September 9, 2019

Science of Aging

#70 – David Sinclair, Ph.D.: How cellular reprogramming could slow our aging clock (and the latest research on NAD)

Read Time 24 minutes

In this episode, David Sinclair, Ph.D., a Professor in the Department of Genetics at Harvard Medical School and co-Director of the Paul F. Glenn Center for the Biological Mechanisms of Aging, returns to the podcast to discuss the content of his new book, Lifespan: Why We Age – and Why We Don’t Have To. This conversation focuses on the biological mechanisms involved in what David terms the Information Theory of Aging which provides insights into the “clock” that determines our aging and to what degree it can be manipulated. Our discussion on aging of course leads us into interconnected topics of epigenetics, sirtuins, cellular senescence, as well as what compounds David is personally taking for his own longevity. Additionally, we discuss the most up to date information related to NAD and longevity by looking at the potential benefits (if any) of supplemental agents (NAD precursors, NR, NMR, etc.) that pose a promise of increasing NAD.


We discuss:

  • SIR genes and cellular identity [8:45];
  • Sirtuins regulate gene expression [14:30];
  • DNA is methylated at the deepest layer of the epigenome [17:45];
  • Methylation pattern and determining cellular age [20:15];
  • Cellular reprogramming [33:45];
  • Yamanaka factors to push cells “back in time”  [41:00];
  • Human cellular reprogramming viability [57:00];
  • Measuring the rate of aging [1:02:45];
  • Cellular reprogramming for longevity [1:14:45];
  • Compounds David takes for his own longevity [1:29:15]
  • NAD precursors (NR, NMN) and pterostilbene [1:40:00];
  • The current field of sirtuin activators [2:03:15];
  • David’s artistic work [2:05:15] and;
  • More.


SIR genes and cellular identity [8:45]

The SIR gene – silent information regulator – is a gene that controls other genes

  • One of the roles it is most well-known for, is its implication in longevity:  In a study by Matt Kaeberlin Sir2 was shown to control the aging process in yeast
  • The gene group’s primary roles are to:
    • Silence other genes 
    • Repair damaged DNA

The SIR enzyme is the master regulator of this cellular survival circuit

  • The SIR gene cannot silence other genes and serve a cellular repair function at the same time
    • silenced genes are temporarily “turned on” while the damage is repaired by the enzyme protein
    • “turned on” genes help with the repair  
    • the protein then returns to its “silencing post” 

Figure 1. When SIR enzyme proteins detect stress in the cell (e.g. DNA breakage) the protein leaves the silent region to go and repair the DNA. When the problem is fixed, it returns to its original post, silencing genes. Image credit: (Alves-Fernandes and Jasiulionis, 2019)

Overtime, in the back-and-forth of repair…  SIR genes lose track of which genes should be silenced or not

  • In aging yeast, the loss of cellular identity results in a sterility phenotype
  • With age, our cells lose their “program” but early evidence in mice suggests that the original “hard disk program” can be recovered; restored to the original programming

“We have some early evidence from mice that we can actually find that hard disk drive and reinstall the software so that it’s pristine again and we find that we can actually improve the health quite dramatically in parts of a mouse’s body.” — David Sinclair, Ph.D

What does Claude Shannon’s Information Theory of Communication have to do with aging?…

  • In his 1940 paper, mathematician Claude Shannon presented his Information Theory of Communication 
  • He presented how to encode information and make sure that information gets to the receiver 
  • Shannon figured out how to preserve information: make a repository and reset the system

{end of show notes preview}

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David Sinclair, Ph.D.

David A. Sinclair, Ph.D. is a Professor in the Department of Genetics at Harvard Medical School and co-Director of the Paul F. Glenn Center for the Biological Mechanisms of Aging.

He is best known for his work on understanding why we age and how to slow its effects. He obtained his Ph.D. in Molecular Genetics at the University of New South Wales, Sydney in 1995. He worked as a postdoctoral researcher at M.I.T. with Dr. Leonard Guarente where he co-discovered a cause of aging for yeast as well as the role of Sir2 in epigenetic changes driven by genome instability. In 1999 he was recruited to Harvard Medical School where his laboratory’s research has focused primarily on understanding the role of sirtuins in disease and aging, with associated interests in chromatin, energy metabolism, mitochondria, learning and memory, neurodegeneration, and cancer. He has also contributed to the understanding of how sirtuins are modulated by endogenous molecules and pharmacological agents such as resveratrol.

