{ "_meta": { "title": "Geroscope — evidence-based longevity interventions (raw data export)", "site": "https://42-apps.github.io/longevity/", "count": 135, "license": "Open for independent review and correction.", "disclaimer": "Educational synthesis, NOT medical advice. The 0-100 component scores are an informed, curated judgement, not measured quantities. Independent fact-checking is explicitly welcomed — please flag errors in study citations, effect sizes, evidence grading, or scores.", "scoring": { "components": { "evi": "Evidence strength — rigor/reproducibility of the BEST available study, any species", "hum": "Human translation — how well the benefit is demonstrated IN HUMANS", "imp": "Impact — magnitude of effect on lifespan/healthspan where shown (null/harmful effects score low)", "safe": "Safety — risk profile at the relevant dose (higher = safer)" }, "scale": "0-100 each", "overall_formula": "overall = 0.30*evi + 0.28*hum + 0.22*imp + 0.20*safe", "tiers": "S >=78 | A 68-77 | B 56-67 | C 44-55 | D <44", "evidenceType_ladder_strongest_first": [ "human-rct-hard", "human-rct-surrogate", "human-cohort", "animal-itp", "animal-other", "human-other", "in-vitro", "mechanistic" ] }, "field_guide": { "id": "slug", "name": "", "aka": "alternate/brand names", "category": "one of 12 categories", "klass": "drug/compound/intervention class", "mechanism": "1-line mechanism of action", "hallmarks": "Hallmarks of Aging targeted", "evidenceType": "tier of the best available evidence", "evidence": "2-3 sentence summary of best evidence + limitations", "keyStudies": "array of {ref, finding, url} — url is a verified DOI/PubMed/official link (or a Google Scholar lookup for a few diffuse refs)", "effect": "effect magnitude (with 95% CI for marquee human-outcome interventions)", "human": "state of human evidence", "safety": "risk profile", "dose": "typical protocol", "status": "regulatory/usage status", "accessibility": "otc | rx | clinic-only | experimental | lifestyle", "caveats": "biggest caveat", "sources": "verified source URLs", "evi": "score 0-100", "hum": "score 0-100", "imp": "score 0-100", "safe": "score 0-100", "overall": "computed", "tier": "computed", "rank": "computed (by overall, desc)" }, "provenance": "Compiled by a 7-agent web-research sweep of 2023-2026 literature, then audited by a 10-agent adversarial fact-check pass and a 10-agent citation-resolution pass (190/193 key studies linked to canonical sources). Independently fact-checked with no errors found by Gemini, Grok and GPT (mid-2026); their feedback added 95% confidence intervals to marquee figures and 6 gap-fill interventions." }, "interventions": [ { "id": "smoking-cessation", "name": "Smoking Cessation", "aka": "Quitting tobacco", "category": "lifestyle", "klass": "Removing a major mortality risk", "mechanism": "Eliminates exposure to oxidants/carcinogens that accelerate genomic instability, vascular damage and senescence", "hallmarks": [ "Genomic instability", "Chronic inflammation", "Cellular senescence", "Telomere attrition" ], "evidenceType": "human-cohort", "evidence": "The benchmark high-effect-size intervention: quitting before ~40 restores life expectancy nearly to never-smokers (~10 years gained quitting at 25-34), with mortality risk halving within ~10-15 years. Evidence is overwhelming, consistent and near-causal.", "keyStudies": [ { "ref": "Jha et al., NEJM 2013", "finding": "Quitting at 25-34/35-44/45-54 gains ~10/9/6 years", "url": "https://doi.org/10.1056/NEJMsa1211128" } ], "effect": "Quitting by mid-40s regains ~6-9 yrs life expectancy (quit at 35-44 ~9 yr, 45-54 ~6 yr; life-table estimates, no CI); continuing smokers' all-cause mortality HR ~2.8-3.0 vs never-smokers (99% CI 2.4-3.3) — Jha NEJM 2013, n=202,248", "human": "Overwhelming consistent cohort evidence with clear age gradient", "safety": "Only upside; transient withdrawal; cessation aids generally safe", "dose": "Complete permanent cessation (+ support/NRT/varenicline)", "status": "Highest-priority guideline", "accessibility": "lifestyle", "caveats": "Observational by necessity, but causal inference robust; benefit depends on age at quitting", "sources": [ "https://doi.org/10.1056/NEJMsa1211128" ], "evi": 82, "hum": 92, "imp": 85, "safe": 95, "overall": 88, "tier": "S", "rank": 1 }, { "id": "aerobic-exercise", "name": "Aerobic / Endurance Exercise", "aka": "Cardio, MVPA", "category": "exercise", "klass": "Physical activity", "mechanism": "Improves mitochondrial biogenesis, endothelial function, insulin sensitivity and cardiac output", "hallmarks": [ "Mitochondrial dysfunction", "Chronic inflammation", "Deregulated nutrient sensing", "Cellular senescence" ], "evidenceType": "human-cohort", "evidence": "Among the strongest and most consistent evidence in all of longevity: pooled cohorts (>660,000) show meeting the ~150 min/wk guideline yields ~31% lower all-cause mortality, with most benefit from the first increments, supported by RCTs on fitness/CV surrogates.", "keyStudies": [ { "ref": "Arem et al., JAMA IM 2015 (n=661,137)", "finding": "Guideline activity HR 0.69; up to ~39% reduction at higher doses", "url": "https://doi.org/10.1001/jamainternmed.2015.0533" } ], "effect": "All-cause mortality HR 0.69 (95% CI 0.67-0.70) at ~150 min/wk; plateau HR 0.61 (95% CI 0.59-0.62) at 3-5x minimum, no harm at >=10x — Arem JAMA Intern Med 2015, n=661,137", "human": "Large consistent cohorts + RCTs on surrogates", "safety": "Very safe; rare acute cardiac events in high-risk unscreened individuals", "dose": "150-300 min/wk moderate or 75-150 vigorous", "status": "Established guideline", "accessibility": "lifestyle", "caveats": "Mortality evidence observational, but triangulated with RCT surrogate data", "sources": [ "https://doi.org/10.1001/jamainternmed.2015.0533" ], "evi": 80, "hum": 92, "imp": 80, "safe": 92, "overall": 86, "tier": "S", "rank": 2 }, { "id": "cardiorespiratory-fitness-vo2max", "name": "Cardiorespiratory Fitness / VO2max", "aka": "CRF, Zone 2 training", "category": "exercise", "klass": "Trainable aerobic capacity", "mechanism": "VO2max integrates cardiac output and mitochondrial oxidative capacity — a measure of whole-body metabolic resilience", "hallmarks": [ "Mitochondrial dysfunction", "Altered intercellular communication", "Chronic inflammation" ], "evidenceType": "human-cohort", "evidence": "One of the strongest single predictors of mortality: in 122,007 treadmill-tested adults, higher fitness tracked with markedly lower mortality with NO upper ceiling — elite vs low fitness ~5x lower mortality, a larger adjusted effect than smoking or diabetes. Partly trainable via aerobic base + intervals.", "keyStudies": [ { "ref": "Mandsager et al., JAMA Netw Open 2018 (n=122,007)", "finding": "Elite vs low fitness ~5x lower mortality; no upper limit", "url": "https://doi.org/10.1001/jamanetworkopen.2018.3605" } ], "effect": "All-cause mortality HR 0.20 (95% CI 0.16-0.24), ~80% lower, elite vs low fitness; low fitness risk exceeds smoking/diabetes — Mandsager JAMA Netw Open 2018, n=122,007", "human": "Very large cohort with objectively measured fitness", "safety": "Achieving via exercise is very safe", "dose": "Aerobic base (Zone 2) + higher-intensity intervals", "status": "Prognostic marker / training target", "accessibility": "lifestyle", "caveats": "Observational; CRF is partly genetic, so raising it may not yield the full association-sized benefit", "sources": [ "https://doi.org/10.1001/jamanetworkopen.2018.3605" ], "evi": 78, "hum": 90, "imp": 82, "safe": 90, "overall": 85, "tier": "S", "rank": 3 }, { "id": "mediterranean-diet", "name": "Mediterranean Diet", "aka": "MedDiet, PREDIMED pattern", "category": "diet", "klass": "Whole-dietary pattern", "mechanism": "High MUFA, polyphenols, fiber and omega-3s reduce inflammation/oxidative stress and improve lipids and the microbiome", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication", "Dysbiosis", "Mitochondrial dysfunction" ], "evidenceType": "human-rct-hard", "evidence": "PREDIMED, a primary-prevention RCT in ~7,447 high-risk adults, found a MedDiet (+olive oil or nuts) cut major cardiovascular events ~30% vs control; large cohorts consistently link adherence to lower mortality. Among the strongest hard-outcome dietary evidence in longevity.", "keyStudies": [ { "ref": "Estruch et al., NEJM 2018 (PREDIMED)", "finding": "~30% lower major CV events (HR 0.69-0.72)", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa1800389" } ], "effect": "Major CV events HR 0.69 (95% CI 0.53-0.91) with EVOO and HR 0.72 (95% CI 0.54-0.95) with nuts vs control — PREDIMED (Estruch NEJM 2018, republished), n=7,447", "human": "Primary-prevention RCT with hard CV endpoints + extensive cohorts", "safety": "Very safe; nutrient-dense", "dose": "High EVOO + nuts + vegetables/legumes/fish; low red/processed meat", "status": "Established guideline", "accessibility": "lifestyle", "caveats": "PREDIMED was retracted/republished over randomization issues (results unchanged); all-cause mortality reduction not individually significant", "sources": [ "https://www.nejm.org/doi/full/10.1056/NEJMoa1800389" ], "evi": 86, "hum": 88, "imp": 60, "safe": 95, "overall": 83, "tier": "S", "rank": 4 }, { "id": "resistance-training", "name": "Resistance / Strength Training", "aka": "Weight training", "category": "exercise", "klass": "Physical activity", "mechanism": "Mechanical loading drives muscle protein synthesis, countering sarcopenia and improving glucose/bone/myokines", "hallmarks": [ "Stem cell exhaustion", "Loss of proteostasis", "Deregulated nutrient sensing", "Mitochondrial dysfunction" ], "evidenceType": "human-cohort", "evidence": "Muscle-strengthening ~2x/wk is associated with ~10-21% lower all-cause mortality (J-shaped, peak ~30-60 min/wk), and combining with aerobic exercise gives ~40% lower mortality. RCTs robustly show strength/function gains and sarcopenia treatment.", "keyStudies": [ { "ref": "Momma et al., BJSM 2022", "finding": "~30-60 min/wk: 10-20% lower mortality", "url": "https://pubmed.ncbi.nlm.nih.gov/35228201/" }, { "ref": "Saeidifard 2019", "finding": "RT+aerobic HR 0.60 all-cause mortality", "url": "https://doi.org/10.1177/2047487319850718" } ], "effect": "All-cause mortality RR 0.85 (95% CI 0.79-0.93) for muscle-strengthening alone; RR 0.60 (95% CI 0.54-0.67) combined with aerobic — Momma BJSM 2022", "human": "Cohort mortality data + strong RCT evidence for strength/function", "safety": "Very safe with proper form; valsalva BP spikes in uncontrolled hypertension", "dose": ">=2 sessions/wk, all major muscle groups", "status": "Established guideline", "accessibility": "lifestyle", "caveats": "Mortality evidence observational; muscle-mass gains modest in oldest-old; best added to aerobic", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/35228201/", "https://doi.org/10.1177/2047487319850718" ], "evi": 75, "hum": 88, "imp": 72, "safe": 90, "overall": 81, "tier": "S", "rank": 5 }, { "id": "sleep-optimization", "name": "Sleep Optimization", "aka": "Healthy sleep duration & quality", "category": "lifestyle", "klass": "Behavioral/circadian", "mechanism": "Adequate sleep enables glymphatic clearance, metabolic/immune regulation and restrains inflammation", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication", "Loss of proteostasis" ], "evidenceType": "human-cohort", "evidence": "Large meta-analyses show a U-shaped sleep-mortality curve with a nadir ~7 hours; healthy-sleep scores predict multi-year life-expectancy gains. Consistent and mechanistically grounded, but observational (long sleep is heavily confounded by illness).", "keyStudies": [ { "ref": "Yin et al., JAHA 2017", "finding": "U-shaped; short and long sleep raise mortality vs 7h", "url": "https://www.ahajournals.org/doi/10.1161/JAHA.117.005947" } ], "effect": "U-shaped all-cause mortality: RR 1.06/h (95% CI 1.04-1.07) for short sleep and RR 1.13/h (95% CI 1.11-1.15) for long sleep, nadir ~7h — Yin et al. JAHA 2017 dose-response meta-analysis", "human": "Large consistent cohorts; RCTs only on surrogate markers", "safety": "No downside to healthy sleep (sedatives carry own risks)", "dose": "7-9 h/night, regular schedule; treat apnea/insomnia", "status": "Established guideline", "accessibility": "lifestyle", "caveats": "Long-sleep risk largely reverse causation; causal benefit of extending short sleep unproven by RCT", "sources": [ "https://www.ahajournals.org/doi/10.1161/JAHA.117.005947" ], "evi": 74, "hum": 88, "imp": 60, "safe": 95, "overall": 79, "tier": "S", "rank": 6 }, { "id": "empagliflozin-dapagliflozin", "name": "Empagliflozin / Dapagliflozin", "aka": "Jardiance, Farxiga (SGLT2i class)", "category": "pharma", "klass": "SGLT2 inhibitors", "mechanism": "Glucosuria, natriuresis and mild ketosis reduce cardiac/renal stress beyond glucose lowering", "hallmarks": [ "Deregulated nutrient sensing", "Chronic inflammation", "Mitochondrial dysfunction" ], "evidenceType": "human-rct-hard", "evidence": "Among the strongest HUMAN hard-outcome evidence in the field: large RCTs cut cardiovascular death, all-cause mortality and kidney-disease progression, including in non-diabetics. But trials enrolled people with established disease, not healthy aging.", "keyStudies": [ { "ref": "EMPA-REG, NEJM 2015", "finding": "All-cause mortality HR 0.68; CV death HR 0.62 in diabetics with CVD", "url": "https://doi.org/10.1056/NEJMoa1504720" }, { "ref": "DAPA-CKD, NEJM 2020", "finding": "All-cause mortality HR 0.69 in CKD +/- diabetes", "url": "https://doi.org/10.1056/NEJMoa2024816" } ], "effect": "All-cause mortality HR 0.68 (95% CI 0.57-0.82) empagliflozin in T2D+CVD (EMPA-REG, n=7,020); HR 0.69 (95% CI 0.53-0.88) dapagliflozin in CKD (DAPA-CKD, n=4,304)", "human": "Multiple positive hard-outcome RCTs, some incl. non-diabetics", "safety": "Genital/urinary infections, volume depletion, rare euglycemic DKA; no amputation signal", "dose": "Empagliflozin 10-25 mg/d; dapagliflozin 10 mg/d", "status": "FDA-approved (diabetes/HF/CKD)", "accessibility": "rx", "caveats": "Mortality benefit shown only in diseased populations; untested for lifespan extension in healthy people", "sources": [ "https://doi.org/10.1056/NEJMoa1504720", "https://doi.org/10.1056/NEJMoa2024816" ], "evi": 86, "hum": 82, "imp": 55, "safe": 75, "overall": 76, "tier": "A", "rank": 7 }, { "id": "omega-3-epa-dha", "name": "Omega-3 Fatty Acids (EPA/DHA)", "aka": "Fish oil, marine omega-3", "category": "supplement", "klass": "Essential fatty acids", "mechanism": "Anti-inflammatory eicosanoids/resolvins; membrane and lipid effects", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "human-rct-hard", "evidence": "Among the strongest longevity-relevant supplement evidence: in DO-HEALTH, 1 g/d slowed several epigenetic aging clocks and reduced infections/falls, and combined with vitamin D + exercise cut invasive cancer. CV outcomes are mixed (generic fish oil failed VITAL/ASCEND; Rx high-dose EPA cut MACE in REDUCE-IT).", "keyStudies": [ { "ref": "DO-HEALTH, Nature Aging 2025", "finding": "1 g/d slowed PhenoAge/GrimAge2/DunedinPACE clocks", "url": "https://www.nature.com/articles/s43587-024-00793-y" }, { "ref": "DO-HEALTH, JAMA 2020 (n=2,157)", "finding": "Omega-3 cut infections ~11% and falls ~10%; no benefit on primary bone/memory/muscle endpoints", "url": "https://pubmed.ncbi.nlm.nih.gov/33170239/" }, { "ref": "DO-HEALTH, Frontiers in Aging 2022", "finding": "3-way combo cut invasive cancer 61% (HR 0.39)", "url": "https://doi.org/10.3389/fragi.2022.852643" } ], "effect": "Epigenetic-clock slowing ~3-4 mo/3yr (GrimAge2 d -0.32, 95% CI -0.59 to -0.06) in DO-HEALTH (n=777); CV benefit only with Rx EPA — MACE HR 0.75 (95% CI 0.68-0.83), REDUCE-IT 2019", "human": "Multiple large RCTs; positive on aging biomarkers, mixed on CV", "safety": "Very safe; mild GI; modest AFib/bleeding signal at high dose", "dose": "~1-2 g/day EPA+DHA", "status": "OTC; Rx icosapent ethyl", "accessibility": "otc", "caveats": "Generic fish oil failed CV hard-outcome trials; clock benefit not yet proven to extend lifespan", "sources": [ "https://www.nature.com/articles/s43587-024-00793-y", "https://pubmed.ncbi.nlm.nih.gov/33170239/", "https://doi.org/10.3389/fragi.2022.852643" ], "evi": 80, "hum": 82, "imp": 48, "safe": 90, "overall": 76, "tier": "A", "rank": 8 }, { "id": "daily-steps-walking", "name": "Daily Steps / Walking", "aka": "Step count, ambulation", "category": "exercise", "klass": "Low-intensity activity (volume)", "mechanism": "Accumulated low-intensity movement improves vascular function, glucose handling and reduces sedentary time", "hallmarks": [ "Chronic inflammation", "Deregulated nutrient sensing", "Mitochondrial dysfunction" ], "evidenceType": "human-cohort", "evidence": "A device-measured meta-analysis (~47,000) found mortality declines with more steps, plateauing ~6,000-8,000/day for older adults — debunking the arbitrary 10,000 target. Each +1,000 steps/day ~15% lower mortality. Observational but device-measured.", "keyStudies": [ { "ref": "Paluch et al., Lancet PH 2022", "finding": "Mortality plateaus ~6,000-8,000 steps/day (>=60 yr)", "url": "https://doi.org/10.1016/S2468-2667(21)00302-9" } ], "effect": "All-cause mortality HR 0.47 (95% CI 0.39-0.57), ~53% lower, highest vs lowest step quartile; optimum plateaus ~6,000-8,000/day (>=60y), ~8,000-10,000/day (<60y) — Paluch Lancet Public Health 2022", "human": "Strong device-measured cohort data; no RCT (impractical)", "safety": "Extremely safe", "dose": "~7,000-8,000+ steps/day (benefit begins below)", "status": "Public-health target", "accessibility": "lifestyle", "caveats": "Observational; reverse causation (frail people walk less) likely inflates low-step risk", "sources": [ "https://doi.org/10.1016/S2468-2667(21)00302-9" ], "evi": 72, "hum": 82, "imp": 55, "safe": 95, "overall": 76, "tier": "A", "rank": 9 }, { "id": "alcohol-moderation", "name": "Alcohol Moderation / Abstention", "aka": "Reducing alcohol intake", "category": "lifestyle", "klass": "Reducing a modifiable toxin", "mechanism": "Ethanol/acetaldehyde are carcinogens promoting DNA damage, hepatic injury and inflammation; reducing intake lowers this burden", "hallmarks": [ "Genomic instability", "Chronic inflammation", "Mitochondrial dysfunction" ], "evidenceType": "human-cohort", "evidence": "The 2023 Zhao/Naimi meta-analysis (107 cohorts, ~4.8M) overturned the old 'J-curve': after correcting for abstainer-bias, low-moderate drinking showed no mortality benefit, with clear harm above ~25 g/d (women)/45 g/d (men). Mendelian randomization supports monotonic harm. Consensus: no safe level for cancer.", "keyStudies": [ { "ref": "Zhao/Naimi, JAMA Netw Open 2023", "finding": "No mortality benefit at low/moderate intake; harm at higher", "url": "https://doi.org/10.1001/jamanetworkopen.2023.6185" } ], "effect": "No mortality benefit at low intake — RR 0.93 (95% CI 0.85-1.01, NS) for 1.3-24 g/d vs lifetime nondrinkers; harm >=25 g/d women (RR 1.21, 95% CI 1.08-1.36) and >=45 g/d men (RR 1.15, 95% CI 1.03-1.28) — Zhao/Naimi JAMA Netw Open 2023, n=4.8M", "human": "Bias-corrected meta-analysis + Mendelian randomization converge against the J-curve", "safety": "Alcohol is a Group 1 carcinogen; harms rise with dose; dependence risk", "dose": "Lowest risk is zero", "status": "Guidelines revised toward 'less is better'", "accessibility": "lifestyle", "caveats": "Prior 'protective' findings reflected abstainer bias; residual debate on CV-specific endpoints only", "sources": [ "https://doi.org/10.1001/jamanetworkopen.2023.6185" ], "evi": 76, "hum": 82, "imp": 50, "safe": 92, "overall": 75, "tier": "A", "rank": 10 }, { "id": "vitamin-d3", "name": "Vitamin D3", "aka": "Cholecalciferol", "category": "supplement", "klass": "Secosteroid / fat-soluble vitamin", "mechanism": "VDR-mediated gene regulation; calcium, immune and possible telomere/inflammation effects", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication", "Telomere attrition" ], "evidenceType": "human-rct-hard", "evidence": "Large RCTs (VITAL, ASCEND) show 2000 IU/d does not reduce total cancer, CV events or all-cause mortality in mostly-replete people. Meta-analyses show a modest ~12% reduction in cancer MORTALITY and lower autoimmune disease. Benefit concentrated in the deficient.", "keyStudies": [ { "ref": "VITAL, NEJM 2019 (n=25,871)", "finding": "No reduction in cancer incidence or major CV events", "url": "https://pubmed.ncbi.nlm.nih.gov/30415629/" }, { "ref": "Keum et al. meta-analysis", "finding": "Daily vitamin D cut cancer mortality ~12-13%", "url": "https://pubmed.ncbi.nlm.nih.gov/30796437/" } ], "effect": "Total cancer mortality RR 0.87 (95% CI 0.79-0.96), ~13% lower (daily dosing); no effect on cancer incidence (RR 0.98, 95% CI 0.93-1.03); negligible CV/all-cause in replete people — Keum Ann Oncol 2019", "human": "Definitive RCTs: neutral for most hard endpoints except modest cancer-mortality signal", "safety": "Safe at <=4000 IU/d; high bolus dosing raises fall/fracture risk", "dose": "1000-2000 IU/day; correct deficiency", "status": "Ubiquitous OTC vitamin", "accessibility": "otc", "caveats": "Benefit largely limited to deficient people; routine high-dose in replete adults shows no mortality benefit", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/30415629/", "https://pubmed.ncbi.nlm.nih.gov/30796437/" ], "evi": 80, "hum": 82, "imp": 42, "safe": 88, "overall": 74, "tier": "A", "rank": 11 }, { "id": "hiit", "name": "High-Intensity Interval Training", "aka": "HIIT, 4x4 intervals", "category": "exercise", "klass": "Interval exercise", "mechanism": "Brief near-maximal efforts maximally stress cardiac output and mitochondria, producing potent VO2max gains per unit time", "hallmarks": [ "Mitochondrial dysfunction", "Deregulated nutrient sensing", "Chronic inflammation" ], "evidenceType": "human-rct-hard", "evidence": "The Generation 100 RCT (n=1,567, age 70-77, 5 yr) found overall mortality did not differ significantly, but the HIIT subgroup had the lowest (non-significant) mortality and best VO2max/quality-of-life gains. HIIT reliably outperforms moderate training for raising VO2max.", "keyStudies": [ { "ref": "Stensvold et al., BMJ 2020 (Gen100)", "finding": "HIIT subgroup ~3% vs ~4.7-6% control mortality (NS); best fitness gains", "url": "https://pubmed.ncbi.nlm.nih.gov/33028588/" } ], "effect": "Non-significant mortality reduction; superior VO2max gains", "human": "One large RCT (underpowered for mortality) + many fitness RCTs", "safety": "Safe in older adults under guidance; higher acute risk than moderate exercise", "dose": "e.g. 4x4 min at 85-95% max HR, ~2x/wk", "status": "Established for fitness; mortality suggestive", "accessibility": "lifestyle", "caveats": "Flagship RCT underpowered for mortality with an active control; clearest benefit is VO2max", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/33028588/" ], "evi": 70, "hum": 78, "imp": 65, "safe": 82, "overall": 74, "tier": "A", "rank": 12 }, { "id": "social-connection", "name": "Social Connection", "aka": "Combating loneliness/isolation", "category": "lifestyle", "klass": "Psychosocial determinant", "mechanism": "Strong social ties buffer chronic stress, lower inflammatory/neuroendocrine load and promote healthy behaviors", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "human-cohort", "evidence": "Holt-Lunstad's meta-analyses found strong social relationships associated with ~50% greater survival odds, with isolation/loneliness raising mortality ~26-32% — effect sizes rivaling smoking. Observational; intervention trials aren't powered for mortality.", "keyStudies": [ { "ref": "Holt-Lunstad et al., PLOS Med 2010 (148 studies)", "finding": "Strong ties ~50% higher survival odds (OR 1.50)", "url": "https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1000316" }, { "ref": "Holt-Lunstad et al., Perspect Psychol Sci 2015", "finding": "Isolation OR 1.29, loneliness 1.26, living alone 1.32 (~26-32% higher mortality)", "url": "https://doi.org/10.1177/1745691614568352" } ], "effect": "Stronger social ties: OR 1.50 (95% CI 1.42-1.59) for survival, rising to OR 1.91 (95% CI 1.63-2.23) for complex social integration — Holt-Lunstad PLoS Med 2010 (148 studies, n=308,849)", "human": "Large meta-analytic cohort data; no mortality-powered RCT", "safety": "No risk", "dose": "Regular meaningful relationships and community engagement", "status": "Established risk factor (Surgeon General advisory)", "accessibility": "lifestyle", "caveats": "Observational; reverse causation/confounding; causal mortality reduction not shown by RCT", "sources": [ "https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1000316", "https://doi.org/10.1177/1745691614568352" ], "evi": 66, "hum": 78, "imp": 60, "safe": 95, "overall": 74, "tier": "A", "rank": 13 }, { "id": "statins", "name": "Statins", "aka": "Atorvastatin, rosuvastatin, simvastatin", "category": "pharma", "klass": "HMG-CoA reductase inhibitors", "mechanism": "Lower LDL cholesterol; pleiotropic anti-inflammatory/endothelial effects", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "human-rct-hard", "evidence": "Backed