NMN, NR, Resveratrol, Metformin & Other Longevity Molecules | Lifespan with Dr. David Sinclair #4
In a Nutshell
David Sinclair reviews longevity molecules targeting sirtuins, AMPK, and mTOR pathways: NAD boosters like NR (OTC, extends mouse lifespan 9%, safe at 250mg-1g/day) and NMN (superior in mice, improves human insulin sensitivity at 250mg, Sinclair takes 1g daily); resveratrol (1g with fat, mimics calorie restriction); senolytics fisetin/quercetin (0.5g daily); rapamycin (low-dose mTOR inhibitor); spermidine (1g, boosts autophagy/memory); metformin (800mg evenings, AMPK activator, TAME trial pending); and berberine (1-2g alternative). Animal studies show 10-30% lifespan extensions; human trials confirm NAD rises, better insulin/glucose, reduced inflammation, with minimal side effects—monitor liver/bloodwork and consult physicians. Sinclair's regimen: morning resveratrol (1g), NMN (1g), fisetin/quercetin (0.5g each), spermidine (1g); evening metformin (800mg, skipped on exercise days).
These notes were generated by AI and may contain inaccuracies.
Welcome to the Lifespan podcast discussing the science of aging and how to be healthier at any stage of life. David Sinclair is a professor at Harvard Medical School and Co-director of the Paul F. Glenn Center for Aging Research, joined by co-author and cohost Matthew LaPlante.
This series deep dives into ways to slow, stop, and reverse aging. Today's episode covers supplements and molecules people have been asking about: NR, NMN, Metformin, and others.
Not medical doctors. David is a PhD researcher who reads the literature. Consult a physician before trying supplements or changing diet radically, as they can affect the body positively or dangerously depending on the individual.
Goal is to enable informed conversations with physicians.
- Levels: App syncs with continuous glucose monitor to interpret glucose data. David joined as advisor. Shows food impacts like grapes and white rice spiking glucose, potatoes less so. Join at levels.link/sinclair to skip waitlist.
- Inside Tracker: Analyzes blood and DNA data for personalized nutrition. David uses for over a decade, chairs advisory board. Easy blood tests at home or clinic, dashboard with recommendations. InnerAge 2.0 shows biological age using AI algorithm David helped develop. Try at insidetracker.com/sinclair for 25% off with code sinclair.
- Athletic Greens: All-in-one daily drink with 75 vitamins, minerals, whole foods, adaptogens, probiotics, digestive enzymes, vitamin C, zinc citrate. David drinks it mornings for nutrients despite imperfect diet and travel. Go to athleticgreens.com/sinclair for five free travel packs, year supply vitamin D3 and K2.
Adversity mimetics like fasting and exercise mirror evolutionary stresses, but modern sedentary lifestyles persist. Aging occurred even pre-modern times, so additional boost may be needed.
David has used supplements since early thirties. Focus on major supplements and medicines with greatest scientific evidence for wellness now and long-term health.
Drugs are chemicals, some natural or OTC under GRAS (generally recognized as safe) if in food supply. Plant molecules available despite higher concentrations; monitor liver with blood work.
Drugs are regulated due to potential damage and side effects; discuss with doctor even if safe like Metformin.
NAD boosters, Metformin, berberine, rapamycin, spermidine, resveratrol, fisetin, quercetin. Show notes timestamped with scientific references and David's disclosures on sinclairlab.com (never sold supplements, discloses all work outside Harvard).
Categorize by sirtuins, AMPK, mTOR. Pathways respond to environment (exercise, fasting), communicate as a network. Optimal combinations per individual unknown; present cutting-edge science.
Research shows molecules affect multiple pathways.
NAD (nicotinamide adenine dinucleotide, vitamin B3 + sugar + phosphate) essential for transferring hydrogen atoms, making ATP energy, discovered 100 years ago in yeast. Most abundant molecule after ATP.
Co-discovered NAD activates sirtuins (defensive enzymes). NAD declines with age, impairing aging defense. Exercise and fasting raise NAD, but levels still drop in later life; boosters aim to restore youthful levels.
NR (nicotinamide riboside): B3 + sugar. Available OTC since 2014, 250 mg or 1g/day safe, raises NAD in blood after 9-10 days, no negative side effects.
