Dr. Matt Kaeberlein’s Longevity Protocol — Optispan (2025-2026)
Overall evidence: Grade BEvery supplement independently graded on human evidence — dose, the rationale, and where the science actually lands.
Matt Kaeberlein is deliberately a supplement minimalist, and that skepticism IS the story: he argues exercise, sleep, diet, and muscle maintenance dwarf any pill, and that a supplement is only worth taking to correct a measured deficiency or optimize a specific marker. The short list he actually endorses — creatine, dietary protein, omega-3, vitamin D (for deficiency), magnesium, fiber, and B12/methylfolate for his MTHFR variant — maps onto the items with the best human evidence. He is publicly scathing about the hype items, refusing NMN/NAD boosters, resveratrol (the most debunked longevity intervention of all time), and metformin for healthy people. He personally experiments with rapamycin (cyclical) and speculative adds like low-dose lithium and calcium-AKG, but is explicit these are bets on animal data with no human longevity proof.
Rapamycin (sirolimus)
UnprovenWhy Longevity takes it: Strongest, most reproducible drug in animal lifespan studies (NIA ITP); used cyclically under the precautionary principle. — Optispan podcast; Attia/Sabatini podcast #272
What the evidence says: Rapamycin robustly extends lifespan in mice at three independent NIA ITP sites (Harrison 2009) — the single strongest pharmacologic longevity signal in mammals. But no human RCT shows it extends lifespan; the best human geroscience trial of an mTOR inhibitor (RTB101, Mannick 2021) was positive in phase 2 yet NULL in phase 3. Human longevity benefit is unproven — grade D despite grade-A animal data.
Creatine monohydrate
SupportsWhy Longevity takes it: No-brainer for muscle maintenance; growing brain-energy rationale. — Optispan podcast; Levels interview
What the evidence says: Muscle/strength benefit with resistance training is grade-A. Cognitive benefit is grade-B: meta-analyses (Prokopidis 2023; Xu 2024) show small but significant gains in memory and processing speed, strongest in older adults. Net B+ — one of the few supplements with a genuine evidence base.
Protein (whey/dietary)
SupportsWhy Longevity takes it: Foundational for lean-mass preservation and satiety. — Optispan podcast; Levels interview
What the evidence says: Landmark meta-analysis (Morton 2018, 49 RCTs) shows protein augments resistance-training gains in muscle mass and strength up to ~1.6 g/kg/day. Strong for the muscle/sarcopenia endpoint; direct mortality RCT data are lacking, so graded B.
Omega-3 (EPA/DHA fish oil)
MixedWhy Longevity takes it: Reasonable evidence, low risk; one of only ~3 supplements he broadly endorses. — Optispan podcast; Levels interview
What the evidence says: Genuinely mixed: one meta-analysis (Hu 2019, 127,477 people) found modest reductions in MI and total CVD; a larger pooled analysis (Aung 2018, 77,917 people) found NO significant CVD or all-cause-mortality benefit. No convincing lifespan effect — a defensible low-risk maybe.
Vitamin D3
MixedWhy Longevity takes it: Take only to correct a measured deficiency, not blindly. — Optispan podcast; Levels interview
What the evidence says: For correcting genuine deficiency the evidence is solid. But the large VITAL RCT (Manson 2019, 25,871 adults) found NO reduction in cancer, cardiovascular events or mortality in replete adults. Benefit is deficiency-specific — exactly Kaeberlein's framing.
Magnesium
SupportsWhy Longevity takes it: Cheap, safe, common dietary shortfall; supports BP/sleep. — Optispan supplement AMA
What the evidence says: Meta-analysis of 34 double-blind RCTs (Zhang 2016) shows magnesium modestly lowers systolic (~2.0 mmHg) and diastolic BP at ~368 mg/day. Real but small effect on a surrogate; no direct longevity RCT.