by very large RCTs and CTT meta-analyses with hard endpoints: ~10% lower all-cause mortality per 1 mmol/L LDL drop, mainly in secondary prevention. Benefit in low-risk primary prevention and the very elderly is smaller. Targets cardiovascular disease, not aging per se.", "keyStudies": [ { "ref": "CTT, Lancet 2010 (>170k)", "finding": "~10% lower all-cause mortality per 1 mmol/L LDL reduction", "url": "https://doi.org/10.1016/S0140-6736(10)61350-5" }, { "ref": "JUPITER, NEJM 2008", "finding": "Rosuvastatin cut all-cause mortality HR 0.80 in high-CRP adults", "url": "https://doi.org/10.1056/NEJMoa0807646" } ], "effect": "All-cause mortality RR 0.90 (95% CI 0.87-0.93) and major vascular events RR 0.78 (95% CI 0.76-0.80) per 1 mmol/L LDL-C reduction — CTT Lancet 2010 (26 trials, n~170,000)", "human": "Strong for CV mortality; modest/uncertain in low-risk primary prevention", "safety": "Generally safe; myalgia, rare myopathy, small diabetes risk", "dose": "Disease-based dosing", "status": "FDA-approved (dyslipidaemia/CV prevention)", "accessibility": "rx", "caveats": "Targets atherosclerosis not aging broadly; benefit risk-dependent; not a validated geroprotector", "sources": [ "https://doi.org/10.1016/S0140-6736(10)61350-5", "https://doi.org/10.1056/NEJMoa0807646" ], "evi": 86, "hum": 80, "imp": 45, "safe": 75, "overall": 73, "tier": "A", "rank": 14 }, { "id": "semaglutide", "name": "Semaglutide", "aka": "Ozempic, Wegovy", "category": "pharma", "klass": "GLP-1 receptor agonist", "mechanism": "Activates GLP-1 receptors to reduce appetite/weight, improve glucose control and lower inflammation", "hallmarks": [ "Deregulated nutrient sensing", "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "human-rct-hard", "evidence": "Genuine large-RCT hard outcomes: SELECT cut major cardiovascular events 20% in non-diabetic adults with obesity and prior CVD — the first proof that treating obesity pharmacologically improves CV outcomes. Untested for lifespan; concerns include muscle-mass loss and weight regain on stopping.", "keyStudies": [ { "ref": "SELECT, NEJM 2023 (n=17,604)", "finding": "MACE HR 0.80 in non-diabetic obesity; ~9% weight loss", "url": "https://doi.org/10.1056/NEJMoa2307563" } ], "effect": "MACE HR 0.80 (95% CI 0.72-0.90), 20% lower, in non-diabetic obesity; mean weight -9.4% vs -0.9% placebo — SELECT (Lincoff NEJM 2023), n=17,604", "human": "Strong CV hard-outcome RCT; no aging-endpoint trial", "safety": "GI effects, pancreatitis/gallbladder risk, lean-mass loss, weight regain after stopping; rodent thyroid signal", "dose": "2.4 mg SC weekly (obesity)", "status": "FDA-approved (diabetes/obesity/CV)", "accessibility": "rx", "caveats": "No aging-specific evidence; muscle loss; dependence on continued use", "sources": [ "https://doi.org/10.1056/NEJMoa2307563" ], "evi": 84, "hum": 80, "imp": 55, "safe": 68, "overall": 73, "tier": "A", "rank": 15 }, { "id": "rapamycin", "name": "Rapamycin", "aka": "Sirolimus, Rapamune; rapalogs", "category": "pharma", "klass": "mTOR inhibitor", "mechanism": "Inhibits mTORC1, mimicking caloric restriction and inducing autophagy", "hallmarks": [ "Deregulated nutrient sensing", "Disabled macroautophagy", "Cellular senescence", "Loss of proteostasis" ], "evidenceType": "animal-itp", "evidence": "The most reproducible pharmacological lifespan extender in animals and the standout of the NIA Interventions Testing Program, working even when started late in life. Human trials (PEARL, RTB101) show safety and immune/biomarker effects but no lifespan data.", "keyStudies": [ { "ref": "Harrison et al., Nature 2009 (ITP)", "finding": "First drug to extend mouse lifespan started in old age; +9% male/+14% female at age of 90% mortality", "url": "https://doi.org/10.1038/nature08221" }, { "ref": "Miller et al., Aging Cell 2014 (ITP)", "finding": "Dose-dependent median lifespan +23% male/+26% female at 42 ppm", "url": "https://doi.org/10.1111/acel.12194" }, { "ref": "PEARL RCT 2024 (n=114)", "finding": "Low-dose weekly rapamycin safe over 48 weeks; lean-mass/pain gains in women", "url": "https://www.medrxiv.org/content/10.1101/2024.08.21.24312372v1" } ], "effect": "+10-26% median lifespan (mice, dose-dependent)", "human": "Phase-2 safety/biomarker RCTs; widely used off-label; no lifespan RCT", "safety": "Generally safe at low intermittent doses; immunosuppression, mouth sores, glucose/lipid effects at higher doses", "dose": "~5-6 mg once weekly (off-label longevity protocols)", "status": "FDA-approved (transplant); off-label for longevity", "accessibility": "rx", "caveats": "No human lifespan RCT; optimal dose/schedule unresolved — most-hyped longevity drug yet thin human proof", "sources": [ "https://doi.org/10.1038/nature08221", "https://doi.org/10.1111/acel.12194", "https://www.medrxiv.org/content/10.1101/2024.08.21.24312372v1" ], "evi": 88, "hum": 52, "imp": 86, "safe": 60, "overall": 72, "tier": "A", "rank": 16 }, { "id": "caloric-restriction", "name": "Caloric Restriction", "aka": "CR", "category": "diet", "klass": "Sustained energy restriction", "mechanism": "Lowers nutrient-sensing (insulin/IGF-1, mTOR), induces autophagy and stress resistance", "hallmarks": [ "Deregulated nutrient sensing", "Chronic inflammation", "Disabled macroautophagy", "Stem cell exhaustion", "Epigenetic alterations" ], "evidenceType": "human-rct-surrogate", "evidence": "The most-studied lifespan intervention in animals. In humans, the CALERIE-2 RCT (~12% restriction, 2 yr) slowed the DunedinPACE pace-of-aging clock, reduced cardiometabolic risk and regenerated thymic volume — but on surrogate endpoints, with low adherence to deep restriction.", "keyStudies": [ { "ref": "Waziry et al., Nat Aging 2023 (CALERIE-2)", "finding": "Slowed DunedinPACE ~2-3% over 2 years", "url": "https://doi.org/10.1038/s43587-022-00357-y" }, { "ref": "Spadaro/Dixit, Science 2022", "finding": "Increased thymic functional volume", "url": "https://doi.org/10.1126/science.abg7292" } ], "effect": "Large in animals; modest biological-age slowing in humans", "human": "Landmark RCT (surrogate) + primate studies", "safety": "Risk of muscle/bone loss, hunger, cold intolerance, disordered eating if overdone", "dose": "~12-15% sustained reduction with adequate protein/micronutrients", "status": "Lifestyle / investigational", "accessibility": "lifestyle", "caveats": "Hard-outcome human benefit unproven; sustained deep restriction has low adherence", "sources": [ "https://doi.org/10.1038/s43587-022-00357-y", "https://doi.org/10.1126/science.abg7292" ], "evi": 74, "hum": 70, "imp": 76, "safe": 64, "overall": 71, "tier": "A", "rank": 17 }, { "id": "nut-consumption", "name": "Nut Consumption", "aka": "Tree nuts and peanuts", "category": "diet", "klass": "Whole food (unsaturated fat, fiber, polyphenols)", "mechanism": "Unsaturated fats, fiber, plant protein, magnesium and polyphenols lower LDL, improve endothelial function/insulin sensitivity and reduce inflammation", "hallmarks": [ "Chronic inflammation", "Deregulated nutrient sensing", "Mitochondrial dysfunction" ], "evidenceType": "human-rct-hard", "evidence": "Large cohorts (Bao 2013 ~119k; Aune 2016 meta ~819k) show ~20% lower all-cause mortality with regular intake, and PREDIMED randomized high-CV-risk adults to a Mediterranean diet plus mixed nuts with a hard CV-event reduction. Limitation: mortality data are observational, and the RCT tests a whole pattern (with added nuts), not nuts in isolation.", "keyStudies": [ { "ref": "Bao et al., NEJM 2013 (NHS+HPFS, n=118,962)", "finding": "Nuts 7+/wk vs never: total mortality HR 0.80 (95% CI 0.73-0.86)", "url": "https://pubmed.ncbi.nlm.nih.gov/24256379/" }, { "ref": "Aune et al., BMC Medicine 2016 (20 studies, n=819,448)", "finding": "Per 28 g/day: all-cause mortality RR 0.78 (95% CI 0.72-0.84)", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC5137221/" } ], "effect": "~20-22% lower all-cause mortality (HR 0.80, 95% CI 0.73-0.86); RCT CV events HR 0.72 (0.54-0.97)", "human": "Strong cohort mortality data plus an RCT with hard cardiovascular endpoints", "safety": "Very safe; calorie-dense but no net weight gain at typical portions; tree-nut/peanut allergy is the one contraindication", "dose": "~28 g/day (a small handful)", "status": "Endorsed by dietary guidelines; component of the Mediterranean pattern", "accessibility": "otc", "caveats": "Mortality figures observational; the hard-endpoint RCT (PREDIMED) tests a whole pattern not nuts alone (and was retracted/re-analyzed 2018)", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/24256379/", "https://pmc.ncbi.nlm.nih.gov/articles/PMC5137221/" ], "evi": 68, "hum": 70, "imp": 55, "safe": 93, "overall": 71, "tier": "A", "rank": 18 }, { "id": "dietary-fiber", "name": "Dietary Fiber", "aka": "Soluble and insoluble fiber", "category": "diet", "klass": "Fermentable/viscous carbohydrate (microbiome substrate)", "mechanism": "Fermentable fiber feeds gut microbiota producing anti-inflammatory short-chain fatty acids (butyrate); viscous fiber slows glucose absorption, binds bile acids to lower LDL, and increases satiety", "hallmarks": [ "Dysbiosis", "Chronic inflammation", "Deregulated nutrient sensing" ], "evidenceType": "human-cohort", "evidence": "The WHO-commissioned Reynolds (Lancet 2019) synthesis pooled ~135 million person-years across 185 prospective studies plus 58 RCTs and found the highest fiber consumers had 15-30% lower all-cause and CV mortality with a near-linear dose-response judged potentially causal (GRADE moderate). Mortality outcomes are predominantly observational; the included RCTs measured intermediate cardiometabolic markers.", "keyStudies": [ { "ref": "Reynolds et al., Lancet 2019 (WHO meta-analysis)", "finding": "Highest vs lowest fiber: 15-30% lower all-cause + CV mortality; ~13 fewer deaths/1,000", "url": "https://pubmed.ncbi.nlm.nih.gov/30638909/" }, { "ref": "Park et al. (NIH-AARP, n=388,122), Arch Intern Med 2011", "finding": "Highest vs lowest quintile all-cause mortality RR ~0.78 (95% CI 0.73-0.82)", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC3513325/" } ], "effect": "~15-30% lower all-cause mortality (highest vs lowest intake); large cohorts converge near RR 0.78", "human": "Strong, consistent observational mortality evidence; RCTs support only intermediate markers", "safety": "Very safe; GI tolerance the main issue if increased too fast (escalate gradually with fluids)", "dose": "~25-29 g/day or more (most adults get only ~15-20 g) from whole grains, legumes, vegetables, fruit", "status": "Core dietary-guideline recommendation", "accessibility": "lifestyle", "caveats": "Mortality evidence mostly observational with likely healthy-user confounding; RCT support limited to cardiometabolic surrogates", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/30638909/", "https://pmc.ncbi.nlm.nih.gov/articles/PMC3513325/" ], "evi": 66, "hum": 66, "imp": 58, "safe": 93, "overall": 70, "tier": "A", "rank": 19 }, { "id": "creatine", "name": "Creatine", "aka": "Creatine monohydrate", "category": "supplement", "klass": "Phosphagen substrate", "mechanism": "Replenishes phosphocreatine/ATP in muscle and brain, supporting energy availability", "hallmarks": [ "Mitochondrial dysfunction", "Stem cell exhaustion", "Loss of proteostasis" ], "evidenceType": "human-rct-surrogate", "evidence": "Among the best-evidenced supplements for the aging musculoskeletal system: meta-analyses show creatine PLUS resistance training increases strength and lean mass in older adults more than training alone — relevant to sarcopenia. Cognitive benefits are plausible but unsettled.", "keyStudies": [ { "ref": "Meta-analyses, creatine + RT in older adults", "finding": "Greater strength/lean-mass gains vs training + placebo", "url": "https://doi.org/10.1186/s11556-025-00392-9" } ], "effect": "Meaningful added strength/lean-mass with training; cognition uncertain", "human": "Robust RCT/meta-analytic evidence for muscle (with training)", "safety": "Very safe, extensively studied; mild water-weight gain; no kidney harm in healthy people", "dose": "3-5 g/day", "status": "OTC supplement", "accessibility": "otc", "caveats": "Muscle benefit largely requires concurrent resistance training; not a standalone longevity drug", "sources": [ "https://doi.org/10.1186/s11556-025-00392-9" ], "evi": 70, "hum": 72, "imp": 45, "safe": 90, "overall": 69, "tier": "A", "rank": 20 }, { "id": "polypill", "name": "Cardiovascular Polypill", "aka": "Fixed-dose combination; Polycap; Trinomia", "category": "pharma", "klass": "Fixed-dose combination (statin + antihypertensives +/- aspirin)", "mechanism": "One daily tablet lowers LDL and blood pressure (plus antiplatelet if aspirin included), maximizing long-term adherence", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "human-rct-hard", "evidence": "Large randomized trials with hard CV endpoints converge on ~30% fewer major cardiovascular events: TIPS-3 (n=5,713, placebo-controlled primary prevention) and PolyIran (50,045, pragmatic cluster-RCT), pooled RR 0.71. Its innovation is adherence/simplicity, not a novel mechanism, and all-cause mortality was not individually significant.", "keyStudies": [ { "ref": "Yusuf et al. (TIPS-3), NEJM 2021", "finding": "Primary CV composite HR 0.79 (95% CI 0.63-1.00); polypill+aspirin HR 0.69 (0.50-0.97)", "url": "https://pubmed.ncbi.nlm.nih.gov/33186492/" }, { "ref": "Roshandel et al. (PolyIran), Lancet 2019", "finding": "Major CV events HR 0.66 (95% CI 0.55-0.80); high-adherence HR 0.43 (0.33-0.55)", "url": "https://pubmed.ncbi.nlm.nih.gov/31448738/" } ], "effect": "~21-34% fewer major CV events (pooled RR 0.71, 95% CI 0.63-0.80); all-cause mortality not individually significant", "human": "Strong hard-outcome RCT evidence for CV-event reduction in primary prevention", "safety": "Well tolerated; modest excess dizziness/hypotension; aspirin versions carry bleeding risk", "dose": "One daily fixed-dose tablet (statin + 2-3 antihypertensives +/- low-dose aspirin)", "status": "Marketed in several countries; on the WHO Essential Medicines List", "accessibility": "rx", "caveats": "Proven on CV events not all-cause mortality; an adherence/packaging strategy over drug classes already listed separately (statins, ACEi/ARBs)", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/33186492/", "https://pubmed.ncbi.nlm.nih.gov/31448738/" ], "evi": 80, "hum": 66, "imp": 55, "safe": 72, "overall": 69, "tier": "A", "rank": 21 }, { "id": "hearing-aids", "name": "Hearing Aid Use", "aka": "Hearing-loss treatment; OTC hearing aids", "category": "lifestyle", "klass": "Sensory-restoration device (dementia-risk modification)", "mechanism": "Restoring auditory input reduces effortful-listening cognitive load, reverses sensory deprivation, sustains social engagement and slows temporal-lobe atrophy", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation" ], "evidenceType": "human-rct-hard", "evidence": "The ACHIEVE RCT (Lancet 2023, n=977) found a hearing intervention did NOT slow 3-year global cognitive decline overall, but in the prespecified higher-risk ARIC subgroup it slowed decline ~48%. This sits atop the Lancet Commission ranking hearing loss as the largest modifiable midlife dementia risk factor and a 31-study observational meta-analysis (HR 0.81). The primary RCT endpoint was null overall, so the benefit is a subgroup/observational signal.", "keyStudies": [ { "ref": "Lin et al. (ACHIEVE), Lancet 2023", "finding": "3-yr cognition: full cohort null; high-risk ARIC subgroup ~48% slower decline (diff 0.191, 95% CI 0.022-0.360)", "url": "https://pubmed.ncbi.nlm.nih.gov/37478886/" }, { "ref": "Yeo et al. meta-analysis (31 studies, n=137,484), JAMA Neurol 2023", "finding": "Hearing-device use: cognitive decline HR 0.81 (95% CI 0.76-0.87)", "url": "https://jamanetwork.com/journals/jamaneurology/fullarticle/2799139" } ], "effect": "High-risk RCT subgroup ~48% slower 3-yr cognitive decline; pooled observational HR 0.81 (0.76-0.87)", "human": "Mixed RCT (null primary, strong high-risk subgroup) + consistent observational cognition data", "safety": "Essentially no risk; non-invasive; worst case minor discomfort/feedback/cost", "dose": "Daily wear of fitted hearing aids for adults with hearing loss; benefit greatest with earlier, consistent use", "status": "OTC hearing aids available without prescription in the US since Oct 2022", "accessibility": "otc", "caveats": "The flagship RCT's primary endpoint was null in the full cohort — the 48% benefit is a high-risk subgroup finding; most supporting data are observational", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/37478886/", "https://jamanetwork.com/journals/jamaneurology/fullarticle/2799139" ], "evi": 70, "hum": 60, "imp": 55, "safe": 95, "overall": 69, "tier": "A", "rank": 22 }, { "id": "coq10-ubiquinol", "name": "CoQ10 / Ubiquinol", "aka": "Coenzyme Q10, ubiquinone", "category": "supplement", "klass": "Mitochondrial electron carrier", "mechanism": "Electron-transport-chain cofactor and lipid-phase antioxidant", "hallmarks": [ "Mitochondrial dysfunction", "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "human-rct-hard", "evidence": "Standout is KiSel-10: CoQ10 200 mg + selenium for 4 years roughly halved cardiovascular mortality in elderly Swedes, persisting at 12-year follow-up. Combined with selenium (confound) and strongest in deficient/older/cardiac populations.", "keyStudies": [ { "ref": "Alehagen et al., KiSel-10", "finding": "CoQ10+selenium cut CV mortality ~50% (HR 0.51), persisting 12 yr", "url": "https://doi.org/10.1371/journal.pone.0193120" }, { "ref": "Q-SYMBIO, JACC HF 2014", "finding": "CoQ10 reduced major cardiac events in heart failure", "url": "https://doi.org/10.1016/j.jchf.2014.06.008" } ], "effect": "CV mortality HR 0.51 (95% CI 0.36-0.74), ~49% lower (5.9% vs 12.6%), with CoQ10 200mg + selenium 200ug/d in selenium-low elderly — KiSel-10 (Alehagen 2013), n=443", "human": "Positive hard-outcome RCTs (elderly/HF), but bundled with selenium", "safety": "Very safe; mild GI; interacts with warfarin", "dose": "100-200 mg/day (ubiquinol better absorbed)", "status": "OTC supplement", "accessibility": "otc", "caveats": "Flagship benefit came combined with selenium in a likely-deficient cohort", "sources": [ "https://doi.org/10.1371/journal.pone.0193120", "https://doi.org/10.1016/j.jchf.2014.06.008" ], "evi": 70, "hum": 68, "imp": 48, "safe": 88, "overall": 68, "tier": "A", "rank": 23 }, { "id": "menopausal-hormone-therapy", "name": "Menopausal Hormone Therapy", "aka": "MHT, HRT, estrogen +/- progesterone", "category": "hormone", "klass": "Sex steroid hormone", "mechanism": "Replaces declining estrogen (with progestogen to protect the endometrium); ER signaling across bone, vasculature, brain", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation", "Stem cell exhaustion" ], "evidenceType": "human-rct-hard", "evidence": "The 'timing hypothesis' (WHI re-analyses, ELITE) holds that starting MHT near menopause (<60y) is associated with lower all-cause mortality and possibly reduced coronary risk, whereas late initiation raises stroke/VTE risk. It is the most effective treatment for vasomotor symptoms and prevents fractures; the longevity signal is associational.", "keyStudies": [ { "ref": "Manson et al., WHI, JAMA 2017", "finding": "No increase in all-cause/CV/cancer mortality over 18 yr", "url": "https://doi.org/10.1001/jama.2017.11211" }, { "ref": "Hodis et al., ELITE, NEJM 2016", "finding": "Early estradiol slowed carotid IMT; late did not", "url": "https://doi.org/10.1056/NEJMoa1505241" } ], "effect": "Best therapy for hot flushes; reduces fractures; possible mortality benefit if started early", "human": "Large RCTs + cohorts; favorable for symptomatic women starting near menopause", "safety": "Small absolute increases in breast cancer (combined oral), VTE, stroke; transdermal lowers VTE risk", "dose": "Lowest effective dose (transdermal estradiol + progesterone if uterus)", "status": "Approved for vasomotor symptoms/osteoporosis", "accessibility": "rx", "caveats": "Window-of-opportunity matters; not a blanket anti-aging therapy; real (if small) risks", "sources": [ "https://doi.org/10.1001/jama.2017.11211", "https://doi.org/10.1056/NEJMoa1505241" ], "evi": 80, "hum": 78, "imp": 45, "safe": 62, "overall": 68, "tier": "A", "rank": 24 }, { "id": "sauna-finnish-dry-heat", "name": "Finnish Sauna Bathing", "aka": "Dry sauna, heat therapy", "category": "thermal", "klass": "Passive heat exposure / hormesis", "mechanism": "Heat stress induces heat-shock proteins, improves endothelial function, lowers BP — a mild cardiovascular load", "hallmarks": [ "Loss of proteostasis", "Altered intercellular communication", "Chronic inflammation" ], "evidenceType": "human-cohort", "evidence": "The Finnish KIHD cohort links 4-7 sauna sessions/wk to ~40% lower all-cause and sharply lower cardiovascular/sudden-cardiac mortality. But the one controlled trial (8 weeks, CAD patients) was NULL on vascular surrogates, so causality and healthy-user bias remain unresolved.", "keyStudies": [ { "ref": "Laukkanen et al., JAMA IM 2015 (KIHD)", "finding": "4-7/wk vs 1/wk: ~40% lower all-cause mortality", "url": "https://pubmed.ncbi.nlm.nih.gov/25705824/" }, { "ref": "Lee/Laukkanen, J Appl Physiol 2023 RCT", "finding": "No change in FMD/BP/stiffness in CAD (null)", "url": "https://doi.org/10.1152/japplphysiol.00322.2023" } ], "effect": "All-cause mortality HR 0.60 (95% CI 0.46-0.80) at 4-7 sessions/wk vs 1/wk; fatal CVD HR 0.50 (95% CI 0.33-0.77) — Laukkanen JAMA Intern Med 2015 (KIHD, n=2,315 men); RCT surrogate data ~null", "human": "Strong cohorts; only RCT negative on vascular surrogates", "safety": "Generally safe; dehydration, orthostatic hypotension, caution with unstable cardiac disease", "dose": "4-7 sessions/wk, ~15-20 min at ~80-100C", "status": "Lifestyle / investigational", "accessibility": "lifestyle", "caveats": "Cohort benefit likely confounded by healthy-user bias; the one RCT showed no vascular benefit", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/25705824/", "https://doi.org/10.1152/japplphysiol.00322.2023" ], "evi": 64, "hum": 70, "imp": 55, "safe": 82, "overall": 67, "tier": "B", "rank": 25 }, { "id": "coffee", "name": "Coffee / Caffeine", "aka": "Caffeinated and decaffeinated coffee", "category": "diet", "klass": "Polyphenol-rich beverage (chlorogenic acids + caffeine)", "mechanism": "Chlorogenic acids and caffeine act as antioxidants, activate AMPK/autophagy and suppress NF-kB inflammation while improving glucose/lipid metabolism", "hallmarks": [ "Chronic inflammation", "Deregulated nutrient sensing", "Mitochondrial dysfunction" ], "evidenceType": "human-cohort", "evidence": "Very large prospective cohorts (EPIC ~521k; UK Biobank ~498k) and a 40-study dose-response meta-analysis (~3.85M) consistently show ~10-18% lower all-cause mortality at ~3-4 cups/day, with decaffeinated coffee showing similar benefit (implicating non-caffeine compounds). All evidence is observational, so residual confounding and reverse causation can't be excluded; no long-term mortality RCT exists.", "keyStudies": [ { "ref": "Kim, Je & Giovannucci, Eur J Epidemiol 2019 (40-study meta, 3.85M)", "finding": "All-cause mortality nadir at ~3.5 cups/day RR 0.85 (95% CI 0.82-0.89)", "url": "https://pubmed.ncbi.nlm.nih.gov/31055709/" }, { "ref": "Loftfield et al. (UK Biobank, n=498,134), JAMA Intern Med 2018", "finding": "2-3 cups/day HR 0.88 (95% CI 0.84-0.93); decaf also inverse; independent of caffeine-metabolism genotype", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6143111/" } ], "effect": "~12-18% lower all-cause mortality at ~3-4 cups/day (RR 0.85, 95% CI 0.82-0.89); observational", "human": "Large, consistent observational mortality evidence across continents; not proven causal", "safety": "Safe for most adults up to ~400 mg caffeine/day; caveats: pregnancy (<=200 mg/day), anxiety/insomnia, unfiltered coffee raises LDL via cafestol", "dose": "~3-4 cups/day, preferably filtered (the dose-response nadir)", "status": "Strong, widely-accepted observational evidence; likely modest net benefit at moderate intake", "accessibility": "otc", "caveats": "Entirely observational — coffee drinkers differ systematically and the ill cut back (reverse causation), so causality is unestablished", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/31055709/", "https://pmc.ncbi.nlm.nih.gov/articles/PMC6143111/" ], "evi": 64, "hum": 68, "imp": 50, "safe": 90, "overall": 67, "tier": "B", "rank": 26 }, { "id": "tirzepatide", "name": "Tirzepatide", "aka": "Mounjaro, Zepbound", "category": "pharma", "klass": "GIP/GLP-1 dual agonist", "mechanism": "Co-agonizes GIP and GLP-1 receptors for greater weight loss and glycaemic control", "hallmarks": [ "Deregulated nutrient sensing", "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "human-rct-surrogate", "evidence": "Produces the largest pharmacological weight loss yet (~22.5% in SURMOUNT-1) and broad cardiometabolic improvement; the dedicated morbidity/mortality trial (SURMOUNT-MMO) is ongoing, so hard aging-relevant outcomes are not yet read out.", "keyStudies": [ { "ref": "SURMOUNT-1, NEJM 2022", "finding": "Up to 22.5% weight loss over 72 weeks", "url": "https://doi.org/10.1056/NEJMoa2206038" }, { "ref": "SURPASS-CVOT, 2025", "finding": "Non-inferior to dulaglutide for MACE (HR ~0.92)", "url": "https://doi.org/10.1056/NEJMoa2505928" } ], "effect": "Up to ~22.5% weight loss; mortality data pending", "human": "Strong surrogate data; morbidity/mortality trial not yet reported", "safety": "GI effects, pancreatitis/gallbladder risk, lean-mass loss, weight regain; rodent thyroid signal", "dose": "2.5-15 mg SC weekly", "status": "FDA-approved (diabetes/obesity)", "accessibility": "rx", "caveats": "Hard-outcome/mortality data pending; no aging-endpoint trial; muscle-loss concern", "sources": [ "https://doi.org/10.1056/NEJMoa2206038", "https://doi.org/10.1056/NEJMoa2505928" ], "evi": 68, "hum": 70, "imp": 52, "safe": 66, "overall": 65, "tier": "B", "rank": 27 }, { "id": "ace-inhibitors-arbs", "name": "ACE Inhibitors / ARBs", "aka": "Captopril, ramipril; losartan, telmisartan", "category": "pharma", "klass": "Renin-angiotensin inhibitors", "mechanism": "Block angiotensin-II signaling, lowering BP and RAS-driven oxidative stress, fibrosis and inflammation", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation", "Mitochondrial dysfunction" ], "evidenceType": "animal-itp", "evidence": "Unusual breadth: RAS inhibition extends lifespan from worms to rats (ramipril ~doubled hypertensive-rat lifespan), captopril was a positive ITP hit, and ACEi/ARBs cut CV mortality in high-risk humans (HOPE). No trial in healthy normotensives.", "keyStudies": [ { "ref": "Strong et al., ITP 2022", "finding": "Captopril +4-5% female mouse lifespan", "url": "https://doi.org/10.1111/acel.13724" }, { "ref": "HOPE, NEJM 2000", "finding": "Ramipril cut all-cause mortality HR 0.84 in high-risk patients", "url": "https://doi.org/10.1056/NEJM200001203420301" } ], "effect": "Up to ~2x lifespan in hypertensive rats; human all-cause HR ~0.84 (high-risk)", "human": "CV mortality benefit in high-risk groups; no healthy-aging trial", "safety": "ACEi: cough, hyperkalaemia, angioedema; ARBs better tolerated; both contraindicated in pregnancy", "dose": "Disease-based dosing", "status": "FDA-approved (hypertension/HF/CKD)", "accessibility": "rx", "caveats": "Human mortality data in diseased groups; lifespan benefit in healthy people untested", "sources": [ "https://doi.org/10.1111/acel.13724", "https://doi.org/10.1056/NEJM200001203420301" ], "evi": 70, "hum": 68, "imp": 45, "safe": 72, "overall": 64, "tier": "B", "rank": 28 }, { "id": "nicotinamide", "name": "Nicotinamide (NAM)", "aka": "Niacinamide", "category": "nad", "klass": "NAD+ precursor (vitamin B3 amide)", "mechanism": "Salvaged directly to NAD+ via NAMPT; at high doses inhibits sirtuins/PARPs", "hallmarks": [ "Genomic instability", "Deregulated nutrient sensing", "Mitochondrial dysfunction" ], "evidenceType": "human-rct-hard", "evidence": "Unusual for a positive hard-outcome RCT — but for skin-cancer prevention, not aging: ONTRAC showed 500 mg twice daily cut new non-melanoma skin cancers 23% in high-risk patients. Reflects DNA-repair/energy support in skin; a later transplant trial was negative.", "keyStudies": [ { "ref": "Chen et al., NEJM 2015 (ONTRAC)", "finding": "-23% non-melanoma skin cancer over 12 months", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa1506197" } ], "effect": "23% fewer non-melanoma skin cancers (hard endpoint); not an established longevity effect", "human": "Strong cancer-prevention RCT; not shown to extend healthspan", "safety": "Very safe at 500 mg x2/day (no flushing); very high doses risk hepatotoxicity/sirtuin inhibition", "dose": "500 mg twice daily (skin cancer)", "status": "OTC vitamin; used in dermatology", "accessibility": "otc", "caveats": "Proven benefit is skin-cancer prevention, not anti-aging; high doses inhibit sirtuins", "sources": [ "https://www.nejm.org/doi/full/10.1056/NEJMoa1506197" ], "evi": 72, "hum": 65, "imp": 35, "safe": 80, "overall": 64, "tier": "B", "rank": 29 }, { "id": "trt", "name": "Testosterone Replacement Therapy", "aka": "TRT, androgen replacement", "category": "hormone", "klass": "Androgen (steroid hormone)", "mechanism": "Restores serum testosterone via androgen-receptor signaling; affects muscle, bone, libido, erythropoiesis", "hallmarks": [ "Altered intercellular communication", "Stem cell exhaustion" ], "evidenceType": "human-rct-hard", "evidence": "The large TRAVERSE RCT found TRT non-inferior to placebo for major cardiac events in hypogonadal men, settling a CV-safety question — but with MORE atrial fibrillation, AKI, PE and (unexpectedly) fractures. It improves libido/lean mass/BMD in true deficiency, but there is NO evidence it extends lifespan and it should not be an anti-aging tonic in men with normal testosterone.", "keyStudies": [ { "ref": "Lincoff et al., TRAVERSE, NEJM 2023 (n=5,246)", "finding": "MACE non-inferior to placebo; more atrial fibrillation, AKI and PE", "url": "https://pubmed.ncbi.nlm.nih.gov/37326322/" }, { "ref": "TRAVERSE Fracture sub-trial, NEJM 2024", "finding": "More clinical fractures on testosterone (3.5% vs 2.5%)", "url": "https://pubmed.ncbi.nlm.nih.gov/38231621/" } ], "effect": "Clear gains in hypogonadism; no longevity benefit; net harms in higher-risk older men", "human": "Definitive large RCT; CV-safe at replacement doses but not life-extending", "safety": "Erythrocytosis, atrial fibrillation, fracture/PE risk, infertility, sleep-apnea worsening", "dose": "Replacement to mid-normal range", "status": "Rx for diagnosed hypogonadism", "accessibility": "rx", "caveats": "Benefit only in true deficiency, with real adverse effects and no survival gain", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/37326322/", "https://pubmed.ncbi.nlm.nih.gov/38231621/" ], "evi": 80, "hum": 75, "imp": 35, "safe": 55, "overall": 64, "tier": "B", "rank": 30 }, { "id": "zoledronate", "name": "Zoledronate / Bisphosphonates", "aka": "Zoledronic acid, Reclast; alendronate", "category": "pharma", "klass": "Bisphosphonate (osteoclast inhibitor)", "mechanism": "Inhibits bone resorption; emerging senolytic/senomorphic and DNA-damage-resilience effects", "hallmarks": [ "Cellular senescence", "Chronic inflammation", "Stem cell exhaustion", "Genomic instability" ], "evidenceType": "human-rct-hard", "evidence": "Beyond fracture prevention, annual zoledronic acid cut mortality 28% after hip fracture (HORIZON-RFT) — more than fracture reduction explains, prompting geroscience interest, with preclinical senolytic activity now reported. Mortality signal is in frail post-fracture patients.", "keyStudies": [ { "ref": "HORIZON-RFT, NEJM 2007", "finding": "Annual zoledronate cut all-cause mortality 28% post-hip-fracture", "url": "https://doi.org/10.1056/NEJMoa074941" }, { "ref": "Samakkarnthai et al., Aging 2023", "finding": "Selectively killed senescent cells, lowered SASP, improved grip in aged mice", "url": "https://doi.org/10.18632/aging.204701" } ], "effect": "All-cause mortality -28% post-fracture; senolytic effects preclinical", "human": "Hard-outcome mortality benefit, but only in frail post-fracture patients", "safety": "Acute flu-like reaction, hypocalcaemia; rare jaw osteonecrosis/atypical fractures", "dose": "5 mg IV once yearly", "status": "FDA-approved (osteoporosis); experimental as senolytic", "accessibility": "clinic-only", "caveats": "Mortality data confined to post-fracture cohort; senolytic mechanism preclinical", "sources": [ "https://doi.org/10.1056/NEJMoa074941", "https://doi.org/10.18632/aging.204701" ], "evi": 74, "hum": 62, "imp": 50, "safe": 62, "overall": 63, "tier": "B", "rank": 31 }, { "id": "urolithin-a", "name": "Urolithin A", "aka": "Mitopure", "category": "supplement", "klass": "Gut-microbial metabolite (mitophagy)", "mechanism": "Induces mitophagy (clearance of damaged mitochondria), improving mitochondrial quality", "hallmarks": [ "Mitochondrial dysfunction", "Disabled macroautophagy", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "One of the better-evidenced novel geroprotectors at the biomarker level: RCTs show improved muscle mitophagy gene expression, ~12% strength/endurance gains, and (2025) shifts toward less-exhausted T cells. Surrogate-only; ~60% of people can't make UA from diet, hence supplementation.", "keyStudies": [ { "ref": "Singh/Liu et al., Cell Rep Med 2022", "finding": "~12% muscle-strength gain, improved endurance & mitophagy markers", "url": "https://doi.org/10.1016/j.xcrm.2022.100633" }, { "ref": "D'Amico et al., Nature Aging 2025", "finding": "Reduced markers of immune aging", "url": "https://doi.org/10.1038/s43587-025-00996-x" } ], "effect": "~10-12% muscle strength/endurance; immune-aging marker shifts", "human": "Several RCTs on muscle/immune surrogates; no hard outcomes", "safety": "Well tolerated to 1000 mg/d", "dose": "500-1000 mg/day (Mitopure)", "status": "FDA GRAS; branded supplement", "accessibility": "otc", "caveats": "Surrogate-only and partly industry-funded; no lifespan data", "sources": [ "https://doi.org/10.1016/j.xcrm.2022.100633", "https://doi.org/10.1038/s43587-025-00996-x" ], "evi": 60, "hum": 62, "imp": 45, "safe": 88, "overall": 63, "tier": "B", "rank": 32 }, { "id": "mind-diet", "name": "MIND Diet", "aka": "Mediterranean-DASH for neurodegeneration", "category": "diet", "klass": "Hybrid brain-targeted pattern", "mechanism": "Combines Mediterranean + DASH (leafy greens, berries, nuts) to reduce neuroinflammation and vascular damage", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication", "Mitochondrial dysfunction" ], "evidenceType": "human-rct-hard", "evidence": "Cohorts linked high adherence to ~35-53% slower cognitive decline, but the definitive 3-year RCT (NEJM 2023) found no cognitive/MRI advantage over a mild-CR control. Strong observational signal not confirmed by RCT; the diet remains healthy and low-risk.", "keyStudies": [ { "ref": "Barnes et al., NEJM 2023", "finding": "No significant cognitive advantage vs control over 3 years", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2302368" }, { "ref": "Morris et al., 2015 (cohort)", "finding": "~53% lower Alzheimer's incidence (observational)", "url": "https://doi.org/10.1016/j.jalz.2014.11.009" } ], "effect": "Observational dementia-risk reduction; RCT null on cognition", "human": "Strong cohort data contradicted by a null definitive RCT", "safety": "Very safe; nutrient-dense", "dose": "Daily leafy greens, berries, nuts, whole grains, fish", "status": "Healthy pattern (RCT-null)", "accessibility": "lifestyle", "caveats": "Definitive RCT was null; observational benefit likely confounded by healthy lifestyle", "sources": [ "https://www.nejm.org/doi/full/10.1056/NEJMoa2302368", "https://doi.org/10.1016/j.jalz.2014.11.009" ], "evi": 60, "hum": 62, "imp": 40, "safe": 92, "overall": 63, "tier": "B", "rank": 33 }, { "id": "metformin", "name": "Metformin", "aka": "Glucophage", "category": "pharma", "klass": "Biguanide", "mechanism": "AMPK activation, complex-I inhibition, improved insulin sensitivity, microbiome effects", "hallmarks": [ "Deregulated nutrient sensing", "Mitochondrial dysfunction", "Chronic inflammation" ], "evidenceType": "human-cohort", "evidence": "Decades of safe use and provocative cohort signals (diabetics on metformin sometimes outliving non-diabetics) motivate the TAME geroprotection trial — still only partially funded. Notably it FAILED to extend lifespan in the ITP and may blunt exercise adaptations.", "keyStudies": [ { "ref": "Bannister et al., Diab Obes Metab 2014", "finding": "Metformin-treated diabetics had lower mortality than matched non-diabetics (confounded)", "url": "https://doi.org/10.1111/dom.12354" }, { "ref": "MASTERS, Aging Cell 2019", "finding": "Metformin blunted resistance-training muscle gains in older adults", "url": "https://doi.org/10.1111/acel.13039" } ], "effect": "No lifespan extension in ITP mice; human benefit only shown in diabetics", "human": "Large diabetes cohorts; TAME RCT pending; unproven in non-diabetics", "safety": "Very safe; GI upset, B12 depletion, rare lactic acidosis", "dose": "500-2000 mg/day", "status": "FDA-approved (diabetes); off-label for longevity", "accessibility": "rx", "caveats": "May attenuate exercise/muscle gains; geroprotection in healthy people unproven; ITP-negative", "sources": [ "https://doi.org/10.1111/dom.12354", "https://doi.org/10.1111/acel.13039" ], "evi": 66, "hum": 60, "imp": 42, "safe": 80, "overall": 62, "tier": "B", "rank": 34 }, { "id": "canakinumab", "name": "Canakinumab", "aka": "Ilaris (anti-IL-1b)", "category": "pharma", "klass": "Anti-IL-1b monoclonal antibody", "mechanism": "Neutralizes IL-1b, blocking a key driver of inflammaging and the senescent-cell SASP", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication", "Cellular senescence" ], "evidenceType": "human-rct-hard", "evidence": "CANTOS is proof-of-concept that targeting inflammaging improves human outcomes: IL-1b inhibition cut recurrent CV events independent of lipids and reduced lung-cancer mortality. But it did NOT reduce all-cause mortality (fatal infections offset benefits) and is costly/immunosuppressive.", "keyStudies": [ { "ref": "CANTOS, NEJM 2017 (n=10,061)", "finding": "MACE HR 0.85; no all-cause mortality benefit; more fatal infections", "url": "https://doi.org/10.1056/NEJMoa1707914" } ], "effect": "MACE -15%; lung-cancer mortality reduced; all-cause mortality unchanged", "human": "Hard-outcome RCT validating anti-inflammaging, but no all-cause benefit", "safety": "Increased fatal infections/sepsis, neutropenia; potent immunosuppression", "dose": "150 mg SC every 3 months", "status": "FDA-approved (auto-inflammatory syndromes)", "accessibility": "clinic-only", "caveats": "No all-cause mortality benefit; infection risk and high cost preclude broad use", "sources": [ "https://doi.org/10.1056/NEJMoa1707914" ], "evi": 80, "hum": 70, "imp": 42, "safe": 45, "overall": 62, "tier": "B", "rank": 35 }, { "id": "magnesium", "name": "Magnesium", "aka": "Mg (glycinate, citrate, etc.)", "category": "supplement", "klass": "Essential mineral / enzyme cofactor", "mechanism": "Cofactor for 300+ enzymes incl. ATP metabolism and DNA repair; vascular/neuromuscular regulation", "hallmarks": [ "Genomic instability", "Mitochondrial dysfunction", "Chronic inflammation" ], "evidenceType": "human-cohort", "evidence": "Strong cohort evidence: each +100 mg/d dietary magnesium associated with ~10% lower all-cause mortality and lower heart-failure/stroke risk. But intake correlates with diet quality, and RCT benefit is concentrated in deficiency/hypertension.", "keyStudies": [ { "ref": "Fang et al., BMC Med 2016", "finding": "+100 mg/d: all-cause mortality -10%, HF -22%", "url": "https://link.springer.com/article/10.1186/s12916-016-0742-z" } ], "effect": "All-cause mortality RR 0.90 (95% CI 0.81-0.99) per 100 mg/d dietary intake; stronger for T2D (RR 0.81, 95% CI 0.77-0.86) and stroke (RR 0.93, 95% CI 0.89-0.97) — Fang BMC Med 2016 cohort meta-analysis", "human": "Strong cohort; RCT benefits mainly in deficiency/hypertension", "safety": "Very safe from food; supplements cause diarrhoea; caution in renal impairment", "dose": "~300-400 mg/day elemental", "status": "OTC mineral", "accessibility": "otc", "caveats": "Association partly reflects overall diet quality; limited benefit beyond adequacy", "sources": [ "https://link.springer.com/article/10.1186/s12916-016-0742-z" ], "evi": 60, "hum": 62, "imp": 40, "safe": 88, "overall": 62, "tier": "B", "rank": 36 }, { "id": "time-restricted-eating", "name": "Time-Restricted Eating", "aka": "TRE, 16:8", "category": "diet", "klass": "Daily eating-window restriction", "mechanism": "Aligns feeding with circadian rhythm and extends the overnight fast to lower insulin and trigger autophagy", "hallmarks": [ "Deregulated nutrient sensing", "Altered intercellular communication", "Disabled macroautophagy", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "RCTs and meta-analyses show modest improvements in glucose, weight and BP, largely from incidental calorie reduction; head-to-head it roughly equals plain calorie restriction. A contested (non-peer-reviewed) 2024 analysis linked <8h windows to higher CV mortality.", "keyStudies": [ { "ref": "Lowe et al., TREAT, JAMA IM 2020", "finding": "16:8 gave no metabolic advantage over 3 meals/day", "url": "https://doi.org/10.1001/jamainternmed.2020.4153" } ], "effect": "Small weight/glucose/BP improvements; no demonstrated mortality benefit", "human": "Many short RCTs on surrogates; mortality data conflicting", "safety": "Generally well tolerated; caution with diabetes meds, eating disorders", "dose": "6-10h daily eating window", "status": "Popular practice / investigational", "accessibility": "lifestyle", "caveats": "Benefits largely explained by calorie reduction; one observational analysis suggests possible CV harm", "sources": [ "https://doi.org/10.1001/jamainternmed.2020.4153" ], "evi": 60, "hum": 64, "imp": 42, "safe": 84, "overall": 62, "tier": "B", "rank": 37 }, { "id": "intermittent-fasting", "name": "Intermittent Fasting (ADF / 5:2)", "aka": "Alternate-day, 5:2", "category": "diet", "klass": "Intermittent energy restriction", "mechanism": "Recurrent fasts trigger ketogenic switch, autophagy and lowered insulin/IGF-1/mTOR", "hallmarks": [ "Deregulated nutrient sensing", "Disabled macroautophagy", "Chronic inflammation", "Mitochondrial dysfunction" ], "evidenceType": "human-rct-surrogate", "evidence": "Network meta-analyses show all IF forms reduce weight and improve glucose/lipids vs usual diet (alternate-day often largest), but certainty is low and IF roughly equals continuous CR. Benefits appear driven by energy deficit; no hard outcomes.", "keyStudies": [ { "ref": "Trepanowski et al., JAMA IM 2017", "finding": "ADF weight loss similar to daily CR, higher dropout", "url": "https://doi.org/10.1001/jamainternmed.2017.0936" } ], "effect": "~3-8% weight loss; improved insulin sensitivity comparable to CR", "human": "Numerous RCTs on surrogates; no hard-outcome trials", "safety": "Hunger, irritability; hypoglycaemia risk on glucose-lowering meds", "dose": "5:2 or alternate-day (~25% intake)", "status": "Popular practice", "accessibility": "lifestyle", "caveats": "Effects largely attributable to calorie deficit; adherence drops; low evidence certainty", "sources": [ "https://doi.org/10.1001/jamainternmed.2017.0936" ], "evi": 60, "hum": 64, "imp": 42, "safe": 82, "overall": 62, "tier": "B", "rank": 38 }, { "id": "colchicine", "name": "Colchicine (low-dose)", "aka": "Lodoco; LoDoCo", "category": "pharma", "klass": "Anti-inflammatory / NLRP3 inflammasome inhibitor", "mechanism": "Binds tubulin to block microtubule assembly, suppressing NLRP3 inflammasome activation and IL-1b/IL-18 release (targets 'inflammaging')", "hallmarks": [ "Chronic inflammation", "Cellular senescence" ], "evidenceType": "human-rct-hard", "evidence": "Two large double-blind RCTs (LoDoCo2 n=5,522; COLCOT n=4,745) show 0.5 mg/day cuts major CV events ~25-31% on top of statins, earning the first FDA approval (2023) of an anti-inflammatory drug for atherosclerotic CVD. But the benefit is non-fatal ischemic events only: NO reduction in CV or all-cause mortality, and pooled data show a significant excess of non-cardiovascular death.", "keyStudies": [ { "ref": "Nidorf et al. (LoDoCo2), NEJM 2020", "finding": "Primary CV composite HR 0.69 (95% CI 0.57-0.83); non-CV death HR 1.51 (0.99-2.31)", "url": "https://pubmed.ncbi.nlm.nih.gov/32865380/" }, { "ref": "Akl et al. meta-analysis (8 RCTs, 12,151), 2024", "finding": "MACE OR 0.70 (95% CI 0.60-0.83); all-cause mortality OR 1.11 (NS); non-CV death OR 1.54 (1.10-2.15)", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10950412/" } ], "effect": "~25-31% fewer major CV events (pooled OR 0.70, 95% CI 0.60-0.83); no mortality benefit", "human": "Strong hard-outcome RCT evidence for CV events; no survival benefit shown", "safety": "Generally tolerated at 0.5 mg/day; signal of excess non-CV death; dangerous with CYP3A4/P-gp inhibitors and in renal/hepatic impairment", "dose": "0.5 mg orally once daily, added to standard secondary prevention", "status": "FDA-approved 2023 for CV risk reduction in ASCVD", "accessibility": "rx", "caveats": "Cuts non-fatal events only — no CV or all-cause mortality benefit, and a significant excess of non-cardiovascular deaths in pooled data", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/32865380/", "https://pubmed.ncbi.nlm.nih.gov/31733140/" ], "evi": 80, "hum": 52, "imp": 50, "safe": 62, "overall": 62, "tier": "B", "rank": 39 }, { "id": "curcumin", "name": "Curcumin", "aka": "Turmeric extract", "category": "botanical", "klass": "Polyphenol (curcuminoid)", "mechanism": "Pleiotropic anti-inflammatory/antioxidant; inhibits NF-kB/COX-2, modulates Nrf2/AMPK", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication", "Cellular senescence" ], "evidenceType": "human-rct-surrogate", "evidence": "Large RCT base shows reductions in CRP, IL-6 and TNF-a and OA pain relief comparable to NSAIDs with bioavailable formulations. No hard-outcome/lifespan data; dismal bioavailability of unformulated curcumin is the key limitation.", "keyStudies": [ { "ref": "Curcumin vs diclofenac OA, Trials 2019", "finding": "Comparable knee-OA pain relief with fewer GI effects", "url": "https://pubmed.ncbi.nlm.nih.gov/30975196/" } ], "effect": "CRP reductions; OA pain relief comparable to NSAIDs (formulated)", "human": "Robust RCT evidence for surrogate/symptomatic outcomes; no longevity endpoints", "safety": "Very well tolerated; CYP inhibition; rare hepatotoxicity at high dose", "dose": "500-2000 mg/day curcuminoids (bioavailable forms)", "status": "Supplement / spice", "accessibility": "otc", "caveats": "Unformulated curcumin is poorly absorbed; results hinge on formulation — but high-bioavailability/piperine forms are also those linked to a rising number of drug-induced liver-injury cases", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/30975196/" ], "evi": 60, "hum": 62, "imp": 38, "safe": 84, "overall": 61, "tier": "B", "rank": 40 }, { "id": "aged-garlic-allicin", "name": "Aged Garlic Extract / Allicin", "aka": "Kyolic, Allium sativum", "category": "botanical", "klass": "Organosulfur compounds", "mechanism": "NO-mediated vasodilation, modest lipid modulation, anti-inflammatory/antiplatelet effects", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation", "Mitochondrial dysfunction" ], "evidenceType": "human-rct-surrogate", "evidence": "Among the better-evidenced botanicals for cardiovascular surrogates: meta-analyses show reductions in systolic BP (~2.5-4 mmHg) and LDL, strongest at >=1200 mg/day and in those with CVD. No powered hard-outcome RCT.", "keyStudies": [ { "ref": "AGE BP/lipid meta-analysis 2025 (19 trials)", "finding": "SBP -2.5 mmHg, LDL reductions; stronger in CVD", "url": "https://pubmed.ncbi.nlm.nih.gov/40628369/" } ], "effect": "SBP -2.5-4 mmHg (up to ~10 in uncontrolled HTN); small LDL reductions", "human": "Consistent RCT/meta-analytic evidence for BP/lipids; no hard-outcome RCT", "safety": "Very safe; garlic odor, GI; antiplatelet (bleeding caution)", "dose": "AGE >=1200 mg/day", "status": "Supplement / food", "accessibility": "otc", "caveats": "Allicin is unstable; effects require adequate (>=1200 mg) dosing", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/40628369/" ], "evi": 60, "hum": 62, "imp": 38, "safe": 84, "overall": 61, "tier": "B", "rank": 41 }, { "id": "green-tea-beverage", "name": "Green Tea (Whole Beverage)", "aka": "Camellia sinensis tea", "category": "botanical", "klass": "Polyphenol-rich beverage", "mechanism": "Antioxidant/anti-inflammatory polyphenols, endothelial NO support, modest metabolic effects", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication", "Mitochondrial dysfunction" ], "evidenceType": "human-cohort", "evidence": "Whole-beverage tea has large cohort evidence for lower mortality: a 2024 meta-analysis (38 cohorts, ~1.96M) found highest intake associated with ~10% lower all-cause and ~14% lower CV mortality, plateauing ~2 cups/day. The pooled data cover all tea types (green in Asian, black in European cohorts), not green tea alone. Observational, but the strongest signal among these botanicals — and the beverage avoids EGCG-extract hepatotoxicity.", "keyStudies": [ { "ref": "Tea & mortality meta-analysis 2024 (38 cohorts)", "finding": "All-cause HR 0.90, CVD HR 0.86 at highest intake", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC11573487/" } ], "effect": "~10-15% lower all-cause/CV mortality at highest intake (associative)", "human": "Strong cohort mortality association; no RCT proving causal lifespan extension", "safety": "Very safe as a beverage; caffeine effects", "dose": "~1.5-3 cups/day", "status": "Food/beverage", "accessibility": "lifestyle", "caveats": "Observational only; the meta-analysis pooled all tea types (not