it has clearly already signalled strong expectations in future revenue growth & impact through this acquisition.
The Longevity Blog approached Alex to inquire about an interview to dive ‘Deep’ into the details on this new venture, prior to the announcement of this acquisition - which will now see Alex move into the fitting role of ‘Chief Longevity Officer’.
In this post, The Longevity Blog (LB) sits down with Alex (AZ) to better understand his vision of the future of longevity, how it might benefit our community and what hard work remains to be done.
What is Deep Longevity?
LB: Let’s start with the new venture - Deep Longevity. It looks to have a very close relationship to Insilico Medicine. Could you provide us with a bit of background on this relationship?
Our zoom interview revealed Alex to be not only a friendly and charming individual - but also phenomenally knowledgeable on the subject of quantifying biological age.
AZ: Insilico Medicine started-up in 2014, at the dawn of the AI revolution. Our main focus area is, of course, target discovery. We discover novel molecular targets in a variety of diseases and also develop the capability to generate really good chemistry to validate those targets very quickly [via AI - Artificial Intelligence].
Many of the targets that we've discovered at Insilico are related to age related diseases. So, we are looking at age related diseases through a prism of longitudinal data and changes. [This includes] training AI to predict your biological age and to look for individual targets that might be implicated in disease.
LB: Insilico has always had a strong inclination toward longevity technology, I’m sure that reflects your own vision. What changes have recently occurred at Insilico to lead to this new venture?
AZ: After we raised our last [investment] round from [series] B, we realized that the work at Insilico on aging and longevity - specifically in the biomarkers - might be consuming too much of our time. We had to refocus the company efforts on drug discovery to servicing the pharmaceutical companies and also building our own internal software systems for target discovery and small molecule chemistry generation.
LB: It is very important for a new business to be laser focussed on the problems they are aiming to solve. So there was a growing mismatch between drug discovery and developing capabilities in longevity?
AZ: The aging research part was largely neglected over the past year … none of us wanted to happen because aging research is the most important cause out there to pursue. We decided to spin-out the aging research business inside a separate company.
Insilico will continue focusing on target discovery, generation of novel chemistry and prediction of clinical trials outcomes - servicing the pharmaceutical industry. That includes pursuing a pipeline of small molecules, therapeutic programs targeting cancer and fibrosis, but also age related diseases and senescence itself. Insilico will still have some assets that we are developing for aging.
LB: It sounds like Deep Longevity could best be described as a spin-out of Insilico?
AZ: The aging biomarkers business has been spun off into Deep Longevity - a company which predicts your biological age using pretty much every data type that is predictive of biological age. And not only biological age, we're looking at many other endpoints. It's a standalone company, and I'm the CEO of both companies. That's that's kind of, you know, pulling Elon Musk and longevity here [joking].
Note: At the time of publishing, Alex has now been named as the “Chief Longevity Officer” at Deep Longevity and is no longer CEO.
LB: I like your style
AZ: Yeah, as you can imagine, investors in both companies need to have a lot of clarity when that happens, right? You are running two separate businesses, you need to ensure that you spend adequate amount of time on both. You need to ensure that you prioritize your role within the two very distinct businesses... these are elite investors - elite biotech and elite AI investors.
LB: It’s not easy ‘wearing two hats’ so to speak. I’ve been there before myself.
AgingAI is one of the foremost longevity tools created by Insilico.
Help us understand the technology transfer here - will the AgingAI and YoungAI tools effectively become part of Deep Longevity’s technology, in practical terms?
AZ: AgingAI is transferred to Insilico. Young AI is also transferred. We are taking this body of knowledge, of published papers, and patents - some already granted - to form a new company. This also includes a substantial number of scientists who were doing the original work transferring from Insilico to Deep Longevity, or are joining Deep Longevity from the outside. It is definitely built on a lot of prior effort.
Partnership with Human Longevity Inc
LB: In addition to Insilico medicine, there is also a relationship between Deep Longevity and Human Longevity Inc, including investment. Tell us about that.
AZ: The partnership with Human Longevity Inc is a huge milestone for us. It is actually a milestone for the entire industry. To my knowledge this is the first partnership where an ‘aging clock’ company partners with a clinical organization. The Health Nucleus, Human Longevity Inc, those are the best doctors on the planet.
The Health Nucleus will make you say ‘wow’, read more in this four part interview with Dr. Keegan Duchicela.
LB: The blog has previously covered my own personal experience at the Health Nucleus, and interviewed their Medical Director Dr. Keegan Duchicela. There are some very high quality folks working there.
AZ: They are not only high quality folks, the people who come to Human Longevity Inc, they are doctors from Harvard, the Cleveland Clinic Mayo Clinic - and they have been exposed to very high end medicine before. But when they come to Human Longevity Inc - it still makes them go ‘wow!’”
These elite people, elite doctors at Human Longevity Inc - the way they analyze you is a depth of analysis which is much more granular, much deeper than even other elite clinics elsewhere.
LB: Explain to us why Deep Longevity and HLI coming into collaboration is so important
AZ: The fact that HLI has started working on aging clocks is extremely important, extremely impressive. It actually made history in a way - it turns aging clocks into a clinical support tool that allow you to detect changes that are taking the the patient into the wrong direction… that there is room to for a correction, for an intervention, I that is a very powerful utility that was not available before.
Longevity as a Service
LB: It sounds like you may now be describing longevity-as-a-service.
AZ: These are the first steps to longevity medicine and longevity as a service. Traditional medicine looks at you within within the reference range for your age group… if you are coming to a doctor and when you are 60 or 70 they will compare you to the other people within the same age group from you know 60 to 80 or 60 to 70.