- Yeast: +30% lifespan via sirtuins, mimicking calorie restriction, increasing genome/epigenome stability.
- Mice: +9% lifespan when given late (700 days old, ~70 human years); more mitochondria, athleticism, less inflammation; enhanced oxidative metabolism, fat burning, anti-diabetes.
Human studies short-term: raises NAD, lowers inflammation, minor body composition changes; no consistent blood sugar, insulin sensitivity, mitochondria improvements yet. May need longer exposure.
Promising: NR + pterostilbene (resveratrol-like) improved daily function in ALS patients.
Vitamin B3 raises NAD less than NR; NR less than NMN (closer to NAD, phosphate key).
NR cheaper without phosphate. Labs (David's, Matt Long at Wash U) found NMN works better than NR at same dose in mitochondrial disorder treatment and treadmill mice; reason unclear, possibly phosphate.
NMN uptake debated; SLC12A8 transporter discovered by Shin-ichiro Imai's team at Wash U takes NMN directly into cells. NAD IV used by some, but cells often break down/re-uptake components.
Animal studies show effects; human mechanisms being learned.
NMN restores NAD levels, enhances insulin sensitivity. No study shows NMN's effect across entire lifespan yet. Shin Imai showed it slowed aging effects over half a lifespan but stopped due to lack of NMN. Now NMN is available. In Sinclair's lab, ongoing studies for last few years: mice have less frailty, seem younger, better activity, better mitochondrial function, run further. Lifespan looks promising; done once, mice live longer on NMN at doses of 400 mg per kg. Lifespan extension about 10-15%, particularly strong in females. Similar to NR results, but slightly better; mice healthier, more active, youthful. More pronounced in females in first phase (fewer females, now repeating with larger cohort).
Mice live 2-3 years on average; lifespan extension studies take time. Average experiment takes 3 years, repeat is 6 years, analysis and publication another 3-4 years—decade per experiment. Careers allow about 5 such experiments, but running in parallel and mimicking in tissues changes that.
In animals, NR and NMN lengthen lifespan, restore mitochondrial activity, restore NAD levels, enhance insulin sensitivity. Human studies for NR haven't always confirmed exact same effects.
Helping group doing clinical trials at Harvard Medical School giving molecule similar to NMN; no negative side effects. Upcoming results (hopefully by 2022) on energy, mitochondrial function, blood flow, endurance—like in mice.
Less human research on NMN than NR, but recent flood of studies. Yoshino et al. 2021: 10-week randomized placebo-controlled study, 250 mg dose (low; Sinclair takes 1-2 g), improved insulin-stimulated glucose disposal (insulin sensitivity)—hallmark of longevity, keeps glucose low. Exciting as first proof NMN works in humans like in mice.
Need to check endurance, organ protection (kidney, heart), wound healing. NMN protects organs from damage in other labs. Kidney injury huge; most heart surgeries damage kidneys. Studies at Harvard promising, more next year. Better NAD boosters (NCEs, new chemical entities) entering human studies soon.
NR creates NMN, NMN creates NAD. Why not IV NAD? Some do long drips (over hour) in Florida/LA under medical supervision, not research settings. Anecdotal: better mood, energy; used for addiction (drugs/alcohol), depression, hangovers. No placebo-controlled trials; cannot conclude without them.
Hangover: alcohol dehydrogenase (detoxifies alcohol) needs NAD; Asians often lack it. Hangover depletes NAD in liver; NMN/NR restores, helps eliminate alcohol. Makes sense, not just placebo, but needs hardcore proof.
Research started in yeast (early 2000s Harvard): NAD too big, not taken up by cells. NMN has transporter; smaller NR taken up even better. NMN may be sweet spot.
Swallowing capsules or powder raises NAD 2-3 fold. Tablets given to subjects. Sublingual or injection possible; swallowing proven to raise NAD.
Two main mouse studies. Washington University: knocking down NAD in brain tumors slowed growth (not same as NAD causes cancer). 2019 study: NAMPT (NAD boosting gene) increases senescent cells, more inflammatory (SASP, senescence-associated secretory phenotype). In pancreatic cancer-predisposed mice, NMN increased precancerous/cancerous growths, possibly down-regulating tumor suppressor P53.