green-specific); benefit is from the beverage, not concentrated extracts", "sources": [ "https://pmc.ncbi.nlm.nih.gov/articles/PMC11573487/" ], "evi": 60, "hum": 62, "imp": 40, "safe": 86, "overall": 61, "tier": "B", "rank": 42 }, { "id": "blood-flow-restriction-training", "name": "Blood-Flow Restriction Training", "aka": "BFR, occlusion training", "category": "therapy", "klass": "Low-load resistance + occlusion", "mechanism": "Partial venous occlusion during light-load exercise creates metabolic stress driving hypertrophy at low loads", "hallmarks": [ "Stem cell exhaustion", "Deregulated nutrient sensing", "Altered intercellular communication" ], "evidenceType": "human-rct-surrogate", "evidence": "Meta-analyses show low-load BFR builds strength/hypertrophy comparable to heavy resistance training — valuable for frail/older or injured people who can't lift heavy. Muscle surrogates, not longevity; in some trained groups it is inferior to heavy lifting.", "keyStudies": [ { "ref": "Sports Med Open 2024 meta-analysis", "finding": "Low-load BFR matched high-load training for strength/hypertrophy", "url": "https://doi.org/10.1186/s40798-024-00719-3" } ], "effect": "Hypertrophy/strength comparable to heavy lifting at ~20-40% 1RM", "human": "Robust RCT evidence for muscle; no aging/mortality data", "safety": "Generally safe done correctly; theoretical clot risk, discomfort, bruising", "dose": "~20-40% 1RM, high reps, cuff ~40-80% occlusion", "status": "Established in rehab/strength training", "accessibility": "otc", "caveats": "An exercise method valuable for those who can't lift heavy, not a validated systemic anti-aging therapy", "sources": [ "https://doi.org/10.1186/s40798-024-00719-3" ], "evi": 60, "hum": 66, "imp": 42, "safe": 78, "overall": 61, "tier": "B", "rank": 43 }, { "id": "glucosamine", "name": "Glucosamine", "aka": "Glucosamine sulfate", "category": "supplement", "klass": "Amino-monosaccharide", "mechanism": "Cartilage substrate; proposed systemic anti-inflammatory / AMPK (CR-mimetic) effects", "hallmarks": [ "Chronic inflammation", "Deregulated nutrient sensing" ], "evidenceType": "human-cohort", "evidence": "Large cohorts (UK Biobank, ~495k) link regular glucosamine use to ~15% lower all-cause and ~18% lower CV mortality, with mouse data suggesting CR-mimetic effects. All longevity data are observational (healthy-user bias); a dedicated UK Biobank + Mendelian-randomization analysis found glucosamine associated with LOWER incident heart failure (HR ~0.87), so the earlier heart-failure concern is not supported.", "keyStudies": [ { "ref": "Li et al., Ann Rheum Dis 2020 (UK Biobank, ~495k)", "finding": "All-cause mortality HR 0.85; CV HR 0.82", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC7286049/" }, { "ref": "Ma et al., Mayo Clin Proc 2023 (UK Biobank + MR)", "finding": "Glucosamine associated with LOWER incident heart failure (HR 0.87; MR HR 0.92)", "url": "https://pubmed.ncbi.nlm.nih.gov/37422736/" } ], "effect": "All-cause mortality HR 0.85 (95% CI 0.82-0.89), ~15% lower, in regular users; CVD HR 0.82 (95% CI 0.74-0.90) — Li UK Biobank 2020 cohort association, n=495,077", "human": "Strong cohort associations; no RCT; HF link is protective in MR analysis", "safety": "Very safe; mild GI; may slightly raise glucose", "dose": "1500 mg/day", "status": "OTC (Rx in some EU countries)", "accessibility": "otc", "caveats": "All longevity data observational/healthy-user-confounded; no RCT for hard outcomes", "sources": [ "https://pmc.ncbi.nlm.nih.gov/articles/PMC7286049/", "https://pubmed.ncbi.nlm.nih.gov/37422736/" ], "evi": 58, "hum": 60, "imp": 42, "safe": 82, "overall": 60, "tier": "B", "rank": 44 }, { "id": "blue-zones-plant-forward", "name": "Blue Zones / Plant-Forward Pattern", "aka": "Longevity dietary pattern", "category": "diet", "klass": "Whole-food plant-forward pattern", "mechanism": "Legume/whole-grain/vegetable-rich, low ultra-processed, moderate calories — reduces inflammation and improves the microbiome", "hallmarks": [ "Chronic inflammation", "Dysbiosis", "Deregulated nutrient sensing", "Altered intercellular communication" ], "evidenceType": "human-cohort", "evidence": "The Blue Zones concept is observational and overlaps with RCT-supported diets (Mediterranean) and Adventist cohorts (vegetarians ~12% lower mortality). But the underlying centenarian demographics face serious data-quality critiques (missing birth records, pension fraud). A hypothesis-generating pattern.", "keyStudies": [ { "ref": "Adventist Health Study-2, JAMA IM 2013", "finding": "Vegetarian patterns ~12% lower mortality (HR 0.88)", "url": "https://doi.org/10.1001/jamainternmed.2013.6473" }, { "ref": "Newman, 2024 (critique)", "finding": "Many extreme-age records attributable to error/fraud", "url": "https://doi.org/10.1101/704080" } ], "effect": "Plant-forward cohorts ~12% lower mortality; Blue Zone magnitude disputed", "human": "Observational; overlaps with RCT-backed MedDiet; demographics contested", "safety": "Very safe if well-planned; watch B12/iron/omega-3", "dose": "Plant-forward whole foods, daily legumes, minimal ultra-processed", "status": "Popular pattern (hypothesis-generating)", "accessibility": "lifestyle", "caveats": "Core longevity claims rest on disputed age records and confounded data", "sources": [ "https://doi.org/10.1001/jamainternmed.2013.6473", "https://doi.org/10.1101/704080" ], "evi": 52, "hum": 60, "imp": 45, "safe": 90, "overall": 60, "tier": "B", "rank": 45 }, { "id": "meditation-mindfulness", "name": "Meditation / Mindfulness", "aka": "MBSR, stress reduction", "category": "lifestyle", "klass": "Stress-reduction practice", "mechanism": "Down-modulates HPA-axis and sympathetic tone, potentially lowering cortisol/inflammation that damage telomeres", "hallmarks": [ "Chronic inflammation", "Telomere attrition", "Altered intercellular communication" ], "evidenceType": "human-rct-surrogate", "evidence": "Meta-analyses report small-to-moderate increases in telomerase activity and small reductions in inflammatory markers, but telomere-length effects are weak and the rigorous 18-month Age-Well RCT was null. Stress/well-being benefits are well established; biological-aging effects modest.", "keyStudies": [ { "ref": "Schutte & Malouff 2014", "finding": "Increased telomerase activity (d~0.46)", "url": "https://pubmed.ncbi.nlm.nih.gov/24636500/" }, { "ref": "Age-Well RCT 2024", "finding": "No significant telomere effect", "url": "https://doi.org/10.1016/j.bpsgos.2024.100398" } ], "effect": "Modest telomerase increase; small inflammation reduction; telomere effect inconsistent", "human": "RCTs on biomarkers/well-being; biological-aging signal weak", "safety": "Very safe; rare transient anxiety in intensive retreats", "dose": "~10-40 min/day or MBSR (8 weeks)", "status": "Established for stress; investigational for aging", "accessibility": "lifestyle", "caveats": "Strongest biological-aging data from confounded long-term-meditator comparisons; RCTs largely null on telomeres", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/24636500/", "https://doi.org/10.1016/j.bpsgos.2024.100398" ], "evi": 56, "hum": 60, "imp": 35, "safe": 92, "overall": 60, "tier": "B", "rank": 46 }, { "id": "therapeutic-plasma-exchange", "name": "Therapeutic Plasma Exchange", "aka": "TPE, plasmapheresis, plasma dilution", "category": "therapy", "klass": "Blood-fraction replacement", "mechanism": "Removing plasma and replacing with albumin dilutes pro-aging circulating factors, shifting the proteome younger", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation", "Cellular senescence" ], "evidenceType": "human-rct-hard", "evidence": "The AMBAR Phase 2b/3 RCT (n~347) in Alzheimer's found TPE with albumin slowed cognitive/functional decline vs sham — the strongest controlled evidence for any plasma-based aging-adjacent intervention. Effect was modest and disease-specific; biological-age data are preliminary.", "keyStudies": [ { "ref": "Boada et al., Alz & Dementia 2020 (AMBAR)", "finding": "Slowed decline in moderate Alzheimer's vs sham", "url": "https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12137" } ], "effect": "Slowed AD progression (modest, disease-specific); biological-age reduction reported in small study", "human": "One large RCT (Alzheimer's) + small biomarker studies; no general-aging RCT", "safety": "Generally well tolerated; hypotension, citrate reactions, line/infection risks", "dose": "AMBAR: weekly x6 then monthly x12 months", "status": "FDA-approved (autoimmune neuro); anti-aging experimental", "accessibility": "clinic-only", "caveats": "Best RCT is in Alzheimer's with modest effect; general anti-aging benefit hypothesis-driven", "sources": [ "https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12137" ], "evi": 68, "hum": 60, "imp": 50, "safe": 60, "overall": 60, "tier": "B", "rank": 47 }, { "id": "spermidine", "name": "Spermidine", "aka": "Wheat-germ extract", "category": "supplement", "klass": "Natural polyamine (autophagy)", "mechanism": "Induces autophagy, promoting cellular renewal and proteostasis", "hallmarks": [ "Disabled macroautophagy", "Loss of proteostasis", "Chronic inflammation" ], "evidenceType": "human-cohort", "evidence": "Best human evidence is observational: cohorts link higher dietary spermidine to lower all-cause/CV mortality. But the key RCT (SmartAge) was NULL — 12 months did not improve memory or biomarkers. Strong animal autophagy/lifespan data; human causal benefit unproven.", "keyStudies": [ { "ref": "Kiechl et al., AJCN 2018 (Bruneck)", "finding": "Higher intake linked to markedly lower mortality", "url": "https://pubmed.ncbi.nlm.nih.gov/29955838/" }, { "ref": "SmartAge RCT, JAMA Netw Open 2022", "finding": "NULL on memory/biomarkers at tested dose", "url": "https://doi.org/10.1001/jamanetworkopen.2022.13875" } ], "effect": "Strong cohort mortality association; RCT showed no cognitive effect", "human": "Strong cohort signal but rigorous RCT was null", "safety": "Well tolerated; no notable adverse effects", "dose": "~1-6 mg/day (or diet: wheat germ, natto)", "status": "OTC supplement / food", "accessibility": "otc", "caveats": "Cohort data likely confounded by diet quality; the one good RCT failed its endpoint", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/29955838/", "https://doi.org/10.1001/jamanetworkopen.2022.13875" ], "evi": 56, "hum": 58, "imp": 42, "safe": 86, "overall": 59, "tier": "B", "rank": 48 }, { "id": "nac", "name": "N-Acetylcysteine (NAC)", "aka": "Acetylcysteine", "category": "supplement", "klass": "Cysteine donor", "mechanism": "Cysteine/glutathione precursor; replenishes glutathione, scavenges ROS", "hallmarks": [ "Loss of proteostasis", "Mitochondrial dysfunction", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "Solid disease-specific evidence (reduces COPD exacerbations; acetaminophen antidote), but aging-specific human data are confined to glutathione/oxidative surrogates and to GlyNAC. Mouse lifespan data come within GlyNAC.", "keyStudies": [ { "ref": "COPD meta-analyses", "finding": "~10-25% fewer COPD exacerbations", "url": "https://doi.org/10.1183/16000617.00002215" } ], "effect": "COPD exacerbation reduction; aging effects surrogate-level", "human": "Strong for COPD/overdose; aging benefit mostly as GlyNAC component", "safety": "Very safe orally; antioxidants may blunt some exercise adaptations", "dose": "600-1800 mg/day", "status": "Rx drug + OTC supplement (US status contested)", "accessibility": "otc", "caveats": "Standalone anti-aging benefit unproven", "sources": [ "https://doi.org/10.1183/16000617.00002215" ], "evi": 58, "hum": 58, "imp": 38, "safe": 85, "overall": 59, "tier": "B", "rank": 49 }, { "id": "selenium", "name": "Selenium", "aka": "Selenomethionine", "category": "supplement", "klass": "Essential trace mineral", "mechanism": "Incorporated into selenoproteins (glutathione peroxidases) for antioxidant defense", "hallmarks": [ "Genomic instability", "Chronic inflammation", "Mitochondrial dysfunction" ], "evidenceType": "human-rct-hard", "evidence": "A cautionary U-shaped nutrient: the large SELECT RCT (n=35,533) found selenium did not prevent cancer. The statistically significant prostate-cancer increase in SELECT came from vitamin E, not selenium (selenium alone HR 1.09, NS); a diabetes signal with selenium comes mainly from the earlier NPC trial. Benefit appears confined to deficiency (e.g. with CoQ10 in KiSel-10); supplementing the replete is neutral.", "keyStudies": [ { "ref": "SELECT, JAMA 2011 (n=35,533)", "finding": "No cancer prevention; selenium alone NS for prostate cancer (HR 1.09); the significant increase was from vitamin E (HR 1.17)", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC4169010/" }, { "ref": "Alehagen et al., KiSel-10", "finding": "Selenium+CoQ10 cut CV mortality in selenium-deficient elderly", "url": "https://pubmed.ncbi.nlm.nih.gov/22626835/" } ], "effect": "No cancer-prevention benefit; benefit largely confined to deficiency", "human": "Large RCT (SELECT) shows no cancer-prevention benefit; harms with selenium alone were non-significant", "safety": "Narrow window; frank excess causes selenosis; a diabetes signal seen in some trials (NPC); high-dose caution", "dose": "~55 ug/day RDA; avoid high-dose if replete", "status": "OTC mineral (flagged for harm in repletion)", "accessibility": "otc", "caveats": "Beneficial mainly in deficiency; high-dose carries selenosis/diabetes concern. Note: the significant prostate-cancer harm in SELECT was from vitamin E, not selenium.", "sources": [ "https://pmc.ncbi.nlm.nih.gov/articles/PMC4169010/", "https://pubmed.ncbi.nlm.nih.gov/22626835/" ], "evi": 78, "hum": 70, "imp": 22, "safe": 58, "overall": 59, "tier": "B", "rank": 50 }, { "id": "berberine", "name": "Berberine", "aka": "'Nature's metformin'", "category": "botanical", "klass": "Isoquinoline alkaloid", "mechanism": "AMPK activation with downstream effects on gluconeogenesis, lipogenesis and autophagy", "hallmarks": [ "Deregulated nutrient sensing", "Disabled macroautophagy", "Chronic inflammation", "Dysbiosis" ], "evidenceType": "human-rct-surrogate", "evidence": "Among botanicals this has strong mechanistic plausibility (genuine AMPK activator) and good human metabolic RCT data — meaningful reductions in fasting glucose, HbA1c, triglycerides and LDL, with glucose-lowering approaching metformin. Surrogate-only; bioavailability poor.", "keyStudies": [ { "ref": "T2D meta-analysis 2022", "finding": "Reduced FBG/HbA1c comparably to metformin", "url": "https://pubmed.ncbi.nlm.nih.gov/36467075/" } ], "effect": "HbA1c ~-0.5-0.8% (up to ~1% at high baseline); meaningful lipid reductions", "human": "Good RCT/meta-analytic evidence for metabolic surrogates; no hard outcomes", "safety": "GI effects in ~20-35%; potent CYP3A4/2D6 inhibitor (interactions); avoid in pregnancy", "dose": "500 mg 2-3x/day with meals", "status": "OTC supplement (Rx in some countries)", "accessibility": "otc", "caveats": "Poor bioavailability and notable drug interactions; metabolic adjunct, not metformin replacement", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/36467075/" ], "evi": 62, "hum": 62, "imp": 42, "safe": 70, "overall": 59, "tier": "B", "rank": 51 }, { "id": "fasting-mimicking-diet", "name": "Fasting-Mimicking Diet", "aka": "FMD, ProLon", "category": "diet", "klass": "Periodic low-calorie/low-protein cycles", "mechanism": "5-day low-cal/low-protein cycles mimic water-fast physiology — downregulate IGF-1/mTOR, induce autophagy and post-cycle regeneration", "hallmarks": [ "Deregulated nutrient sensing", "Disabled macroautophagy", "Stem cell exhaustion", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "Longo's group reported 3-4 monthly FMD cycles lowered estimated biological age ~2.5 years and improved insulin resistance/liver fat across two cohorts. Surrogate (biological-age) endpoints, short-term, from groups with commercial interest; no hard outcomes.", "keyStudies": [ { "ref": "Brandhorst/Longo, Nat Commun 2024", "finding": "3-4 FMD cycles reduced biological age ~2.5 yr", "url": "https://doi.org/10.1038/s41467-024-45260-9" } ], "effect": "~2.5-year reduction in estimated biological age; improved metabolic markers", "human": "Small RCTs/cohorts on biomarkers; industry-affiliated", "safety": "Generally well tolerated; transient fatigue/hunger; caution in diabetes/frailty", "dose": "5-day low-cal cycles, repeated monthly x3", "status": "Investigational (commercial product)", "accessibility": "otc", "caveats": "Biomarker-only endpoints, short follow-up, sponsor involvement; durability unproven", "sources": [ "https://doi.org/10.1038/s41467-024-45260-9" ], "evi": 56, "hum": 56, "imp": 50, "safe": 80, "overall": 59, "tier": "B", "rank": 52 }, { "id": "low-dose-aspirin", "name": "Low-dose Aspirin", "aka": "Acetylsalicylic acid, baby aspirin", "category": "pharma", "klass": "COX inhibitor / antiplatelet", "mechanism": "Irreversibly inhibits COX-1/2, reducing thromboxane/prostaglandins (antiplatelet, anti-inflammatory)", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "human-rct-hard", "evidence": "A cautionary translation failure: a modest ITP mouse signal but the large ASPREE RCT found no benefit and numerically HIGHER all-cause mortality (cancer deaths) plus more major bleeding in healthy older adults.", "keyStudies": [ { "ref": "ASPREE, NEJM 2018 (n=19,114)", "finding": "No disability-free-survival benefit; all-cause mortality HR 1.14; more haemorrhage", "url": "https://doi.org/10.1056/NEJMoa1800722" }, { "ref": "Strong et al., ITP 2008", "finding": "+8% male mouse median lifespan", "url": "https://doi.org/10.1111/j.1474-9726.2008.00414.x" } ], "effect": "Net harm in healthy elderly (all-cause HR ~1.14)", "human": "Negative/harmful for primary prevention; benefit only in secondary prevention", "safety": "Major risk is GI/intracranial haemorrhage", "dose": "75-100 mg/d (not advised for primary prevention)", "status": "OTC; not supported for healthy-aging prevention", "accessibility": "otc", "caveats": "Animal-to-human translation failure; net harm in healthy elderly", "sources": [ "https://doi.org/10.1056/NEJMoa1800722", "https://doi.org/10.1111/j.1474-9726.2008.00414.x" ], "evi": 78, "hum": 70, "imp": 22, "safe": 50, "overall": 58, "tier": "B", "rank": 53 }, { "id": "glynac", "name": "GlyNAC (Glycine + NAC)", "aka": "Glycine + N-acetylcysteine", "category": "supplement", "klass": "Glutathione-precursor stack", "mechanism": "Supplies both glutathione precursors, restoring redox, mitochondrial function and lowering inflammation", "hallmarks": [ "Mitochondrial dysfunction", "Loss of proteostasis", "Chronic inflammation", "Deregulated nutrient sensing" ], "evidenceType": "human-rct-surrogate", "evidence": "Baylor (Sekhar) RCTs in older adults show GlyNAC corrects glutathione deficiency and improves a broad panel of aging surrogates (oxidative stress, inflammation, insulin resistance, gait, strength). But trials are small, single-lab and biomarker-based; mouse lifespan +24%.", "keyStudies": [ { "ref": "Kumar et al., J Gerontol 2023 RCT", "finding": "Improved glutathione, oxidative stress, gait, strength, cognition vs placebo", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9879756/" } ], "effect": "Large improvements in oxidative-stress/inflammation/insulin-resistance surrogates", "human": "Promising small RCTs; needs large independent replication", "safety": "Well tolerated; high amino-acid load", "dose": "~100 mg/kg glycine + 100 mg/kg NAC", "status": "OTC (separate or combo)", "accessibility": "otc", "caveats": "Small single-lab studies with dramatic biomarker claims; effects likely shrink in larger trials", "sources": [ "https://pmc.ncbi.nlm.nih.gov/articles/PMC9879756/" ], "evi": 52, "hum": 52, "imp": 48, "safe": 84, "overall": 58, "tier": "B", "rank": 54 }, { "id": "sulforaphane", "name": "Sulforaphane", "aka": "Broccoli sprout extract", "category": "supplement", "klass": "Isothiocyanate (Nrf2 activator)", "mechanism": "Activates Keap1-Nrf2-ARE, inducing endogenous antioxidant/detox enzymes", "hallmarks": [ "Chronic inflammation", "Genomic instability", "Loss of proteostasis" ], "evidenceType": "human-rct-surrogate", "evidence": "The prototypical dietary Nrf2 activator with many small RCTs showing reproducible Nrf2-target induction, lowered fasting glucose/HbA1c in diabetics (via reduced hepatic glucose output), and lower inflammatory markers. Results are biomarker-level and variable; bioavailability depends heavily on formulation.", "keyStudies": [ { "ref": "Axelsson et al., Sci Transl Med 2017", "finding": "Lowered fasting glucose/HbA1c in type-2 diabetes", "url": "https://pubmed.ncbi.nlm.nih.gov/28615356/" } ], "effect": "Modest glycaemic and oxidative/inflammatory improvements; reliable Nrf2 induction", "human": "Many small RCTs on surrogates", "safety": "Generally safe; GI upset; bioavailability varies hugely", "dose": "~10-40 mg/day (myrosinase-active)", "status": "OTC supplement / functional food", "accessibility": "otc", "caveats": "Highly variable bioavailability; no longevity outcome data despite strong mechanism", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/28615356/" ], "evi": 56, "hum": 58, "imp": 38, "safe": 84, "overall": 58, "tier": "B", "rank": 55 }, { "id": "ergothioneine", "name": "Ergothioneine", "aka": "EGT, 'longevity vitamin'", "category": "supplement", "klass": "Sulfur amino-acid antioxidant", "mechanism": "Cytoprotective antioxidant accumulated via a dedicated transporter in high-stress tissues", "hallmarks": [ "Chronic inflammation", "Mitochondrial dysfunction", "Genomic instability" ], "evidenceType": "human-cohort", "evidence": "A proposed 'longevity vitamin' (humans have a dedicated transporter). Strongest data are cohort — higher plasma ergothioneine predicted lower CV and all-cause mortality over 21 years. Compelling but observational; intervention evidence only early-stage.", "keyStudies": [ { "ref": "Smith et al., Heart 2019 (Malmo)", "finding": "Higher plasma EGT: all-cause mortality HR ~0.86 over 21 yr", "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229907/" } ], "effect": "All-cause mortality ~-14% per SD (cohort)", "human": "Strong cohort/mechanistic case; intervention RCTs early-stage", "safety": "Appears very safe; accumulates selectively", "dose": "~5-30 mg/day (or mushrooms)", "status": "OTC supplement (GRAS)", "accessibility": "otc", "caveats": "Mortality data associational; whether supplementing replicates the cohort benefit is unproven", "sources": [ "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229907/" ], "evi": 56, "hum": 55, "imp": 40, "safe": 86, "overall": 58, "tier": "B", "rank": 56 }, { "id": "collagen-peptides", "name": "Collagen Peptides", "aka": "Hydrolyzed collagen", "category": "supplement", "klass": "Hydrolyzed structural protein", "mechanism": "Provides glycine/proline + bioactive peptides that may signal fibroblast collagen synthesis", "hallmarks": [ "Altered intercellular communication", "Stem cell exhaustion" ], "evidenceType": "human-rct-surrogate", "evidence": "For skin aging the evidence is reasonably solid: meta-analyses of RCTs find ~3 months improves skin hydration, elasticity and wrinkles; joint data are positive but variable. Many trials are industry-funded; endpoints cosmetic/functional, not longevity.", "keyStudies": [ { "ref": "Skin-aging meta-analysis, Am J Med 2025", "finding": "Improved hydration, elasticity, fewer wrinkles vs placebo", "url": "https://www.amjmed.com/article/S0002-9343(25)00283-9/abstract" } ], "effect": "Measurable skin elasticity/hydration gains; modest joint relief", "human": "Multiple positive RCTs on skin; weaker on joints", "safety": "Very safe", "dose": "2.5-15 g/day", "status": "OTC supplement / food", "accessibility": "otc", "caveats": "Mostly cosmetic surrogates and industry-funded; no evidence it affects systemic aging", "sources": [ "https://www.amjmed.com/article/S0002-9343(25)00283-9/abstract" ], "evi": 56, "hum": 60, "imp": 30, "safe": 90, "overall": 58, "tier": "B", "rank": 57 }, { "id": "acarbose", "name": "Acarbose", "aka": "Precose, Glucobay", "category": "pharma", "klass": "Alpha-glucosidase inhibitor", "mechanism": "Blunts post-prandial glucose spikes by slowing carbohydrate digestion (CR-mimetic)", "hallmarks": [ "Deregulated nutrient sensing", "Chronic inflammation" ], "evidenceType": "animal-itp", "evidence": "One of the most reproducible ITP hits, with a striking male-biased lifespan extension confirmed across doses and sites. Combined with rapamycin it produced one of the largest ITP effects on record. No human longevity data.", "keyStudies": [ { "ref": "Harrison et al., Aging Cell 2014 (ITP)", "finding": "+22% male / +5% female median lifespan", "url": "https://doi.org/10.1111/acel.12170" }, { "ref": "Strong et al., Aging Cell 2022 (ITP)", "finding": "Rapamycin+acarbose ~+37% male median lifespan", "url": "https://doi.org/10.1111/acel.13724" } ], "effect": "+22% male median lifespan (mice, ITP)", "human": "No human longevity trial; glycemic surrogate data only", "safety": "Metabolically