Dietary fiber / prebiotic (inulin, chia)
SupportsWhy Longevity takes it: Gut health, lipid clearance, metabolic control. — Optispan podcast
What the evidence says: A large series of meta-analyses (Reynolds 2019, Lancet; ~185 studies) links higher fiber intake to 15-30% lower all-cause and cardiovascular mortality, with RCTs confirming lower BP, weight and cholesterol; optimal ~25-29 g/day. Mortality data are observational (hence B), but the dose-response is striking.
Lithium (low-dose orotate)
UnprovenWhy Longevity takes it: Ecological dementia-incidence data + emerging Alzheimer's mechanism; a speculative bet. — Optispan podcast
What the evidence says: The human signal rests on confounded ecological data: trace lithium in drinking water showed a NON-linear association with dementia (Kessing 2017), with some bands showing HIGHER risk. No RCT of low-dose lithium for longevity/dementia exists. Grade D — a hypothesis, not a proven intervention.
Calcium alpha-ketoglutarate (Ca-AKG / Rejuvant)
UnprovenWhy Longevity takes it: Strong mouse frailty/lifespan data (discloses advisory-board conflict). — Optispan podcast (COI disclosed)
What the evidence says: CaAKG extends lifespan and compresses morbidity in mice (Asadi Shahmirzadi 2020). The only human data (Demidenko 2021) is a 42-person retrospective, uncontrolled, industry-authored analysis of a methylation-age test — no placebo, no hard outcomes. Animal plus weak biomarker only: grade D.
Vitamin B12 + methylfolate
SupportsWhy Longevity takes it: Correct a documented deficiency/methylation variant, not blanket use. — Kaeberlein stack write-ups; Optispan
What the evidence says: Targeted, not universal: the VITACOG RCT (Smith 2010) showed high-dose folate+B12+B6 slowed brain atrophy in older adults with mild cognitive impairment, concentrated in those with elevated homocysteine. Strong for correcting deficiency; no benefit implied for replete people.
NMN — CONSIDERED & REJECTED
UnprovenWhy Longevity takes it: REJECTED BY KAEBERLEIN — insufficient evidence for NAD boosters; early animal effects did not reproduce. — Optispan podcast; Levels interview
What the evidence says: Human RCTs raise NAD, and one industry-funded trial reported better 6-minute-walk and a biological-age score (Yi 2023), but an independent RCT in older diabetics found NO improvement in grip strength or gait speed (Akasaka 2022). Surrogate-level, inconsistent, no hard-outcome data. Kaeberlein explicitly does not take it.
Resveratrol — CONSIDERED & REJECTED
RefutedWhy Longevity takes it: REJECTED BY KAEBERLEIN — the most debunked longevity intervention of all time; ~zero median effect. — Levels interview; Optispan podcast
What the evidence says: Meta-analyses show only inconsistent surrogate effects — improved flow-mediated dilation but NO blood-pressure change (Akbari 2019), and mixed signals in diabetics (Nyambuya 2020) — with no human longevity outcomes; the sirtuin-activation lifespan story failed to replicate. Grade D and effectively refuted.
Metformin (for healthy people) — CONSIDERED & REJECTED
AgainstWhy Longevity takes it: REJECTED BY KAEBERLEIN — ITP showed no mouse lifespan extension; blunts exercise adaptations. — Optispan podcast; Attia podcast
What the evidence says: In healthy non-diabetics there is no RCT showing metformin extends lifespan, and the MASTERS trial (Walton 2019) showed it BLUNTS resistance-training gains in older adults. Observational diabetic data and pending TAME keep it mixed (C), but for a fit person the risk-benefit is a net negative — hence Kaeberlein rejects it.
How this stack works
Kaeberlein's approach is subtractive, not additive: he targets the few interventions with real human evidence (protein + resistance training for muscle, fiber for metabolic/mortality, deficiency correction) and treats rapamycin, lithium and Ca-AKG as explicit animal-data bets, while publicly rejecting NMN, resveratrol and metformin-for-the-healthy.
