Episode 4: NMN, NR, Resveratrol, Metformin & Other Longevity Molecules The Science Of Setting & Achieving Goals | Lifespan With Dr. David Sinclair

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Key Takeaways

  • “Insulin sensitivity is a hallmark of wellness. Keeping the glucose out of the bloodstream, keeping low levels is a hallmark of wellness and longer life.” – David Sinclair
  • NAD is critical to our body – without it, we can’t make energy and would be dead in less than a minute
  • NAD naturally decreases with aging, even with protective measures like exercise
  • NAD boosters: NR, NMN, resveratrol, fisetin, and quercetin
  • Taking 250mg of NR daily will likely increase NAD and decrease inflammation, but changes in body composition and mitochondria are debatable in humans
  • Despite what you may hope, you can’t actually drink enough red wine to get the therapeutic effects of resveratrol – it would take hundreds of glasses a day
  • Rapamycin inhibits mTor and mimics the effects of fasting, but dosing is tricky and can turn toxic
  • Spermidine a potentially exciting rapalog (mimics effects of rapamycin) works by stimulating autophagy and stabilizes changes to the epigenome
  • Metformin inhibits mTor, activates AMPK, and raises NAD levels
  • Remarkably, people with type 2 diabetes on a metformin regimen have been shown to live longer than their counterparts without metformin
  • Berberine may be a good over the counter substitute for metformin (check with your doctors)
  • It’s important to regularly monitor bloodwork, particularly liver enzymes when supplementing


Dr. David Sinclair is a biologist, professor of genetics at Harvard, author, and expert on aging and longevity. His research and biotech companies focus on understanding why we age and how to slow its effects.

In this episode of Lifespan, you’ll learn which drugs and supplements may help combat various aspects of aging. David Sinclair & Matthew LaPlante review data for NAD boosters, resveratrol, resveratrol, fisetin, quercetin, rapamycin, spermidine, metformin, berberine – and much more.

Host: David Sinclair (@davidsinclair)  Co-Host: Matthew LaPlante (@mdlaplante)

Book: Lifespan: Why We Age and Why We Don’t Have To by David Sinclair

Intro To Drugs & Supplements

  • Try as we may, our modern lives are built on sedentary activities
  • Most drugs are chemicals either naturally occurring or over the counter
  • It’s ideal to monitor bloodwork while on any supplement, drug, medication, etc. in case of effects on the liver or other systems
  • Government regulates harsher drugs in an attempt to mitigate risk to consumer
  • Drugs and supplements respond to lifestyle and environment

Review Of NAD

  • NAD stands for nicotinamide (vitamin B3) adenine (sugar) dinucleotide (phosphate)
  • NAD is critical to our body – without it, we can’t make energy and would be dead in less than a minute
  • Our cells use NAD to transfer hydrogen atoms between proteins and DNA
  • NAD also activates sirtuins, defensive enzymes
  • As we age, we make less NAD and burn more of it
  • Exercise can raise NAD levels – but you’ll still have less as you age
  • NAD synthesis genes are activated under mild stressors

NAD Booster: Nicotinamide Riboside (NR)

  • Nicotinamide riboside (NR) is the most well-known and well-studied NAD booster and is a compound of the nicotinamide +sugar without the phosphate
  • Note, vitamin B3 is a precursor to NR but is not effective in raising NAD levels
  • 250mg of NR will raise NAD levels on blood tests
  • NR is over the counter, well-tolerated, and considered safe
  • When given to mice late in life (the equivalent of 70-year-old human), NR increased mitochondria, extended lifespan, reduced, increased athleticism, enhanced oxidative metabolism
  • Because of the length of lifespan and difficulty controlling all variables, there are no longitudinal human studies showing increases in lifespan because of taking NR
  • The studies in humans of NR have been mixed – some have shown changes in body composition and lower inflammation, but decreases in blood sugar, changes in mitochondria have not been found yet
    • Studies have been short-term so it’s possible we just need longer ones – or it’s possible we don’t have the same response as mice

NAD Booster: Nicotinamide Mononucleotide (NMN)  

