David Sinclair's Longevity Stack: NMN, Resveratrol & Anti-Aging Science

David Sinclair, a professor of genetics at Harvard Medical School and author of Lifespan: Why We Age—and Why We Don't Have To, is perhaps the most visible scientist advocating for the possibility of slowing, stopping, or even reversing biological aging. Over the past several years, Sinclair has publicly shared the supplement stack he takes daily, sparking enormous interest in compounds like NMN (nicotinamide mononucleotide) and resveratrol.

In this guide, we examine each component of the Sinclair longevity stack, the science behind it, and important caveats you should know.

The Core Theory: NAD+ and Sirtuins

Sinclair's research centers on two key concepts:

1. NAD+ (Nicotinamide Adenine Dinucleotide) — A coenzyme found in every cell, essential for energy metabolism and DNA repair. NAD+ levels decline significantly with age, dropping by approximately 50% between ages 40 and 60. This decline is associated with mitochondrial dysfunction, genomic instability, and cellular senescence.
2. Sirtuins — A family of seven proteins (SIRT1–SIRT7) that regulate aging-related pathways including DNA repair, inflammation, metabolism, and stress resistance. Sirtuins require NAD+ as a cofactor to function. Less NAD+ means less sirtuin activity.

Sinclair's supplementation strategy is designed to boost NAD+ levels (through NMN) and activate sirtuins (through resveratrol), mimicking some of the molecular effects of caloric restriction—the most robustly proven lifespan-extending intervention in animal models.

David Sinclair's Supplement Stack

Based on his public statements across podcasts, interviews, and his book, Sinclair's daily protocol includes:

• NMN — 1,000 mg in the morning
• Resveratrol — 1,000 mg in the morning, mixed into yogurt (fat aids absorption)
• TMG (Trimethylglycine / Betaine) — 500–1,000 mg (as a methyl donor to offset NMN's methyl group consumption)
• Vitamin D3 — daily (dose not always specified, likely 2,000–5,000 IU)
• Vitamin K2 — daily (to work synergistically with D3)
• Metformin — 1,000 mg in the evening (prescription; not on workout days as it may blunt exercise adaptations)
• Low-dose aspirin — 83 mg daily
• Quercetin and Fisetin — periodically (potential senolytic agents)

Note: Sinclair has stated these are his personal choices and he does not formally recommend them to others. This is not medical advice.

NMN: The NAD+ Precursor

What It Does

NMN (nicotinamide mononucleotide) is a direct precursor to NAD+. When you take NMN orally, it is converted to NAD+ through the salvage pathway. A 2022 clinical trial published in Science (PMID: 35484304) demonstrated that 250 mg of NMN daily increased blood NAD+ levels and improved muscle insulin sensitivity in overweight postmenopausal women.

A 2024 randomized, placebo-controlled study (PMID: 36482258) in middle-aged adults found that 600–900 mg of NMN daily for 60 days increased blood NAD+ concentrations by approximately 38% and improved six-minute walk distance, suggesting enhanced physical capacity.

Dosage

Sinclair takes 1,000 mg (1 g) per day, typically in the morning. Clinical trials have studied doses ranging from 250 mg to 1,200 mg. The optimal dose for longevity in humans has not been definitively established, but 500–1,000 mg appears to be the most common range among longevity enthusiasts.

NMN vs. NR (Nicotinamide Riboside)

NR (sold as Niagen by ChromaDex) is another popular NAD+ precursor. Both raise NAD+ levels, but they use slightly different metabolic pathways. Sinclair has expressed a personal preference for NMN based on his lab's research, though both have supporting evidence. NR has more published human clinical trials, while NMN has been gaining ground rapidly in recent years.

Resveratrol: The Sirtuin Activator

What It Does

Resveratrol is a polyphenol found in red grape skins, berries, and peanuts. In Sinclair's framework, resveratrol serves as a SIRT1 activator—it directly stimulates the sirtuin enzyme that is most closely linked to caloric restriction mimicry and DNA repair. A 2006 study from Sinclair's lab (PMID: 17086191) found that resveratrol extended lifespan in mice on a high-fat diet and improved metabolic parameters.

Bioavailability Challenges

Resveratrol's biggest limitation is poor oral bioavailability. It is rapidly metabolized by the liver and gut. Sinclair addresses this by taking his resveratrol with a fat source (yogurt or olive oil), which has been shown to improve absorption. A 2011 study (PMID: 21688389) confirmed that taking resveratrol with food (especially fat-containing food) significantly increased plasma concentrations.

