Longevity Supplements: A Complete Evidence Review (2026)

The Evidence Problem in Longevity Supplementation

The longevity supplement industry generates over $25 billion annually and is growing at roughly 8% per year. The scientific literature it draws from is genuinely interesting — mechanistic studies in yeast, worm, fly, and mouse models have identified dozens of compounds that extend lifespan or slow biological ageing in these organisms. The problem is that the translation from model organism to human is far more difficult in ageing biology than in any other field, for several reasons.

First, mice live two to three years. A compound that extends mouse lifespan by 15% in a 24-month study is testing a very different time horizon and metabolic context than human supplementation across decades. Second, most mouse longevity studies use inbred strains in highly controlled environments that do not replicate the genetic and environmental heterogeneity of human populations. Third, and most practically, the primary endpoints in longevity research — lifespan extension and healthspan improvement — take decades to test in humans, so intermediate surrogate endpoints (biological age clocks, inflammatory markers, physical function tests) are used, and their relationship to actual longevity is still being validated.

None of this means longevity supplements are ineffective. It means the consumer deserves an honest account of what the evidence actually supports, stratified by evidence tier. To understand why the hallmarks of ageing these compounds target matter, and how biological age differs from chronological age, those articles provide essential context for interpreting any supplement's effects.

Tier 1: Compounds with Human RCT Evidence

Rapamycin — mTOR Inhibition

Rapamycin (sirolimus) is the compound with arguably the strongest evidence base for longevity intervention in biology. Discovered in soil bacteria from Easter Island (Rapa Nui, hence the name) in the 1970s, it was approved as an immunosuppressant for organ transplantation before its longevity properties were characterised. The landmark 2009 NIA Interventions Testing Program result — that rapamycin extended median and maximum lifespan in genetically heterogeneous mice even when started at 20 months of age (equivalent to roughly 60 human years) — was among the most impactful longevity findings in decades, because it suggested that significant benefits were achievable even in already-aged animals.

Rapamycin inhibits mTORC1, the master nutrient-sensing kinase that promotes cellular growth and suppresses autophagy when nutrients are abundant. As explored in our article on caloric restriction and mTOR signalling, the mTOR pathway is one of the most consistently implicated pathways in ageing across species. Intermittent mTOR inhibition with rapamycin recapitulates many of the benefits of caloric restriction — improved autophagy, reduced senescent cell accumulation, enhanced stress resistance — without caloric restriction's practical difficulty.

In humans, the PEARL trial (published 2022) in adults over 50 found that 5 mg weekly rapamycin significantly improved immune function (enhanced response to influenza vaccine) with a mild and reversible side effect profile. Matt Kaeberlein's ongoing Dog Aging Project rapamycin trial in middle-aged companion dogs has produced positive preliminary data on cardiac function and biological age. Multiple physician-supervised longevity cohort studies (Attia's, Konovalenko's) have reported years of intermittent rapamycin use without serious adverse events in healthy adults, though none are blinded RCTs. The dose protocols range from 1 to 10 mg weekly; most researchers use 5–6 mg. See our full article on rapamycin as a longevity drug — and note that rapamycin is a prescription medication with real risks that requires medical supervision.

NMN and NR — NAD+ Precursors

NAD+ (nicotinamide adenine dinucleotide) is a coenzyme involved in hundreds of metabolic reactions and is the substrate for sirtuins (SIRT1–7), the deacetylase enzymes that regulate cellular stress responses, DNA repair, and circadian rhythm. NAD+ levels decline by roughly 50% between young adulthood and old age across most tissues. This decline impairs sirtuin activity, reduces mitochondrial efficiency, slows DNA repair, and disrupts circadian timing — touching multiple hallmarks of ageing simultaneously.

Our dedicated article on NAD+ and the science of ageing covers the full mechanistic picture. On the human trial evidence specifically: as of 2026, more than twelve randomised controlled trials have been published on NMN or NR supplementation in humans. All trials testing NAD+ levels show that oral NMN and NR raise blood and in some cases tissue NAD+ measurably. The clinical endpoint picture is more mixed: trials have found improvements in insulin sensitivity in prediabetic women (NMN, Yoshino et al., 2021), reduced arterial stiffness in older adults (NR, Martens et al., 2018), improved muscle function and reduced fatigue in older men (NMN, 250 mg/day, Igarashi et al., 2022), and improved sleep quality in one trial (NR). Effect sizes are modest — these are not dramatic interventions — but the consistency of the NAD+-raising effect and the multi-target biology downstream of NAD+ make this one of the better-supported supplement strategies.

