David Sinclair, Ph.D. – The Joe Rogan Experience #1349

For the most comprehensive take on all of David Sinclaior’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

  • Sirtuins are genes which protect all organisms from deterioration and disease
    • They need NAD+ to function
  • NR and NMN is an NAD+ precursor which you can supplement with
    • When it comes to a brand of NR, we can’t recommend Elysium Basis enough (use the code “podcas10” at checkout to receive 10% off). We, Matt and Yoni, have been researching the company and trying Basis out for the past 3 months. Basis is a proprietary formulation of crystalline NR and pterostilbene that supports cellular health by increasing and sustaining NAD+.
    • NMN also improves blood flow, one of the major benefits associated with exercise
  • Resveratrol is thought to increase sirtuin activity
  • They’ll come a time when you can’t tell how old someone is
    • To add – “In the future, 90 will feel like 50”
  • As best as you can, try to be hungry at least once a day
    • Sirtuins are activated when you’re hungry due to a rise in NAD+ levels
  • Wear sunscreen
    • Over time, the sun causes DNA damage which accelerates aging (x-rays and airport scanners also do this)
  • CRISPR and genetic reprogramming will revolutionize medicine

Products & Supplements Mentioned


Examining a Recent Aging Study

  • A recent study showed that a combination of metformin, DHEA, and human growth hormone resulted in a decrease of ~2 years in terms of biological age
    • BUT – the study only involved 9 people
    • “Is aging truly reversible? That’s what this study suggests… One day we could be 80, but biologically be 30.”
  • The above study also saw a reduction of a protein called C 38
    • C 38 resides on immune cells and increases in quantity as we age
    • C 38 is the main enzyme in our body that degrades NAD+ – NAD+ is required for sirtuins to function (sirtuins are genes which protect all organisms from deterioration and disease)

The Horvath Clock | How Biological Age is Measured

  • What is it?
    • On letter C of DNA (remember – DNA consists of 4 letters: A, C, T, and G), there are chemical modifications that change in very linear and predictable ways
      • Reading these chemical modifications allows one to determine biological age AND the age at which you’re likely to die
  • “Now that we know how to measure aging, we think that the Horvath clock is part of the aging process. We’re learning how to reverse it too.”
    • “I think, as we use this clock, we’re going to figure out a whole bunch of stuff that we can do to not just slow aging, but reverse it. And not just by 2.5 years. With some of the technology I talk about in my book, I think we could turn the clock back by a decade or more.”

The CORRECT Theory of Aging

  • The old theory stated that we age because we lose DNA/it’s damaged
  • David has a new proposal:
    • We age because our DNA gets modified and our cells lose the ability to read it the way they used to

Antioxidants & Resveratrol

  • “Antioxidants have been the biggest disappointment in the aging field… Antioxidants have, with very few exceptions, failed to extend the lifespan of any organism.”
  • That being said, David still supplements with resveratrol
    • Resveratrol is a mild antioxidant – “But the way it really works is it stimulates the body’s defenses against aging and disease”
      • How? – It binds to sirtuins which, as mentioned, are sort of like the body’s defenders 
    • David mixes his resveratrol with yogurt every morning – he takes ~0.5 grams
      • Why yogurt? It’s important to take the resveratrol with fat to increase absorption
        • In David’s studies (in both humans and mice), if resveratrol was not given with fat, absorption was 5-fold less
        • David makes the yogurt himself out of whole milk 
  • David has found that treating mice with resveratrol makes them resistant to the negative side effects associated with eating a high-fat/Western diet
    • What dose? – A human equivalent of 250 mg/day
    • Specifically – their livers, arteries, and metabolic markers mimicked those of healthy, lean, and young mice


  • NMN is a precursor to NAD+
    • David takes 1 gram every morning mixed in with his yogurt
  • In mice, tt’s been found that NMN improves blood flow
    • “They get the benefit of exercise without having to exercise”
    • AND – the NMN was found to increase the amount of time these mice ran until exhaustion 

Metformin Decreases Physical Performance

  • Although metformin may have an anti-aging effect, some studies show it decreases physical performance in athletes 
    • Because of this, David only takes metformin on days he doesn’t exercise
  • Why does metformin decrease physical performance?
    • David has a hypothesis – Metformin is interfering with our mitochondria and disrupts its energy production
      • Because of this, later on, the body responds by making more mitochondria to make up for the energy loss (hence the benefit of metformin)

David’s Workout Routine

  • David only spends ~3 hours a week in the gym (and he does it all in one day)
    • “I’d work out more if I had time. I’m usually working until midnight.”
    • He lifts weights for ~1 hour, stretches, and then does some hot/cold therapy (a sauna/cold tub)

