david sinclair

Sirtuins and NAD+: The Secret Sauce for Extending the Human Lifespan – David Sinclair, Ph.D. on The Rich Roll Podcast

Check out The Rich Roll Podcast Episode Page & Show Notes

We put together a comprehensive Q&A Guide on NAD+ based on all of David Sinclair’s, Rhonda Patrick’s, and Peter Attia’s podcasts.

Key Takeaways

  • Sirtuins are a class of proteins that have two jobs:
    • 1) Regulate gene expression
    • 2) Help repair DNA damage
  • Sirtuins need NAD+ to function properly. Without it, aging is accelerated.
  • As we age, our NAD+ levels drop
    • By the time we’re 50, our NAD+ levels are about half what they were when we were 20
  • You can boost NAD+ through precursor supplementation, exercise, fasting, and by exposing yourself to cold/heat stress
  • Your genes aren’t your destiny
    • “80% of our health in old age is due to our lifestyle and how we live; only 20% is genetic” David Sinclair
  • The best thing you can do to live longer: eat less often

Supplements Mentioned

  • The two best NAD+ precursors:
    • NR
      • For us at Podcast Notes, based on their unmatched quality standards and our personal experience, we strongly recommend Elysium Basis (use the code “podcast10” at checkout to receive 10% off)
    • NMN
      • David supplements with 1 gram of capsulized NMN every morning (he doesn’t disclose his preferred brand)
  • Resveratrol, in addition to NAD+, also aids sirtuin function
    • David supplements with ~1 gram of powdered resveratrol every morning mixed in with some yogurt (once again, brand not disclosed)
      • Why yogurt? It’s essential to take the resveratrol with fat to increase absorption.


Getting Your Body Out of its Comfort Zone Helps Fight Aging & Disease

  • “The bottom line is you’ve got to get your body out of its comfort zone—hormesis is what we call it. The problem with today’s world is that we just want to be relaxed and fed. We don’t want to feel discomfort, and that’s leading to a whole bunch of problems. If we’re not always telling our body that things could be problematic, our bodies don’t care—they don’t fight against disease; they don’t fight against aging.”David Sinclair

The Science of Xenohormesis: Eating Stressed Plants Provides Us with Beneficial Polyphenolic Compounds

  • Xenohormesis = xeno (between species) + hormesis (what doesn’t kill you makes you stronger)
  • Which polyphenolic/xenohormetic compounds?
    • Things like resveratrol (which you’ll learn more about below) and quercetin
    • (As a general rule: the denser a plant or fruit’s color, the more polyphenolic compounds it has)
  • What do the polyphenolic compounds do?
    • Activate longevity-related enzymes, thus slowing the aging process 
  • Why?
    • The reason isn’t exactly known, but thinking evolutionarily, eating stressed plants (i.e., fruit that just made it through a massive drought) allowed our body to sense when the food supply might potentially be running out 
      • Think of it this way: the beneficial molecules in the stressed plants are basically telling the body, “Hey! This plant’s not going to be around for much longer! You better activate your longevity enzymes to survive!”

Sirtuins: The Pianist That Plays the Genetic Piano

  • NAD+ is the fuel for a class of enzymes/proteins/genes known as sirtuins
    • Sirtuins control whether a cell’s genetic information is on/off (they regulate gene expression)—think of them as the “pianist that plays the genetic piano”
      • When sirtuins lose function, it’s as if the pianist becomes “demented and starts making a lot of mistakes”—this is a primary driver of the aging process
  • Sirtuins become distracted from their primary job (regulating gene expression) by their second job: fixing DNA damage
    • (Thus, DNA damage accelerates aging)

Hw do we keep sirtuins active, and thus, slow aging?