Dosing in human trials has ranged from 250 mg to 1,200 mg daily. Higher doses raise NAD+ more but the dose-response curve for clinical endpoints is not well established. Both compounds are considered safe; at high doses, some users report flushing (more with nicotinic acid forms than NMN or NR), mild gastrointestinal discomfort, and in rare cases elevated liver enzymes. The NMN vs NR question is covered in detail in our FAQ below.

Senolytics — Clearing Senescent Cells

Senolytics are compounds that selectively eliminate senescent cells — cells that have permanently exited the cell cycle but remain metabolically active and secrete a harmful cocktail of inflammatory cytokines, proteases, and growth factors known as the SASP (senescence-associated secretory phenotype). As explained in our articles on senolytics and ageing cells and the latest senolytic clinical trials, the field has moved from animal studies to human trials with notable speed.

The dasatinib + quercetin (D+Q) combination pioneered by James Kirkland at the Mayo Clinic remains the most clinically advanced senolytic protocol. Dasatinib is a tyrosine kinase inhibitor (an approved cancer drug); quercetin is a flavonoid abundant in onions, capers, and apples. Together, they hit complementary survival pathways that senescent cells rely on. Key human trials: (1) In idiopathic pulmonary fibrosis (IPF), a Phase 2 open-label trial found that three weeks of D+Q improved physical function (6-minute walk distance, gait speed, chair-stand time) and reduced circulating senescent cell markers. (2) In diabetic kidney disease, a pilot RCT showed reduced senescent cell burden in adipose tissue biopsies and reduced circulating SASP factors. (3) A frailty trial found improvements in physical function with a well-tolerated intermittent dosing schedule (3 days on, 4 days off for two weeks).

Fisetin, a flavonoid found in strawberries, has shown senolytic activity in multiple mouse models and a small human trial showing measurable reduction in senescent cell markers in blood and adipose tissue at 20 mg/kg for two consecutive days (a dose achievable with supplementation). Larger fisetin trials are underway. The practical advantage of fisetin over D+Q is that it does not involve a prescription chemotherapy drug.

An important caveat: UNITY Biotechnology's navitoclax and UBX0101 trials for knee osteoarthritis failed at Phase 2, which is a reminder that senescent cell clearance is not a universal fix — the specific tissue context and patient population matter enormously. Senolytics are a promising intervention but not a proven cure for ageing-related conditions broadly.

Tier 2: Promising Human Data, Replication Needed

Spermidine — Autophagy Induction

Spermidine is a polyamine found in high concentrations in aged cheese (particularly blue cheese and parmesan), wheat germ, mushrooms, soy, and legumes. It is the most orally bioavailable food-derived autophagy inducer identified to date. Spermidine activates autophagy through inhibition of the EP300 acetyltransferase, and it extends lifespan in yeast, worms, flies, and mice (Eisenberg et al., 2009; various follow-up studies). In humans, higher dietary spermidine intake is associated with reduced all-cause mortality in epidemiological data, though dietary associations always carry confounding concerns.

The SmartAge trial (2022) was a 12-month double-blind RCT testing spermidine supplementation (1.2 mg/day) against placebo in older adults at risk for dementia. Supplemented participants showed significantly better memory performance on a mnemonic discrimination task, a test specifically sensitive to hippocampal neurogenesis. This is a rigorous positive trial for a specific endpoint in a relevant population; whether the effect extends to other cognitive domains or to longevity itself remains to be demonstrated. Spermidine is generally well tolerated; no significant adverse effects have been reported in human trials at doses up to 6 mg/day.

Alpha-Ketoglutarate (AKG)

Alpha-ketoglutarate (AKG) is a citric acid cycle intermediate that serves as a cofactor for the TET enzymes that demethylate DNA — the epigenetic modification relevant to epigenetic clocks and biological age measurement. AKG levels decline markedly with age (roughly 10-fold between young adulthood and old age in C. elegans), and supplementation extends lifespan in worms and mice, including the ITP mouse trial. In humans, the Rejuvant trial (2021) found that calcium AKG supplementation for 7 months reduced biological age (measured by a DNA methylation clock) by approximately 8 years compared to baseline in a middle-aged cohort. This is a single uncontrolled study and the clock-measured biological age reduction requires replication in an RCT with a placebo arm, but the effect size is striking enough to warrant serious attention. AKG also has a role as a substrate for prolyl hydroxylases that regulate HIF-1α and mTOR signalling, adding mechanistic complexity beyond pure epigenetic effects. Doses used in the Rejuvant trial: 2,000 mg calcium AKG daily.