Evidence summary
Across 13 items: ~6 grade B (creatine, protein, vitamin D, magnesium, fiber, B12), 3 C (omega-3, NMN, metformin), 4 D (rapamycin, lithium, Ca-AKG, resveratrol). The strongest-evidence items are precisely the ones he endorses; every D-grade item is a personal experiment or one he actively rejects. Overall B: an evidence-weighted, deficiency-driven protocol whose defining feature is restraint.
Risks & interactions
Rapamycin (off-label, cyclical) is an immunosuppressant needing medical supervision; low-dose lithium and Ca-AKG are unproven personal experiments. The endorsed core (protein, creatine, fiber, omega-3, vitamin D, magnesium, B12) is low-risk. His prescription items (empagliflozin, PCSK9 inhibitor) are out of scope here and require a physician.
Who this is for
The most evidence-disciplined template on the site: anyone wanting the short list that actually has human support, minus the hype. The rejected items (NMN, resveratrol, metformin for healthy people) are as instructive as the endorsed ones. His restraint — not a big stack — is the takeaway.
Sources
- Harrison DE (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. doi:10.1038/nature08221 · PMID 19587680
- Mannick JB (2021). Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. Lancet Healthy Longev. doi:10.1016/S2666-7568(21)00062-3 · PMID 33977284
- Prokopidis K (2023). Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of RCTs. Nutr Rev. doi:10.1093/nutrit/nuac064 · PMID 35984306
- Xu C (2024). The effects of creatine supplementation on cognitive function in adults: a systematic review and meta-analysis. Front Nutr. doi:10.3389/fnut.2024.1424972 · PMID 39070254
- Morton RW (2018). A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults. Br J Sports Med. doi:10.1136/bjsports-2017-097608 · PMID 28698222
- Hu Y (2019). Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 RCTs Involving 127477 Participants. J Am Heart Assoc. doi:10.1161/JAHA.119.013543 · PMID 31567003
- Aung T (2018). Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77917 Individuals. JAMA Cardiol. doi:10.1001/jamacardio.2017.5205 · PMID 29387889
- Manson JE (2019). Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease (VITAL). N Engl J Med. doi:10.1056/NEJMoa1809944 · PMID 30415629
- Zhang X (2016). Effects of Magnesium Supplementation on Blood Pressure: A Meta-Analysis of Randomized Double-Blind Placebo-Controlled Trials. Hypertension. doi:10.1161/HYPERTENSIONAHA.116.07664 · PMID 27402922
- Reynolds A (2019). Carbohydrate quality and human health: a series of systematic reviews and meta-analyses. Lancet. doi:10.1016/S0140-6736(18)31809-9 · PMID 30638909
- Kessing LV (2017). Association of Lithium in Drinking Water With the Incidence of Dementia. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2017.2362 · PMID 28832877
- Asadi Shahmirzadi A (2020). Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Cell Metab. doi:10.1016/j.cmet.2020.08.004 · PMID 32877690
- Demidenko O (2021). Rejuvant, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging. Aging (Albany NY). doi:10.18632/aging.203736 · PMID 34847066
- Yi L (2022). The efficacy and safety of beta-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, dose-dependent clinical trial. GeroScience. doi:10.1007/s11357-022-00705-1 · PMID 36482258
- Akasaka H (2023). Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study. Geriatr Gerontol Int. doi:10.1111/ggi.14513 · PMID 36443648
- Nyambuya TM (2020). A Meta-Analysis of the Impact of Resveratrol Supplementation on Markers of Renal Function and Blood Pressure in Type 2 Diabetic Patients. Molecules. doi:10.3390/molecules25235645 · PMID 33266114
- Akbari M (2019). The Effects of Resveratrol Supplementation on Endothelial Function and Blood Pressures Among Patients with Metabolic Syndrome and Related Disorders: A Systematic Review and Meta-Analysis of RCTs. High Blood Press Cardiovasc Prev. doi:10.1007/s40292-019-00324-6 · PMID 31264084
- Walton RG (2019). Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults (MASTERS trial). Aging Cell. doi:10.1111/acel.13039 · PMID 31557380
- Smith AD (2010). Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial (VITACOG). PLoS One. doi:10.1371/journal.pone.0012244 · PMID 20838622
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