Supplements for living longer & better

Significant reduction in CV mortality, non-fatal MI, and coronary events in meta-analysis of 38–40 RCTs with >135,000 participants (Khan et al., EClinicalMedicine 2021; Bernasconi et al., Mayo Clin Proc 2021). DHA in the top quartile is associated with 21% lower all-cause mortality in UK Biobank (Harris et al., Mayo Clin Proc 2024). Target Omega-3 Index ≥8%.

D3 alone + K2 reduce coronary artery calcification progression in subgroups of the AVADEC study (JACC 2022) and improve lumbar bone mineral density and reduce fractures in meta-analysis of 16 RCTs (n=6,425) in postmenopausal women (Ma et al., Front Public Health 2022). The D3+K2 pairing directs calcium to bone and away from arteries.

Cofactor in over 600 enzymatic reactions, critical for DNA repair, mitochondrial function, and sleep. Approximately 48% of adults are below the RDI. The threonate form crosses the blood-brain barrier and is the preferred choice of Attia, Huberman, and Patrick for cognitive function and sleep.

Improves memory (especially in adults 66–76 years, SMD=0.88), processing speed, and attention in meta-analysis of 16 RCTs (Xu et al., Front Nutr 2024; Prokopidis et al., Nutr Rev 2023). Synergy with strength training for sarcopenia, bone, cognitive, and metabolic health. Women appear to benefit more. Universally recommended by Attia, Patrick, and Huberman.

Geroprotective amino acid validated by the NIA ITP (Miller 2019, extends lifespan in mice). In humans, 3 g pre-sleep improves subjective quality, latency, daytime sleepiness, and cognitive performance (Bannai & Kawai, Front Neurol 2012). Glutathione precursor (see GlyNAC).

Dietary mitochondrial antioxidant proposed as a longevity vitamin by Bruce Ames (Beelman et al., PNAS 2020). Has a dedicated cellular transporter (SLC22A4/OCTN1), suggesting an evolutionarily essential role. Dietary intake is inversely correlated with mortality and neurological disease. Small RCTs show increased plasma antioxidants and improved cognition in mild cognitive impairment.

The Q-SYMBIO RCT (n=420, 2 years) showed 43% reduction in MACE, 42% in all-cause mortality, and 43% in CV mortality in heart failure with CoQ10 vs placebo (Mortensen et al., JACC HF 2014). Especially important in statin users (induced depletion). Ubiquinol > ubiquinone in those over 60.

Ellagitannin postbiotic and mitophagy activator with the strongest human evidence base in the field. RCTs show ~12% improvement in muscle strength, aerobic endurance, and mitochondrial biomarkers in middle-aged adults (Singh et al., Cell Rep Med 2022); in 2025 demonstrates improvement in immune aging and expansion of memory stem T cells in phase 1 RCT (Denk et al., Nat Aging 2025/2026). Only 30–40% of people produce UA endogenously from pomegranates/walnuts; supplementation guarantees the effect.

Robustly raise NAD⁺ in blood and tissues in humans. NR improves inflammatory markers and has greater historical clinical base; NMN has emerging meta-analyses showing improved physical performance and sleep (Wen et al., Cureus 2024). Head-to-head, both double NAD⁺ at 1,000 mg/day. The mechanism and NAD⁺ rise are confirmed; hard clinical outcomes still emerging; no RCT has demonstrated extension of human lifespan. Combine with TMG if monitoring methylation cycle.

Induces mitochondrial biogenesis via PGC-1α; reduces CRP and improves oxidative stress markers in small RCTs. Reasonable synergy with CoQ10. Keep if already in stack but not a priority.

Useful for diabetic neuropathy and insulin sensitivity. Its role as a geroprotector is doubtful: ALA in the ITP did not extend lifespan in mice and high doses shortened lifespan in SAMP8 mice (Lee et al., Aging Cell 2004; Farr et al., J Alzheimer's Dis 2012).

Mitochondrial fatty acid transport; ALCAR crosses the blood-brain barrier and improves cognitive function in mild impairment. Specifically useful in those over 60 or vegetarians (alongside creatine).

Flavonoid senolytic. The best-studied natural senolytic outside the pharmaceutical clinical setting, with good safety and preclinical evidence of senescent burden reduction. Human trials underway (NCT04210986).

Component of the senolytic cocktail D+Q (dasatinib + quercetin), the only senolytic protocol that has demonstrated reduction of senescent cells in humans (RCT in diabetic kidney disease, EBioMedicine 2019) and improvement of bone markers in postmenopausal women in phase 2 RCT (n=60, Mayo Clinic 2024). Alone it is a modest senomorphic; it shines in combination.

