David Sinclair, Ph.D. on Extending Human Lifespan & the Science Behind Aging – The Rich Roll Podcast

Check out The Rich Roll Podcast Episode Page & Show Notes

For the most comprehensive take on all of David Sinclair’s recommendations and the best ideas on optimizing healthspan, check out The Table of Longevity | The 5 Pillars to Optimize for Increasing Healthspan and Living Your Best Life

Key Takeaways

  • Aging should be classified as a disease
  • The main cause of aging is not a loss of genetic information, but the loss of epigenetic information
  • Sirtuins are genes which protect all organisms from deterioration and disease
  • Sirtuins need NAD to work
    • As we get older, our NAD levels drop  – by the time you’re 50, your NAD levels are about half what they were when you were 20
  • NMN is a precursor to NAD – the body turns it into NAD with just one step
    • This step is activated by hormetic stress – like exercising, fasting, or using the sauna
      • So when you’re fasting, NAD levels increase
  • David supplements with the antioxidant resveratrol, also thought to have a positive effect on sirtuin genes
  • By some estimates, only 25% of how you age is due to your genetics – the rest is due to how you live and your environment
  • One of the best things you can do to increase your chances of living longer – don’t overeat

Supplements and Products Mentioned

  • David takes 1 g of NMN and 0.5 g of resveratrol every morning mixed in with some yogurt
    • Note – he doesn’t get specific with brands, but he does say the resveratrol is in powder form
  • Meditating, as well as wearing blue light blocking glasses, prior to bed has helped David get better sleep
    • No specific brand was mentioned, but we recommend these


Life and Death

  • “I feel like we still don’t really think about death. We certainly don’t talk about it. Death is almost a verboten subject. Our exposure to the reality of death and aging in its most late and mature forms is something we do our best to white wash and remove from our field of vision.” – Rich
  • “Death is a pretty sad thing…it’s worth appreciating that we’re here right now, and that most of us are healthy, but we need to realize that it won’t last” – David
  • It’s actually thought that we’re the only animals conscious of our own mortality

Looking Back

  • In the introduction to his new book coming out in September, David talks about his grandmother
    • One piece of advice she left him with – “Make the most of your life, stay young, don’t listen to the naysayers, and leave a mark – do what’s good for humanity”
      • “Her goal and my goal is the same. Nothing matters except making the world a better place after you’ve been here.”
      • “I keep my eye on the goal, which is to help humanity, so the daily battles of research don’t get me down so much.”
  • David first got interested in the field of anti-aging after hearing a lecture from Lenny Guarente at MIT about yeast aging (David was studying yeast for his PhD at the time in Wales)

What is aging?

  • “Aging is a condition, but it should be declared a disease.”
    • The Merk Manual of Geriatrics defines something as a disease if it happens to the minority (less than <50% of people), and something “natural” as happening to >50% of people
  • Think:
    • Smoking increases your risk of getting lung cancer 5x
    • Getting to the age of 60 increases your risk of getting cancer 1,000 fold
      • Aging GREATLY increases your risk for cancer/disease
        • “If we can figure out why we get old and how to program the cells of the body to be young again, we won’t get those diseases, and even if we have those diseases, the body can heal itself”

Aging on a Cellular Level

  • There are a set of genes in yeast cells, and our bodies as well, called the sirtuins (sirtuins = SIR genes)
    • For example: SIR2 = Silent Information Regulator #2
      • So these sirtuins are “silencing genes” – they switch other genes on/off
    • David and his team at MIT discovered that if you mutate these sirtuin genes, yeast cells live longer
  • So…
    • The main cause of aging is not a loss of genetic information, but the loss of epigenetic information
      • Genetics = what makes up our DNA (our GENOME)
        • Our DNA strands are tightly packaged in proteins called histones
        • These histones can silence genes by tightly bundling up and essentially blocking certain genes from being read (or they can do the opposite)
      • Our EPIGENOME
        • This is the system that controls how our genes are packaged and read (how tight the histones are)
        • It switches genes on/off – whether they are/are not expressed
  • Let’s relate this:
    • Picture a scratched CD – it can no longer be read
      • This is a metaphor for how we age – our genome can no longer be read due to a damaged epigenome
    • SO – In order to slow aging, we need to prevent the scratches – the damage to our epigenome
  • Back to sirtuins
    • Sirtuins “sit” on the genes, bundling them up (controlling how tightly the histones are wound), and making sure they stay off

Here’s Why DNA Damage Matters

  • The sirtuins SIR1 and SIR6 also have the job of repairing DNA breaks
    • So when DNA needs repairing, they’ll move away from the genes that they should be silencing, and in turn, those genes come on temporarily
      • In theory, the sirtuins should go back to the genes they came from, but this doesn’t always happen
      • Over time, these sirtuins get mis-localized – and certain genes get silenced that shouldn’t

Nicotinamide Adenine Dinucleotide (NAD)

  • Sirtuins also act as enzymes to help modify other proteins, allowing them to do a better job of repairing the body
    • How do they modify other proteins? – By removing a chemical group called acetyls 
      • BUT – They can only remove acetyl pieces if they have NAD present
  • NAD also enables sirtuins to go about their work of repairing DNA and finding their way back to the gene’s they’re supposed to be silencing
  • Once you hit age 50, your NAD level is about half what it is at 20

NMN Explained

  • NMN is a precursor to NAD – the body turns it into NAD with just one step
    • That step is activated by stress
      • What type of stress? – In yeast, this might be a lack of glucose/sugar, heat stress, or a lack of amino acids
        • This also occurs in humans – when we exercise or fast, our NAD levels increase
  • David takes 1 gram of NMN every morning mixed with yogurt

Cool NMN Science

  • David did a study on mice showing that NMN supplementation led to mice having a 60-80% boost in athletic output on a treadmill
    • Side note: As we age, sirtuins in the lining of our blood vessels aren’t very active – this is thought to be due to a lack of NAD
  • Older mice given NMN appeared to have an aerobic capacity associated with heavy training even though they hadn’t been doing any exercise
  • Mice given NMN on top of exercise became “superathletes”, beyond what exercise along could get them

NMN and Heart Disease

  • It’s been found that SIR1 is very important for protecting the cardiovascular system from plaque build up
  • A study showed that giving NMN to older mice improved blood vessel plasticity and resilience

Are there any negative side effects of NMN supplementation?