Berberine and Metformin — AMPK Activators

Metformin, the world's most widely used diabetes drug, has attracted longevity interest because diabetic patients on metformin have lower all-cause mortality than age-matched non-diabetic individuals not on metformin — a striking epidemiological finding. Metformin activates AMPK (AMP-activated protein kinase), the cellular energy sensor that is the mirror image of mTOR: when AMPK is activated, it suppresses mTOR, stimulates autophagy, reduces inflammation, and improves insulin sensitivity. The TAME (Targeting Aging with Metformin) trial, a 3,000-person multi-site RCT launched in 2023, will be the most definitive human test of whether metformin delays ageing-related disease composites in non-diabetic older adults. Results are expected in 2028.

Berberine, an isoquinoline alkaloid found in goldenseal, barberry, and several other plants, activates AMPK through a similar mechanism to metformin and has been called "natural metformin" in popular health media. Multiple RCTs confirm that berberine reduces fasting glucose, HbA1c, and LDL cholesterol comparably to metformin in type 2 diabetics. Its longevity-specific human evidence is thin, but its metabolic effects are consistent with the AMPK biology underpinning metformin's putative longevity mechanism. A common caution: berberine inhibits CYP3A4 and P-glycoprotein and has significant drug interactions. It should not be taken without considering current medications.

CoQ10 and Ubiquinol

Coenzyme Q10 (CoQ10) is an electron carrier in the inner mitochondrial membrane, shuttling electrons from complexes I and II to complex III and serving as a lipid-soluble antioxidant that protects mitochondrial membranes from oxidative damage. As covered in our piece on CoQ10 and mitochondrial function, endogenous CoQ10 production declines with age and is further suppressed by statin drugs. The most compelling human evidence for CoQ10 is cardiovascular: the Q-SYMBIO trial found that 300 mg CoQ10 daily reduced cardiovascular mortality by 42% in chronic heart failure patients (a disease defined by mitochondrial dysfunction). The KiSel-10 trial found that CoQ10 plus selenium combined reduced cardiovascular mortality in a Swedish elderly cohort over 48 months.

For healthy older adults without cardiac disease, the evidence for CoQ10 on longevity-specific endpoints is weaker — it is a maintenance supplement rather than a potent longevity intervention. Its strongest use case is in people on statins (who have demonstrably depleted CoQ10 from drug-induced HMG-CoA reductase inhibition), people with mitochondrial disease or dysfunction, and people doing high-volume exercise. Ubiquinol (the reduced, active form) has better bioavailability than ubiquinone (the oxidised form) and is preferred, particularly in older adults whose capacity to reduce ubiquinone to ubiquinol in the gut decreases with age. Dose: 100–300 mg ubiquinol daily; with fatty food for absorption.

Tier 3: Mechanistically Compelling but Clinically Unproven

Resveratrol — The Cautionary Tale

No longevity supplement has been more hyped or more disappointing in human trials than resveratrol. The story is instructive. In 2003, David Sinclair and Lenny Guarente published that resveratrol activated SIRT1 in yeast, linking it to the longevity pathway of caloric restriction. In 2006, Sinclair's group published that resveratrol extended the lifespan of obese mice on a high-fat diet. The popular press, entrepreneurs, and supplement companies ran with these findings before the human data existed.

What followed was a series of largely negative or inconclusive human trials. The SIRT1 activation findings were disputed — subsequent work suggested the fluorescent substrate used in the original assay produced a false positive, and resveratrol may not directly activate SIRT1 at all. Human bioavailability is extremely poor: resveratrol is rapidly conjugated and metabolised in the gut and liver, achieving plasma levels orders of magnitude below the concentrations required for SIRT1 activation in cell culture. Multiple RCTs in older adults with metabolic syndrome, cardiovascular risk, or cognitive decline found no significant benefit on any primary endpoint; one trial actually found that resveratrol impaired the cardioprotective adaptations to exercise.

Resveratrol is not dangerous, and it has genuine antioxidant and anti-inflammatory properties. But as a longevity intervention in 2026, its evidence record does not support the premium it commands or the central role it plays in many longevity stacks. It belongs in Tier 3.