Dosage

Sinclair takes 1,000 mg per day of resveratrol, in the morning with yogurt. This is a high dose relative to what you would get from dietary sources (a glass of red wine contains roughly 1–2 mg of resveratrol).

TMG (Trimethylglycine)

TMG, also called betaine, is a methyl donor that Sinclair takes to offset a potential side effect of high-dose NMN supplementation. When NAD+ is synthesized from NMN, the process can consume methyl groups, potentially increasing homocysteine levels. TMG donates methyl groups to remethylate homocysteine back to methionine, maintaining healthy methylation balance.

Dosage: 500–1,000 mg per day.

Metformin: The Controversial Addition

Metformin is a prescription diabetes drug that Sinclair and other longevity researchers believe may have anti-aging properties. It activates AMPK, reduces mTOR signaling, and has been associated with lower cancer rates in diabetic populations (PMID: 15998259). The TAME (Targeting Aging with Metformin) trial is currently underway to test metformin specifically as an anti-aging drug in non-diabetic adults.

However, a 2019 study (PMID: 30548390) found that metformin blunted some of the benefits of exercise, particularly mitochondrial adaptations. This is why Sinclair reportedly does not take metformin on days he exercises. Peter Attia has discussed this issue extensively and has moved away from recommending metformin for people who exercise regularly.

Senolytics: Quercetin and Fisetin

Senescent cells are "zombie cells" that stop dividing but do not die, accumulating with age and secreting inflammatory molecules. Senolytics are compounds that selectively kill these cells. Quercetin (often combined with dasatinib in research settings) and fisetin are natural flavonoids with senolytic potential.

A 2018 study in Nature Medicine (PMID: 29988130) found that the combination of dasatinib and quercetin cleared senescent cells and improved physical function in mice. Fisetin was shown to extend lifespan in aged mice by 10% in a 2018 study (PMID: 30279143). Human trials are still in early stages.

Important Caveats and Criticisms

While the science is exciting, several caveats are important:

• Most longevity research is in animals. Mouse lifespan studies do not always translate to humans. Resveratrol extended lifespan in obese mice but has not shown the same effect in lean mice or humans.
• NMN and NR raise NAD+, but we do not yet know if raising NAD+ extends human lifespan. The logic is compelling (NAD+ declines with age, replenishing it improves markers), but the definitive human longevity trial has not been done.
• Sinclair has financial ties to companies in this space. He co-founded Metro International Biotech (NMN research) and previously co-founded Sirtris Pharmaceuticals (acquired by GlaxoSmithKline for $720 million). This does not invalidate his research but is worth noting.
• FDA regulatory actions. In late 2022, the FDA took steps to reclassify NMN as a drug rather than a supplement, creating regulatory uncertainty. As of this writing, NMN remains available from supplement companies, but the regulatory landscape may change.

Building a Practical Longevity Stack

If you are inspired by Sinclair's approach, here is a simplified, practical starting point without prescription drugs:

1. NMN: 500–1,000 mg in the morning
2. Resveratrol: 500–1,000 mg with a fat-containing meal
3. TMG: 500 mg daily
4. Vitamin D3 + K2: per your blood levels (aim for 40–60 ng/mL 25-OH vitamin D)
5. Omega-3s: 2+ g EPA+DHA (see our dosage guide)

For a broader perspective on longevity, also read our guide on Peter Attia's exercise framework for longevity.

Frequently Asked Questions

Is NMN safe for long-term use?

Short-term clinical trials (up to 12 weeks) have shown NMN to be well-tolerated with no serious adverse effects at doses up to 1,200 mg/day. Long-term human safety data beyond one year is still limited, though animal studies using NMN for over 12 months have not revealed significant toxicity.

Can I take NMN and NR together?

There is no established benefit to combining them, as they both raise NAD+ through related pathways. Most experts recommend choosing one or the other. Some people alternate between the two, though there is no scientific basis for this approach.

Does resveratrol really work in humans?

The evidence in humans is mixed. Resveratrol has shown benefits for cardiovascular markers, inflammation, and glucose metabolism in some trials, but results are inconsistent. The most reliable benefits appear in people with metabolic dysfunction (overweight, diabetic). Whether it slows aging in healthy humans is unknown.

What is the best time to take NMN?

Most people, including Sinclair, take NMN in the morning. There is some theoretical rationale for this, as NAD+ levels naturally peak during the day. Some people report that NMN taken late in the day disrupts sleep, possibly due to its energizing effects, though this is anecdotal.

How much does the Sinclair stack cost per month?

At current prices, a quality NMN + resveratrol + TMG stack typically costs $80–$150 per month, depending on brands and dosages. NMN is the most expensive component. Prices have been declining as more manufacturers enter the market.