  • David isn’t too concerned because really all that’s happening is the replacement of something lost with age (NAD)
  • They haven’t seen any negative side effects with mice (studies have only been done on mice up to this point)


  • Free radicals cause DNA damage
    • Antioxidants (in food and supplements) “mop up” free radicals
      • BUT – David thinks that the benefits of antioxidants are more so from their downstream effect on activating sirtuins, rather than their impact on free radicals
  • A popular antioxidant which David supplements with – resveratrol
    • In these Podcast Notes, David said – “You can think of resveratrol as the accelerator pedal for the sirtuin genes, and NMN as the fuel”
  • Resveratrol has been found to activate SIR1
  • Taking quercetin with resveratrol has been found to increase the length at which both of them act in the body
  • Resveratrol can be found in nuts and grapes, but its concentration is highest in red wine (however, the best way to get adequate amounts is by supplementing)
    • David takes his resveratrol powder with yogurt to increase absorption (you want to consume it with some sort of fat)

Diet, Hormesis, and Anti-Aging

  • By some estimates, only 25% of how you age is due to your genetics – the rest is due to how you live and your environment
  • “If I could tell you to do one thing to live longer, it would be to eat less”
    • “Calorie restriction is the most robust way to prevent cancer, heart disease, and pretty much all other diseases”
      • Sirtuin and mTOR pathways respond to how much we’re eating
        • If we eat less, these pathways get kicked into action
    • When you’re hungry, NAD levels go up
      • This means your sirtuins are active and repairing the body, making sure the body doesn’t lose its epigenomic stability (or accumulate any “scratches”)
        • The more you fast, the slower scratches accumulate
  • Limiting your protein intake also seems to boost NAD levels
    • “Eating a lot of steak would be about the worst thing you could do”
  • In general, any form of mild stress (aka hormesis) acts to increase NAD levels
    • For this reason, it’s beneficial to expose your body to changes in temperature 
  • Exercise also raises NAD levels

Protein and mTOR

  • Protein (made of amino acids) activates a pathway in the body called mTOR
    • It’s been shown that continuous activation of mTOR leads to accelerated aging
      • You can disable mTOR by fasting (or limiting your protein intake) or by supplementing with something known as rapamycin
      • If mTOR is always on, it’s essentially telling the body to grow, rather than hunker down/repair/survive
        • “Just telling the body to grow and build muscle all the time, is basically sending the wrong message for a long lifespan”

What’s David excited about?

  • Cellular Reprogramming
    • This is the term for the true resetting of the epigenome
    • “It’s essentially telling the cell to go and find the information that existed when it was young, and ignore all the other information that accumulated over time (aka epigenetic noise)”
      • It’s about communicating to the cell that its DNA should be wrapped up within histones in a specific way and to ignore all the other changes that have occurred over time
      • How?
        • It’s been found that by turning on 4 specific genes (aka Yamanaka factors) in cells (hair cells, liver cell, skin cells etc.), you can take an adult cell and turn it into a pluripotent stem cell
          • These pluripotent stem cells can then be made into any other cell type (like a sperm cell, an egg cell, etc.)
            • So it’s like you’re sending the adult cell back in time
          • It’s been found that by cycling these 4 genes on/off every 2 days or so causes mice to live 30-40% longer
    • But would this work in a human?
      • It’s very likely – a yeast or mouse is 99.99% of the way there
        • “If you ask a yeast cell, we’re basically a giant mouse”


  • “If you don’t have a mission in life, go get one. It will keep you happier and probably longer lived as well.”
  • It’s when many people lose purpose in life, that things start to go down hill
  • “Society would be so much better if people stayed healthy, but were also able to contribute. It’s about getting up in the morning and knowing you have something to do that’s important.”

David’s Daily Routine

  • He has a yogurt for breakfast mixed with pharmaceutical-grade resveratrol powder and NMN
  • He exercises on the weekends (he only exercises once a week due to extensive travel)
    • It’s some weight training mixed with high-intensity running
  • “I try to eat smaller meals, I try not to overeat, and I try to skip meals”
    • David frequently skips lunch
  • David always tries to get adequate sleep
    • It’s thought that being underslept has negative effects on sirtuins and NAD levels
    • Meditating, as well as wearing blue light blocking glasses, prior to bed has helped his sleep


  • ~40% of the population ends up getting heart disease
  • Epigenetic information can be passed from one generation to another
    • If a female mouse is stressed/made obese – the offspring are more prone to diabetes due to the epiegenetic transferability
  • David had his DNA sequences with 23andMe and found that he has a genetic susceptibility for emphysema (COPD) (his lungs aren’t that well optimized for clearing out toxins from smoking)
    • For this reason, David tries to avoid dust or secondhand smoke
  • Other anti-aging supplements (not discussed)
  • Many of the people who live well into their 100s tend not to get sick much in their younger years
  • In 2050, half the world will be obese
  • David and his team have reversed sight loss in older mice
  • David has found that NMN seems to reduce jet lag
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