With longevity as a service, you are viewed in the context of your optimal performance... how far away are you from [when you were] 20 to 30? … How are you doing in terms of the context of the overall lifespan performance? So, longevity is a service the objective of this paradigm. I think I coined that term
LB: So we’re paving new ground by even discussing it?
Read Alex’s thought-leadership piece on Medium.
AZ: I wrote a blog about this when we when we raised our first round of funding from Juvenescence, and my thinking on the concept evolved over time. Longevity medicine and longevity as a service is applying cutting edge technology to bring the person back to the reference range of optimal performance and optimal well-being.
LB: Optimal performance, optimal well-being. It sounds as if Longevity as a Service seems will have a close relationship with aging clocks?
AZ: So the idea is to reverse as many of those clocks as possible. Let's say 20 to 40 [years old], or that ideal range of 20 to 30, right? That's where humans are supposed to function at the best of their abilities. That's where evolution kind of wants us to ‘stop’… longevity as a service wants you to remain at that state for as long as possible - where you convert money into years of high performance life.
LB: This, again, seems to suggest that aging clocks are likely to be a key metric in the longevity-as-a-service paradigm?
AZ: We have seen a major acceleration in longevity as a service as a goal in the industry, primarily in the advent of aging clocks. Aging clocks are the major innovation, I think, over the past 10 years
Aging clocks are ticking at different rates, and are driven by different properties. The fact that we have started studying them, and there is an acceleration in this area - that’s extremely promising, and is the big step towards longevity medicine and longevity as a service.
Biological Aging Clocks
LB: This is the perfect opportunity to transition into some deeper discussion on aging clocks, as you are a certainly a global expert on this topic. Aging clocks are, most commonly referred to as ‘biological age tests’ are propagating very quickly, and becoming commercially available for the layperson.
If a layperson uses an aging clock to learn their biological age - what does that information actually mean?
AZ: It depends on the property or the specific clock and on how you design it. A given clock can tell you that you have a lower risk of dying for some specific cause or all causes.
LB: So, of course, the science is much more complicated than the marketing! Could you help user better understand ‘design’ of aging clocks in the world of AI?
The Longevity Blog is continually covering new ways to test biological age - just check out this post on Chronomics, a DNA methylation based aging clock company.
AZ: You have your training data set up in a way that that's very actionable and that it serves some purpose. So for example, if you're discovering novel targets, from data using AI, you want to ensure that the data you start with is target rich. So that's the philosophy we follow at Insilico.
LB: ‘Target rich’ data, explain this concept in context in a bit more detail.
AZ: [It is] data economics, right? Some data types are more valuable than the others, but for aging clocks it’s not obvious. Some data types are very predictive of age, but they're not actionable. And some data types are very relevant to certain diseases, but they are not actionable. And some data types are actually actionable but not very predictive. So you really need to understand the data type and the combination of multiple data types in terms of the value of the intervention for disease or mortality..
LB: We need predictive data on actionable insights related to aging - this is clearly quite challenging. How does Insilico/Deep Longevity find those valuable predictors?
AZ: We do a lot of work on feature engineering - [the data] that will go into the [AI] networks for training. You start with a certain number of parameters from a blood test, a transcriptome or a methylome, [which] can be mixed and matched because all of them are linked to age. Then you train your deep neural network to predict the age. Or, you can predict, for example, the age and the health status - the age and specific conditions.
LB: So the feature engineering process helps to identify useful predictors, complete AI training and then predict biological age and health condition. With different feature sets, it is possible to predict varying age and health condition outcomes. Could you give us a more specific example?
AZ: There are multiple properties of each aging clock that you need to evaluate and analyze and use. Not every clock has the same properties - one of these properties is disease relevance.
For example, if the aging clock is predictive of disease status, and [that clock] predicts you to be older than your chronological age, this is predictive of that disease.
A second property of aging clocks would be on relevance to mortality - the risk of death from certain cause or from all causes. If a clock is predictive of mortality, there is a higher chance of dying or for any cause or a specific cause if you’re ‘older’, and vice versa.
The Accuracy and Representativeness of Biological Age Clocks
LB: Thank you for unpacking that. These two properties are quite important.
The relevance of the clock to disease state is very important for readers to understand. An ‘age’ from a clock is relevant to the disease, phenotype or mortality risk it was built to represent.
Keeping that in mind, how can we conceptually understand the accuracy of age predictions provided by aging clocks?
AZ: Every aging clock has a specific error rate. Within a specific range [of age], the clock may be accurate and inaccurate. [As an example] say plus minus five years. If that clock predicts to be three or four years younger, it might not actually mean much.. the prediction is just within that [accuracy] range.
All of this depends on how you design the clock and how you validate the clock, because every time you design the clock, you need to test these properties. This is usually done by cross validation - testing the clock on completely unrelated data sets.
LB: So against the backdrop of the propagation of many different biological age tests - we need to carefully analyse an aging clock’s relevance and accuracy before applying the age prediction to an individual.
AZ: Exactly. So that's, that's, that's the exact point. And also, not it's not just the way it's built. It's also the way it's validated. Because very often when you build the clock, you don't have a clue where it's going to work.
LB: Aging clocks take on many forms, not just the AI based one we have discussed so far. What about methylation clocks, an epigenetic approach? Recent coverage by EndPoints suggested your view was that these had not proven very accurate. Could you clarify?
AZ: That was actually not what I said.
LB: Ok - consider this is an opportunity for you to set the record straight!