well tolerated; dose-dependent flatulence/diarrhea limit adherence", "dose": "~25-100 mg with carb meals (extrapolated)", "status": "FDA-approved (diabetes); experimental for longevity", "accessibility": "rx", "caveats": "Robust in mice but male-specific; zero human lifespan data; GI side effects", "sources": [ "https://doi.org/10.1111/acel.12170", "https://doi.org/10.1111/acel.13724" ], "evi": 64, "hum": 35, "imp": 60, "safe": 72, "overall": 57, "tier": "B", "rank": 58 }, { "id": "canagliflozin", "name": "Canagliflozin", "aka": "Invokana (SGLT2 inhibitor)", "category": "pharma", "klass": "SGLT2 inhibitor", "mechanism": "Blocks renal glucose reabsorption, inducing a mild fasting-like metabolic state", "hallmarks": [ "Deregulated nutrient sensing", "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "animal-itp", "evidence": "An ITP success in males — extended male mouse lifespan and delayed tumours, with no female lifespan effect. The SGLT2 class has strong human CV/kidney mortality data, but canagliflozin specifically carries an amputation-risk signal.", "keyStudies": [ { "ref": "Miller et al., ITP 2020", "finding": "+14% male median lifespan; no female effect; delayed neoplasia", "url": "https://doi.org/10.1172/jci.insight.140019" }, { "ref": "CANVAS, NEJM 2017", "finding": "Lower MACE but ~2x amputation risk in diabetics", "url": "https://doi.org/10.1056/NEJMoa1611925" } ], "effect": "+14% male median lifespan (mice, ITP)", "human": "No longevity RCT; class CV/renal mortality benefit in disease", "safety": "Genital infections, volume depletion, euglycemic DKA; amputation/fracture signal unique to canagliflozin", "dose": "100-300 mg/day (therapeutic)", "status": "FDA-approved (diabetes/CKD); experimental for longevity", "accessibility": "rx", "caveats": "Male-only mouse benefit; amputation signal makes other SGLT2i safer; no human aging data", "sources": [ "https://doi.org/10.1172/jci.insight.140019", "https://doi.org/10.1056/NEJMoa1611925" ], "evi": 62, "hum": 50, "imp": 55, "safe": 60, "overall": 57, "tier": "B", "rank": 59 }, { "id": "alpha-lipoic-acid", "name": "Alpha-Lipoic Acid", "aka": "ALA, thioctic acid", "category": "supplement", "klass": "Organosulfur antioxidant", "mechanism": "Universal antioxidant; regenerates other antioxidants; mitochondrial cofactor; AMPK effects", "hallmarks": [ "Mitochondrial dysfunction", "Chronic inflammation", "Deregulated nutrient sensing" ], "evidenceType": "human-rct-surrogate", "evidence": "Best evidence is for diabetic neuropathy (symptom improvement short-term), though the long-term NATHAN-1 RCT missed its primary endpoint. Other RCTs show reduced oxidative markers and modest metabolic improvement. Aging-specific data absent.", "keyStudies": [ { "ref": "Ziegler et al., NATHAN-1, Diab Care 2011", "finding": "Missed primary endpoint; improved some neuropathy measures", "url": "https://diabetesjournals.org/care/article/34/9/2054/38685/" } ], "effect": "Symptomatic neuropathy improvement; modest metabolic effects", "human": "RCTs in neuropathy/metabolic disease; no aging data", "safety": "Generally safe; can lower glucose; rare insulin-autoimmune syndrome", "dose": "300-600 mg/day", "status": "OTC supplement (Rx for neuropathy abroad)", "accessibility": "otc", "caveats": "Evidence is disease-specific, not longevity; flagship neuropathy RCT missed its primary endpoint", "sources": [ "https://diabetesjournals.org/care/article/34/9/2054/38685/" ], "evi": 56, "hum": 56, "imp": 35, "safe": 82, "overall": 57, "tier": "B", "rank": 60 }, { "id": "infrared-sauna", "name": "Infrared Sauna", "aka": "Far-infrared sauna, Waon therapy", "category": "thermal", "klass": "Radiant heat therapy", "mechanism": "Lower-temperature radiant heat raises core temperature, improving endothelial function and cardiac output", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "Best evidence is the Japanese Waon-therapy program in chronic heart failure — small RCTs show improved cardiac function, exercise tolerance and lower BNP. Surrogate/functional endpoints in disease populations, mostly from one research group; no healthy-population longevity data.", "keyStudies": [ { "ref": "Tei/Kihara, Waon therapy (CHF)", "finding": "Improved cardiac function and exercise tolerance in CHF", "url": "https://pubmed.ncbi.nlm.nih.gov/11869837/" } ], "effect": "CHF: improved ejection fraction/BNP/6-min walk; healthy longevity effect unknown", "human": "RCTs positive in heart failure; no healthy-population longevity data", "safety": "Generally safe; lower thermal load than traditional sauna", "dose": "Waon: ~60C 15 min + 30 min rest", "status": "Clinical (Japan, CHF); consumer units unregulated", "accessibility": "lifestyle", "caveats": "Most positive data from one group in heart-failure patients; consumer units differ from clinical Waon", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/11869837/" ], "evi": 52, "hum": 56, "imp": 42, "safe": 82, "overall": 57, "tier": "B", "rank": 61 }, { "id": "dasatinib-quercetin", "name": "Senolytics: Dasatinib + Quercetin", "aka": "D+Q", "category": "senolytic", "klass": "Senolytic combination", "mechanism": "Transiently kills senescent cells by disabling their pro-survival pathways", "hallmarks": [ "Cellular senescence", "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "human-rct-surrogate", "evidence": "The best-validated senolytic combination in humans, but evidence is early-phase and mostly on biomarkers/feasibility. Small trials show reduced senescent-cell burden (diabetic kidney disease) and improved physical function (IPF); a 2025 Alzheimer's pilot was single-arm. No placebo-controlled hard-outcome win yet.", "keyStudies": [ { "ref": "Hickson et al., EBioMedicine 2019", "finding": "3-day D+Q reduced senescent-cell markers and SASP in patients", "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796530/" }, { "ref": "Justice et al., EBioMedicine 2019", "finding": "Improved 6-min walk/gait in small IPF pilot", "url": "https://www.sciencedirect.com/science/article/pii/S2352396418306297" } ], "effect": "Large in mice (healthspan); human clinical benefit unproven", "human": "Small early-phase RCTs; target engagement shown, efficacy not", "safety": "Dasatinib (a chemo drug) carries cytopenias, effusions, bleeding risk; intermittent dosing", "dose": "Intermittent 'hit-and-run' (e.g. 2-3 days, repeated)", "status": "Investigational; dasatinib off-label", "accessibility": "experimental", "caveats": "Dasatinib is a real chemo agent; no placebo-controlled hard-outcome win; DIY use hazardous", "sources": [ "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796530/", "https://www.sciencedirect.com/science/article/pii/S2352396418306297" ], "evi": 56, "hum": 46, "imp": 68, "safe": 55, "overall": 56, "tier": "B", "rank": 62 }, { "id": "vitamin-k2-mk7", "name": "Vitamin K2 (MK-7)", "aka": "Menaquinone-7", "category": "supplement", "klass": "Fat-soluble vitamin", "mechanism": "Carboxylates matrix-Gla protein (inhibits vascular calcification) and osteocalcin (bone)", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation" ], "evidenceType": "human-cohort", "evidence": "Strong observational case (Rotterdam Study linked high intake to ~50% lower aortic calcification and ~25% lower all-cause mortality), with a well-established mechanism — but RCTs have been largely null on hard calcification/clinical endpoints.", "keyStudies": [ { "ref": "Geleijnse et al., Rotterdam Study", "finding": "Highest K2 intake: ~25% lower all-cause mortality", "url": "https://doi.org/10.1093/jn/134.11.3100" }, { "ref": "K2+D aortic-valve RCT, Circulation 2022", "finding": "No significant slowing of calcification", "url": "https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.057008" } ], "effect": "Large cohort associations; RCTs mostly null on hard endpoints", "human": "Strong observational + mechanism, but RCTs underwhelming", "safety": "Very safe; interacts with warfarin", "dose": "90-200 ug/day MK-7", "status": "OTC supplement", "accessibility": "otc", "caveats": "'Reverses arterial calcification' claims rest on cohorts/surrogates; RCTs have largely failed to confirm", "sources": [ "https://doi.org/10.1093/jn/134.11.3100", "https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.057008" ], "evi": 54, "hum": 52, "imp": 38, "safe": 86, "overall": 56, "tier": "B", "rank": 63 }, { "id": "silymarin-milk-thistle", "name": "Silymarin (Milk Thistle)", "aka": "Silybum marianum", "category": "botanical", "klass": "Flavonolignan complex", "mechanism": "Hepatoprotective antioxidant; reduces lipid peroxidation and inflammation in liver", "hallmarks": [ "Chronic inflammation", "Mitochondrial dysfunction", "Genomic instability" ], "evidenceType": "human-rct-surrogate", "evidence": "Best evidence is for liver biomarkers: meta-analyses show silymarin lowers transaminases and improves liver fat in NAFLD/NASH. Surrogate (enzymes/imaging), not histological hard outcomes; bioavailability poor. A liver-targeted, not general-longevity, agent.", "keyStudies": [ { "ref": "NAFLD meta-analysis 2024 (26 trials)", "finding": "Improved liver enzymes and hepatic fat", "url": "https://doi.org/10.1016/j.aohep.2023.101174" } ], "effect": "ALT/AST reductions; modest liver-fat improvement", "human": "Good RCT/meta evidence for liver surrogates; no hard-outcome data", "safety": "Very well tolerated; mild GI; CYP/UGT interactions", "dose": "~420 mg/day silymarin", "status": "Supplement / liver-disease adjunct", "accessibility": "otc", "caveats": "Poor bioavailability; benefit is liver-specific, not systemic anti-aging", "sources": [ "https://doi.org/10.1016/j.aohep.2023.101174" ], "evi": 56, "hum": 56, "imp": 32, "safe": 84, "overall": 56, "tier": "B", "rank": 64 }, { "id": "nicotinamide-riboside", "name": "NR (Nicotinamide Riboside)", "aka": "Niagen, Tru Niagen", "category": "nad", "klass": "NAD+ precursor (vitamin B3)", "mechanism": "Converted via NMN to NAD+, supporting sirtuin/PARP/mitochondrial function", "hallmarks": [ "Deregulated nutrient sensing", "Mitochondrial dysfunction", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "The best-studied NAD+ precursor in humans — dependably raises NAD+, but clinical benefits are limited and inconsistent and it did NOT extend lifespan in the rigorous ITP. The NICE trial improved 6-min walk only modestly; other trials were largely null.", "keyStudies": [ { "ref": "NICE trial, Nat Commun 2024", "finding": "1000 mg/d improved 6-min walk +17.6 m (small)", "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11176364/" }, { "ref": "NIA ITP 2021", "finding": "NR did not extend mouse lifespan", "url": "https://doi.org/10.1111/acel.13328" } ], "effect": "Reliably raises NAD+; small/mostly-null clinical effects; no mouse lifespan extension", "human": "Many RCTs confirming NAD+ rise and safety; benefits modest/heterogeneous", "safety": "Very good; safe up to 2 g/day in trials", "dose": "300-1000 mg/day", "status": "Widely sold supplement", "accessibility": "otc", "caveats": "Did NOT extend lifespan in the gold-standard ITP; biomarker change != healthspan benefit", "sources": [ "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11176364/", "https://doi.org/10.1111/acel.13328" ], "evi": 52, "hum": 55, "imp": 35, "safe": 80, "overall": 55, "tier": "C", "rank": 65 }, { "id": "melatonin", "name": "Melatonin", "aka": "N-acetyl-5-methoxytryptamine", "category": "supplement", "klass": "Indoleamine hormone", "mechanism": "Circadian regulator; potent mitochondrial antioxidant and anti-inflammatory", "hallmarks": [ "Mitochondrial dysfunction", "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "human-rct-surrogate", "evidence": "Strong for sleep-onset/circadian use and a good mitochondrial antioxidant, but longevity 'mortality benefit' claims rest on animal/mechanistic data. New 2025 cohort data link long-term use to higher heart-failure and mortality — possibly confounding, but it tempers the 'safe longevity supplement' narrative.", "keyStudies": [ { "ref": "AHA 2025 cohort", "finding": "Long-term use linked to ~89% higher incident HF and ~2x mortality (observational)", "url": "https://www.ahajournals.org/doi/10.1161/circ.152.suppl_3.4371606" } ], "effect": "Reliable for sleep latency; mortality effect unproven and possibly adverse", "human": "Good for sleep; longevity benefit unproven, 2025 safety signal", "safety": "Short-term very safe; 2025 data flag possible HF/mortality association with chronic use", "dose": "0.5-3 mg before bed", "status": "OTC (US); Rx in much of EU/UK", "accessibility": "otc", "caveats": "Hyped as anti-aging antioxidant, but human longevity evidence weak and a 2025 safety question exists", "sources": [ "https://www.ahajournals.org/doi/10.1161/circ.152.suppl_3.4371606" ], "evi": 56, "hum": 58, "imp": 35, "safe": 70, "overall": 55, "tier": "C", "rank": 66 }, { "id": "ashwagandha", "name": "Ashwagandha", "aka": "Withania somnifera, KSM-66", "category": "botanical", "klass": "Adaptogenic herb (withanolides)", "mechanism": "HPA-axis modulation lowering cortisol; GABAergic/serotonergic and antioxidant effects", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation", "Mitochondrial dysfunction" ], "evidenceType": "human-rct-surrogate", "evidence": "One of the better-supported adaptogens for stress: meta-analyses of ~15 RCTs show significant reductions in perceived stress, anxiety and cortisol. Short-term and symptom/biomarker based; no aging/lifespan outcomes.", "keyStudies": [ { "ref": "Stress/anxiety meta-analysis, BJPsych Open 2025", "finding": "Reduced Perceived Stress Scale, HAM-A and serum cortisol", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12242034/" } ], "effect": "Perceived-stress and cortisol reductions", "human": "Good short-term RCT evidence for stress/anxiety; no longevity endpoints", "safety": "Generally well tolerated short term; a recognized idiosyncratic cholestatic liver-injury signal (rare, incl. isolated acute liver failure); may affect thyroid; caution in autoimmune/pregnancy", "dose": "300-600 mg/day standardized root extract", "status": "Supplement / Ayurvedic herb", "accessibility": "otc", "caveats": "Perceived-stress benefit is contested across 2025 meta-analyses (cortisol reduction more consistent); a documented idiosyncratic liver-injury signal; extract heterogeneity", "sources": [ "https://pmc.ncbi.nlm.nih.gov/articles/PMC12242034/" ], "evi": 56, "hum": 58, "imp": 32, "safe": 75, "overall": 55, "tier": "C", "rank": 67 }, { "id": "oleuropein-olive-leaf", "name": "Oleuropein / Olive Leaf Extract", "aka": "OLE, hydroxytyrosol", "category": "botanical", "klass": "Secoiridoid phenolics", "mechanism": "NO-mediated vasodilation and antioxidant signaling; modest insulin-sensitizing effects", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation", "Deregulated nutrient sensing" ], "evidenceType": "human-rct-surrogate", "evidence": "RCT meta-analyses show olive leaf extract lowers systolic BP (~4-5 mmHg) and triglycerides; olive polyphenol (hydroxytyrosol) carries an EFSA claim for LDL-oxidation protection. Surrogate endpoints; no hard-outcome RCT.", "keyStudies": [ { "ref": "OLE CV meta-analysis 2022 (12 studies)", "finding": "SBP -3.9 mmHg; in hypertensives SBP -4.8 mmHg", "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9585795/" } ], "effect": "SBP -4-5 mmHg; triglyceride reductions", "human": "RCT/meta evidence for BP/lipid surrogates; no hard-outcome data", "safety": "Very well tolerated; additive with antihypertensives", "dose": "~500-1000 mg/day OLE", "status": "Supplement (EFSA olive-polyphenol claim)", "accessibility": "otc", "caveats": "Glucose effects inconsistent; oleuropein content varies", "sources": [ "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9585795/" ], "evi": 52, "hum": 54, "imp": 34, "safe": 84, "overall": 55, "tier": "C", "rank": 68 }, { "id": "red-light-therapy-pbm", "name": "Red Light Therapy / Photobiomodulation", "aka": "PBM, LLLT", "category": "thermal", "klass": "Photobiomodulation", "mechanism": "Red/near-infrared photons absorbed by cytochrome c oxidase boost mitochondrial ATP and modulate inflammation", "hallmarks": [ "Mitochondrial dysfunction", "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "human-rct-surrogate", "evidence": "The mechanism is well established, and human RCTs support specific dermatologic (wrinkles, wound healing) and musculoskeletal pain endpoints. An umbrella review found benefits across outcomes but rated certainty low-to-moderate with non-standardized protocols; no aging/lifespan outcomes.", "keyStudies": [ { "ref": "Umbrella review, Syst Rev 2025", "finding": "Improved pain/skin/mucositis outcomes; certainty low-to-moderate", "url": "https://doi.org/10.1186/s13643-025-02902-3" } ], "effect": "Outcome-specific: skin rejuvenation, wound healing, some pain", "human": "Multiple RCTs for surrogate endpoints; nothing on aging/lifespan", "safety": "Very safe for skin; eye protection needed; dose-response is biphasic", "dose": "630-850nm, ~10-60 J/cm2, minutes per area", "status": "FDA-cleared for specific indications; broad anti-aging claims unproven", "accessibility": "otc", "caveats": "Strong mechanism but longevity claims extrapolate from surrogate/in-vitro data; protocols not standardized", "sources": [ "https://doi.org/10.1186/s13643-025-02902-3" ], "evi": 52, "hum": 55, "imp": 38, "safe": 80, "overall": 55, "tier": "C", "rank": 69 }, { "id": "whole-body-vibration", "name": "Whole-Body Vibration", "aka": "WBV, vibration platform", "category": "therapy", "klass": "Mechanical/neuromuscular stimulus", "mechanism": "Mechanical accelerations stimulate reflexive muscle contraction and bone mechanotransduction", "hallmarks": [ "Stem cell exhaustion", "Altered intercellular communication" ], "evidenceType": "human-rct-surrogate", "evidence": "Meta-analyses in older adults show modest, region-specific bone-density gains and improved strength/balance/fall measures, but effects are inconsistent across skeletal sites. No mortality or systemic aging outcomes.", "keyStudies": [ { "ref": "WBV meta-analysis 2026 (1,447 older adults)", "finding": "BMD gains at trochanter/Ward's; inconsistent at femoral neck/spine across meta-analyses", "url": "https://doi.org/10.1186/s12891-026-09504-7" } ], "effect": "Small site-specific BMD gains; modest strength/balance improvement", "human": "RCTs positive for BMD/strength surrogates; no longevity data", "safety": "Generally safe; caution with thrombosis, recent fractures, pregnancy", "dose": "~20-40 Hz, minutes/session, 3x/wk", "status": "Used in physiotherapy/fitness", "accessibility": "otc", "caveats": "Benefits modest, site-dependent, limited to musculoskeletal surrogates", "sources": [ "https://doi.org/10.1186/s12891-026-09504-7" ], "evi": 54, "hum": 58, "imp": 32, "safe": 80, "overall": 55, "tier": "C", "rank": 70 }, { "id": "ginkgo-biloba", "name": "Ginkgo Biloba", "aka": "EGb 761", "category": "botanical", "klass": "Standardized leaf extract", "mechanism": "Improves microcirculation/cerebral blood flow; antioxidant; PAF antagonism", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation", "Mitochondrial dysfunction" ], "evidenceType": "human-rct-hard", "evidence": "For treating existing mild dementia, EGb 761 at 240 mg/day shows benefits on cognition and function. But for prevention it FAILED: the large GEM and GuidAge trials showed it does not prevent dementia in healthy older adults. A symptomatic agent, not a prevention/longevity tool.", "keyStudies": [ { "ref": "GEM Study, JAMA 2008", "finding": "Did NOT reduce incidence of dementia/Alzheimer's", "url": "https://doi.org/10.1001/jama.2008.683" }, { "ref": "GuidAge, Lancet Neurol 2012 (n>2,800)", "finding": "Long-term EGb 761 did NOT prevent Alzheimer's in elders with memory complaints", "url": "https://pubmed.ncbi.nlm.nih.gov/22959217/" }, { "ref": "EGb 761 mild-dementia meta-analysis", "finding": "240 mg/d superior to placebo for cognition/ADL", "url": "https://doi.org/10.1080/15622975.2024.2446830" } ], "effect": "Modest symptomatic benefit in established dementia; no preventive benefit", "human": "Positive for treating dementia, clearly negative for prevention", "safety": "Generally well tolerated; antiplatelet/bleeding risk", "dose": "EGb 761 240 mg/day", "status": "Supplement (Rx phytomedicine in EU)", "accessibility": "otc", "caveats": "Does not prevent dementia/aging despite popular belief; bleeding risk", "sources": [ "https://doi.org/10.1001/jama.2008.683", "https://pubmed.ncbi.nlm.nih.gov/22959217/", "https://doi.org/10.1080/15622975.2024.2446830" ], "evi": 58, "hum": 58, "imp": 30, "safe": 70, "overall": 54, "tier": "C", "rank": 71 }, { "id": "saffron-crocin", "name": "Saffron (Crocin)", "aka": "Crocus sativus, affron", "category": "botanical", "klass": "Carotenoid-rich spice", "mechanism": "Serotonergic/dopaminergic modulation; antioxidant and anti-inflammatory effects", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication", "Mitochondrial dysfunction" ], "evidenceType": "human-rct-surrogate", "evidence": "A relatively strong RCT base for mood: 20+ RCTs and meta-analyses show large effects for depression and anxiety, comparable to SSRIs with fewer adverse events. Endpoints are psychiatric scales, not aging; trials mostly short and group-clustered.", "keyStudies": [ { "ref": "Depression/anxiety meta-analysis", "finding": "Large effect vs placebo (g~0.99); comparable to SSRIs", "url": "https://academic.oup.com/nutritionreviews/article/77/8/557/5499264" } ], "effect": "Clinically meaningful antidepressant/anxiolytic effect", "human": "Good RCT/meta evidence for mood; no longevity data", "safety": "Well tolerated at supplement doses; high doses (>1.5 g) toxic; avoid in pregnancy", "dose": "~30 mg/day standardized extract", "status": "Supplement / spice", "accessibility": "otc", "caveats": "Dose-toxicity margin and frequent adulteration; trials short/group-clustered", "sources": [ "https://academic.oup.com/nutritionreviews/article/77/8/557/5499264" ], "evi": 56, "hum": 58, "imp": 30, "safe": 74, "overall": 54, "tier": "C", "rank": 72 }, { "id": "bacopa-monnieri", "name": "Bacopa Monnieri", "aka": "Brahmi", "category": "botanical", "klass": "Nootropic herb (bacosides)", "mechanism": "Cholinergic modulation, dendritic/synaptic effects, hippocampal antioxidant action", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication", "Genomic instability" ], "evidenceType": "human-rct-surrogate", "evidence": "Meta-analyses with chronic (>=12 week) dosing show improved cognition, especially attention speed and memory; ranks among top botanicals for executive function in older adults. Effects modest, require sustained dosing; cognitive surrogates only.", "keyStudies": [ { "ref": "Bacopa cognition meta-analysis", "finding": "Improved speed of attention with chronic dosing", "url": "https://pubmed.ncbi.nlm.nih.gov/24252493/" } ], "effect": "Small improvements in attention speed and memory", "human": "Multiple RCTs for cognitive surrogates; no longevity data", "safety": "Generally well tolerated; dose-related GI effects common", "dose": "300 mg/day standardized (>=12 weeks)", "status": "Supplement / Ayurvedic herb", "accessibility": "otc", "caveats": "Requires weeks of dosing; GI side effects; modest effect sizes", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/24252493/" ], "evi": 52, "hum": 54, "imp": 30, "safe": 76, "overall": 53, "tier": "C", "rank": 73 }, { "id": "dhea", "name": "DHEA", "aka": "Dehydroepiandrosterone, prasterone", "category": "hormone", "klass": "Adrenal steroid precursor", "mechanism": "Adrenal prohormone converted to androgens/estrogens; weak direct receptor activity", "hallmarks": [ "Altered intercellular communication", "Stem cell exhaustion" ], "evidenceType": "human-rct-surrogate", "evidence": "RCTs and a meta-analysis show at most small, sex-specific effects (modest BMD gain in older women, slight body-composition changes in men) and no consistent benefit for muscle, cognition or well-being. No mortality or anti-aging endpoint met despite age-related decline of DHEA-S.", "keyStudies": [ { "ref": "Corona et al., JCEM 2013 meta-analysis", "finding": "Small body-composition gain in men; no clear clinical benefit", "url": "https://doi.org/10.1210/jc.2013-1358" }, { "ref": "Weiss/Villareal DHEA-bone RCTs (50 mg/d)", "finding": "Modest lumbar-spine BMD gain in older women; no bone benefit in men", "url": "https://pubmed.ncbi.nlm.nih.gov/19321570/" } ], "effect": "Small lumbar-spine BMD gain in women; minor body-composition shifts; no longevity effect", "human": "Multiple RCTs; marginal sex-specific benefits", "safety": "Generally tolerated at 50 mg/d; androgenic effects; theoretical hormone-sensitive cancer concern", "dose": "25-50 mg/day oral", "status": "OTC supplement (US); WADA-banned", "accessibility": "otc", "caveats": "Popular as anti-aging but evidence shows only marginal surrogate benefits and no survival effect", "sources": [ "https://doi.org/10.1210/jc.2013-1358", "https://pubmed.ncbi.nlm.nih.gov/19321570/" ], "evi": 56, "hum": 55, "imp": 30, "safe": 70, "overall": 53, "tier": "C", "rank": 74 }, { "id": "nmn", "name": "NMN", "aka": "Nicotinamide mononucleotide", "category": "nad", "klass": "NAD+ precursor", "mechanism": "Converted to NAD+ to support sirtuins, DNA repair and mitochondrial metabolism", "hallmarks": [ "Deregulated nutrient sensing", "Mitochondrial dysfunction", "Altered intercellular communication" ], "evidenceType": "human-rct-surrogate", "evidence": "Reliably raises blood NAD+ and a few small RCTs report modest functional signals (walking speed, aerobic capacity), but evidence is limited, mixed and surrogate. No hard-outcome or lifespan data; NMN was never tested in the ITP (its relative NR was, and failed).", "keyStudies": [ { "ref": "Igarashi et al., 2024 RCT", "finding": "250 mg/d x12wk maintained walking speed (vs decline on placebo) and improved sleep in older adults", "url": "https://doi.org/10.1007/s11357-024-01204-1" }, { "ref": "Liao et al., 2021 RCT", "finding": "Dose-dependent aerobic-capacity gains in runners", "url": "https://doi.org/10.1186/s12970-021-00442-4" } ], "effect": "Reliably raises NAD+; modest, inconsistent functional gains", "human": "Several small short RCTs (surrogate endpoints)", "safety": "Well tolerated up to 1200 mg/d short-term; long-term unknown", "dose": "250-900 mg/day", "status": "Supplement (US regulatory limbo)", "accessibility": "otc", "caveats": "Raising NAD+ does not prove longevity benefit; trials small/short; US status contested", "sources": [ "https://doi.org/10.1007/s11357-024-01204-1", "https://doi.org/10.1186/s12970-021-00442-4" ], "evi": 48, "hum": 50, "imp": 38, "safe": 76, "overall": 52, "tier": "C", "rank": 75 }, { "id": "niacin", "name": "Niacin (Nicotinic Acid)", "aka": "Vitamin B3", "category": "nad", "klass": "NAD+ precursor / lipid agent", "mechanism": "Salvaged to NAD+ (Preiss-Handler); activates GPR109A (flushing); modifies lipids", "hallmarks": [ "Mitochondrial dysfunction", "Deregulated nutrient sensing", "Altered intercellular communication" ], "evidenceType": "human-rct-surrogate", "evidence": "Striking NAD+-restoration in a rare disease (mitochondrial myopathy) — niacin normalized muscle NAD+ and improved strength. But as a lipid drug, large CV outcome trials (HPS2-THRIVE) found no benefit and more harm, and a metabolite (4PY) may raise CV risk. 