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NMN, NR, Resveratrol, Metformin & Other Longevity Molecules The Science Of Setting & Achieving Goals

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

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

Dr. 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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