Astaxanthin — Mitochondrial Antioxidant

Astaxanthin is a keto-carotenoid produced by the microalgae Haematococcus pluvialis and responsible for the pink colouration of salmon, flamingos, and shrimp. Unlike most antioxidants, which are water-soluble or fat-soluble but not both, astaxanthin spans the mitochondrial membrane, enabling antioxidant activity at both the hydrophilic outer surface and the hydrophobic inner core. Its antioxidant capacity in vitro is roughly 550 times that of vitamin E. In model organisms, astaxanthin extends lifespan in C. elegans and reduces oxidative damage in ageing mice. Human trials are small and limited to surrogate endpoints: improved skin elasticity and reduced UV-induced DNA damage in cosmetic trials, reduced exercise-induced muscle damage, and reduced LDL oxidation in cardiovascular risk studies. No human RCT has tested astaxanthin against longevity-relevant endpoints. Safety is excellent; it is found naturally in the diet and has been used in aquaculture for decades with no identified toxicity. Dose: 8–12 mg daily; absorption is strongly food-dependent (requires fat).

Micro-dose Lithium

Lithium is best known as a psychiatric medication at doses of 900–1,800 mg daily. But an entirely separate body of evidence has accumulated around the biological effects of micro-dose lithium — concentrations in the 0.3–10 mg range — that arise naturally from drinking water and dietary sources and produce effects through different pathways than high-dose pharmacological lithium. Epidemiological studies have found that regions with higher natural lithium in drinking water have lower rates of suicide, dementia, and all-cause mortality — associations that have replicated across Japan, Texas, Austria, Greece, and other populations. In C. elegans, low-dose lithium extends lifespan by approximately 46% through inhibition of GSK-3β and activation of autophagy (Zarse et al., 2011). Small human trials at doses of 0.3–1 mg daily have found reductions in inflammatory markers and in one trial, slower cognitive decline in Alzheimer's disease. The compound deserves more research attention than it receives; RCTs are limited.

Stack Design: Do Combinations Make Sense?

The longevity supplement field is increasingly moving toward combination protocols targeting multiple hallmarks simultaneously, following the logic that the hallmarks of ageing are interconnected and no single intervention can address more than a fraction of them. Bryan Johnson's Blueprint protocol, reviewed in our article on the science behind Blueprint, includes over 50 compounds and has generated impressive biological age data — though the inability to isolate individual compound effects makes it impossible to attribute outcomes to any specific supplement.

A rational, evidence-anchored longevity stack in 2026 might look like: NMN or NR for NAD+ restoration; spermidine for autophagy; CoQ10 or ubiquinol for mitochondrial support; intermittent rapamycin under medical supervision for mTOR modulation; and periodic senolytic cycles (fisetin or D+Q under physician guidance) for senescent cell clearance. This targets four distinct hallmarks — NAD+ depletion, impaired autophagy, mitochondrial dysfunction, and cellular senescence — with compounds that have the best-supported human evidence.

One important caution: several compounds in longevity stacks have genuine pharmacological activity and drug interactions. Rapamycin interacts with CYP3A4 substrates. Berberine interacts with P-glycoprotein substrates. Dasatinib is a chemotherapy drug. NMN at high doses has theoretical concerns about feeding NAD+ into oncogenic sirtuin signalling in active cancer (contested but worth noting). Anyone designing a comprehensive longevity stack should do so with appropriate medical guidance, and should not take a positive animal study result as sufficient justification for human supplementation with pharmacologically active compounds.

Testing Your Baseline: What to Measure Before You Start

The single most common mistake in longevity supplementation is starting a protocol without a baseline. Without baseline measurements, you cannot know whether any subjective or objective improvements represent real biological changes or placebo effect, seasonal variation, or lifestyle changes made simultaneously. Our guide to longevity biomarkers to track covers this comprehensively. For supplement-specific baseline testing:

For NAD+ precursors: Baseline whole blood or PBMC NAD+ measurement (Jinfiniti Precision Medicine offers this directly to consumers). Retest at 8–12 weeks. If blood NAD+ has not risen measurably, the formulation has an absorption or stability problem.

For senolytics: Baseline inflammatory markers (hs-CRP, IL-6, TNF-alpha, MMP-9 if available), along with epigenetic clock testing. The GrimAge clock is particularly sensitive to inflammation-driven ageing, making it a useful senolytic outcome measure.

For rapamycin: CBC, complete metabolic panel, lipids, fasting insulin and glucose, IGF-1, and trough rapamycin level after reaching steady state. Rapamycin can elevate triglycerides and fasting glucose at some doses; monitoring allows dose adjustment.

For biological age as a global outcome: A DNA methylation clock test (TruDiagnostic, Elysium, or similar) at baseline, then again after 12 months of a consistent protocol, provides the most comprehensive available read-out of whether your biological age is changing in the intended direction.