'More niacin' is not benign.", "keyStudies": [ { "ref": "Pirinen et al., Cell Metab 2020", "finding": "Restored muscle NAD+ and strength in mitochondrial myopathy", "url": "https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30190-X" }, { "ref": "HPS2-THRIVE, NEJM 2014", "finding": "No CV benefit, increased adverse effects (>25,000 patients)", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa1300955" } ], "effect": "Disease-specific NAD+ rescue; null/harmful for general CV prevention at high dose", "human": "Strong in a niche deficiency disease; harmful in large CV trials", "safety": "Marked flushing; high doses cause hepatotoxicity, hyperglycaemia, gout; CV harm signal", "dose": "Disease: 750-1000 mg/d; RDA ~14-16 mg", "status": "Vitamin / Rx lipid agent", "accessibility": "otc", "caveats": "NAD+ rescue specific to mitochondrial myopathy; high-dose niacin failed/harmed in CV trials", "sources": [ "https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30190-X", "https://www.nejm.org/doi/full/10.1056/NEJMoa1300955" ], "evi": 60, "hum": 55, "imp": 35, "safe": 55, "overall": 52, "tier": "C", "rank": 76 }, { "id": "carnosine", "name": "Carnosine / L-Carnosine", "aka": "Beta-alanyl-L-histidine", "category": "supplement", "klass": "Endogenous dipeptide (anti-glycation)", "mechanism": "Anti-glycation carbonyl scavenger, pH buffer, antioxidant, metal chelator", "hallmarks": [ "Loss of proteostasis", "Chronic inflammation", "Cellular senescence" ], "evidenceType": "human-rct-surrogate", "evidence": "Mechanistically attractive anti-glycation dipeptide. RCTs (2 g/d) show improved glycaemic control and some cognitive-speed gains, but cognitive benefit appeared only in the youngest subgroup; rapidly degraded by serum carnosinase (bioavailability issue).", "keyStudies": [ { "ref": "de Courten et al. RCT", "finding": "Improved glucose control in pre-diabetes/T2DM", "url": "https://doi.org/10.1016/j.numecd.2023.10.012" } ], "effect": "Modest glycaemic improvement; age-dependent cognitive effect", "human": "Small RCTs on glycaemia/cognition; bioavailability-limited", "safety": "Well tolerated at gram doses", "dose": "1-2 g/day", "status": "OTC supplement", "accessibility": "otc", "caveats": "Serum carnosinase rapidly degrades oral carnosine; benefits small and not shown for aging in older adults", "sources": [ "https://doi.org/10.1016/j.numecd.2023.10.012" ], "evi": 46, "hum": 48, "imp": 35, "safe": 84, "overall": 52, "tier": "C", "rank": 77 }, { "id": "hesperidin", "name": "Hesperidin", "aka": "Citrus flavanone", "category": "botanical", "klass": "Citrus flavanone glycoside", "mechanism": "Improves endothelial function and NO bioavailability; anti-inflammatory/antioxidant", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "A 2023 dose-response meta-analysis (13 RCTs) found hesperidin significantly lowers LDL (~5 mg/dL); fasting glucose and CRP were non-significant overall (positive only in subgroups), and adhesion molecules were not assessed. Endothelial/FMD improvement (~2-2.5%) is seen in separate small RCTs. Surrogate endpoints; bioavailability poor and microbiome-dependent.", "keyStudies": [ { "ref": "Cardiometabolic meta-analysis, Front Nutr 2023 (13 RCTs)", "finding": "LDL -5.3 mg/dL (significant); fasting glucose and CRP non-significant overall", "url": "https://doi.org/10.3389/fnut.2023.1177708" }, { "ref": "Citrus/orange-juice RCTs", "finding": "Improved FMD ~2-2.5% in elevated-BP subjects" } ], "effect": "Modest LDL reduction; improved FMD in small RCTs; glucose/inflammation effects inconsistent", "human": "Meta-analysis shows LDL reduction; glucose/CRP null overall; no longevity data", "safety": "Very well tolerated; additive with antihypertensives", "dose": "~500 mg/day", "status": "Supplement / food component", "accessibility": "otc", "caveats": "Low/variable bioavailability dependent on gut microbiota", "sources": [ "https://doi.org/10.3389/fnut.2023.1177708" ], "evi": 47, "hum": 48, "imp": 32, "safe": 86, "overall": 52, "tier": "C", "rank": 78 }, { "id": "cold-water-immersion", "name": "Cold Exposure / Cold-Water Immersion", "aka": "Cold plunge, ice bath", "category": "thermal", "klass": "Cold hormesis / thermogenesis", "mechanism": "Cold activates brown fat and mitochondrial biogenesis, raises norepinephrine and improves insulin sensitivity", "hallmarks": [ "Mitochondrial dysfunction", "Deregulated nutrient sensing", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "Small trials show cold activates brown fat, raises energy expenditure and insulin sensitivity (~40% in one mild-cold protocol); norepinephrine/mood effects are reproducible. No human longevity evidence, and acute immersion carries real cardiovascular and drowning risk.", "keyStudies": [ { "ref": "van der Lans et al., JCI 2013", "finding": "10 days mild cold improved insulin sensitivity ~43% and recruited brown fat", "url": "https://doi.org/10.1172/JCI68993" } ], "effect": "Insulin sensitivity +~40% (mild cold); large transient norepinephrine surge", "human": "Surrogate/metabolic RCTs; no longevity/hard-outcome data", "safety": "Acute cold-shock, arrhythmia, drowning, post-immersion hypotension; dangerous with cardiac disease", "dose": "~10-15 min/wk cumulative at ~10-15C, or short plunges", "status": "Wellness practice", "accessibility": "lifestyle", "caveats": "Metabolic effects real but small/short-lived; no human longevity evidence and non-trivial acute danger", "sources": [ "https://doi.org/10.1172/JCI68993" ], "evi": 50, "hum": 55, "imp": 40, "safe": 65, "overall": 52, "tier": "C", "rank": 79 }, { "id": "nr-pterostilbene", "name": "NR + Pterostilbene", "aka": "Basis (Elysium Health)", "category": "nad", "klass": "NAD+ precursor + stilbenoid combination", "mechanism": "NR raises NAD+ while pterostilbene is proposed to activate sirtuins (synergy unproven)", "hallmarks": [ "Deregulated nutrient sensing", "Mitochondrial dysfunction", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "Reliably raises NAD+ and is safe, but human clinical benefit is weak and synergy unproven — the pivotal NAFLD RCT MISSED its primary endpoint (no change in liver fat).", "keyStudies": [ { "ref": "Dellinger et al., Hepatology 2023", "finding": "NRPT missed primary NAFLD endpoint (hepatic fat unchanged)", "url": "https://onlinelibrary.wiley.com/doi/full/10.1002/hep.32778" } ], "effect": "Reliable NAD+ rise; weak/subset-only functional signals; primary NAFLD endpoint negative", "human": "Several RCTs; safe but mostly null clinical outcomes", "safety": "Well tolerated", "dose": "250 mg NR + 50 mg pterostilbene/day", "status": "Branded supplement (Basis)", "accessibility": "otc", "caveats": "Heavily marketed but pivotal trial missed its primary endpoint; pterostilbene's added benefit unproven", "sources": [ "https://onlinelibrary.wiley.com/doi/full/10.1002/hep.32778" ], "evi": 48, "hum": 52, "imp": 33, "safe": 76, "overall": 51, "tier": "C", "rank": 80 }, { "id": "glycine", "name": "Glycine", "aka": "Aminoacetic acid", "category": "supplement", "klass": "Amino acid (glutathione precursor)", "mechanism": "Glutathione precursor; one-carbon/methionine modulation; possible methionine-restriction mimetic", "hallmarks": [ "Loss of proteostasis", "Mitochondrial dysfunction", "Deregulated nutrient sensing" ], "evidenceType": "animal-other", "evidence": "Promising animal data — glycine modestly extended median lifespan in the ITP and in worms. Human data limited to short-term metabolic/sleep endpoints and to its role within GlyNAC; no standalone longevity trials.", "keyStudies": [ { "ref": "NIA ITP 2019", "finding": "Small but significant median-lifespan increase in mice", "url": "https://pubmed.ncbi.nlm.nih.gov/30916479/" } ], "effect": "Modest mouse median-lifespan extension; human effects metabolic/sleep only", "human": "No human longevity trials", "safety": "Very safe; GI upset at high doses", "dose": "3-15 g/day", "status": "OTC supplement (GRAS)", "accessibility": "otc", "caveats": "Most aging evidence animal/mechanistic or bundled with NAC", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/30916479/" ], "evi": 46, "hum": 38, "imp": 40, "safe": 88, "overall": 51, "tier": "C", "rank": 81 }, { "id": "taurine", "name": "Taurine", "aka": "2-aminoethanesulfonic acid", "category": "supplement", "klass": "Amino-acid derivative", "mechanism": "Osmolyte/antioxidant supporting mitochondria, calcium handling and reduced senescence", "hallmarks": [ "Mitochondrial dysfunction", "Cellular senescence", "Chronic inflammation" ], "evidenceType": "animal-other", "evidence": "A 2023 Science paper showed taurine extended mouse lifespan ~10-12% and improved healthspan in mice/monkeys — but a 2025 NIH follow-up found taurine does NOT decline with age in humans/monkeys/mice, undercutting the core premise. No human lifespan RCT.", "keyStudies": [ { "ref": "Singh et al., Science 2023", "finding": "+10-12% mouse median lifespan; healthspan gains", "url": "https://doi.org/10.1126/science.abn9257" }, { "ref": "Fernandez et al., Science 2025", "finding": "Taurine does not decline with age in humans/primates (contests biomarker premise)", "url": "https://doi.org/10.1126/science.adl2116" } ], "effect": "~+10-12% mouse lifespan; human longevity effect unknown", "human": "No human lifespan RCT; 2025 data question the rationale", "safety": "Very safe at gram doses", "dose": "1-6 g/day (RCTs ongoing)", "status": "OTC supplement (GRAS)", "accessibility": "otc", "caveats": "High-profile 2023 result contested by 2025 human/primate data — strong hype-vs-evidence gap", "sources": [ "https://doi.org/10.1126/science.abn9257", "https://doi.org/10.1126/science.adl2116" ], "evi": 46, "hum": 35, "imp": 45, "safe": 88, "overall": 51, "tier": "C", "rank": 82 }, { "id": "panax-ginseng", "name": "Panax Ginseng", "aka": "Korean/Asian ginseng", "category": "botanical", "klass": "Adaptogenic herb (ginsenosides)", "mechanism": "Ginsenoside effects on CNS, anti-fatigue, anti-inflammatory and antioxidant signaling", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication", "Mitochondrial dysfunction" ], "evidenceType": "human-rct-surrogate", "evidence": "Meta-analyses suggest modest benefits for cognition and fatigue, with small trials showing improved memory and reduced stress. Trials are heterogeneous in preparation/dose; outcomes are cognitive/symptom surrogates with no longevity data.", "keyStudies": [ { "ref": "Cognition meta-analysis, Phytother Res 2024", "finding": "Improves aspects of cognitive function vs control", "url": "https://doi.org/10.1002/ptr.8359" } ], "effect": "Modest cognitive and anti-fatigue effects", "human": "Multiple RCTs for cognition/fatigue surrogates; no longevity data", "safety": "Generally safe; insomnia, headache; may lower glucose; warfarin interaction", "dose": "200-400 mg/day standardized extract", "status": "Supplement / traditional medicine", "accessibility": "otc", "caveats": "Heterogeneous preparations and modest effect sizes", "sources": [ "https://doi.org/10.1002/ptr.8359" ], "evi": 50, "hum": 52, "imp": 30, "safe": 72, "overall": 51, "tier": "C", "rank": 83 }, { "id": "protein-methionine-restriction", "name": "Protein / Methionine Restriction", "aka": "Low-protein, methionine restriction", "category": "diet", "klass": "Selective amino-acid restriction", "mechanism": "Lowering protein/methionine downregulates mTORC1 and IGF-1, shifting toward stress resistance and autophagy", "hallmarks": [ "Deregulated nutrient sensing", "Disabled macroautophagy", "Cellular senescence", "Loss of proteostasis" ], "evidenceType": "animal-other", "evidence": "Methionine restriction robustly extends lifespan in rodents/flies. Short human trials lower IGF-1/LDL, and cohorts link high protein in midlife to higher mortality but the OPPOSITE after 65. Strongly age-dependent; no human lifespan RCT.", "keyStudies": [ { "ref": "Levine et al., Cell Metab 2014 (NHANES)", "finding": "High protein at 50-65 linked to higher mortality; reversed after 65", "url": "https://doi.org/10.1016/j.cmet.2014.02.006" } ], "effect": "Animal lifespan +30-40% (methionine restriction); human surrogate/age-stratified signals", "human": "Short metabolic trials + cohorts; no lifespan RCT; age-dependent", "safety": "Risk of sarcopenia/frailty, esp. in elderly; hard to achieve without near-vegan diet", "dose": "Moderate protein (~0.8 g/kg) midlife; plant-forward", "status": "Investigational", "accessibility": "lifestyle", "caveats": "Strongly age-dependent — beneficial midlife but harmful (sarcopenia) in older adults", "sources": [ "https://doi.org/10.1016/j.cmet.2014.02.006" ], "evi": 50, "hum": 45, "imp": 50, "safe": 60, "overall": 51, "tier": "C", "rank": 84 }, { "id": "ketogenic-diet", "name": "Ketogenic Diet", "aka": "Keto, very-low-carb", "category": "diet", "klass": "Very-low-carb high-fat diet", "mechanism": "Carb restriction shifts fuel to ketones (BHB, an HDAC inhibitor/signaling molecule)", "hallmarks": [ "Deregulated nutrient sensing", "Mitochondrial dysfunction", "Chronic inflammation", "Epigenetic alterations" ], "evidenceType": "human-cohort", "evidence": "Longevity evidence is mixed/weak: one NHANES analysis linked a higher ketogenic ratio to ~24% lower mortality, yet other cohorts find animal-based very-low-carb associated with HIGHER mortality, and keto often raises LDL. Mouse cyclic-keto reduced midlife mortality. No long-term human RCT for lifespan.", "keyStudies": [ { "ref": "Newman et al., Cell Metab 2017 (mice)", "finding": "Cyclic keto reduced midlife mortality and improved memory in aging mice", "url": "https://doi.org/10.1016/j.cmet.2017.08.004" }, { "ref": "Roberts et al., Cell Metab 2017 (mice)", "finding": "Continuous keto extended median lifespan and preserved function in adult mice", "url": "https://doi.org/10.1016/j.cmet.2017.08.005" }, { "ref": "Seidelmann et al., Lancet PH 2018", "finding": "U-shaped carb-mortality; animal-based low-carb worse", "url": "https://doi.org/10.1016/S2468-2667(18)30135-X" } ], "effect": "Mixed: one cohort -24% mortality; others higher; LDL often rises", "human": "Conflicting cohort data; no lifespan RCT", "safety": "LDL elevation in many; keto flu, nutrient gaps; fat source matters", "dose": "~20-50 g carb/day, high fat", "status": "Investigational for longevity", "accessibility": "lifestyle", "caveats": "Longevity evidence contradictory; CV safety depends heavily on fat source", "sources": [ "https://doi.org/10.1016/j.cmet.2017.08.004", "https://doi.org/10.1016/j.cmet.2017.08.005", "https://doi.org/10.1016/S2468-2667(18)30135-X" ], "evi": 50, "hum": 52, "imp": 38, "safe": 65, "overall": 51, "tier": "C", "rank": 85 }, { "id": "contrast-therapy", "name": "Contrast Therapy (Hot-Cold)", "aka": "Contrast water therapy", "category": "thermal", "klass": "Alternating thermal hormesis", "mechanism": "Alternating vasodilation/vasoconstriction acts as a vascular pump and modulates autonomic tone", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "Meta-analyses in athletes show contrast therapy reduces muscle soreness/strength loss better than passive rest, but not clearly better than cold-water immersion. Evidence is confined to short-term exercise recovery; no aging/healthspan data.", "keyStudies": [ { "ref": "Bieuzen et al., PLOS ONE 2013", "finding": "Reduced soreness/strength loss vs passive recovery", "url": "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062356" } ], "effect": "Moderate reduction in soreness/strength loss vs rest", "human": "Recovery RCTs only; no longevity evidence", "safety": "Generally safe; combines heat and cold cautions", "dose": "~1 min cold / 1-2 min hot, ~10-15 min total", "status": "Sports-recovery practice", "accessibility": "lifestyle", "caveats": "Benefits limited to acute recovery; no evidence it affects aging biology", "sources": [ "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062356" ], "evi": 46, "hum": 52, "imp": 28, "safe": 80, "overall": 51, "tier": "C", "rank": 86 }, { "id": "msc-therapy", "name": "Mesenchymal Stem Cell Therapy", "aka": "Lomecel-B, laromestrocel, MSCs", "category": "frontier", "klass": "Allogeneic cell therapy", "mechanism": "Infused MSCs act mainly via paracrine/immunomodulatory signaling to reduce inflammation and improve function", "hallmarks": [ "Chronic inflammation", "Stem cell exhaustion", "Altered intercellular communication" ], "evidenceType": "human-rct-surrogate", "evidence": "Longeveron's randomized Phase 2b (n=148, age 70+) for aging frailty did NOT meet its prespecified primary 6-minute-walk endpoint overall, but showed a significant dose-response — higher-dose arms improved 6MWT vs placebo with supportive patient-reported outcomes (Cell Stem Cell 2026). Among the better-controlled aging cell-therapy trials, but on functional surrogates; the wider 'stem cell clinic' market is largely unproven and risky.", "keyStudies": [ { "ref": "Longeveron Phase 2b (Lomecel-B), Cell Stem Cell 2026", "finding": "Primary 6MWT endpoint not met overall; significant dose-response, higher-dose arms improved 6MWT vs placebo", "url": "https://doi.org/10.1016/j.stem.2026.01.017" } ], "effect": "Dose-dependent 6-min-walk improvement (higher-dose arms); primary endpoint not met overall", "human": "One randomized Phase 2b positive on function; no hard-outcome/longevity data", "safety": "Generally well tolerated; infusion reactions; unregulated clinics pose real risks", "dose": "Single IV infusion of allogeneic MSCs", "status": "Investigational (frailty); many illegitimate clinics", "accessibility": "experimental", "caveats": "Primary endpoint missed; benefit limited to higher-dose subgroups on functional surrogates; commercial market largely unproven/risky", "sources": [ "https://doi.org/10.1016/j.stem.2026.01.017" ], "evi": 52, "hum": 50, "imp": 45, "safe": 55, "overall": 51, "tier": "C", "rank": 87 }, { "id": "quercetin", "name": "Quercetin", "aka": "Flavonol (D+Q component)", "category": "senolytic", "klass": "Flavonol polyphenol", "mechanism": "Weak standalone senolytic (potentiated by dasatinib); anti-inflammatory, mild BP/glucose effects", "hallmarks": [ "Cellular senescence", "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "human-rct-surrogate", "evidence": "As a standalone senolytic, quercetin is weak and cell-type-selective; most human senolytic data come from D+Q, not quercetin alone. Standalone RCTs show modest BP/glucose effects; bioavailability is poor.", "keyStudies": [ { "ref": "Zhu et al., Aging Cell 2015", "finding": "Senolytic for senescent endothelial cells but not preadipocytes; D+Q broader", "url": "https://onlinelibrary.wiley.com/doi/10.1111/acel.12344" }, { "ref": "Quercetin BP meta-analysis", "finding": "SBP -3 mmHg at >=500 mg/day", "url": "https://doi.org/10.1161/JAHA.115.002713" } ], "effect": "Modest, cell-type-selective senolysis; small BP/glucose effects", "human": "Limited standalone; mostly studied within D+Q", "safety": "Very safe at supplement doses; CYP3A4/P-gp interactions", "dose": "500-1000 mg/day", "status": "Widely sold supplement", "accessibility": "otc", "caveats": "Poor bioavailability and weak standalone senolytic activity; 'food senolytic' marketing overstated", "sources": [ "https://onlinelibrary.wiley.com/doi/10.1111/acel.12344", "https://doi.org/10.1161/JAHA.115.002713" ], "evi": 45, "hum": 45, "imp": 35, "safe": 80, "overall": 50, "tier": "C", "rank": 88 }, { "id": "ubx1325", "name": "UBX1325 (foselutoclax)", "aka": "Unity Biotechnology senolytic", "category": "senolytic", "klass": "Intravitreal BCL-xL inhibitor", "mechanism": "Inhibits BCL-xL to kill senescent cells in diseased retinal vasculature", "hallmarks": [ "Cellular senescence", "Altered intercellular communication", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "The most advanced senolytic in human trials — but in eye disease, on a surrogate (visual acuity), via local injection. In Phase 2b ASPIRE a single injection MISSED the primary non-inferiority endpoint vs aflibercept at weeks 20/24, reaching non-inferiority (not superiority) only by week 36. Says little about systemic aging.", "keyStudies": [ { "ref": "ASPIRE Phase 2b 2025 (n=52)", "finding": "+5.2 letters at 24wk; missed the primary non-inferiority endpoint at wk20/24, reached non-inferiority by wk36; no intraocular inflammation", "url": "https://clinicaltrials.gov/study/NCT06011798" } ], "effect": "~+5 letters visual-acuity gain; missed primary endpoint (reached non-inferiority, not superiority, to aflibercept by wk36)", "human": "Controlled Phase 2/2b ophthalmology data (local, not systemic)", "safety": "Well tolerated intravitreally", "dose": "Single intravitreal 10 ug injection", "status": "Investigational (DME)", "accessibility": "clinic-only", "caveats": "Strongest human senolytic data but confined to retinal disease and surrogate endpoints", "sources": [ "https://clinicaltrials.gov/study/NCT06011798" ], "evi": 58, "hum": 40, "imp": 35, "safe": 70, "overall": 50, "tier": "C", "rank": 89 }, { "id": "ca-akg", "name": "Calcium Alpha-Ketoglutarate", "aka": "Ca-AKG, Rejuvant", "category": "supplement", "klass": "TCA-cycle metabolite salt", "mechanism": "Co-substrate for dioxygenases (TET/JmjC); modulates epigenetic methylation, mTOR and inflammation", "hallmarks": [ "Epigenetic alterations", "Chronic inflammation", "Deregulated nutrient sensing" ], "evidenceType": "animal-other", "evidence": "Best evidence is animal: in aged mice Ca-AKG extended lifespan ~12% and cut frailty ~46%. Human evidence is weak — the cited 'biological age -8 years' came from a small uncontrolled retrospective pilot; the controlled RCT (ABLE) is unpublished.", "keyStudies": [ { "ref": "Asadi Shahmirzadi et al., Cell Metab 2020", "finding": "Reduced frailty ~46% and extended lifespan (significant in females: median +16.6%; NS in males)", "url": "https://pubmed.ncbi.nlm.nih.gov/32877690/" } ], "effect": "Mouse healthspan/frailty large, lifespan ~12%; human 'age reversal' uncontrolled", "human": "Only a small uncontrolled retrospective pilot", "safety": "Well tolerated; AKG is endogenous", "dose": "~1 g/day sustained-release", "status": "OTC supplement", "accessibility": "otc", "caveats": "Marketed '8 years younger' rests on an uncontrolled n=42 pilot; controlled proof pending", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/32877690/" ], "evi": 44, "hum": 35, "imp": 48, "safe": 82, "overall": 50, "tier": "C", "rank": 90 }, { "id": "thymosin-alpha-1", "name": "Thymosin Alpha-1", "aka": "Ta1, thymalfasin, Zadaxin", "category": "hormone", "klass": "Immunomodulatory peptide", "mechanism": "Modulates T-cell maturation and dendritic/TLR signaling, restoring lymphocyte function", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation" ], "evidenceType": "human-rct-hard", "evidence": "Approved