AZ: I must say on record that I consider Steve Horvath as a hero. He is really a pioneer. There is some kind of debate about who was the first to publish the methylation agent clock. But he did it as a single author. He published it in a perfect journal... He really goes into the annals of aging research as a mastermind of aging clocks... if you look at the stream of papers coming out of his lab, and also many labs over the world, all over the world - you can really clearly see that.
LB: Thanks for clarifying, and making it clear that methylation clocks may offer a valuable tool in the efforts to quantify aging. Could you give us some examples of where the Horvath methylation clock is being used in research?
AZ: Researchers are trying it everywhere. Can you predict menopause? Can you predict the stage of Alzheimer's? Can you predict severity of the disease? There are hundreds of different attempts and successes, some of them might be very credible, some of them might not be super credible.
Especially when people claim that there is substantial age reversal using certain interventions. I saw those claims - they need to be validated multiple times. We also need to understand why it's happening to understand the cause and effect.
LB: Pivoting back to aging clocks more generally, and the continual development of more of them - what can be done to ensure we have several, robust and useful clocks for quantifying aging?
AZ: When you're developing an aging clock, using any data type, it is of course important to think about the future - Where will it be applicable? How relevant is going to be? We really need to put the best practices into this.
Very often you're not gonna know where [the aging clock] is going to work. So you really need to validate on independent data sets. Ideally the best validation is always prospective and in the wild. So you really need to deploy those clocks in a clinical setting where people measure those clocks. They basically use those clocks over time, and then correlate those predictions to various outcomes.
Ageing Interventions
LB: Let’s again draw from your previous comments on Deep Longevity. In that same article - you said “you cannot intervene, if you cannot measure”.
We’ve discussed aging clocks in terms of their ability to ‘measure’, considering relevance, accuracy and how to engineer them. Let’s move onto ‘intervention’.
This concept clearly will resonate with many in the longevity community, where we’ve long talked about intervention, but have still been stuck in ‘exercise more, sleep well, eat less’. Could you give us an example of an intervention being tied to an aging clock?
AZ: Some clocks are very sensitive to interventions. So for example, using the composition of your gut flora we can guess your age. I was actually very surprised when this first worked. I think [Insilico] were the first ones to do that.
This clock is quite sensitive to intervention - you can see if any of the drugs that you're taking or any of the foods that you are eating are influencing the predicted age.
So for example, if you drink some alcohol and we know that alcohol kills bacteria - does it make you “younger” or does it make you “older”? This aging clock is very intervention relevant, because many interventions will affect the microbiome
Some aging clocks are sensitive to intervention, others are not sensitive to intervention at all. This makes understanding the intervention relevance extremely important. Sometimes the only way to test the intervention relevance is to really conduct a clinical study
LB: So, with the right, well-designed clock, we can measure the impacts of intervention. This is precisely what the longevity community is interested in. This brings us full circle with respect to longevity as a service and the new venture Deep Longevity.
Tell us - what milestone does the launch of Deep Longevity represent for longevity as a service becoming reality?
AZ: From one perspective, we see a major acceleration of longevity-as-a-service as an industry, through the advent of aging clocks. That’s the major innovation over the past ten years - thanks to Steve Horvath and many others.
Once again - you cannot intervene if you cannot measure - Steve Horvath established one dimensionality to measure, we came up with more than twenty different dimensionalities. We are also aging on many different dimensionalities that we have not even thought about yet - we need to measure it at every level… the fact that we have started studying this, and that there is an acceleration in this area is extremely promising
From a second perspective, we now have interventions that are available like NAD boosters for example...senolytics are a very promising area… there are rapalogues… metformin....
Looking into the Future of Longevity Technology
LB: So we can measure, we are increasingly able to intervene…. Where does the launch of Deep Longevity fit in the longevity technology future?
We are standing before the inflection point. If you think about the internet or personal computer or the iPhone or Facebook, these exponential technologies that took over the world - with respect to PCs we are currently in the 60s, if you compare us to the internet, you are probably in the late 80s…”
LB: You have the backing of some very smart investors, and a like-minded community who are in admiration of your work and supporting you from around the world.
Alex, we’ve used up all of your available time for today. Any closing thoughts?
AZ: Thanks so much. We have built a community of people who don’t prioritise anything else over longevity research. I recommend everyone do the same - this is the most important aspect of life to focus on - if we accelerate now, we will reap the benefits later.
LB: You’ve dedicated your life to this effort, and that is evident in the impact you’ve had to date Alex, thank you.
—- End —-
Did you enjoy this interview with Alex?
You can hear more from him by following him on Twitter, or if science is your thing - review his Google Scholar profile.
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
I post related #Longevity content to Instagram as well, follow me @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Self Experimentation with NMN Nicotinamide Mononucleotide
NMN Before and After with Biological Age
Given the introduction of nicotinamide riboside (NR) and more recently nicotinamide mononucleotide (NMN) as supplements over the past four years, many in the longevity community are self-experimenting with these molecules which boost NAD+ levels.
Looking for an NMN supplier? I recommend DoNotAge, who offer a third party tested pure product, have a bulk supply option (100g) with further savings when you subscribe to regular shipments. Use the code ‘longevityblog’ to save a further 10%.
Get the details in Part 3 of this NMN self experiment series
As discussed in the previous post on NMN risk management, there are three key questions that Longevity Blog will engage with on the topic of NMN. These are:
NMN
How can we self-experiment to determine efficacy?
In this post, I’ll discuss how we can self-experiment to determine the efficacy of NMN supplementation. Let’s do it!
