Wednesday, December 6, 2023
Mitochondrial Health

Dr. Sinclair’s first human NMN study. Is this to be believed?

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[1] Pencina KM, Valderrabano R, Wipper B, et al. Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study. J Clin Endocrinol Metab. 2023;108(8):1968-1980. doi:10.1210/clinem/dgad027


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45 thoughts on “Dr. Sinclair’s first human NMN study. Is this to be believed?
  1. I decided not to nerd out completely on the statistics, because it would have led to a boring video, but here is some added nerding out for the few that are interested:

    If you look at any of the data shown (like @2:43), the data is displayed as a ‘relative change from baseline’ and does not show the absolute values. So, the baseline is roughly the same in these graphs, but if we look at the absolute values (as shown @4:18), we can see that they are not the same. This way of displaying the data allows the researchers to indicate a change (as we see comparing placebo vs NMN); however, if we were to use the absolute values and re-test the statistics, I’d wager that there wouldn’t be a difference between the two groups, because the absolute values would actually be closer together between groups after 28 days of supplementation.

    Second thing – the researchers rely on ‘between treatment’ statistical comparisons, but they don’t do any ‘within-treatment’ comparisons, which would be useful to see. I’d guess that there would be little to no change in either condition (statistically speaking).

    Ultimately, both of these issues aren’t deal breakers or anything, but they call into question how meaningful these statistically significant effects really are (my point in the video).

    Maybe I should have gone into it more, but I’m always playing a delicate game of balancing video time and not getting too bogged down in the minutia – hope this helped.

  2. Seems like the NMN results are just like David Sinclair's claims on Resveratrol. Underwhelming and not replicable. (Given what the other 12 NMN studies showed.)

  3. What's the rub? : I went looking for the answer. I thought it was related to the phrase "Rubbing the wrong way" but it actually isn't:

    " In Shakespeare’s “Hamlet,” when Hamlet was contemplating suicide, he said, ““To sleep; perchance to dream: ay there’s the rub: for in that sleep of death what dreams may come?”

    But, what does “the rub” mean and from where did it originate?

    “Rub” in this sense means drawback or impediment. Most sources say it comes from the ancient game of bowls—the ancestor of the game bocce ball—in which a ball (known as a bowl) is rolled toward a smaller stationary ball, called a jack. The object is to roll one’s bowls so that they come to rest nearer to the jack than those of an opponent. A rub is a flaw in the playing surface that interferes with the ball’s trajectory. "

  4. In my view, the transition from rats to humans presents a significant challenge, primarily because of the differences in lifespan. The chosen measurement points may not be dependable indicators in this context. While I maintain that the hypotheses remain valid, they have not yet risen to the level of becoming a recognized theory, and I have doubts whether they ever will. Only time will tell.

  5. I would appreciate the reference to the study.
    The molecular structures of NMN and NR are roughly the same, except NMN has an added phosphate group. This added phosphate group makes NMN a larger molecule than NR. Some scientists believe NMN is too large to cross cellular membranes and must convert to NR before entering cells, where NAD+ biosynthesis occurs.

  6. Dear Nicolas, thank you so much for your extensive and detailed review of the available scientific data on NMN. Since the 1st incentive in taking NMN is to increase one's NAD level, the question that comes to mind after your review of Dr Sinclair's study is: If there was already an "advantage" of 20-30 points in the base line values for example in the total cholesterol, LDL & Liver fat values, and so on, in the control group, was it also the case for the blood NAD level? Thank you again ?

  7. besides the discussion of the quality of that study – what is the conclusion and big picture and are we focussing on a useful analysis overall? Still confused. half of the population has strongly (up to -30%) reduced levels of a molecule, that seems to do a lot of things in the body, like being necessary for cell repair. and it can be rised again. we‘ve seen statistics about small metabolic short-term effects which are rather not interesting so far. but why should NAD+ have these type of effects – and why not completely different or just long-term effects? or is NAD+ really completely unimportant and which information is given up to now to discuss this core question? instead of assessing bad information sources it would be more intetesting to discuss some good ones? I would really like to learn about the function and effect of NAD+ levels – not what they not do, but what they really do ?. and if no information about this is available …. this would also be a clear statement.

  8. “there’s the rub” is from shakespeare’s tragedy Hamlet. Hamlet is contemplating suicide, but he realizes that in dying we face reckoning with God, as in final judgment. if i stay there are problems…if i go ( by my own hand, which is forbidden), the problem may be worse ( eternal damnation )… the “ rub” is the difficulty of that choice: stay alive and face a terrible situation or commit suicide and face one that is worse.

  9. I thought the value in taking NMN (which I do) was to potentially increase lifespan by increasing NAD levels. That’s what I thought Sinclair’s animal studies showed, that the mice given NMN had longer and healthier lifespans.

    I started taking NMN several months ago. I take 1,000mg a day along with other supplements for heath and potential anti aging benefits. Even though I have always exercised and followed a healthy diet, I noticed a big difference in energy when I added NMN. It works particularly well when combined with CA-AKG.

    I appreciate your summary of these studies on NMN. I can’t discount the findings but I don’t intend to stop taking NMN, at least for now. I really feel a benefit when I take it.

  10. NMN was not designed to lower lipids, fatty liver, unless you actually do the exercise work along with it. Many if these studies dont incorporate wgat is needed to get results from NMN. NMN without resveratrol or other sirtuin activaters is like putting fuel unto a car with no engine

  11. Dr. David Sinclair has a connection to MetroBiotech, a company that develops anti-aging products based on NMN. Dr. Sinclair is a co-founder and board member of MetroBiotech. He is also involved in the research and development of MIB-626, a pharmaceutical-grade tablet of NMN that MetroBiotech produces.