  • Provide them with enough fuel (NAD+)
    • Without adequate NAD+, sirtuins lose function—they may take charge of fixing DNA damage, but they’re more likely to “lose their way back” to the cell, thus impacting a cell’s gene expression
  • Secondly, resveratrol helps “activate” sirtuins (if sirtuins are the car, and NAD+ is the fuel, resveratrol is the accelerator pedal)

Horvath’s Methylation Clock is Central to the Information Theory of Aging

  • (Named after Steve Horvath)
  • In short, Horvath’s methylation clock is a measurement assessment for someone’s biological age
    • This all comes back to sirtuins. Remember, from the above, that when sirtuins lose function, it’s as if the pianist becomes demented and starts making a lot of mistakes. Sirtuins may take charge of fixing DNA damage, but they’re more likely to “lose their way back” to the cell, thus impacting a cell’s gene expression. Horvath’s methylation clock allows one to measure this loss of gene expression (AKA, how “demented” the pianist is).
  • Digging into the specifics:
    • Our DNA has chemicals (methyls) on it, which tell specific genes to be on/off—we’re born with a particular “methylation pattern”
      • As as we age, due to a loss of sirtuin function, these methyls start coming off, and thus, gene expression is altered. Horvarht’s method measures how these methyls change over time, and therefore, your biological age.

Lipolysis Byproducts and Olive Oil—In Addition to Resveratrol—Both Activate Sirtuins

  • “The byproducts of lipolysis—the breakdown of fat when you’re hungry—produce monounsaturated fatty acids, which are also found in olive oil. Those molecules circulating in the blood are about a thousand times more potent than resveratrol at activating sirtuins.” David Sinclair
    • So, by fasting (or eating olive oil), you’re aiding sirtuin function 
      • (In a sense, then, supplementing with resveratrol mimics the body’s fasting state)

One Quick Note

  • We’ve mentioned resveratrol several times now. If you chose to supplement, because resveratrol is relatively insoluble, taking it with a fatty solvent, such as yogurt, increases absorption 5-10 fold.

All Stressors Activate the Same Longevity Pathway

  • Which stressors?
    • Exercise, fasting, cold/heat stress, etc.
  • All of the above work in the same way: by acting on a gene called PNC1 that makes NAD+
    • Thus, by exercising, fasting, or using the sauna, you’re increasing your NAD+ levels
  • Additionally: NAMPT, a gene activated by heat stress, also boosts NAD+ production

The Impacts of David’s Anti-Aging Work: Quote Style

  • “We could have a world, by the time we’re elderly, where people in their 80s are just starting a new career … That’s a world that would save trillions of dollars on healthcare.”David Sinclair
  • “The FDA has agreed that, if we do certain clinical trials with metformin—the diabetes drug—that we think might slow aging, if we can hit certain endpoints and show things are working, they’re well-prepared to consider calling aging a treatable condition—if not a disease—that we can prescribe medicines for.” – David Sinclair
  • Perhaps the biggest reason to fight aging: “Let’s not be silly about it—aging is what’s driving cancer, heart disease. and Alzheimer’s disease; it’s the main cause of disease and disability on this planet.” – David Sinclair
  • “We’ve got to throw away our preconceptions of what being old is … Being 50 isn’t old anymore … Even 80 isn’t old if you take care of yourself. If you extrapolate that into the future, they’ll come a day when being 100 isn’t old.”David Sinclair
  • “We’ve been on this trajectory of living healthier and being more youthful in old age for the last few hundred years. A child born today, if we stay on that trajectory here in the U.S., can expect to live to 104. That means they’ll still be healthy at age 80 and 90, which is great.” – David Sinclair
  • “I would love a world where people could live to 250 and expect to still be playing tennis at 120. I think something like that is doable; there’s no reason why we can’t do that with our ingenuity.” David Sinclair
  • “What I want is a world where people in their 80s and 90s are not just appreciated, but actually utilized. If they’re healthy, they can be advising or running companies or motivating the youth. That’s the world that I want.” – David Sinclair

Your Genes Aren’t Your Destiny

  • “80% of our health in old age is due to our lifestyle and how we live; only 20% is genetic” – David Sinclair

How To Live Longer

  • Eat less often; hunger facilitates sirtuin activation
    • “I think the most important thing for increasing healthspan, if there’s just one thing I could say, it would be to eat less often. Don’t eat three meals a day.” – David Sinclair
  • Exercise frequently
  • Fast regularly
  • Get adequate sleep
  • Limit meat consumption
    • Why? – Amino acids found in meat activate mTOR, a pathway that turns off our body’s defense mechanisms
      • Essentially, by always activating mTOR, it’s as if you’re telling your body, “Times are good! Time to grow!” (if you’re always in “growth mode,” your body doesn’t spend much time in “protective/defense mode”)

Sirtuins Control the Body’s Sleep/Wake Cycle (Circadian Rhythm)