NMN Self-experimentation: A first draft “how to” guide
Let’s science this and see what happens
As with any good self-experiment, we should design a solid experimental framework based on the principles of the scientific method.
This has caveats however, owing to our inherent complexity as a biological system.
As you up your self-experimentation game (what a biohacker you are!), you’ll find out that self experiments are:
Difficult to control
Often hard to measure directly
Prone to bias and placebo effect
Important to make repeatable
Through this post and others that follow, we will do our best to continually consider these issues with self-experimentation (an example of this can type of thinking can be seen in previous posts).
In your endeavour to self-experiment with NMN, getting the experiment right is particularly important.
It should be our goal to provide insight to the broader self-experimentation community, and facilitate others to effectively self-experiment so we can benefit from collective knowledge sharing.
So let’s aim to get this right, in the name of science!
NMN Before and After, Our Hypothesis: What are we testing?
After thorough consideration, I believe our hypothesis for NMN supplementation can be summarised as follows:
NMN supplementation will boost intracellular NAD+ levels
Boosting NAD+ levels with NMN will measurably improve select characteristics of youthfulness
This hypothesis is formed upon on a large volume of work around NAD+ boosting supplements such as Nicotinamide, Nicotinamide Riboside (NR) and NMN (nicotinamide mononucleotide), which indicate 1) the importance of NAD+ levels on a plethora of cellular processes, 2) the known decline of NAD+ levels with age and 3) the apparently causal relationship in this drop in NAD+ levels with a wide array of age-related diseases.
It also formulated in such a way that we can test it, by gathering related data and analysing them to draw conclusions.
Does NMN Work in Humans? How We Can Test the Hypothesis:
In order to test our hypothesis, we need to determine:
An appropriate NMN dose for raising NAD+ levels
How we will measure the NAD+ levels
What controls we can apply, and adopt defensive positions against bias/placebo
How much NMN should you take?
In order to determine the appropriate dose for the experiment, I suggest we look to the two FDA approved clinical trials which are currently evaluating NMN safety and efficacy:
You can search for clinical trials on any topic you like at clinicaltrials.gov
Clinical Trial #1: Dosing for participants 40-65 years olds set at 300mg/day
Clinical Trial #2: Dosing for post-menopausal women set at 250mg/day
Anecdotes from elsewhere suggest this a good level for supplementation. Consider this 27 year old who was totally ‘buzzed’ on 500mg/day and this discussion thread for a 34 year old (same age as me at the time of writing) settling on ~250mg day.
Setting the NMN supplementation level should be done based on age and moderated based on one’s experience with the dose (e.g. insomnia, flushing, etc can be inferred to mean one should titrate downwards).
Measure: Data Collection for the NMN Self-Experimenter
From first principles, our goal here will be to measure related biometrics before NMN supplementation, and then again after sustained NMN supplementation. However, the details here are challenging. As, unfortunately sampling intracellular NAD+/NADH levels presents a few issues.
So for widespread, democratised access to NAD+/NADH testing, we face these two barriers:
First, direct testing of NAD+/NADH is limited to professional assay test kits (like this one)
This violates our goal to make the experiment repeatable for other self-experimenters.
Secondly, it turns out they are fairly ‘noisy’ data anyway, making interpretation difficult and making representativeness of the measurement problematic
NAD+/NADH levels change dramatically across the day with activity, eating, circadian rhythm (Interestingly, blood glucose exhibits these same characteristics; which is perhaps unsurprising as they are both part of our body’s ‘energy system’ );
even if we could test it directly, we would also need to sample it semi-continuously (many measurements)
However, given the widespread interest, research funding and commercial development of NAD+ boosters, measuring NAD+/NADH is likely to become more widely available in the near future. My research found at least two promising options,:
Liquid chromatography - “high-performance liquid chromatography (HPLC) to accurately measure the levels of NAD+ in cells and tissues”
A bioluminescent biosensor - “for the rapid quantification of NAD+ levels in biological samples, which can be used either in laboratories or at the point of care”
Establishing an NAD+ Proxy
In science, where we can’t measure something directly, we use a suitable proxy. In atmospheric science, to study the past climate, we can use bubbles captured in glacial ice cores to estimate past CO2 concentrations and global temperatures.
Climate researchers do this because they inconveniently didn’t have thermometers sampling the atmosphere 100,000 years ago. Here, our issue is we don't have the ‘thermometer’ for NAD+/NADH levels yet. So what’s our proxy?
I have spent many hours researching and considering this. It is my suggestion is that we leverage several different biomarkers that are representative of youthfulness as our proxies. The reasoning for this reaches back to the hypothesis and the purpose of boosting NAD+ : to restore youthfulness.
There are a few proxies we can draw from the clinical trials mentioned above, these are:
Walking speed tests
Blood pressure
Lipid profile
I suggest we eliminate the walking speed test, as it is really only valuable in advancing aging or for sedentary individuals. The latter three are widely accessible, so we’ll adopt them.
But I suggest we go a bit further in our assessment of expressing a youthful phenotype, and adopt measurements of biological aging. My reasoning for using biological age (BA) is the following:
BA is our target for longevity optimisation
BA measurement and calculation is accessible to others, therefore can be repeated
BA is a wide reaching measurement of overall bodily youthfulness (that is its purpose)
BA has multiple modes of testing available to us; so we can work with more than one
Epigenetic test kits for before and after the Longevity Blog NMN based planned biological age reversal experiment. Read about what I made this choice!
For the NMN self-experimenter, I suggest the following two biological age computation methods.
The first is the Phenotypic Age test, which I cover in this post.
