David Sinclair, PhD
All Protocols
Intermediate

David Sinclair's Longevity Protocol (2025)

David Sinclair, PhD

David Sinclair, PhD

Professor of Genetics, Harvard Medical School. Author of Lifespan.

sinclair.hms.harvard.edu

Dr. David Sinclair is Professor of Genetics at Harvard Medical School and co-director of the Paul F. Glenn Center for Biology of Aging Research. His 2019 book Lifespan and his Information Theory of Aging established him as the most widely read longevity scientist in the world. His protocol has evolved significantly from the one described in Lifespan: he dropped quercetin in 2023 (new research suggested SIRT6/NRF2 interference), largely replaced metformin with berberine (GI tolerance), added rapamycin quarterly, and added nattokinase and spermidine to his stack.

Core Philosophy

  • Aging is a disease — and like all diseases, it can be treated and reversed
  • The Information Theory of Aging: cells lose epigenetic information over time; restoring it is the key to reversing aging
  • NAD+ is the master regulator — sirtuins require it; restoring declining NAD+ (via NMN) is central to his longevity strategy
  • Xenohormesis: compounds made by stressed plants (resveratrol, fisetin, quercetin) activate our own survival pathways
  • Skips breakfast daily — fasting activates AMPK, sirtuins, and autophagy that food shuts down
  • Dropped quercetin (2023), dropped metformin (largely), added rapamycin quarterly — the protocol evolves with evidence

Core Morning Stack

Sinclair's primary daily supplements — unchanged for years at their core, though doses and additions have evolved.

NMN

View in Database

NAD+ restoration — Sinclair was instrumental in popularising NMN as the primary NAD+ precursor

1g
Morning with yogurt (fat improves absorption)Sinclair takes 1g — twice to four times higher than typical clinical trial doses (250–500mg). He argues higher doses are warranted given the steep NAD+ decline with age.

Resveratrol

SIRT1 activator — core of Sinclair's sirtuin activation strategy. Synergistic with NMN.

1g
Morning with olive oil or yogurt — fat required for absorptionResveratrol's human evidence is more contested than Sinclair's own enthusiasm suggests. He acknowledges the human RCT data is mixed — but continues based on mechanistic plausibility and his own biomarkers.

Berberine

View in Database

AMPK activator — largely replaced metformin. Similar mechanism, better GI tolerance, no prescription required.

1g/day
With foodSinclair switched from metformin primarily due to GI side effects. Berberine activates AMPK through a slightly different mechanism (mitochondrial complex I inhibition vs. metformin's direct AMPK activation).

Vitamin D3 + K2

Immune function, bone health, cancer risk reduction — Sinclair considers vitamin D deficiency a significant longevity risk

5,000 IU D3
Morning

Omega-3

View in Database

Cardiovascular protection, anti-inflammatory, brain health

Daily (dose not publicly specified)
With food

Alpha-Lipoic Acid

Mitochondrial antioxidant, glucose disposal, heavy metal chelation

500mg
MorningPart of Sinclair's antioxidant stack. R-ALA form is significantly better absorbed than racemic ALA.

CoQ10

Mitochondrial electron transport, lipid-soluble antioxidant

Daily (dose not specified)
With fat

Senolytics & Autophagy

Sinclair's updated senolytic protocol — quercetin dropped in 2023, fisetin retained, spermidine added for autophagy.

Fisetin

Senolytic — clears senescent cells. Retained after dropping quercetin in 2023. More potent senolytic than quercetin in mouse studies.

500mg daily
With fatSinclair dropped quercetin in 2023 after research suggested possible SIRT6 and NRF2 pathway interference. Fisetin does not have this concern and shows stronger senolytic activity in animal models.

Spermidine

Autophagy inducer — triggers cellular self-cleaning. Found in aged cheese, wheat germ, mushrooms.

1–2mg
MorningSinclair added spermidine after 2022 human studies showed cognitive protection and cardiovascular benefits. The mechanistic case (autophagy induction) is strong; long-term human RCTs are emerging.

Nattokinase

Fibrinolytic enzyme from fermented soybeans — reduces fibrin and clot formation. Emerging cardiovascular data.

Daily (standard dose)
Away from food (best absorbed on empty stomach)Sinclair added nattokinase in 2023. Mechanistically interesting for cardiovascular risk. Human trial data growing but not yet conclusive.

Prescription & Quarterly Interventions

Sinclair's pharmacological longevity interventions — some quarterly pulsed, some daily.

Rapamycin

mTOR inhibition — Sinclair uses a quarterly pulsed protocol rather than Attia's weekly continuous approach

~6mg quarterly (pulsed)
Every 3 monthsRx only. Sinclair argues that intermittent rapamycin may capture mTOR inhibition benefits while minimising immunosuppression. This is a contentious area — the optimal dosing frequency is genuinely unknown.

Low-dose Aspirin

Anti-inflammatory, cardiovascular protection — Sinclair continues despite updated cardiology guidance against routine aspirin in healthy adults

81mg
DailyRx-free but contested. Updated AHA/ACC guidelines (2022) no longer recommend aspirin for primary prevention in most adults. Sinclair continues based on his personal risk assessment.

Statin

Aggressive ApoB/LDL-C lowering for cardiovascular risk reduction

80mg (high-intensity)
EveningRx only. Sinclair is explicit about treating cholesterol aggressively. He views cardiovascular disease as the most preventable of the "four horsemen" of aging.

Metformin (occasional)

AMPK activation — Sinclair reduced metformin use due to GI side effects but has not entirely eliminated it

1g when taken
EveningRx only. Unlike Attia, Sinclair has not publicly abandoned metformin — he uses it more sporadically than previously. The berberine switch is largely pragmatic (GI tolerance) rather than philosophical.

Lifestyle & Fasting

Sinclair's non-supplement longevity practices — which he argues are equal in importance to his pill protocol.

Intermittent Fasting (skip breakfast)

AMPK activation, sirtuin activation, autophagy induction, IGF-1 reduction. Sinclair has skipped breakfast for a decade.

First meal at 1–2 PM, last meal 8–9 PM
DailySinclair's IGF-1 is reported at 40% below population average — consistent with reduced mTOR/IGF-1 signalling that animal longevity models associate with extended lifespan.

Cold Exposure

Xenohormesis — mild stress activates survival pathways. Norepinephrine release, mitochondrial biogenesis.

2–3x/week cold shower or brief outdoor cold
Post-exercise or morningSinclair frames cold exposure as a form of xenohormesis — the same concept as plant polyphenols activating human survival pathways.

Plant-heavy, Low Red Meat Diet

Reduce IGF-1 signalling (mTOR inhibition via lower amino acid load), increase polyphenol intake, gut microbiome diversity

Predominantly plants, minimal red meat
DailySinclair's dietary approach conflicts with Attia's high-protein strategy. The core tension: Attia prioritises anti-sarcopenic protein intake; Sinclair prioritises mTOR inhibition. Both have valid mechanistic cases.

Important Disclaimer

Sinclair's protocol has changed significantly since Lifespan was published in 2019 — always use current interview data, not the book. Rapamycin, statins, and metformin require prescriptions. The scientific community has ongoing debates about several of Sinclair's claims, particularly resveratrol's human efficacy.

LongevityLab earns a commission on some affiliate links.

At a Glance

Supplements14
Est. monthly cost$80–150/month (excluding Rx)
ComplexityIntermediate
ApproachInformation Theory of Aging
Find Your Own Protocol →

Free biological age quiz