  12. something I thought might be of interest. Michael, from the channel "Conquer Aging Or Die Trying", has been using himself a s a gunnie pig and trying to "biohack" aging as he puts it. Yes, he is a sample size of one, but his approach is interesting as he has been tracking a number of biomarkers of aging on a regular basis for years now though various laboratory test. tracking NAD+ levels, various epigenetic markers including DunedinPACE and the Horvath clock, as well as creatinine, eglom filtration, HDL/LDL cholesterol, and just about every other marker you can think of.

    He has tried numerous different methods to see what impact, if any it has on NAD levels, including BOTH NMN, and Nicotinic Acid. Interestingly, despite the fact that NMN offers a shorter metabolic pathway to NAD+, for a given oral dose, Nicotinic acid had a significantly greater effect on raising NAD+ levels, giving him his highest levels of plasma NAD levels of any of his test, by a lot! although the specific mechanism behind this difference is unknowable from the information available, I feel it is some pretty good evidence that there are indeed some absorption issues with oral NMN as this seems the most likely explanation, all things being equal. This isn't to say you don't absorb any NMN, just that on the balance of factors, the reduction in uptake percentage outweighs the metabolic efficiencies, all things being equal for a given dose.

    Another interesting finding though… despite a long history of his epigenetic age test results trending down with time, shortly after the taking the NA and seeing a large increase in NAD levels, his epigenetic age suddenly shot off in the other direction. It appears that this large jump in NAD levels likely actually caused an acceleration in the rate of epigenetic aging!!! talk about counter productive!

    Now, that said, this is not all that unexpected if you know much about the clearance pathway… basically, if you increase NAD+, it will eventually degrade as it gets used up. This will lead to a spike in NAM levels. If NAM levels can not be cleared by the NAMPT via the salvage pathway, it actively suppresses the expression of SIRT1 and parps and must be excreted via the clearance pathway which strips the body of methyl groups, directly affecting the methylation pattern of the epigenome…

    Long story short… you can't just increase NAD without considering the effect on the rest of your systems.

  13. I just finished reading the pre-release of “How Not to Age” by Dr Michael Greger, and after 2 years at 1250mg, I’ve stopped taking NMN, after learning that all these forms of NAD+ boosters are doing significant long term harm, reducing lifespan. This includes NMN, NR, NAD+, Niacin, Niacinamide, NRH, NMNH, etc… and that a far better strategy is the recycling and conservation pathways. By taking NMN, we’ve only been increasing our methylation burden to a point that can’t be offset by other supplements or dietary or lifestyle measures. While there are countless gems for proven strategies on supporting these other pathways, one quick and easy place to start is to add organic wheat germ to every meal. I urge everyone to read this book. It sickens me to think how much money I wasted shortening my lifespan with NMN, when I could have been using all these cheap to free, and infinitely safer and more effective strategies.

  14. 2:33 that table might indicate a larger sample size is necessary, nothing else.
    2:42 same, potentially or very likely underpowered

    What I am missing here is the presentation of the other changes.
    Body weight (difference -1.9 [-3.3, -0.5] kg, P = .008); diastolic blood pressure (difference -7.01 [-13.44, -0.59] mmHg, P = .034); total cholesterol (difference -26.89 [-44.34, -9.44] mg/dL, P = .004), low-density lipoprotein (LDL) cholesterol (-18.73 [-31.85, -5.60] mg/dL, P = .007), and nonhigh-density lipoprotein cholesterol decreased significantly more in the MIB-626 group than placebo.

    This would bring up the question, is NMN as good as a Statin?

    The study size of 9 vs 21 is a bit low, which is surprising as it cant be that hard to find at least 50 fat people. Female and male would be good.

    Also, for 28 days, the results are not that bad. I would prefer the study to run for 6 months at least. Also an arm with 2g NMN and 3g NMN.

  15. If I recall correctly, what’s the rub or there’s the rub came from Hamlet, possibly in general use of the Shakespearean / Elizabethan England at the time Shakespeare wrote Hamlet.

    ‘ Hamlet was thinking in his mind about what it might like to be dead, dead or considered it would be most likely at some point similar to sleep, but then he said, but what if I were to think, perchance to dream? “there’s the rub”.

    My recollection is seconded by what’s posted in an online commentary that says “10 phrases Shakespeare invented

    “There's the Rub
    What it means:
    that's the problem

    How Shakespeare Used It:
    In Hamlet's famous "To be or not to be" soliloquy, "ay, there's the rub" is the tormented prince's acknowledgement that death may not end his difficulties because the dead may perhaps still be troubled by dreams. (Hamlet, Act 3, Scene 1)

    (The original rub predates Shakespeare. On the smooth grassy greens used in lawn bowling, a rub was a bump or uneven area that could send balls off course.) ‘

  16. I used to like Dr Sinclair, but then I noticed that he cherry picks “scientific” research. He ignored the research from most of the Blue Zones and cherry picked a research from the only Blue zone where most people are vegetarians to justify why he became a vegetarian. Plenty people are now becoming vegetarians for political reasons and he strikes me as one of them. I don’t trust vegetarians. I also noticed that he uses filters on his videos to appear younger.

  17. I appreciate your videos, thank you. On the one you did about Omega 3 fish oil, Rhonda Patrick has a paper on it. I think she mentions that phosphhatidyl choline should be taken with it? Could you look up that paper if you haven't already and maybe give us your input on that? Also could you look into Chlorella for us?

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