The second is a biological age test based on measurement of DNA methylation (aka epigenetic age)
While the prior test is a blood test, the latter is direct measurement of methylation at CpG sites in the epigenome.
There is a fundamental connection here between NAD+ levels, which are the ‘fuel’ for the SIRT enzymes which repair DNA and regulate expression of the genome.
In theory, increasing NAD+ levels could improve our bodily ability to regulate the epigenome, so potential improvements could be realised in the epigenetic age.
Epigenetic age kits are also becoming widely accessible very quickly, and therefore are repeatable.
Analysis: How should the self-experimenter analyse their data?
At the most fundamental level, at the very least, one should statistically compare the before & after measurements of our proxy measurements.
An added benefit would be the inclusion of additional baseline measurements from before the experiment begins.
This inherently needs to include some basic corrections for the non-stationary nature of the data. In layperson terms - chronological time is passing over our measurement period.
So the ‘after’ measurements should be corrected in our analysis, considering the amount of time that has passed over the course of the experiment.
Lastly, and perhaps more importantly, we must employ purposeful management of potential confirmation bias.
Anyone who is running an NMN self-experiment and is looking after their longevity wants and likely expects the supplement to work.
Since we know the result we want, therefore we need to be defensive against our bias when we draw conclusions based on this result.
This is particularly relevant for bloggers and social media focussed folks - we inherently want the Ben Greenfield headline to draw clicks and eyeballs.
I refuse to do that to you, and will revisit these issues when we analyse the data and draw our conclusions.
NMN Self-experimentation: What’s Next for Longevity Blog?
We’ve nearly designed our experimental framework, but we’ve not yet discussed the dosing protocol. So here’s what I personally plan to do:
Baseline
Measurements of:
Blood lipids
Blood pressure
Estimation of:
Phenotypic Age (established here)
Epigenetic Age (via Chronomics)
Complete the SF-36 questionnaire
Post Protocol
Measurements of:
Blood lipids
Blood pressure
Estimation of:
Phenotypic Age (established here)
Epigenetic Age (via Chronomics)
Complete the SF-36 questionnaire
So, what will the exact dosing protocol be? It is still in draft form, as I am awaiting potential additional insights from first Chronomics test.
These may provide additional insights on what to add to the protocol to further improve my biological age.
This does step outside of the experimental design for NMN self-experimentation, but let’s delay that discussion until further posts.
NMN Self-experimentation Protocol (DRAFT):
NMN dose will be set at 250mg per day (based on clinical trial dosing levels)
Update: Two months into the protocol, I raised to 500mg per professional advice from a knowledgeable third-party
For risk management, we’ll include 1:1 TMG (as discussed in my last post)
Resveratrol at 500mg/day, taken with a high fat meal (I’ve been doing this for 2+ years)
Inclusion of Resveratrol is based on its role as a SIRTuin activator, which pairs well with NAD+ boosting and potential benefits to the ‘health’ of the epigenome
Will you experiment with NMN? You’ll need a trusted supplier - I recommend DoNotAge, who offer a third party tested pure product, have a bulk supply option (100g) with further savings when you subscribe to regular shipments.
Use the code ‘longevityblog’ to save a further 10%.
Get the details in Part 3 of this NMN self experiment series
Follow me on Twitter for the latest #Longevity news!
-
RT @rebeccavziegler: The cryonics payoff matrix. Choose wisely my friends. https://t.co/l1rzsmOC2w
-
My rate of aging: 0.79 It’s the new street cred What you got? https://t.co/aHzWHAfCnD https://t.co/L3rZC4QFN2
-
It’s official - I’m co-producing and hosting a new #longevity docuseries, and will begin shooting in a few months… https://t.co/wLGqRrBfbp
-
“The #longevity segment opened my eyes to the groundbreaking advances in biotechnology, health, and wellness. The i… https://t.co/F8YB7PAeMW
-
I’m completely mindblown by what AI has done over the past 3-6 months, and it continues to accelerate… https://t.co/hh0JslucRg
-
Longevity legends take on many shapes and sizes https://t.co/X9vGa7gvOe
-
RT @BradStanfieldMD: Avoid These Popular Supplements (shout out to Professor Matt Kaeberlein @mkaeberlein & Professor Brian Kennedy… https://t.co/cy9CXldgUS
-
Who are influential persons in #longevity who are of Asian, African American or other “minority” group in the US?
I post related #Longevity content to Instagram as well, follow me @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
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.
Chronomics - Biological Age, DNA Methylation, Methylation Clocks
Biological Age - DNA Methylation, Methylation Clocks
One for now… One for later! Testing my epigenetic age with Chronomics.
In my previous post on biological age, I introduced you to three free online tools for estimating your biological age.
And while these tools are quite useful, they hardly represent the state of the art in biological age assessment.
To really sample biological age directly, we need to leverage the advent of methylation clocks, which track changes in methyl groups in the epigenome.
The epigenome is the system that controls how our genome is expressed. It’s an incredibly intricate system that goes so far as to actually program your stem cells on what type of cell they should become (e.g. blood cell vs. skin cell).
And while the expression of the genome by the epigenome works excellently when we are young, it is known to change as we age in detrimental ways. This makes managing, delaying or even reversing this age-related process of methylation a key pillar of any longevity strategy.
Quantification of Biological Age
My biological age is 22 years old. I’m 34. How are you doing? Learn how to estimate your biological age with a simple blood test.
This naturally leads us to the nature of quantifying (ie measuring) the amount and intensity of age-related DNA methylation which has occurred in one’s body to date.