Wild Animals & David’s Recent African Safari

  • David recently vacationed in Africa for 16 days with his 3 kids (ages 16, 14, and 12) and father (who just turned 80) – he has some photos on his Instagram
    • Where specifically? – Kenya, Tanzania, and Uganda
      • “The Serengeti was absolutely incredible”
    • “When you see a wildebeest get attacked and chewed on for 45 minutes by a crocodile, there’s nothing better than going back to the camp and having a beer to calm down”
      • “One of the things you realize when your among these animals is it’s a huge privilege to be able to go for a walk without being eaten”‘
    • “I recommend everyone go to Africa, not just to come back a better person and a better human being, but also to support them. They really need our help over there.”
  • Joe saw a grizzly bear once while hunting
    • “Black bears are unnerving, grizzly bears are terrifying”
  • One day, while Joe was driving in Santa Barbara, he saw a mountain lion run across the road
  • “F**k keeping monkeys in a cage. That drives me so crazy. I hate it. I took a pot edible once, a real strong one, and went to the zoo. It was so depressing staring at the chimps. I just sat across from them and watched. I thought, ‘Oh my God, these things are in hell. They’re in prison!'” – Joe

Isn’t aging natural?

  • “People ask me about my work: ‘Isn’t what you’re doing unnatural?’ F**k natural. What about our world is natural anyway?”
    • “I flew here at 30,000 feet drinking a cocktail while surfing the internet… not natural!”
    • “Don’t give me the argument that aging is natural and therefore it’s acceptable”
  • “What’s natural for primates is to change their environment”
    • Using genetics to understand why we age and why we don’t have to is EXACTLY that

The Commonalities Among Centenarian

  • The oldest human to ever live made it to 122 (this is actually debatable – some think the woman was subsumed by her daughter to avoid paying taxes)
    • That being said, people have definitely lived to 117
  • Centenarians often have a specific FOXO3 gene variant
  • “These long-lived people tend to live a long time no matter what they do” 

What problems might result if humans start living longer?

  • One of the things people worry about if we all live longer is that we’ll run out of food and space
    • “If you look at human history… that’s not going to happen”
    • “I’m of the strong belief we can engineer our way out of just about any problem”
  • What about climate change? Won’t it wipe us out?
    • “I don’t think we can stop climate change at this point. It’s definitely happening; you can see it all around. But will it wipe us out? No. Will it cost us trillions of dollars? Yeah.”
      • “It won’t be the end of us, but it’s going to be a challenge to continue to survive and proliferate as a species in the face of all those costs”
    • “That’s one of the reasons I’m excited about extending people’s healthspans and lifespans, it’ll save tens of trillions in the globe each year. That’s money that can be put to combating global warming.”
  • What about work? If people are living to 150-200, what will they do?
    • They’ll continue working 

David’s 80-year-old Father’s Supplement Protocol

  • Just like David, he takes NMN, metformin, a statin, and resverat
  • rol
  • He also does a fair amount of aerobic exercise (rowing and stair climbing)
    • David said he recently climbed 40 flights of stairs in just 15 minutes
  • “He’s looking forward to another 10 years of vigorous life… When you’re healthy, you’re happy.”
  • He recently picked up a new job as a committee member that evaluates clinical trials for ethics

50 is the New 30

  • The older we get, the wiser we become
    • “It’s going to be such a great world when people with 80 years of experience can continue to run companies, be teachers, and educate the young people”
  • “I’m so much wiser at 52 than I was at 42. I just am. I make fewer mistakes and I’m more aware across the board. I was wiser at 42 than I was at 32. At 22, I was basically a chimp. As time goes on, you understand how you’re interfacing with the world. You communicate with people better. You know how to get by. You know what you have to do and what the consequences are of not doing what you have to do.” – Joe
  • David adds:
    • “When I was in my 20s, I thought I knew everything. I looked at myself as a 50-year-old and thought, “Wow, what an old fart.’ It’s not like that at all… 50-year-olds today are just like 30-year-olds twenty years ago.”
    • “A 50-year-old isn’t old anymore. A 50-year-old is just getting going.”
    • “In the future, 90 will feel like 50”
    • “They’ll come a time when you can’t tell how old someone is”


  • David first discovered he had high cholesterol levels when he was 29 
    • He’s been on a super high-dose (~80 mg) statin ever since (a normal dose is ~10 mg)
      • Why such a high dose? – He has REALLY bad genetics when it comes to cholesterol

Try to Be Hungry at Lease Once a Day

  • David intermittent fasts as much as he can (he skips breakfast and has a late lunch)
  • “For anyone that wants to know what the best periodic protocol is…there isn’t one. We don’t know yet.”
  • As best as you can, try to be hungry at least once a day
    • Sirtuins are activated when you’re hungry due to a rise in NAD+ levels (remember – NMN is also thought to raise NAD levels)

Intravenous NAD+

  • David says he’s tried intramuscular NAD+ (it was an injection)
    • “I had tingles in my legs. I felt a little different for maybe 10 minutes and then it went away.”
  • Many people swear by intravenous NAD+, but as Peter Attia explained in these Podcast Notes, there’s just no evidence that the NAD+ is getting into the cells
    • “The fact is, we don’t know if it works yet”