Unique dual mechanism: (a) inhibits CD38, preserving NAD⁺ and synergizing with NMN/NR (Escande et al., Diabetes 2013); (b) senomorphic that suppresses SASP via interference with HSPA8/PRDX6 (bioRxiv 2024). Part of Andrew Huberman's nighttime stack. Small clinical trials emerging.

Autophagy inducer. The Bruneck study (n=829, 15 years) associates higher dietary spermidine intake with 26% lower all-cause mortality (~6 years difference in biological age) (Eisenberg et al., 2018). Improves diastolic cardiac function in aged mice ~10% lifespan; human RCT shows memory improvement in mild cognitive impairment. Safe at 40 mg/day × 28 days in 2024 RCT.

Umbrella meta-analysis of 10 studies with 5,870 participants shows significant reductions in CRP, IL-6, and TNF-α (Naghsh et al., Oxid Med Cell Longev 2023). Rhonda Patrick's preferred choice (Thorne Meriva) over NSAIDs.

SIRT1 activator with ~200 human studies. Reduces inflammatory markers and improves some cardiometabolic parameters but RCTs to hard outcomes are inconsistent (Brown et al., IJMS 2024). Pterostilbene has better bioavailability (80% vs 20%) and longer half-life.

Master NRF2 activator (the only validated target of the compound). Increases detoxification, endogenous antioxidant defenses (GSH, SOD, NQO1), reduces CRP (Houghton et al., Oxid Med Cell Longev 2016). Inducing capacity 13× greater than curcumin, 105× resveratrol. Overlaps with the detox/methylation category.

Selective 5-LOX inhibitor; alternative to NSAIDs in osteoarthritis with superior GI safety profile. Medium-high evidence for joints; medium for systemic inflammaging.

Resolves the arginine paradox: superior precursor for nitric oxide production. Improves endothelial function, aortic stiffness, and blood pressure in postmenopausal hypertensive women; reverses endothelial senescence in cellular and animal studies (Tsuboi et al., PLOS One 2018; Wong et al., Nutrients 2022).

Citrus flavonoid. Meta-analysis shows significant reduction in TG, TC, LDL, TNF-α, and SBP, especially at >500 mg and >8 weeks (Hou et al., Front Nutr 2023).

Reduces TMAO, blood pressure, and progressive coronary calcification. Considered by Huberman to offset TMAO from Alpha-GPC.

Only polyphenol with EFSA-approved health claim: olive oil polyphenols contribute to the protection of blood lipids from oxidative stress at 5 mg/day (EFSA Journal 2025). Regulatorily approved evidence.

Meta-analysis: reduces fasting glucose −0.52 mmol/L, HbA1c −4.5 mmol/mol, fasting insulin −2.4 mU/L, HOMA-IR −0.85 (He et al., J Nutr 2023; Liang et al., Front Pharmacol 2022). Comparable to metformin in mild T2D. Also listed in metabolic section.

The star of this category. Comparable to metformin in mild T2D.

Especially useful in women with PCOS/insulin resistance; surpasses metformin in menstrual frequency and testosterone reduction in network meta-analysis (Zhao et al., Reprod Health 2021).

Modest but consistent effect on fasting glucose and HbA1c in T2D.

Modestly reduces fasting glucose and HbA1c. Honorable mention if diet is already good.

The longevity probiotic. Human proof-of-concept RCT (Depommier 2019, Nat Med) showed improvement in insulin sensitivity, inflammatory markers, and intestinal barrier in obese subjects. Supplementation in aged mice preserves colonic mucous layer thickness and immunity (Van der Lugt et al., Immun Ageing 2019). Association with centenarians.

Bifidobacterium longum specifically inversely linked to age. Useful after antibiotics, for inflammaging, gut-brain axis.

Substrate for SCFA production (butyrate, acetate) which reduce inflammation, improve barrier integrity, and support endogenous Akkermansia. Supplements do not replace dietary diversity.

Direct SCFA for colonic epithelium integrity and HDAC inhibition.

Repeated here for its specific bone importance (see evidence in Essentials section).

Unique oral tolerance mechanism; superior to glucosamine+chondroitin (1,500+1,200 mg) in multicenter RCT of 191 subjects on WOMAC and knee pain (Lugo et al., Nutr J 2016).