This process is occurring as an unfortunate byproduct of your metabolism continually, but is also strongly modulated by environmental factors.
Alcohol, smoking (cigarettes), toxin exposure, stress and environmental pollutants all play a role in DNA methylation, and the science of connecting the dots as to why a given methylation pattern exists in a particular area of the genome is emerging rapidly.
In my view, there are two important capabilities emerging in the biological age testing space which utilise DNA methylation to estimate one’s biological age.
Emerging Capability #1 - Test your Biological Age at Home
The first is the ability to leverage a consumer testing kit to measure your DNA methylation. At my last count, I found six reputable companies who are offering a test which will provide you a biological age estimate through the methylation clock (i.e. Horvath).
They have a wide range of price points, utilise different technologies (blood vs saliva), and fit into a company’s offering in different ways.
Longevity Blog will be covering as many of these test kits as it can… if we can keep up! This space is moving quite fast, and it will be our aim to help you make informed choices.
Emerging Capability #2 - Determine What Aged You
The second capability is harder to find, but in my view is far more valuable as I expect it to provide actionable insights (a key theme of this blog).
This is the newly emerging capability to not just quantify the biological age, but to qualify it. By this I mean, to analyse the biological age and make attributions as to why one has aged.
In my review of the technology in this space, there is only one company who can provide us with this level of detail to date - and that is UK based Chronomics.
In an upcoming post, I’ll be interviewing CSO Dani Martín Herranz to dive a bit deeper into the how and the why beyond their incredible capability in this space. For now, let’s play biohacker guinea pig…
Testing Chronomics Testing Me
Chronomics is not a direct to consumer testing service, and in most cases one has to work with their partnership network in order to access their testing kits.
However, after hearing CEO Tom Stubbs interviewed at the Biohacker Summit in 2019, I knew I had to reach out and find a way to work together. Through our collaboration, Longevity Blog purchased two testing kits from Chronomics.
We will be using these test kits to not only review the company, process and results (sharing them with you of course!), but also to run a unique type of biological age experiment on yours truly (more on this in an upcoming post - be sure to subscribe not to miss it).
The Chronomics testing process involves a saliva sample - very generous volume I might add, which is provided in a test tube with stabilisation medium so that the sample can survive the long trip back to the UK.
From this sample, we’ll be given access to an online dashboard of 35+ different health metrics of which biological age is only part of the ‘health picture’ which will be represented there.
It is my expectation that the specific insights I gain from this process will highlight areas of my DNA methylation that might be ‘reversed’ (a not so subtle hint on what I plan to do with the 2x kits 🤔?)
Chronomics and Biological Age: Some Basics
As a part of our collaboration, I completed a personalised walk-through of their dashboard, I was able to ask a number of preliminary questions about the process, the science and what to expect in my results. Here’s what I asked, and what I found:
LB: Alright, give me some numbers, how much of my genome are we going to analyse?
Chronomics: We’ll be analysing more than 20 million positions in your epigenome using next-generation sequencing, the most comprehensive epigenetic snapshot to date. We’ll also be able to run a community inter-comparison across 1000s of other samples (all anonymous of course).
LB: Rad. Now what will it tell me about my biological age - can I get a number?
Chronomics: Yes, we’ll use those over 20 million positions in your DNA to give you a biological age estimate. We’ll also give you some insights on your age trajectory versus a supercentarian
LB: Love it. But what value will that information provide me. Age is just a number, after all. I need actionable insights.
Chronomics: We’ll use this analysis, along with a detailed personal survey to identify what lifestyle changes you could make to have the biggest impact on your epigenetic age. These include metabolic status, alcohol consumption and cigarette smoking.
LB: Uh oh. I was the guy known for building a two-story beer bong in graduate school. Perhaps that will finally catch up with me. Tell me a bit more about how this works?
Chronomics: It is a cumulative exposure measure, and was built through our internal research team of data scientists, engineers and academic partners. There is actually a specific methylation signature that occurs in the epigenome from this exposure overtime.
LB: Did I also mention I once built a wizard staff of 21 beer cans? Let’s move on… What about cigarette smoking. I’ve enjoyed my fair share of ‘party cigarettes’ and smoky bars - what will your test reveal?
Chronomics: Cigarettes contain certain toxins and heavy metals which are now known to methylate the genome in unique ways. Repeat exposure to chemicals known to be contained in tobacco will damage your DNA and we’ll be able to measure that.
LB: * Chuckles nervously *
Chronomics and Longevity Blog - What’s Next?
In upcoming posts, I’ll interview the team at Chronomics in more detail, review my personalised results and discuss my plans for making the insights actionable.
Follow me on Twitter for the latest #Longevity news!
-
RT @rebeccavziegler: The cryonics payoff matrix. Choose wisely my friends. https://t.co/l1rzsmOC2w
-
My rate of aging: 0.79 It’s the new street cred What you got? https://t.co/aHzWHAfCnD https://t.co/L3rZC4QFN2
-
It’s official - I’m co-producing and hosting a new #longevity docuseries, and will begin shooting in a few months… https://t.co/wLGqRrBfbp
-
“The #longevity segment opened my eyes to the groundbreaking advances in biotechnology, health, and wellness. The i… https://t.co/F8YB7PAeMW
-
I’m completely mindblown by what AI has done over the past 3-6 months, and it continues to accelerate… https://t.co/hh0JslucRg
-
Longevity legends take on many shapes and sizes https://t.co/X9vGa7gvOe
-
RT @BradStanfieldMD: Avoid These Popular Supplements (shout out to Professor Matt Kaeberlein @mkaeberlein & Professor Brian Kennedy… https://t.co/cy9CXldgUS
-
Who are influential persons in #longevity who are of Asian, African American or other “minority” group in the US?