in several countries for hepatitis B/C with a good safety record, but its 'immune rejuvenation' longevity claim is weakly supported: the large Phase-3 TESTS sepsis trial found no overall mortality reduction. No RCT shows it slows aging in healthy adults.", "keyStudies": [ { "ref": "Wu et al., TESTS, BMJ 2025 (n=1,106)", "finding": "28-day all-cause mortality 23.4% vs 24.1% (HR 0.99); no overall sepsis-mortality reduction", "url": "https://pubmed.ncbi.nlm.nih.gov/39814420/" } ], "effect": "Restores T-cell function in immunocompromised states; no proven mortality/anti-aging benefit", "human": "Approved abroad for hepatitis; sepsis/COVID data largely neutral", "safety": "Very well tolerated; injection-site reactions; not FDA-approved in US", "dose": "1.6 mg SC twice weekly (hepatitis regimen)", "status": "Approved abroad; not FDA-approved", "accessibility": "clinic-only", "caveats": "Real immunomodulatory effect, but 'anti-aging' use rests on weak/negative controlled evidence", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/39814420/" ], "evi": 56, "hum": 50, "imp": 30, "safe": 65, "overall": 50, "tier": "C", "rank": 91 }, { "id": "pqq", "name": "PQQ (Pyrroloquinoline Quinone)", "aka": "Methoxatin, BioPQQ", "category": "supplement", "klass": "Redox cofactor (mitochondrial biogenesis)", "mechanism": "Stimulates mitochondrial biogenesis (PGC-1a/CREB) and acts as a redox antioxidant", "hallmarks": [ "Mitochondrial dysfunction", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "One of few compounds shown to stimulate mitochondrial biogenesis in mammals. Small human RCTs report improved fatigue/sleep and raised BDNF/cognition in MCI, but all are small, short and surrogate.", "keyStudies": [ { "ref": "Nakano et al. fatigue RCT", "finding": "20 mg/d x8wk improved fatigue/sleep", "url": "https://doi.org/10.31989/ffhd.v2i8.81" }, { "ref": "MCI RCT 2024", "finding": "Raised serum BDNF, improved some cognitive markers", "url": "https://pubmed.ncbi.nlm.nih.gov/38908296/" } ], "effect": "Modest fatigue/sleep and BDNF/cognitive-biomarker improvements", "human": "Only small short-term RCTs", "safety": "Well tolerated; long-term data limited", "dose": "10-20 mg/day", "status": "OTC supplement (GRAS)", "accessibility": "otc", "caveats": "Tiny, short trials; clinical longevity relevance unproven", "sources": [ "https://doi.org/10.31989/ffhd.v2i8.81", "https://pubmed.ncbi.nlm.nih.gov/38908296/" ], "evi": 42, "hum": 45, "imp": 35, "safe": 80, "overall": 49, "tier": "C", "rank": 92 }, { "id": "resveratrol", "name": "Resveratrol", "aka": "trans-resveratrol", "category": "botanical", "klass": "Stilbenoid polyphenol", "mechanism": "Proposed indirect AMPK/SIRT1 activation; direct sirtuin activation now largely discredited", "hallmarks": [ "Deregulated nutrient sensing", "Mitochondrial dysfunction", "Chronic inflammation" ], "evidenceType": "animal-other", "evidence": "The flagship 'sirtuin activator' story collapsed (the SIRT1 assays were artifacts). It failed to extend lifespan in healthy mice (ITP) and has poor bioavailability; human RCTs are mixed/mostly null. A poster child of hype outrunning evidence.", "keyStudies": [ { "ref": "Strong et al., ITP 2013", "finding": "No lifespan extension in healthy mice", "url": "https://pubmed.ncbi.nlm.nih.gov/22451473/" } ], "effect": "None demonstrated in healthy mammals", "human": "Many RCTs, mostly null; no convincing lifespan/hard-outcome data", "safety": "Generally safe to ~1 g/day; GI upset; CYP inhibition (bleeding risk)", "dose": "150-500 mg/day", "status": "OTC supplement", "accessibility": "otc", "caveats": "Poor bioavailability and debunked sirtuin mechanism; failed translation", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/22451473/" ], "evi": 46, "hum": 45, "imp": 32, "safe": 80, "overall": 49, "tier": "C", "rank": 93 }, { "id": "egcg-green-tea-catechins", "name": "EGCG (Green Tea Catechins)", "aka": "Green tea extract", "category": "botanical", "klass": "Flavan-3-ol polyphenol", "mechanism": "Antioxidant/metabolic signaling (Nrf2, NF-kB, AMPK); iron chelation", "hallmarks": [ "Chronic inflammation", "Genomic instability", "Cellular senescence" ], "evidenceType": "human-rct-surrogate", "evidence": "As concentrated extract, EGCG modestly improves some inflammatory/lipid markers, but the dominant clinical signal is dose-dependent HEPATOTOXICITY above ~800 mg/day. Whole-beverage green tea has far better safety and cohort data (separate entry).", "keyStudies": [ { "ref": "EFSA/COT statement", "finding": "No hepatotoxicity below 800 mg/d EGCG; above that raises liver-injury markers", "url": "https://doi.org/10.2903/j.efsa.2018.5239" } ], "effect": "Small lipid/oxidative improvements", "human": "RCTs on biomarkers; safety, not efficacy, is the defining issue", "safety": "Dose-dependent hepatotoxicity above ~800 mg/d; take with food, avoid fasted", "dose": "<=300-400 mg/d EGCG (beverage-equivalent)", "status": "Supplement (high-dose flagged by EFSA)", "accessibility": "otc", "caveats": "Hepatotoxicity at high doses; pro-oxidant at high concentrations", "sources": [ "https://doi.org/10.2903/j.efsa.2018.5239" ], "evi": 50, "hum": 52, "imp": 35, "safe": 58, "overall": 49, "tier": "C", "rank": 94 }, { "id": "rhodiola-rosea", "name": "Rhodiola Rosea", "aka": "Golden root, arctic root", "category": "botanical", "klass": "Adaptogenic herb", "mechanism": "Monoaminergic modulation; anti-fatigue, antioxidant and redox-balancing effects", "hallmarks": [ "Altered intercellular communication", "Mitochondrial dysfunction", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "Moderate, outcome-specific evidence for fatigue, stress and mild endurance/cognitive benefits; reviews note positive but methodologically limited trials (small, heterogeneous, some industry-funded). Symptom/performance surrogates only.", "keyStudies": [ { "ref": "Fatigue systematic review", "finding": "Positive but methodologically weak/heterogeneous trials", "url": "https://link.springer.com/article/10.1186/1472-6882-12-70" } ], "effect": "Modest reductions in fatigue/stress; small ergogenic effects", "human": "Several small RCTs; quality limited; no longevity data", "safety": "Generally well tolerated; occasional jitteriness/insomnia", "dose": "200-600 mg/day standardized", "status": "Supplement / traditional medicine", "accessibility": "otc", "caveats": "Trials small/heterogeneous; standardization varies widely", "sources": [ "https://link.springer.com/article/10.1186/1472-6882-12-70" ], "evi": 46, "hum": 48, "imp": 28, "safe": 76, "overall": 49, "tier": "C", "rank": 95 }, { "id": "fisetin", "name": "Fisetin", "aka": "Senolytic flavonol", "category": "senolytic", "klass": "Flavonol (senolytic)", "mechanism": "Senolytic flavonoid that clears senescent cells; antioxidant/Nrf2 effects", "hallmarks": [ "Cellular senescence", "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "animal-itp", "evidence": "Strong preclinical credentials but a critical NEGATIVE ITP result: oral fisetin did not extend mouse lifespan in the rigorous NIA program. Human senolytic trials (AFFIRM) are ongoing/unpublished, so there is no positive human efficacy yet — popular hype outruns evidence.", "keyStudies": [ { "ref": "Yousefzadeh et al., EBioMedicine 2018", "finding": "Most potent senolytic flavonoid; extended lifespan in progeroid/aged mice", "url": "https://www.sciencedirect.com/science/article/pii/S2352396418303736" }, { "ref": "NIA ITP 2023", "finding": "Fisetin did NOT extend lifespan in genetically heterogeneous mice", "url": "https://doi.org/10.1007/s11357-023-01011-0" } ], "effect": "Mixed in mice; NULL in the gold-standard ITP", "human": "No published positive human RCT (AFFIRM unpublished)", "safety": "Generally safe, OTC; intermittent high doses in trials; long-term unknown", "dose": "Trials ~20 mg/kg x2 days, intermittent; OTC 100-500 mg/day", "status": "Supplement; investigational senolytic", "accessibility": "otc", "caveats": "The most rigorous animal test (ITP) was NEGATIVE; human efficacy unproven; poor bioavailability", "sources": [ "https://www.sciencedirect.com/science/article/pii/S2352396418303736", "https://doi.org/10.1007/s11357-023-01011-0" ], "evi": 48, "hum": 30, "imp": 50, "safe": 70, "overall": 48, "tier": "C", "rank": 96 }, { "id": "gynostemma-pentaphyllum", "name": "Gynostemma (Jiaogulan)", "aka": "Southern ginseng, Actiponin", "category": "botanical", "klass": "Adaptogenic herb (gypenosides)", "mechanism": "AMPK activation (gypenosides); improves mitochondrial respiration and lipid/glucose metabolism", "hallmarks": [ "Deregulated nutrient sensing", "Mitochondrial dysfunction", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "A plausible AMPK-activating botanical: a small crossover RCT showed increased muscle AMPK phosphorylation and improved mitochondrial function, and an Actiponin RCT showed anti-obesity effects. Trials small/short; no lifespan data.", "keyStudies": [ { "ref": "AMPK RCT 2023 (n=16)", "finding": "Raised post-exercise muscle AMPK and O2 flux; lowered glucose/leptin", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10675532/" } ], "effect": "Modest metabolic/performance and body-fat effects", "human": "A few small RCTs on metabolic surrogates; no longevity data", "safety": "Generally well tolerated short term; mild GI", "dose": "~450 mg/day standardized extract", "status": "Supplement / traditional tea", "accessibility": "otc", "caveats": "Small short trials (key AMPK RCT n=16, healthy untrained males only); variable gypenoside standardization", "sources": [ "https://pmc.ncbi.nlm.nih.gov/articles/PMC10675532/" ], "evi": 44, "hum": 45, "imp": 35, "safe": 72, "overall": 48, "tier": "C", "rank": 97 }, { "id": "gotu-kola-centella", "name": "Gotu Kola (Centella Asiatica)", "aka": "Indian pennywort", "category": "botanical", "klass": "Triterpenoid-saponin herb", "mechanism": "Stimulates collagen synthesis/wound healing; antioxidant; possible neurotrophic effects", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation", "Stem cell exhaustion" ], "evidenceType": "human-rct-surrogate", "evidence": "Strongest human data are for wound healing and venous insufficiency; for cognition the human evidence is weak (a meta-analysis failed to show benefit), with most neuroprotective signals from aged-mouse studies. No human longevity data.", "keyStudies": [ { "ref": "Wound-healing review 2024", "finding": "Accelerates wound closure (diabetic ulcers/burns)", "url": "https://doi.org/10.3390/pharmaceutics16101252" }, { "ref": "Cognition meta-analysis, Sci Rep 2017", "finding": "No clear cognitive benefit in humans", "url": "https://www.nature.com/articles/s41598-017-09823-9" } ], "effect": "Meaningful wound-healing/venous benefit; cognition unproven in humans", "human": "RCTs support wound/venous outcomes; cognitive/longevity benefit not established", "safety": "Generally well tolerated; rare hepatotoxicity/dermatitis", "dose": "60-120 mg/day triterpene fraction", "status": "Supplement / topical", "accessibility": "otc", "caveats": "Cognitive/anti-aging claims rest largely on animal data", "sources": [ "https://doi.org/10.3390/pharmaceutics16101252", "https://www.nature.com/articles/s41598-017-09823-9" ], "evi": 46, "hum": 46, "imp": 28, "safe": 76, "overall": 48, "tier": "C", "rank": 98 }, { "id": "hbot", "name": "Hyperbaric Oxygen Therapy", "aka": "HBOT", "category": "therapy", "klass": "Hyperoxic-hypoxic conditioning", "mechanism": "Intermittent 100% O2 at pressure creates a hyperoxic-hypoxic paradox triggering HIF, angiogenesis and claimed senolysis/telomere effects", "hallmarks": [ "Telomere attrition", "Cellular senescence", "Stem cell exhaustion" ], "evidenceType": "human-rct-surrogate", "evidence": "The Hachmo 2020 trial reported 60 HBOT sessions increased immune-cell telomere length >20% and reduced senescent T-cells, with related Tel Aviv trials reporting cognitive/biological-age changes. These are small (n=35), single-center, uncontrolled surrogate studies; HBOT is approved only for specific indications.", "keyStudies": [ { "ref": "Hachmo et al., Aging 2020 (n=35)", "finding": "B-cell telomeres +37.6%, senescent T-helpers -37.3%", "url": "https://www.aging-us.com/article/202188/text" } ], "effect": "Telomere length +20-38% and senescent-cell reduction (surrogate, single-arm)", "human": "Small trials show biomarker changes; no RCT, no hard outcomes", "safety": "Barotrauma, oxygen-toxicity seizures, reversible myopia; clinic-supervised", "dose": "~60 daily sessions, ~90 min at ~2 ATA", "status": "FDA-approved for specific indications; anti-aging off-label", "accessibility": "clinic-only", "caveats": "Telomere/senescence findings from one small uncontrolled study; needs RCT replication", "sources": [ "https://www.aging-us.com/article/202188/text" ], "evi": 44, "hum": 45, "imp": 50, "safe": 55, "overall": 48, "tier": "C", "rank": 99 }, { "id": "cordyceps", "name": "Cordyceps", "aka": "Cordyceps militaris/sinensis, Cs-4", "category": "botanical", "klass": "Medicinal fungus (cordycepin)", "mechanism": "Proposed improved oxygen utilization and mitochondrial ATP; cordycepin may activate AMPK", "hallmarks": [ "Mitochondrial dysfunction", "Deregulated nutrient sensing", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "Small RCTs suggest modest aerobic/exercise benefits (raised VO2max, time-to-exhaustion), often with multi-ingredient blends and short follow-up. Performance surrogates only; no longevity data.", "keyStudies": [ { "ref": "Ergogenic review 2024 (5 trials)", "finding": "Mushroom-blend VO2max +4.8 mL/kg/min after 3 weeks", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12986667/" } ], "effect": "Modest VO2max/endurance improvements with chronic dosing", "human": "A few small (often multi-ingredient) RCTs; no longevity data", "safety": "Generally well tolerated; contamination risk in wild product", "dose": "~1-3 g/day", "status": "Supplement / traditional medicine", "accessibility": "otc", "caveats": "Most positive trials used multi-ingredient blends; species/quality vary", "sources": [ "https://pmc.ncbi.nlm.nih.gov/articles/PMC12986667/" ], "evi": 42, "hum": 44, "imp": 32, "safe": 74, "overall": 47, "tier": "C", "rank": 100 }, { "id": "reishi-ganoderma", "name": "Reishi (Ganoderma Lucidum)", "aka": "Lingzhi", "category": "botanical", "klass": "Medicinal mushroom (beta-glucans)", "mechanism": "Immunomodulation via beta-glucans (dectin-1/TLR-2); triterpene anti-inflammatory effects", "hallmarks": [ "Chronic inflammation", "Altered intercellular communication", "Cellular senescence" ], "evidenceType": "human-rct-surrogate", "evidence": "A Cochrane review concluded reishi should not be first-line cancer treatment but may have an adjunct immune role; a healthy-volunteer RCT showed increased T-cell subsets and NK activity. Limited, immune-surrogate data, often low-quality; no survival/longevity data.", "keyStudies": [ { "ref": "Jin et al., Cochrane 2016", "finding": "Insufficient for first-line cancer use; possible immune adjunct", "url": "https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007731.pub3/full" } ], "effect": "Measurable immune-marker shifts; clinical benefit unproven", "human": "Limited RCTs on immune surrogates; no longevity data", "safety": "Generally well tolerated; antiplatelet interaction; rare hepatotoxicity", "dose": "~1.5-6 g/day extract", "status": "Supplement / traditional medicine", "accessibility": "otc", "caveats": "Product quality highly inconsistent; evidence base small/low-quality", "sources": [ "https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007731.pub3/full" ], "evi": 42, "hum": 44, "imp": 30, "safe": 72, "overall": 46, "tier": "C", "rank": 101 }, { "id": "ghk-cu", "name": "GHK-Cu", "aka": "Copper tripeptide-1", "category": "hormone", "klass": "Copper-binding tripeptide", "mechanism": "Plasma tripeptide (age-declining) that modulates wound-healing, antioxidant and tissue-remodeling genes", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation", "Stem cell exhaustion" ], "evidenceType": "human-rct-surrogate", "evidence": "A naturally occurring human-plasma tripeptide that stimulates collagen and skin repair. Credible human evidence is dermatologic/topical (improved post-laser healing, skin appearance); no human data support injectable/systemic GHK-Cu for lifespan, and copper dosing carries toxicity concerns.", "keyStudies": [ { "ref": "Pickart & Margolina, IJMS 2018", "finding": "Shifts gene expression toward tissue repair/antioxidant programs", "url": "https://doi.org/10.3390/ijms19071987" } ], "effect": "Real topical skin/wound-healing benefits; no systemic longevity evidence", "human": "Human evidence limited to topical/dermatologic use", "safety": "Topical generally tolerated; systemic/injectable risks copper accumulation; gray-market purity unverified", "dose": "Topical ~1-2 mg/mL (skincare)", "status": "OTC cosmetic ingredient; injectable unapproved", "accessibility": "otc", "caveats": "Genuine topical benefits do not translate to systemic anti-aging evidence; injectable use experimental", "sources": [ "https://doi.org/10.3390/ijms19071987" ], "evi": 48, "hum": 48, "imp": 28, "safe": 60, "overall": 46, "tier": "C", "rank": 102 }, { "id": "astragalus-cycloastragenol-ta65", "name": "Astragalus / Cycloastragenol / TA-65", "aka": "TA-65, telomerase activator", "category": "botanical", "klass": "Triterpenoid saponin", "mechanism": "Claimed transient telomerase (TERT) activation to slow telomere attrition", "hallmarks": [ "Telomere attrition", "Cellular senescence", "Chronic inflammation" ], "evidenceType": "human-rct-surrogate", "evidence": "The canonical 'plausible mechanism vs commercial hype' case: small sponsor-linked RCTs report telomere lengthening and fewer senescent T cells, but telomere length is a contested surrogate, products are costly, and telomerase reactivation carries a theoretical oncogenic concern.", "keyStudies": [ { "ref": "Salvador et al., Rejuv Res 2016 (n=117)", "finding": "TA-65 increased telomere length vs placebo loss", "url": "https://pubmed.ncbi.nlm.nih.gov/26950204/" } ], "effect": "Measurable telomere lengthening of uncertain clinical meaning", "human": "Small (often sponsor-linked) RCTs on surrogates; no hard outcomes", "safety": "No serious AEs in <=12-mo trials, but long-term cancer risk theoretically plausible", "dose": "TA-65 250-1000 'units'/day", "status": "Costly proprietary supplement", "accessibility": "otc", "caveats": "Surrogate-only endpoints, small sponsor trials, high cost, theoretical oncogenic risk", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/26950204/" ], "evi": 44, "hum": 42, "imp": 35, "safe": 60, "overall": 45, "tier": "C", "rank": 103 }, { "id": "low-dose-lithium", "name": "Low-dose Lithium", "aka": "Lithium orotate, trace lithium", "category": "pharma", "klass": "GSK-3b inhibitor / trace element", "mechanism": "Inhibits GSK-3b, enhances autophagy and neurotrophic signaling; trace lithium may be a micronutrient", "hallmarks": [ "Disabled macroautophagy", "Loss of proteostasis", "Chronic inflammation" ], "evidenceType": "animal-other", "evidence": "A patchwork: trace lithium in drinking water inversely correlates with mortality in a large Japanese cohort, it extends lifespan in worms/flies, and a major 2025 Nature study showed brain lithium depletion in Alzheimer's with lithium orotate reversing pathology in mice. Human longevity data are ecological only.", "keyStudies": [ { "ref": "Zarse et al., Eur J Nutr 2011", "finding": "Higher tap-water lithium associated with lower mortality; extends worm lifespan", "url": "https://doi.org/10.1007/s00394-011-0171-x" }, { "ref": "Aron et al., Nature 2025", "finding": "Lithium depleted in Alzheimer's brains; lithium orotate reversed pathology in mice", "url": "https://doi.org/10.1038/s41586-025-09335-x" } ], "effect": "Worm/fly lifespan extension; human ecological mortality association", "human": "Ecological/observational only; no longevity RCT", "safety": "Therapeutic doses risk thyroid/kidney toxicity (narrow window); microdose/orotate appear safer but unproven", "dose": "~1-5 mg elemental/day (microdose interest)", "status": "FDA-approved (bipolar); orotate OTC; experimental", "accessibility": "otc", "caveats": "Human longevity evidence ecological/confounded; 2025 Alzheimer's findings preclinical", "sources": [ "https://doi.org/10.1007/s00394-011-0171-x", "https://doi.org/10.1038/s41586-025-09335-x" ], "evi": 42, "hum": 35, "imp": 45, "safe": 60, "overall": 44, "tier": "C", "rank": 104 }, { "id": "thymus-regeneration", "name": "Thymus Regeneration (TRIIM)", "aka": "Thymic rejuvenation", "category": "frontier", "klass": "Immune rejuvenation", "mechanism": "Growth hormone (with metformin/DHEA) regrows thymic tissue to restore naive T-cell output", "hallmarks": [ "Stem cell exhaustion", "Epigenetic alterations", "Chronic inflammation" ], "evidenceType": "human-other", "evidence": "The TRIIM pilot (n=9 men) reported thymic regeneration on MRI and ~1.5-2.5 year epigenetic age reversal — but it was very small, uncontrolled and used a confounded multi-drug regimen with GH's known risks. The expanded TRIIM-X trial is ongoing.", "keyStudies": [ { "ref": "Fahy et al., Aging Cell 2019 (TRIIM)", "finding": "n=9: thymic regrowth, ~2.5y epigenetic age reversal (uncontrolled)", "url": "https://onlinelibrary.wiley.com/doi/10.1111/acel.13028" } ], "effect": "~1.5-2.5y epigenetic age reduction (tiny, uncontrolled pilot)", "human": "One small uncontrolled pilot; TRIIM-X ongoing", "safety": "GH risks: insulin resistance, oedema, carpal tunnel, theoretical cancer risk", "dose": "GH + DHEA + metformin, ~1 year", "status": "Experimental", "accessibility": "experimental", "caveats": "n=9, no control, multi-drug confound; needs controlled replication", "sources": [ "https://onlinelibrary.wiley.com/doi/10.1111/acel.13028" ], "evi": 40, "hum": 38, "imp": 55, "safe": 45, "overall": 44, "tier": "C", "rank": 105 }, { "id": "growth-hormone", "name": "Growth Hormone (HGH)", "aka": "Somatropin, rhGH", "category": "hormone", "klass": "GH-IGF-1 axis agonist", "mechanism": "Activates GH receptor and raises IGF-1; anabolic but drives pro-growth, pro-aging nutrient-sensing signaling", "hallmarks": [ "Deregulated nutrient sensing", "Stem cell exhaustion", "Genomic instability" ], "evidenceType": "human-rct-surrogate", "evidence": "A cautionary tale: GH raises lean mass (Rudman 1990) but later RCTs found high rates of oedema, arthralgia, carpal tunnel and insulin resistance with NO functional benefit. The longevity literature points the OTHER way — low IGF-1 predicts human longevity, and GH excess (acromegaly) shortens lifespan. Supraphysiologic GH for anti-aging is biologically backwards.", "keyStudies": [ { "ref": "Rudman et al., NEJM 1990", "finding": "+8.8% lean mass but later shown lacking functional benefit, with harms", "url": "https://doi.org/10.1056/NEJM199007053230101" }, { "ref": "Milman et al., Aging Cell 2014", "finding": "Low IGF-1 predicts longer survival", "url": "https://pubmed.ncbi.nlm.nih.gov/24618355/" } ], "effect": "Surrogate body-composition change with harms; mechanistically pro-aging", "human": "RCTs show surrogate change with harms; observational data favor LOW GH/IGF-1", "safety": "Oedema, arthralgia, carpal tunnel, insulin resistance/diabetes; cancer concern; illegal for anti-aging in US", "dose": "Not endorsed; approved only for GH deficiency", "status": "FDA-approved (GH deficiency); anti-aging use illegal in US", "accessibility": "rx", "caveats": "One of the clearest cautionary tales: surrogate gains, real harms, mechanism opposing longevity", "sources": [ "https://doi.org/10.1056/NEJM199007053230101", "https://pubmed.ncbi.nlm.nih.gov/24618355/" ], "evi": 60, "hum": 55, "imp": 15, "safe": 38, "overall": 44, "tier": "C", "rank": 106 }, { "id": "17-alpha-estradiol", "name": "17a-Estradiol", "aka": "17a-E2, alfatradiol", "category": "pharma", "klass": "Non-feminizing estrogen", "mechanism": "Non-feminizing estrogen improving insulin sensitivity and reducing hypothalamic inflammation; effect depends on testicular hormones", "hallmarks": [ "Deregulated nutrient sensing", "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "animal-itp", "evidence": "A reproducible male-specific ITP geroprotector that extends male (not female) mouse lifespan even when started in mid-late life, via improved metabolic health. No human trials at all.", "keyStudies": [ { "ref": "Strong et al., Aging Cell 2016 (ITP)", "finding": "+19% male median lifespan (across-site range ~9-26%); no female effect", "url": "https://doi.org/10.1111/acel.12496" }, { "ref": "Garratt et al., Aging Cell 2018", "finding": "Benefit abolished by castration — depends on male hormones", "url": "https://doi.org/10.1111/acel.12786" } ], "effect": "+19% male median lifespan (mice; ITP site range ~9-26%)", "human": "No human longevity data", "safety": "Largely non-feminizing but reduces male fertility signaling in mice; human systemic safety unknown", "dose": "No human protocol", "status": "Not