Normal mice on NMN live longer/healthier. Predisposition key difference. Something to watch; consult physician.
Early 2000s Harvard (post-MIT with Lenny Guarente): sirtuin gene upregulation extends yeast lifespan, but can't easily upregulate genes. Found safe natural molecules activating sirtuin proteins (enzymes controlling other proteins). Assay for SIRT1 activation (first of 7 sirtuins): fluoresced with activity. Tested thousands; published 20 in Nature 2003. Resveratrol best (13-fold SIRT1 activation). Others like pterostilbene now used. Resveratrol famous from red wine; red wine sales up 30% since, stayed high.
Can't drink enough red wine for effect (hundreds of glasses/day). Purify from grapevines or Polygonum cuspidatum (Asian plant).
Human doses: minimum 250 mg/day; some take 1000-2000 mg/day.
Insoluble like brick dust (hydrophobic); won't absorb if swallowed alone—sinks in water. Mix with food (yogurt, olive oil) for absorption in mice/humans. Some studies failed without fat.
Extended replicative lifespan in yeast; AMPK activation in rodents. Defends body, raises metabolic rate, protects free radicals. Key: protected high-fat (Western) diet mice; obese resveratrol mice lived as long as lean controls—first molecule mimicking caloric restriction while fat.
Some worked: reduced fasting glucose, increased insulin sensitivity (2019). Battista and George et al. 2020: randomized control, 25 individuals (30-60 years, BMI 30), lowered cholesterol, urea (kidney function), raised HDL.
Pre-Sinclair: suppressed cancer (1999 Science: smaller skin cancers post-carcinogen). Effects: body composition, metabolic rate, mitochondrial boosting, glucose. ~1000 animal papers, dozen human. Cardiovascular benefits; French paradox (high-fat diet + wine).
Red wine: cumulative over 30 years? Other polyphenols (xenohermetic) for combo effect.
From early sirtuin activator screen with resveratrol. Also senolytics (kill senescent/zombie cells: stopped dividing, secrete inflammatory/cancer factors due to messed-up epigenome).
Fisetin: extends lifespan in fruit flies, mice (University of Minnesota: young or late-life after 700 days/~75-year human equivalent, up to 30% extension + health via senolytics + SIRT1).
Quercetin: first senolytic (Jim Kirkland, Mayo Clinic) with dasatinib (leukemia drug). In mice/humans: remarkable for age-related diseases. RCTs: reduces fatty liver, inflammation; senescent cells decrease.
Dasatinib regulated; clinical trials only. Fisetin (plant: grapes, apples, strawberries; cheap online): reduces inflammation in humans; early. Affirm light study (Jim Kirkland): 20 mg/kg; results next year on senolytic effects/health.
Inhibit mTOR (mimics fasting). Discovered on Easter Island (Rapanui) from fungus on statue. Used for immune suppression, cancer—life-saving.
Low doses (not immune-suppressing, ~10 mg/week humans) extend lifespan every organism: yeast, worms, flies, mice (even late-life). Likely life-extending in humans.
Rapamycin is potent but could be toxic, requiring extreme caution, and is not currently available. Rapamycin works by inhibiting mTOR (Target Of Rapamycin, how mTOR was discovered). Giving animals rapamycin mimics low protein intake, triggering the body to scavenge protein internally via autophagy.
Spermidine works on autophagy, like rapamycin. It's recently available online. History: Anton van Leeuwenhoek, inventor of microscopy, observed crystals in his sperm, leading to discovery of spermidine (hence the name). Spermidine extends lifespan in yeast, flies, worms, and mice. A compelling study showed mice given spermidine young or late in life live longer with better heart function and youthful capacities. Mechanisms in mammalian cells: stimulates autophagy via mTOR pathway; stabilizes epigenome changes, a major cause of aging.
Human studies on spermidine focus on enhancing memory and addressing memory loss in older Americans, showing greatly improved cognition. Standout study: Schwartz et al., 2018, gave 1.2 grams per day for three months, resulting in significant memory enhancement.
Spermidine sources: not from sperm, but wheat germ (abundant, easier); also soy products.
Metformin, an AMPK activator, is exciting yet boring—used since 1950s as frontline medicine for type 2 diabetes to lower glucose levels. Hundreds of millions take it worldwide; relatively safe. Available over-the-counter in half the world; prescription needed in US, Europe, UK, Australia.