-
The AI powered future is here 🦾 Contrary to the narrative, you’re not going to be replaced in the workplace by AI… https://t.co/BojTzyfDzA
-
I built and exited my first company today A big moment in my entrepreneur journey What’s next? All in on… https://t.co/5oTo3IjSyN
-
I’m seeing tweets from accounts I follow that I have seldom seen over the past two years. Why? Locking your accou… https://t.co/dt21RnfRxT
-
It’s 2023 and I’m using ChatGPT to brainstorm brand names for my next company Welcome to the future 🦾🤖
-
93 year old Buzz Aldrin is a #longevity legend, and he’s at it again… The 2nd man to walk on the moon just married… https://t.co/IXZpfH2S3r
-
In 2021 @ChromaDex tested 22x brands claiming to be NMN The (perhaps not so) shocking outcome? Only 3x met label… https://t.co/PiqiQ581Ra
-
What #longevity books should I be reading in 2023?
I post related #Longevity content to Instagram as well, follow me @nickengerer
FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
Prerequisites to Micronutrient Testing - What to do and why
Micronutrient testing is a powerful tool for the self-quantified
Hello blood draw - may know? What is in you?
Micronutrient testing is a powerful tool, in this post you’ll learn:
How micronutrient testing can reveal critical levels of certain nutrients
What you need to do prior to getting a micronutrient test to ensure it is effective
Why we recommend tracking micronutrient intake with Cronometer prior to your test
How using Cronometer could mean you don’t actually need to pay for micronutrient testing (it is expensive!)
Why tracking your supplement intake prior to a micronutrient test is MUST have
Micronutrient Testing Can Reveal Critical Health Information
This is illustrated perfectly by the results of my own micronutrient test - which revealed I was critically low in three important micronutrients - an amino acid (Glutamine), a mineral (Chromium) and a vitamin (K1).
The first of these two could be traced back to my athletic level of physical activity, whereby my glutamine intake and reserves were slurped up by my muscle recovery and the chromium which was lost through my sweat and is only present in relatively low amounts in dietary intake.
In this post, I want to guide you a little deeper into the topic and share what I’ve learned from my first round of micronutrient testing, so as to guide your own use of this powerful blood test.
Making Your Micronutrient Test Actionable Takes a Plan
A key theme of the Longevity Blog is diving through the many points of data available to measure your wellness, and determine which of these are actionable, how and why.
With my previous anecdote of micronutrient testing revealing a critical lack of important nutrients in my serum and blood cells, it is clear that in the case of deficiency, the actionable path is fairly straightforward.
I immediately began a supplementation plan for these three micronutrients, and noticed sudden improvements to my health.
Notably with glutamine supplementation, I observed a noticeable strengthening of my gut resilience.
However, these three data points are only a small subsample of the information that one will glean after completing a micronutrient test.
How can we ensure that we have decision making capacity around these other data points?
The straightforward answer is we need to have a plan, and that means we’ll require preparation prior to completing the test.
I’ll use an illustration from my own micronutrient testing results, before I dive into the two key elements of this plan, which are:
1) detailed dietary tracking with Cronometer
and
2) having a complete record of your supplement routine prior to your first micronutrient test.
Illustration - Results from my Micronutrient Test at NextHealth
When I gave 15 vials of blood at NextHealth in November 2019, I knew I could expect an impressive collection of biometric data.
But of the several blood test products I undertook, the results of the micronutrient test were the most daunting.
Firstly, there are two main categories of data presented for each micronutrient
The serum level, which represents the amount of each micronutrient present in my blood serum directly. This component is inherently more variable, as the process of micronutrients entering the bloodstream and being taken up by the various metabolic pathways in the body is quite dynamic. This value can very much be thought of as a ‘snapshot’ of this quickly changing process.
Then there is the amount of micronutrient present within the actual cell, which is more steady-state, and can better represents the long-term average concentration of a micronutrient. In most micronutrient tests, these are sampled in the White Blood Cell (WBC) and/or Red Blood Cell (RBC), depending on which is most representative of a given micronutrient. RBC lifetimes are on the order of 100-120 days (3-4 months) whereas WBC lifetimes are measured on the order of 10-14 days (1 to 2 weeks).
Here are the results of my vitamin panel:
As you can see, we have a concentration of the micronutrient in both categories, along with a reference range provided by the laboratory (Vibrant America). We won’t be able to dive into the basis of the reference ranges in this post, but suffice it to say they are based off a combination of population statistics and published studies.
Why Dietary Intake Tracking Prior to Micronutrient Testing is Important
Now, let’s consider for minute that one has taken their micronutrient test and was blind to their dietary intake, had not kept a good record of their supplementation routine. What actions can they take based on this result? As you can see, with the exception of Vitamin K1 serum levels, I was ‘green’ across the board.
The answer on what is actionable is limited without this information. Based on ‘green’ results, one might decide to ‘stay the course’ on their current lifestyle choices.
However, for self-experimenters like yourself, who are likely interested in self-optimisation (that’s why you read this blog after all, no?), this is an unsatisfying result. Never mind the fact that any deviation on dietary intake could result in sudden withdrawal of a source of micronutrient near the low end of the reference range.
Take for example my Vitamin A or Vitamin K2 intake - should I suddenly discontinue my penchant for sweet potatoes (a rich source of beta carotene, a form of Vitamin A) in favour of another carbohydrate (e.g. a white potato), I could perhaps drop out of the reference range within a matter of a few weeks.