Dr. Sinclair is the co-founder of several biotechnology companies (Sirtris, Ovascience, Genocea, Cohbar, MetroBiotech, ArcBio, Liberty Biosecurity) and is on the boards of several others. He is also co-founder and co-chief editor of the journal Aging. His work is featured in five books, two documentary movies, 60 Minutes, Morgan Freeman’s “Through the Wormhole” and other media.

He is an inventor on 35 patents and has received more than 25 awards and honors including the CSL Prize, The Australian Commonwealth Prize, Thompson Prize, Helen Hay Whitney Postdoctoral Award, Charles Hood Fellowship, Leukemia Society Fellowship, Ludwig Scholarship, Harvard-Armenise Fellowship, American Association for Aging Research Fellowship, Nathan Shock Award from the National Institutes of Health, Ellison Medical Foundation Junior and Senior Scholar Awards, Merck Prize, Genzyme Outstanding Achievement in Biomedical Science Award, Bio-Innovator Award, David Murdock-Dole Lectureship, Fisher Honorary Lectureship, Les Lazarus Lectureship, Australian Medical Research Medal, The Frontiers in Aging and Regeneration Award, Top 100 Australian Innovators, and TIME magazine’s list of the “100 most influential people in the world”. [] His new book, Lifespan, explains why we age and why we don’t have to. 

David on LinkedIn: David A. Sinclair, Ph.D. A.O.

David on Twitter: @davidasinclair 

David on Instagram: davidsinclairphdDavid’s book website:

BOSTON, MA - MAY 16: David A. Sinclair, Professor of Genetics and Director of the Paul F. Glenn Center for the Biology of Aging, poses for a portrait in the lab at Harvard Medical School in Boston on May 16, 2018. (Photo by Craig F. Walker/The Boston Globe via Getty Images)

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  1. Eating and not exercising our way to decreased longevity?

    I believe it’s well-known that opiate overdose is the cause of the decrease in this country (USA) in recent years. (Subsequently acknowledged, indirectly, by the guest, David Sinclair)

  2. Great conversation! Appreciate all the info you put out. Have a question regarding Gerovital-H 3, or procaine hydrochloride that a Dr. Aslan created maybe 50 years ago as an anti ager. I’m curious why no one talks about it. I realize there’s a lot of supplements out there… But a lot of people seem to have great results from it. Thanks again!

  3. A solution to the valuation problem you mention (around 1:00:00) is to sell therapies to the government. NBER/GAO (maybe a new group – whatever) could relatively easily determine valuation based on expected benefits to society, government could buy the rights to the therapy based on that valuation, then structure its administration in a way that maximizes benefit. People get the therapy, society gets its benefits, and developers gets paid – I think probably significantly more than monopoly pricing to the rich. There are issues here, but I think they’re far more surmountable than those arising when you charge “high hundreds of thousands of dollars” for a single dose of a single therapy. You like to talk about “area under the curve”. Think of the total benefits of my suggestion – making something immediately available – versus the slow decay of a model that begins with a tiny fraction of the population receiving the benefits and fans out from there.

  4. Excellent discussion! One question to clarify: At 1:36:50, Dr. Sinclair talks about an ITP study he ran with a Resveratrol dosage of “twenty four migs per kig to 240 migs per kig” in mice which I interpret to be 24mg/kg to 240mg/kg. He stated that he takes 1 gram/day, “a high dose.”
    I weigh 160 pounds or ~73kg. So that would be 1,745mg/day to 17,455mg/day. Most commercially available sources of Resveratrol fall in the range from 100-1,500mg capsules (further evidence that there is some confusion on the proper dosing). Is the correct interpretation that an average size adult male could beneficially take 1,700+mg/day, or is this dose specifically metered for mice, with human dosing not related? What am I missing?

    • Why did you call 1000 mg of resveratrol a high dose? Assuming david weighs about 70 kg shouldnt the minimum dose (24mg/kg ) be at least 1680 mg ?

      • Dr. Sinclair calls his dose of 1,000 mg/day “a high dose.” Direct quotation from the podcast.
        That is why I am confused. Because his 24-240mg/kg dosing would indicate a dose of 1,680 – 16,800 mg/day if he weighs 70 kg. So 1,000mg is not a “high dose.”