  • What is it?
    • Certain molecules (stress-response chemicals) are produced within plants to make them healthier in response to stress
      • As a side effect, the plants turn more colorful 
  • “I believe we’ve evolved to sense those chemicals in our food supply”
    • Our bodies benefit from these stress-response chemicals – they enter our bloodstream and turn on a variety of defense mechanisms against disease
  • Red wine is filled with tons of healthy xenohormetic molecules – Resveratrol, quercetin, and polyphenols to name a few


  • David gets between 6-7 hours a night
  • He wears an Oura Ring to track his sleep
  • Check out the Podcast Notes from Dr. Matthew Walker’s appearance on Joe’s podcast. A few things they discussed:
    • There’s a direct correlation between a lack of sleep and Alzheimer’s disease
    • Avoid Ambien 
      • David will occasionally take a very small dose (~1 mg) if he’s struggling with jet lag. He’ll sometimes take a small dose of melatonin as well.
  • Wearing blue light blocking glasses a few hours before bed has greatly improved David’s sleep quality

Let’s Sum Up | How to Increase Your Healthspan

  • Exercise
  • Be hungry at least once a day
  • Use cold/hot therapy (using the sauna in combination with a cold shower)
  • Supplement with NMN and resveratrol
  • Another tip – wear sunscreen
    • Why? – Over time, the sun causes DNA damage (it “breaks ” chromosomes) which accelerates aging (x-rays and airport scanners also do this)
      • Going through an airport scanner gives you the same radiation dose you’d get on a 5-hour flight
      • David has shown, in mice, that NMN protects against the effects of radiation
        • For this reason, it might be a good idea to supplement with NMN before/after a flight or getting an x-ray

Nicotinamide Riboside (NR)

  • NR is another NAD+ precursor (it’s thought to also boost NAD+ levels) – reputable brands include:


  • “I’m a big believer in CRISPR in the sense that it’ll revolutionize medicine”
  • What is it?
    • It’s an acronym for a bacterial system used to kill/destroy the DNA of invading organisms (like viruses)
    • We can now use that system to cut and change specific parts of our own genomes
      • It can also be used to insert new genes into the genome after cutting out unfavorable ones
  • From David’s last appearance on Joe’s podcast:
    • Recently, a Chinese researcher engineered twin baby girls with CRISPR to be resistant to HIV/AIDS – see more here
      • The chance of getting HIV in China is 1/1000
      • In theory, he could have made them resistant to anything (like cancer or heart disease) – HIV was only the first test

Digging Deeper Into Genetics | Genetic Reprogramming

  • David and his team have, using a set of genes known as reprogramming factors (AKA Yamanaka factors), have been able to repair eyesight in mice
    • 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
    • “It’s only been a year since we’ve known about this. Imagine what we’ll be able to do in 50 or even 10. It’s going to be a remarkable future.”
    • David next plans to attempt repairing spinal injuries in mice using this same method


  • This is another field David is very excited about
  • What are senolytics? – Drugs (a pill or injection) that kill off senescent cells
  • Senescent cells = zombie cells (AKA shut down cells)
    • It’s been shown in animal studies that they cause aging
    • One study found that by genetically deleting the senescent cells which had accumulated in old mice, their aging was delayed
    • Senescent cells raise a variety of inflammatory markers
  • Senolytic therapies are close to becoming popularized

Wrapping Up

  • TONS of aging research is on the horizon – it’s an exciting time to be in the field
  • “We have things we can do in our daily lives, in both lifestyle and molecules you can take, that give us a VERY good chance of living beyond what’s naturally possible”

Additional Notes

  • Humans first tamed fire 500,000 years ago
  • Joe and David are drinking coffee mixed with Laird Hamilton’s Superfood Vegan Tumeric Coffee Creamer
  • Last time David was on the podcast, he and Joe did cryotherapy afterward
  • Laird Hamilton rides his Assualt AirBike IN the sauna
    • Joe tried turning his dry sauna up as high as Laird recommends (~220 F) and was NOT a fan – “I think it cooked my lungs
  • Joe recalls an insane stat – In Kyrgyzstan, 20% of all marriages begin in kidnapping
  • Joe says World War Z is a “f***ing great movie”
    • Also – “The novel is supposed to be excellent”
  • David’s grandmother had her father when she was only 15
    • “She wanted me to do the best I could with my life. She said, ‘David – do what you can to make this world a better place. Make sure you leave this world better than you found it.’ That’s what I’m trying to do.”
  • “One of the things that’s been highlighted when you read books and studies on happiness is goal-setting, working towards those goals, and achieving progress. These are critical components of happiness for human beings.” – Joe
  • David wears an Apple Watch
    • His resting heart rate is 46 BPM
  • David uses a standing desk
  • Joe visits Digg once a day
  • Rhonda Patrick, using a continuous glucose monitor, has found that grapes are one of the worst foods when it comes to spiking blood glucose levels
    • Another thing she learned: potatoes don’t raise blood sugar as much as you’d think
    • Joe adds – “99% of my nutrition knowledge I get from Rhonda Patrick”
  • David once tried the Okinawa diet which consists of eating only fish and tofu
    • He stopped once he had kids
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