But this would likely escape my detection if I were not tracking my diet! So, onto pre-requisite #1!
Tracking Dietary Intake of Micronutrients with Cronometer (Pre-requisite #1)
Cronometer is an excellent diet tracking app with micronutrient data included! It is free to use!
This illustration, along with my sage advice aimed at you spending your self-quantification dollars wisely, strongly suggests that you track your dietary intake for at least 3 months prior to your micronutrient test.
This recommendation of ‘3 months’ is based on the expected RBC lifecycle, and is made from a first principles viewpoint (there simply isn’t a robust source of peer reviewed science on this topic).
For this purpose, I suggest you us cronometer. Cronometer is a detailed dietary tracking app which offers the key advantage of providing micronutrient tracking (sorry MyFitnessPal).
Vitamin micronutrient tracking information for myself this week. I’m avoiding eggs at the moment and so I am supplementing choline! Looks like it is time to take it! And the B-Vitamin complex too!
Using Cronometer is absolutely essential for making your micronutrient testing outcomes actionable.
You simply won’t know what to change or keep the same, in order to achieve the outcome you desire for any given micronutrient without this information.
This tracking will come with the added benefit of identifying potential areas of deficiency in your diet in the first instance, prior to the micronutrient test.
Cronometer is the only dietary tracking app which enables detailed tracking of micronutrients.
In fact, using Cronometer over a few weeks or months is likely to highlight which micronutrients you are likely deficient in.
Given that the app is FREE, it could save you several hundred dollars and give you the answer you’re looking for (Am I deficient in a given micronutrient).
The simple fact is - if you’re not including a micronutrient at recommended levels, the chances of you being deficient in that micronutrient skyrocket.
Going back to my personal example above - tracking my dietary intake of chromium revealed low levels in the foods I was eating.
I could have seen this ahead of time with Cronometer!
Micronutrient Supplementation Tracking is a MUST (Pre-requisite #2)
Just as you must track your micronutrient intake from your diet, the same is also true of any supplements that you may be taking. (Hey, I’d know - I take a few myself).
From the perspective of my first point, this seems, well, bloody obvious (pun intended?)! But, I speak from experience. I was still settling into a solid supplementation routine leading up to my micronutrient test, and did not keep a high quality record (oops! don’t be like Nick!).
Was I taking the 15mg of zinc or had I bumped it to 22mg by then And if so, when? When did I change that vitamin D supplement in favour of one that included K2 in the formulation, again?
The truth is, I didn’t have the answers to these details, and when it comes to making your micronutrient test actionable - details are important!! I found out the hard way when trying to make my own micronutrient test actionable. I thought I knew what I was taking, but when it came down to the details - I didn’t have the records I needed.
Keep a record of your supplements, using an app or a simple spreadsheet. Keep track of the supplement name, the concentration of micronutrient, its form, the timing of your dosage and the start/end date + frequency (e.g. every other day? once per week?).
READY TO TEST YOUR MICRONUTRIENT STATUS?
We’ve found three valuable DIY options for you! No doctor required!
ULTAWELLNESS (USA)
Budget Option (25% of the cost)
HEALTHLABS USA)
I-SCREEN (AUSTRALIA)
Follow us on Twitter for the latest #Longevity news!
-
RT @nickengerer: Join a team, do a sport. Staying fit is easier with a clear purpose Bonus: you just might live longer Pic: Byro… https://t.co/L5yHxHJXas
-
Calcium AKG Alpha Keto Glutarate Supplement Review https://t.co/K7keDM3Lyn
-
Mitopure Review - Does this Urolithin A supplement actually work? https://t.co/0Y6Bx4yA7h
-
How Fast are You Aging? A Biological Age Test for Rate of Ageing with Ryan Smith of Trudiagnostic (Part 2) https://t.co/5SZW3Or6JJ
-
What is the Most Accurate Biological Age Test? An Interview with Ryan Smith of Trudiagnostic (Part 1) https://t.co/wdIxtTVeq0
-
One Skin Review - Self-Experiment Before and After Results with OS-01 https://t.co/3hqzLtfVa3
-
Regrowing Knee Cartilage and Restoring Joint Health Naturally. An Interview with Reviiv Light CEO Forrest Smith - P… https://t.co/O671LROvzw
-
RT @nickengerer: 90 years old, what to do? A half Ironman, why not? Hiromu Inada now holds the record for the oldest ever competi… https://t.co/wv7NPhslUM
-
One Skin Before and After - Skin Aging in the Future: An interview with OneSkin CEO Dr Carolina Reis - Part 2 https://t.co/RlLlqRurT6
-
RT @Do_Not_Age: Our new ingredient, Spermidine, reduces amyloid plaques and inflammation of the brain in rodents Check our Science… https://t.co/RgehOqmVtf
-
Longevity: Fasting, Diet, Sleep, Stress - How to Personalise Your Approach https://t.co/NX5HmycJo9
-
We enjoyed discussing this critical question with CEO & Founder at Self-Decode Joe Cohen Importantly - where do ge… https://t.co/RmJdbOyyC9
-
We are big fans of using biological age to run self-experiments! There’s a new test kit on offer from our partner… https://t.co/yZ6j3MBJTD
-
RT @entreprylexia: @longevity_blog The best designed N of 1 experiment I’ve seen to date 🙌🏼
-
Increasing Plant Diversity Improves GlycanAge Significantly - A Self-Experiment https://t.co/cGS4I9Wmdi
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.