In UK Biobank (n=495,077), regular use was associated with 15% lower all-cause mortality, 18% lower CV, 27% lower respiratory (Ma et al., Ann Rheum Dis 2020). Surprisingly one of the supplements with the most robust association to reduced mortality. Mechanism possibly via caloric restriction mimicry/AMPK.

Meta-analysis of 23 RCTs finds net improvements in hydration, elasticity, and wrinkles. Role for joints is weaker than UC-II.

RCTs show consistent improvement in hydration, elasticity, wrinkle depth, and epidermal thickness after 8–12 weeks (Hsu et al., Nutrients 2021; Gao et al., Skin Res Tech 2023).

First-line option for longevity-oriented sleep.

Attia/Huberman's Magtein at 140 mg pre-sleep.

Modulates GABA-A in addition to its senomorphic/CD38 action.

Reduces acute anxiety/stress in systematic review (Williams et al., Plant Foods Hum Nutr 2020) and improves subjective sleep quality and executive function in 4-week RCT (Hidese et al., Nutrients 2019).

Beyond sleep: powerful mitochondrial antioxidant concentrated 100× plasma in mitochondria, regulates mitochondrial biogenesis and dynamics, declines dramatically with age (10× lower in octogenarians vs adolescents) (Reiter et al., Mol & Cell Biochem 2017). Physiological doses (0.3 mg) are preferable to the usual 5–10 mg in marketing.

Meta-analysis of 25 RCTs in 1,353 older men: fat mass reduction but NOT robust improvement in functional outcomes (Corona et al., JCEM 2013). In postmenopausal women: increases testosterone +24 ng/dL and estradiol +7.9 pg/mL. Better risk-benefit in postmenopausal women than in eugonadal men.

Neurosteroid precursor; mechanistic evidence + some RCTs in cognition and mood. Maintain if there is a lab-confirmed deficit.

Robust reducer of perceived cortisol; modestly improves stress, sleep, and testosterone. KSM-66 or Sensoril forms are validated.

Improves testosterone and mood in men with chronic stress/subclinical deficit. In Huberman's stack.

Stimulates NGF/BDNF; RCTs show cognitive improvement in mild impairment. Medium-high evidence for mild cognitive impairment; medium in healthy individuals.

Neuronal membrane component; reduces acute cortisol and improves cognitive function in older adults. Attia's choice for jet lag (400 mg Jarrow PS100).

Improves memory and processing speed after 8–12 weeks in meta-analysis.

Phosphatidylcholine and acetylcholine precursor; improves cognition in vascular impairment and MCI. Safer alternative to Alpha-GPC (concerns with TMAO/stroke).

24-week RCT in older adults shows improvements in glutathione, oxidative stress, mitochondrial function, inflammation, insulin resistance, muscle strength, cognition, and ≥4 hallmarks of aging (Kumar et al., J Gerontol 2022). Probably the most impressive intervention in the multi-hallmark modulation group.

Glutathione precursor; clinically approved for hepatic function, synergizes with glycine (GlyNAC). High clinical evidence, medium specifically for longevity.

Methyl donor; balances the methylation cycle when high-dose NAD⁺ precursors are taken. Medium-high evidence for homocysteine, medium for synergy with NMN/NR.

NRF2 activator inducing phase II detoxification.

Essential for individuals with MTHFR polymorphisms (~30–50% of the population); keeps homocysteine low. Attia takes methyl-B12 and methyl-folate.

The peptide with the best real human evidence for immunosenescence. Approved in over 35 countries for viral hepatitis. RCT in older adults shows +40% antibody response to influenza vaccine; meta-analysis suggests improvement in sepsis (review IJMS 2025). Targets thymic involution (central hallmark of immune aging). Requires prescription.

Only approved and evidenced use: topical for skin (stimulates collagen, elastin, antioxidant, anti-inflammatory). High topical evidence.

Only 3 published human studies (without adequate control group); everything else is animal (review PMC 2025). Flagged by FDA as a safety risk.

Telomerase synthesis in old Russian in vitro/animal studies; in humans only methodologically weak pre-2010 studies. Honorable mention with experimental disclaimer.

The NIA ITP confirmed that astaxanthin extends lifespan in male UM-HET3 mice (Harrison 2024), joining the exclusive group of 15 validated compounds. In humans: improves skin elasticity/hydration, endothelial function, lipids. Probably the most underrated supplement in the field.

Debated efficacy; better evidence for type I bioactive at 10 g.

Consistently improves skin hydration and elasticity.

Main adaptogen with the best evidence for cortisol and sleep.

Reducer of mental fatigue, improves cognitive performance under stress.

Reduces acute anxiety without sedation.