  5. Would transmucosal delivery of NR (with suppository rather than sublingual) provide better bioavailability? Also I must have missed Dr. Sinclair’s overall impression of Pterostilbene that Dr. Attia was probing.

  6. Is this the study discussed at 1:49?

    Nicotinamide Riboside Augments the Aged Human
    Skeletal Muscle NAD+ Metabolome and Induces
    Transcriptomic and Anti-inflammatory Signatures

  7. Fantastic conversation – I’m one of the founders of Chronomics – what you are talking about is literally what we do – let’s chat!
    We find that biological age prediction is also associated with other epigenetic predictors – what will be fascinating is digging into how direct the aging clock is to other markers of aging eg. senescence markers?

    Very exciting times, great podcast.

  8. Great conversation! In my dream version of this podcast would have loved to hear David’s view of what Chris Masterjohn had to say about NAD. What I took away from the latter is that there are good reasons to go NR if you’re going to take a NAD precursor, but also really need to have a plan for managing methyl donors. Such as some combination of supplementing creatine, TMG and phosphatidylcholine.

  9. Wadaminit…isn’t doxycycline preferred treatment for several of the bioterrorism bugs? Additionally, WTH are the antibiotic stewardship folks gonna say about this?
    My concern with ANY of these things is…unintended and/or unforeseen reactions that occur…. focusing in on a certain cell receptor just seems too reductionist.
    Disclaimer: I come from a long line of peeps that won’t take medications for valid medical diagnoses.

  10. On p. 183 of Lifefspan: Why We Age and Why We Don’t Have To, David Sinclair writes that digoxin is used to “reduce build-up of fluid in the heart.” To my knowledge, that is definitely not the most commonly known way the drug works. What I have learned is that digoxin slows the AV node, increasing the time the heart is in diastole. It improves pumping function, and decreases the heart rate.

  11. It’s interesting Dr. Sinclair referring to skin cells losing their “cellular identity” as one ages…

    I’m not an oncologist, but my understanding is that one of the parameters for characterizing tumor malignancy is the degree in which a cellular mass loses their “cellular identity”… Reverting to an “undifferentiated stem cell like state” with stem cell like characteristics and metabolism (anaerobic glycolysis).

    I’ve wondered if their is a deep connection between these 2 facts? I realize cancer does not increase monotonically with age (perhaps if you have protective genes, there is a positive selection effect?) And biology is more complex and there will be exceptions to everything and the issue is cancer is such a broad term describing many modes of uncontrolled growth, but is it possible that some types of cancers (Definitely not all types) have somehow reverted to an uncontrolled stem cell like state? Or someone aging cells losing their cellular identity reverting to a stem cell like state? And there is some deep connection between what Dr. Sinclair is referring to a cancer?

  12. In retrospect… it’s probably more complex… for example I notice Dr. Sinclair Specifically refers to old neurons behaving like skin cells or liver cells (I’ve heard him say this reversion specifically)…
    Skin and neurons derive from ectoderm so some aberration in development or reversion once mature is consistent… but liver cells are derived from endoderm so it is probably more complex and if there is any connection it’s probably minor and definitely more complicating if there is some connection…

  13. Peter said that some people had said that the Rabinowitz paper was flawed because they froze the samples, which would have destroyed the NR. Are there papers or letters to the journal on this? Would you link them?

    David Sinclair claimed here that this trial:
    … showed that high-dose NR raised NAD+ in the muscle. (The show notes have the wrong trial linked: the linked trial did not look at muscle at all, and was using NR at a lower dose). However, it did *not* show that: it showed that NR “elevated the muscle NAD+ *metabolome* , evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products” but not NAD+ or NR itself. This is consistent with NR being used in the liver to make NAD+, releasing NAM, into the circulation and NAM reaching the muscle where it is metabolized into these other metabolites.

    It can’t just be that the Rabinowitz paper didn’t use a high enough dose, as the dose in the Rabinowitz paper was higher than used here after adjusting for the body mass and metabolism of mice.

    Also note that even if NR *had* raised muslce NAD+ (which it didn’t), that’s totally consistent with NR first being metabolized into NAM in the liver, since NAM can be used by NAMPT to make NAD+. A key question at issue is whether taking NR or NMN is actually just equivalent to taking NAM, but spending a lot more money.

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