  • Thus, by living a life geared towards sirtuin optimization (with frequent fasting, exercise, cold/heat stress, etc.), you’ll likely get better sleep
  • For this reason: “If I raise my NAD+ levels, either by fasting, exercising, or taking a supplement, I don’t get the effects of jet lag” – David Sinclair
    • (Remember: NAD+ is like fuel for sirtuins)

David’s Personal Routine

  • David intermittent fasts daily:
    • “I’m skipping one or two meals a day, and it’s changed my life. I feel great. A lot of people say, ‘It makes me feel queasy,’ or that it burns their stomach, but I’ve gotten used to it. If you find that it’s too hard, try drinking a cup of hot water, coffee, or tea—that’s what gets me through the morning.” – David Sinclair
  • David supplements with NMN, a NAD+ precursor
    • You can also supplement with NR, another NAD+ precursor: For us at Podcast Notes, based on their unmatched quality standards and our personal experience, we strongly recommend Elysium Basis (use the code “podcast10” at checkout to receive 10% off)
  • David supplements metformin, a drug commonly given to type 2 diabetics to lower hepatic glucose output; here’s why:
    • To lower disease risk
      • Fact: Compared to type 2 diabetics who don’t take metformin, those who do have a much lower risk of Alzheimer’s disease, cancer, and heart disease over the next five years.
    • To enhance mitochondrial activity (which metformin does through AMPK activation)
    • But what about all the research saying that metformin inhibits exercise’s benefits?
      • David says it doesn’t inhibit muscle hypertrophy nearly as much as people think (the data’s WAY overblown), but out of an abundance of caution, he doesn’t take metformin on days he exercises

We know how to slow the aging process, but what about reversing it?

  • David and his team have, using a set of genes known as reprogramming factors (AKA Yamanaka factors), were able to repair eyesight in mice
    • (It sounds like these reprogramming factors reset the methylation clock mentioned above, thus reversing the age of the cell, as well as redirecting sirtuin proteins to their origin, and by doing so returning gene expression to normal)
    • How? – They put a set of the reprogramming genes into a benign virus and inject it straight into the mouse’s eyeball (the virus is just a way to get the genes into the cells)
      • The genes are then turned on with an antibiotic
    • David started a company centered around making this possible in humans
      • The process will first be used to treat glaucoma and, if proven safe, eventually repair eyesight loss associated with old age
  • Given the above, imagine the future possibilities:
    • If put into an adult skin cell, these reprogramming factors could cause it to reverse in age to a much more primitive version (specifically to a pluripotent stem cell)
      • That pluripotent stem cell can then be grown into a neuron, eye cell, whatever you wish!

Additional Notes

  • Before recording this interview, David spent the morning doing Laird Hamilton’s famous underwater pool workout and using his sauna/ice bath
    • David says Laird keeps his sauna at ~250 degrees Fahrenheit!
  • David gave his wife Ray Cronise & Julieanna Hever’s new book, The Healthspan Solution for Christmas
  • “I do my work not because I’m seeking fame or anything—I’m a pretty shy guy, but because I want to see these anti-aging technologies adopted within our lifetime. It’s fine if future generations do well, but I think it’d be a real shame if our generation was the last to live a normal lifespan.” – David Sinclair
  • On the Australian fires:
    • “Last week, my brother’s family lost their house. It was burnt down … It really brings home the fact that we’re living in dangerous times, and you can deny it. You can deny that the world isn’t changing and we’ve lived through these times before, but let’s just face it; let’s use Occam’s razor. The simplest explanation is that the world is fucking up and we’re the cause of it. It’s not that hard to admit unless you’ve got some other agenda.” – David Sinclair
  • There’s no point in living to 150+ if you don’t have a sense of purpose
    • “Ultimately, what’s the point in living so long if our value system isn’t in alignment with what’s required to be fulfilled, happy, and have a sense of purpose?”Rich Roll
  • “Every year you’re alive, you get an extra three months of life because technology is changing” – David Sinclair

To read more on NAD plus a guide to safety in supplements. Click here.

Rich Roll Podcast : , , , , , , , , , , , , , , , ,
Notes By MMiller

More Notes on these topics

Top Insights and Tactics From

31 Best Podcasts of All Time

FREE when you join over 35,000 subscribers to the
Podcast Notes newsletter

No Thanks