Debated for 50+ years. Leading theory: activates complex one in mitochondria (energy production), lowers ATP energy levels, causing mitohormesis (what doesn't kill the cell makes it stronger). Effects: more mitochondria (more energy days later); inhibits mTOR, improves insulin signaling (sucks high blood sugar out of bloodstream for type 2 diabetes). Also lowers energy, activates AMPK, raises NAD levels (activates sirtuins). Origin: from French hellebore/lilac plant (guanidines known for diabetes treatment over a century); chemically modified with methyls for stability.
Extends worm lifespan 30-40 days. Mouse study (Sinclair involved, with Rafael de Cabo at NIH): healthier, longer-lived mice.
Glucose lowering; more energy, mitochondria; less inflammation; muscle type switching (older muscles become more glycolytic/anaerobic; metformin switches back to athletic-like). Retrospective studies of tens of thousands of elderly on metformin: lowers risk of cancer, heart disease, Alzheimer's, frailty (beyond diabetes control). People on metformin live longer than non-diabetics without it.
Targeting Aging with Metformin (TAME) study, run by Nir Barzilai at Albert Einstein College of Medicine, across many institutes/hospitals, costing tens of millions. Goal: prove to FDA that aging can be targeted/slowed with a drug, making aging a treatable condition. Delayed fundraising due to metformin's cheapness (few cents, off-patent, no profit motive). Half funded by government, rest by donors; now starting. Measures: stability, walking ability, strength, mental acuity, human biological clock.
More doctors prescribing off-label for anti-aging; shift from waiting for full-blown disease to earlier intervention (pre-diabetics, pre-pre-diabetics). Extensive literature convinces doctors. Downsides: lactic acidosis (severe, potentially fatal—be careful); most common: upset stomach, lack of hunger (good for weight loss).
Minimal impact (5% difference in size, negligible except for bodybuilding); muscles as strong, less inflammation. Strategy: take on non-exercise days (reduces energy production, fewer reps). Extra effort in workouts compensates.
Alternative to metformin for ~20% intolerant to it; activates AMPK. From plant bark/roots (yellow, insoluble—take with food like yogurt, olive oil). Binds complex one, reduces energy, triggers mitohormesis: more mitochondria, better insulin sensitivity, lower blood glucose. Lab: works in mice; human studies validate. Doses: 1-2 grams/day. Extends lifespan in mice (chemotherapy-treated and normally aged) and fruit flies. Improves insulin sensitivity, lowers glucose (good health sign). Side effects: similar to metformin (diarrhea, constipation, gas, upset stomach). Natural, available; consult doctor.
Started resveratrol ~2004. Dosing not direct mouse-to-human scale (allometric scaling: mouse x12 for human surface area; e.g., mouse 100mg = human 1.2g; rat x3; mini pig 1:1).
Morning Routine
- Resveratrol: 1 gram with yogurt/olive oil (needs fat; olive oil activates sirtuins, twofer; mix with vinegar/basil; minimal to preserve fast).
- NMN: 1 gram (dissolves easily, in water/under tongue). Based on human studies: 1g/10 days doubles NAD (50% drop by Sinclair's age vs. 20s); up to 2g triples. Taken mornings to match natural NAD/SIRT1 rise (part of 24-hour clock; SIRT1 regulates BMAL1 for circadian genes—hunger, jet lag; NMN prevents jet lag).
- Fisetin and quercetin: 0.5g each daily (maintenance; Mayo Clinic trials: 2g one day/week for months; targets senescent cells).
- Spermidine: 1 gram (recent addition, testing via Inside Tracker; pure, low-gluten from company he advises; promising human trials).
Evening
- Metformin: 800mg at dinner (simulates fast, low glucose overnight, activates repair/survival genes). Pauses on exercise days (stomach upset, reduced performance). Added after poor bloodwork (bad diet, weight gain, sleep/stress); NMN helped, metformin optimized.
Monitor via Inside Tracker, blood tests (AST/ALT for liver). Doctors open to data/science; hard for them to keep up.
Measure effects (liver AST/ALT). Next episode: testosterone, growth hormone, exosomes, peptides.
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