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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