  • Nicotinamide mononucleotide (NMN) seems to be more effective than NR
  • In animal studies, NMN restores NAD levels, enhances insulin sensitivity, and looks promising for slowing aging but further studies need to be done
  • NMN is particularly strong in females
  • There have been fewer human studies of NMN but currently no reports of negative side effects
  • NMN studies are promising and could improve insulin sensitivity, increase wound healing in kidneys and heart
  • We don’t know whether NAD IVs work – but NAD has been used to treat addiction, depression, and hangovers
  • The other side of NAD & NAD boosters:
    • Some concern that NAD boosters stimulate cancer growth
    • A mice study did show an increase in senescent cells when given NMN but the mice were already predisposed to cancer

NAD Boosters: Resveratrol, Fisetin, Quercetin

  • Resveratrol is also an NAD booster which activates sirtuins
  • Resveratrol is found in red wine but it would take hundreds of glasses per day to get therapeutic effects
  • There may be a cumulative effect of resveratrol
  • Dosing of resveratrol: 250mg per day up to 1,000-2,000mg per day
  • Resveratrol is very insoluble and is best mixed with food
  • Benefits of resveratrol: defends the body, protect against free radicals, increases insulin sensitivity, decreases “bad” cholesterol, and increases “good” cholesterol
  • Potentially potent anti-cancer activity of resveratrol but further studies are needed in humans
  • Fisetin & quercetin are also sirtuins activators and kill senescent cells
  • We know much more about quercetin – effects are: reduced adiposity of fatty liver, reduced inflammation in the body, potent killer of senescent cells

Rapamycin & Rapalogs

  • Rapamycin inhibits mTor which mimics the effects of fasting
  • Rapamycin has extended the lifespan of every organism it’s been given to in low doses of about 10mg per week (not immune-suppressing doses)
  • Even late in life, rapamycin extends lifespan in animal studies – but the dosing has to be precise to avoid toxicity
  • Rapalogs mimic the effect of rapamycin, maybe without the toxicity
  • Spermidine works on autophagy and in mice studies has been shown to increase longevity, improve heart function
  • Spermidine works by stimulating autophagy (like rapamycin in mTor pathway) and stabilizes changes to the epigenome
  • Cognition has greatly improved in human studies on spermidine
  • Note: spermidine is made from wheat germ

AMPK Activators

  • Metformin has been used since the 50s to lower glucose in type 2 diabetics
  • Metformin is available over the counter in many countries and considered safe
  • Metformin inhibits mTor, activates AMPK, raise NAD levels
  • Metformin has been shown to have positive effects on longevity in animal studies
  • Benefits of metformin: lower blood sugar, more mitochondrial energy, less inflammation, muscle type switching
  • Remarkably, people with type 2 diabetes on a metformin regimen have been shown to live longer than those without type 2 diabetes
    • A study is ongoing right now to show to FDA that aging is a treatable medical condition
  • Metformin is cheap and not on patent so anyone can make it, and make it cheaply
  • More physicians are open to prescribing metformin for off-label use
  • Downside of metformin: can cause lactic acidosis, reduce appetite, upset stomach, muscle loss
  • Muscle loss: metformin has shown about a 5% change in muscle loss – but the increased longevity may be worth it
    • It may be advised to take metformin on days you don’t exercise
  • Berberine works on the same pathways activating AMPK – mimicking the effects of metformin
  • Berberine dosing: 1-2g per day
  • Berberine seems to work like metformin, improves sensitivity to insulin, lowers glucose, reduces inflammation
  • Berberine is naturally occurring and over the counter – people respond differently to things but there don’t seem to be striking cautions

David Sinclair’s Regimen

  • Morning: 1g of resveratrol (dissolved in olive oil or yogurt) daily (since 2004)
  • Morning: 1g NMN
  • Night: 800mg Metformin, pauses on nights before exercise
  • Testing out the addition of 1g spermidine in the morning
  • Periodically takes 1/2g of fisetin and 1/2g quercetin
  • Bloodwork monitoring: liver enzymes AST, ALT
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Notes By Maryann

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