FDA-approved (systemic); experimental", "accessibility": "experimental", "caveats": "Male-only, mechanism tied to male hormones; no human data; not the same as conventional 17b-estradiol", "sources": [ "https://doi.org/10.1111/acel.12496", "https://doi.org/10.1111/acel.12786" ], "evi": 60, "hum": 12, "imp": 55, "safe": 50, "overall": 43, "tier": "D", "rank": 107 }, { "id": "pterostilbene", "name": "Pterostilbene", "aka": "Methylated resveratrol analog", "category": "botanical", "klass": "Dimethylated stilbenoid", "mechanism": "Better-absorbed resveratrol analog; proposed AMPK/SIRT and antioxidant signaling", "hallmarks": [ "Deregulated nutrient sensing", "Chronic inflammation", "Mitochondrial dysfunction" ], "evidenceType": "human-rct-surrogate", "evidence": "Pharmacokinetically superior to resveratrol, but human RCT data are thin and the key clinical finding is a SAFETY concern: monotherapy raised LDL cholesterol (~17 mg/dL), prompting a major supplier to halt orders.", "keyStudies": [ { "ref": "Riche et al., 2014 RCT", "finding": "Lowered BP but raised LDL ~17 mg/dL", "url": "https://pubmed.ncbi.nlm.nih.gov/25057276/" } ], "effect": "Modest BP reduction; clinically meaningful LDL increase", "human": "Few RCTs; main robust finding is an adverse LDL signal", "safety": "Raises LDL cholesterol; long-term CV implications unclear", "dose": "50-250 mg/day", "status": "OTC supplement", "accessibility": "otc", "caveats": "LDL-raising effect is the standout caveat; longevity benefit unproven", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/25057276/" ], "evi": 40, "hum": 40, "imp": 30, "safe": 65, "overall": 43, "tier": "D", "rank": 108 }, { "id": "partial-reprogramming-osk", "name": "Partial Cellular Reprogramming", "aka": "OSK / Yamanaka-factor rejuvenation", "category": "frontier", "klass": "Epigenetic reprogramming gene therapy", "mechanism": "Transient expression of reprogramming factors (OSK) resets the epigenetic age of cells without erasing identity", "hallmarks": [ "Epigenetic alterations", "Genomic instability", "Stem cell exhaustion" ], "evidenceType": "animal-other", "evidence": "The most exciting frontier idea: in mice, partial reprogramming restored vision after optic-nerve injury and AAV-delivered OSK extended remaining lifespan ~109% in very old mice. Human work just began — Life Biosciences' ER-100 (eye) dosed its first patient in June 2026 — so systemic-aging benefit is unproven and cancer risk is the central concern.", "keyStudies": [ { "ref": "Lu/Sinclair et al., Nature 2020", "finding": "OSK restored vision and reversed epigenetic age in mice", "url": "https://www.nature.com/articles/s41586-020-2975-4" }, { "ref": "Rejuvenate Bio, Cell Reprogram 2024", "finding": "AAV-OSK extended remaining lifespan ~109% in old mice", "url": "https://doi.org/10.1089/cell.2023.0072" } ], "effect": "Mouse: large lifespan/function effects; no human efficacy data", "human": "First human dosing (eye, Phase 1) 2026; no lifespan/healthspan evidence", "safety": "Major theoretical risk of teratoma/cancer; only entering human safety testing", "dose": "Experimental (gene-therapy delivery)", "status": "Preclinical for systemic aging; first localized human trial 2026", "accessibility": "experimental", "caveats": "Spectacular mouse results but human evidence is first-in-human and eye-localized; systemic safety unresolved", "sources": [ "https://www.nature.com/articles/s41586-020-2975-4", "https://doi.org/10.1089/cell.2023.0072" ], "evi": 38, "hum": 12, "imp": 92, "safe": 28, "overall": 41, "tier": "D", "rank": 109 }, { "id": "oxytocin", "name": "Oxytocin", "aka": "'Love hormone'", "category": "hormone", "klass": "Nonapeptide hormone", "mechanism": "Hypothalamic hormone that (beyond social roles) supports muscle stem-cell activation and tissue regeneration; declines with age", "hallmarks": [ "Stem cell exhaustion", "Altered intercellular communication", "Chronic inflammation" ], "evidenceType": "animal-other", "evidence": "An established human hormone with a regenerative role: in mice it is required for muscle maintenance and an oxytocin + TGF-b-inhibitor combination extended lifespan in old frail males. Human longevity data are minimal (a small intranasal study raised lean mass); no lifespan RCT.", "keyStudies": [ { "ref": "Elabd et al., Nat Commun 2014", "finding": "Restored aged muscle stem-cell activation in mice", "url": "https://doi.org/10.1038/ncomms5082" } ], "effect": "Muscle-regenerative/anti-frailty effects in mice; small human lean-mass signal", "human": "Long clinical-use safety record; anti-aging evidence preliminary/small", "safety": "Intranasal/low-dose generally tolerated; high-dose IV can cause hyponatraemia", "dose": "Intranasal ~24 IU (research)", "status": "Approved (obstetric/lactation); anti-aging off-label", "accessibility": "rx", "caveats": "Intriguing regenerative biology, but anti-aging benefit rests on one small study plus mouse data", "sources": [ "https://doi.org/10.1038/ncomms5082" ], "evi": 36, "hum": 30, "imp": 45, "safe": 60, "overall": 41, "tier": "D", "rank": 110 }, { "id": "apigenin", "name": "Apigenin", "aka": "Parsley/chamomile flavone (CD38 inhibitor)", "category": "nad", "klass": "Flavone (CD38 inhibitor)", "mechanism": "Inhibits CD38, the main NAD+-consuming enzyme, indirectly preserving NAD+", "hallmarks": [ "Deregulated nutrient sensing", "Mitochondrial dysfunction", "Chronic inflammation" ], "evidenceType": "animal-other", "evidence": "A credible natural CD38 inhibitor that raises NAD+ and improves metabolic markers in rodents, but essentially no human trial measures NAD+ change with oral apigenin; the cited 'biological age' drop came from a multi-ingredient protocol. Poor oral bioavailability.", "keyStudies": [ { "ref": "Escande et al., Diabetes 2013", "finding": "Potent natural CD38 inhibitor; raised NAD+ in obese mice", "url": "https://doi.org/10.2337/db12-1139" } ], "effect": "Raises NAD+/metabolic markers in rodents; isolated human effect unquantified", "human": "No standalone human NAD+/aging RCT", "safety": "Generally safe dietary flavone; CYP interactions unclear", "dose": "~50 mg/day (no evidence-based dose)", "status": "Supplement", "accessibility": "otc", "caveats": "Human NAD+ evidence for isolated apigenin essentially absent; popular on mechanistic grounds", "sources": [ "https://doi.org/10.2337/db12-1139" ], "evi": 36, "hum": 18, "imp": 35, "safe": 75, "overall": 39, "tier": "D", "rank": 111 }, { "id": "thymalin", "name": "Thymalin", "aka": "Thymic peptide bioregulator (Khavinson)", "category": "hormone", "klass": "Thymic peptide complex", "mechanism": "Proposed to restore thymic/T-cell function and immune homeostasis ('peptide bioregulation')", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation", "Stem cell exhaustion" ], "evidenceType": "human-other", "evidence": "Best known from Khavinson's Russian gerontology program reporting a ~2-fold mortality reduction in the elderly — but this is single-institute, open-label, non-blinded and never independently replicated in the West, so the dramatic figures are provocative but unverified.", "keyStudies": [ { "ref": "Khavinson & Morozov, Neuro Endocrinol Lett 2003", "finding": "Reported ~2x mortality reduction (open-label, single-center)", "url": "https://pubmed.ncbi.nlm.nih.gov/14523363/" } ], "effect": "Reported large mortality reductions in one program; not credible without replication", "human": "Single-institute open-label data only; no Western RCT; LOW quality", "safety": "Reported well tolerated; gray-market product purity unverified", "dose": "10 mg IM daily for 5-10 days, repeated", "status": "Used in Russia; not FDA-approved", "accessibility": "experimental", "caveats": "Headline mortality reductions rest entirely on unreplicated, non-blinded single-center data", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/14523363/" ], "evi": 34, "hum": 30, "imp": 45, "safe": 50, "overall": 39, "tier": "D", "rank": 112 }, { "id": "pregnenolone", "name": "Pregnenolone", "aka": "P5, neurosteroid precursor", "category": "hormone", "klass": "Neurosteroid / steroid precursor", "mechanism": "Upstream precursor to all steroid hormones; neurosteroid modulating NMDA/GABA-A receptors", "hallmarks": [ "Altered intercellular communication" ], "evidenceType": "human-rct-surrogate", "evidence": "The upstream precursor of DHEA and sex steroids; levels decline with age, fueling supplement marketing. A proof-of-concept RCT in schizophrenia (Marx 2009) found pregnenolone reduced negative symptoms with some cognitive correlation, but there is no evidence of cognitive or healthspan benefit in healthy older adults, where controlled trials are scarce.", "keyStudies": [ { "ref": "Marx et al., Neuropsychopharmacology 2009", "finding": "Reduced negative symptoms in schizophrenia with cognitive correlation (disease population, not healthy aging)", "url": "https://doi.org/10.1038/npp.2009.26" } ], "effect": "Memory effects in aged rodents; no demonstrated human cognitive/longevity benefit", "human": "Sparse, largely negative RCTs; no longevity data", "safety": "Limited safety data; unpredictable conversion to androgens/estrogens/cortisol", "dose": "5-50 mg/day (supplement)", "status": "OTC supplement; not approved for any indication", "accessibility": "otc", "caveats": "Marketed on animal data/mechanism; human evidence thin and mostly null", "sources": [ "https://doi.org/10.1038/npp.2009.26" ], "evi": 38, "hum": 35, "imp": 25, "safe": 60, "overall": 39, "tier": "D", "rank": 113 }, { "id": "procyanidin-c1", "name": "Procyanidin C1 (PCC1)", "aka": "Grape-seed trimer", "category": "senolytic", "klass": "Proanthocyanidin", "mechanism": "Suppresses SASP at low dose; senolytic at higher dose via ROS/mitochondrial stress", "hallmarks": [ "Cellular senescence", "Altered intercellular communication", "Mitochondrial dysfunction" ], "evidenceType": "animal-other", "evidence": "A 2021 Nature Metabolism study reported strong single-lab mouse data — fortnightly dosing in very old mice extended remaining median lifespan ~64%. Not yet ITP-validated or tested in humans, and bioavailability of this large polyphenol is uncertain.", "keyStudies": [ { "ref": "Xu et al., Nat Metabolism 2021", "finding": "Biweekly PCC1 in old mice extended remaining median lifespan ~64%", "url": "https://www.nature.com/articles/s42255-021-00491-8" } ], "effect": "Large effect on remaining lifespan in one mouse study; no human data", "human": "None", "safety": "Grape-seed proanthocyanidins generally safe as foods; isolated PCC1 not characterized", "dose": "No human protocol", "status": "Experimental; grape-seed extracts OTC", "accessibility": "experimental", "caveats": "Single-lab mouse result now under a 2026 Editorial Expression of Concern (image-reuse, raw data unavailable); not ITP-validated or human-tested; OTC extracts aren't purified PCC1", "sources": [ "https://www.nature.com/articles/s42255-021-00491-8" ], "evi": 36, "hum": 12, "imp": 55, "safe": 60, "overall": 38, "tier": "D", "rank": 114 }, { "id": "nadh", "name": "NADH Supplement", "aka": "Coenzyme 1, ENADA", "category": "nad", "klass": "Reduced NAD coenzyme (oral)", "mechanism": "Supplies reduced NADH to support mitochondrial ATP; oral stability/absorption limited", "hallmarks": [ "Mitochondrial dysfunction", "Deregulated nutrient sensing" ], "evidenceType": "human-rct-surrogate", "evidence": "Older, small, low-quality RCTs in chronic fatigue and open-label Parkinson's work with weak, inconsistent results; largely outside the modern NAD+ mainstream and of doubtful oral bioavailability.", "keyStudies": [ { "ref": "Forsyth et al., 1999", "finding": "Small CFS crossover suggested symptomatic benefit (preliminary)", "url": "https://pubmed.ncbi.nlm.nih.gov/10071523/" } ], "effect": "Weak/inconsistent symptomatic signals; no aging data", "human": "A few small, mostly old, low-quality studies", "safety": "Well tolerated; mild headache/GI", "dose": "5-20 mg/day", "status": "Supplement", "accessibility": "otc", "caveats": "Dated, low-quality evidence and questionable oral bioavailability", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/10071523/" ], "evi": 32, "hum": 30, "imp": 28, "safe": 70, "overall": 38, "tier": "D", "rank": 115 }, { "id": "klotho-therapy", "name": "Klotho Gene/Protein Therapy", "aka": "s-klotho, recombinant klotho", "category": "frontier", "klass": "Longevity-protein/gene therapy", "mechanism": "Restoring the age-declining longevity protein klotho enhances synaptic plasticity and resilience", "hallmarks": [ "Altered intercellular communication", "Stem cell exhaustion", "Chronic inflammation" ], "evidenceType": "animal-other", "evidence": "A genuine circulating longevity protein: overexpression extends mouse lifespan, and a 2023 study showed a single low-dose injection improved memory in aged rhesus macaques. Supported by human genetics (KL-VS carriers), but no completed human therapeutic trials; the low-dose-only response complicates translation.", "keyStudies": [ { "ref": "Castner et al., Nature Aging 2023", "finding": "Single low-dose klotho enhanced memory in aged macaques", "url": "https://www.nature.com/articles/s43587-023-00441-x" }, { "ref": "Kurosu et al., Science 2005", "finding": "Klotho overexpression extends mouse lifespan", "url": "https://pubmed.ncbi.nlm.nih.gov/16123266/" } ], "effect": "Mouse lifespan + primate cognition; human effect of administration untested", "human": "Biomarker/genetic associations; no completed interventional trials", "safety": "No human safety dataset; affects phosphate/FGF23 axis; non-linear dose-response", "dose": "Experimental (single low dose in primates)", "status": "Preclinical; early development", "accessibility": "experimental", "caveats": "Strong animal/genetic case but unproven and untested as a human therapy; hormetic dosing adds uncertainty", "sources": [ "https://www.nature.com/articles/s43587-023-00441-x", "https://pubmed.ncbi.nlm.nih.gov/16123266/" ], "evi": 38, "hum": 18, "imp": 60, "safe": 40, "overall": 38, "tier": "D", "rank": 116 }, { "id": "heterochronic-fmt", "name": "Fecal Microbiota Transplant (Heterochronic)", "aka": "Young-donor microbiota transfer", "category": "frontier", "klass": "Microbiome transfer therapy", "mechanism": "Transferring young/healthy gut microbiota aims to reverse age-related dysbiosis and reduce systemic inflammation", "hallmarks": [ "Dysbiosis", "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "animal-other", "evidence": "In mice, young-to-aged FMT reverses gut/eye/brain aging hallmarks and improves cognition. Human aging evidence is essentially absent (FMT is approved only for recurrent C. difficile); applying it for longevity is preclinical, with documented infection risks.", "keyStudies": [ { "ref": "Parker et al., Microbiome 2022", "finding": "Young-to-aged FMT reversed gut/brain aging markers in mice", "url": "https://doi.org/10.1186/s40168-022-01243-w" } ], "effect": "Mouse: reversal of gut/brain aging markers; no human aging effect shown", "human": "FMT proven for C. difficile only; no controlled aging data", "safety": "Infection transmission risk (incl. fatal cases); requires rigorous donor screening", "dose": "Experimental for aging", "status": "Approved only for recurrent C. difficile", "accessibility": "experimental", "caveats": "Striking mouse rejuvenation but no human aging evidence; real infection risk", "sources": [ "https://doi.org/10.1186/s40168-022-01243-w" ], "evi": 34, "hum": 25, "imp": 50, "safe": 50, "overall": 38, "tier": "D", "rank": 117 }, { "id": "rilmenidine", "name": "Rilmenidine", "aka": "Albarel, Hyperium", "category": "pharma", "klass": "I1-imidazoline agonist (antihypertensive)", "mechanism": "Engages nischarin/I1-imidazoline receptor, mimicking caloric restriction and inducing autophagy", "hallmarks": [ "Deregulated nutrient sensing", "Disabled macroautophagy", "Loss of proteostasis" ], "evidenceType": "animal-other", "evidence": "An emerging CR-mimetic that extends lifespan/healthspan in C. elegans (even started late) and produces CR-like transcriptional changes in mouse liver/kidney. No mammalian lifespan study and no human longevity data; it is a well-tolerated antihypertensive.", "keyStudies": [ { "ref": "Bennett et al., Aging Cell 2023", "finding": "Extended worm lifespan via nischarin/autophagy; CR-like mouse transcriptome", "url": "https://doi.org/10.1111/acel.13774" } ], "effect": "Lifespan extension in C. elegans; CR-like mouse signatures", "human": "No human longevity data", "safety": "Well tolerated as antihypertensive; longevity-use safety unknown", "dose": "1 mg/day (antihypertensive)", "status": "Approved antihypertensive (EU/Asia); experimental", "accessibility": "experimental", "caveats": "Evidence is worm lifespan + mouse surrogates only; no mammalian lifespan data", "sources": [ "https://doi.org/10.1111/acel.13774" ], "evi": 38, "hum": 12, "imp": 45, "safe": 60, "overall": 37, "tier": "D", "rank": 118 }, { "id": "humanin", "name": "Humanin", "aka": "MT-RNR2-derived peptide", "category": "hormone", "klass": "Mitochondrial-derived peptide", "mechanism": "Cytoprotective peptide modulating apoptosis, IGF-1/IGFBP signaling and metabolic stress responses", "hallmarks": [ "Mitochondrial dysfunction", "Altered intercellular communication", "Deregulated nutrient sensing" ], "evidenceType": "human-cohort", "evidence": "A longevity-associated biomarker: circulating levels generally decline with age but are higher in centenarians and their offspring. Causal data are preclinical (overexpression extends C. elegans lifespan); no human interventional trials and no evidence that giving humanin extends human healthspan.", "keyStudies": [ { "ref": "Yen et al., Aging 2020", "finding": "Centenarians have higher humanin; overexpression extends worm lifespan", "url": "https://www.aging-us.com/article/103534/text" } ], "effect": "Higher endogenous levels associate with longevity; exogenous benefit unproven", "human": "Observational/biomarker data only; no interventional trials", "safety": "No human dosing/safety dataset", "dose": "No validated human dose", "status": "Research compound; not approved", "accessibility": "experimental", "caveats": "Compelling longevity-associated biomarker, but therapeutic value in humans unestablished", "sources": [ "https://www.aging-us.com/article/103534/text" ], "evi": 38, "hum": 25, "imp": 45, "safe": 45, "overall": 37, "tier": "D", "rank": 119 }, { "id": "navitoclax", "name": "Navitoclax (ABT-263)", "aka": "ABT-263", "category": "senolytic", "klass": "BCL-2/BCL-xL inhibitor", "mechanism": "BH3-mimetic that triggers apoptosis of senescent cells via BCL-2 family inhibition", "hallmarks": [ "Cellular senescence", "Chronic inflammation", "Stem cell exhaustion" ], "evidenceType": "animal-other", "evidence": "A potent senolytic in mice (rejuvenates aged stem cells, aids wound healing), but development for aging is blocked by on-target toxicity — BCL-xL inhibition kills platelets, causing severe thrombocytopenia. Studied clinically only in oncology.", "keyStudies": [ { "ref": "Chang et al., Nat Med 2016", "finding": "Selectively killed senescent cells, rejuvenated aged stem cells in mice", "url": "https://doi.org/10.1038/nm.4010" } ], "effect": "Strong senolytic in mice; no anti-aging human data", "human": "Oncology only; toxicity precludes longevity use", "safety": "Dose-limiting thrombocytopenia, neutropenia, bone loss", "dose": "Oncology dosing only", "status": "Investigational oncology agent", "accessibility": "experimental", "caveats": "On-target platelet toxicity makes systemic anti-aging use impractical", "sources": [ "https://doi.org/10.1038/nm.4010" ], "evi": 44, "hum": 15, "imp": 55, "safe": 32, "overall": 36, "tier": "D", "rank": 120 }, { "id": "young-plasma-transfusion", "name": "Young Plasma Transfusion", "aka": "Young blood, heterochronic plasma", "category": "therapy", "klass": "Heterochronic blood-factor transfer", "mechanism": "Infusing young-donor plasma aims to deliver pro-youthful circulating factors (parabiosis-inspired)", "hallmarks": [ "Altered intercellular communication", "Stem cell exhaustion", "Chronic inflammation" ], "evidenceType": "animal-other", "evidence": "Heterochronic parabiosis rejuvenates tissues in mice, but human evidence is weak: the Ambrosia trial was uncontrolled and pay-to-participate, drawing an FDA warning. Many researchers think DILUTION (removing old factors) explains the effect better than adding young factors.", "keyStudies": [ { "ref": "Conboy et al., Nature 2005", "finding": "Parabiosis rejuvenates aged stem-cell function in mice", "url": "https://pubmed.ncbi.nlm.nih.gov/15716955/" }, { "ref": "FDA 2019", "finding": "Warned against young-plasma anti-aging infusions", "url": "https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-director-fdas-center-biologics-evaluation-and-0" } ], "effect": "Robust rejuvenation in mice; no demonstrated human healthspan effect", "human": "Minimal, largely uncontrolled; FDA-flagged", "safety": "Transfusion risks (allergic reactions, TRALI, infection, overload); FDA cautioned against commercial use", "dose": "No validated protocol", "status": "Not approved for aging; FDA warning", "accessibility": "experimental", "caveats": "Human benefit unproven and possibly attributable to dilution; commercial offerings unregulated", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/15716955/", "https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-director-fdas-center-biologics-evaluation-and-0" ], "evi": 36, "hum": 20, "imp": 50, "safe": 45, "overall": 36, "tier": "D", "rank": 121 }, { "id": "telomerase-gene-therapy", "name": "Telomerase Gene Therapy (TERT)", "aka": "AAV-telomerase", "category": "frontier", "klass": "Telomere-extending gene therapy", "mechanism": "AAV delivery of telomerase (TERT) re-extends telomeres, delaying replicative senescence", "hallmarks": [ "Telomere attrition", "Cellular senescence", "Genomic instability" ], "evidenceType": "animal-other", "evidence": "The Blasco-lab study showed AAV9-Tert in adult/old mice extended median lifespan 24%/13% without increasing cancer. Robust mouse evidence, but no rigorous human trials — human use is limited to unregulated self-experiments. Cancer risk remains the key concern.", "keyStudies": [ { "ref": "Bernardes de Jesus et al., EMBO Mol Med 2012", "finding": "+24% (1yr) / +13% (2yr) median mouse lifespan, no excess cancer", "url": "https://doi.org/10.1002/emmm.201200245" } ], "effect": "Mouse: +13-24% median lifespan; no validated human effect", "human": "No controlled human trials; only anecdotal self-experiments", "safety": "Principal concern is cancer (telomerase reactivation); AAV immunogenicity", "dose": "Experimental (single systemic AAV)", "status": "Preclinical; no approved product", "accessibility": "experimental", "caveats": "Strong mouse data but zero rigorous human evidence; oncogenic potential unresolved", "sources": [ "https://doi.org/10.1002/emmm.201200245" ], "evi": 34, "hum": 10, "imp": 70, "safe": 32, "overall": 35, "tier": "D", "rank": 122 }, { "id": "mitochondrial-transplantation", "name": "Mitochondrial Transplantation", "aka": "Mito transfer therapy", "category": "frontier", "klass": "Organelle transplantation", "mechanism": "Isolated healthy mitochondria are delivered into damaged tissue to restore bioenergetics", "hallmarks": [ "Mitochondrial dysfunction" ], "evidenceType": "animal-other", "evidence": "Strong preclinical data show transplanted mitochondria reduce infarct size in ischemia models; limited human use is single-arm autologous transplantation in pediatric cardiac patients. No controlled aging evidence; the aging application is hypothetical.", "keyStudies": [ { "ref": "McCully et al., review 2021", "finding": "Reduced myocardial necrosis; small pediatric cardiac use" } ], "effect": "Animal: reduced infarct size; human: small uncontrolled cardiac use", "human": "Small single-arm ischemia use; no aging trials", "safety": "Early-stage; immunogenicity, delivery and durability are open questions", "dose": "Experimental (injected at reperfusion)", "status": "Early-clinical for ischemia; aging use conceptual", "accessibility": "experimental", "caveats": "Human evidence tiny and disease-specific; longevity application speculative", "sources": [ "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130169/" ], "evi": 32, "hum": 22, "imp": 45, "safe": 45, "overall": 35, "tier": "D", "rank": 123 }, { "id": "minocycline", "name": "Minocycline", "aka": "Minocin", "category": "pharma", "klass": "Tetracycline antibiotic", "mechanism": "Attenuates cytoplasmic translation of aggregation-prone proteins, improving proteostasis; anti-inflammatory", "hallmarks": [ "Loss of proteostasis", "Chronic inflammation" ], "evidenceType": "animal-other", "evidence": "A proteostasis-targeting geroprotector that extended C. elegans lifespan and uniquely worked even in OLD worms (where most compounds fail). No mammalian lifespan or human longevity trial, and chronic antibiotic use raises resistance/microbiome concerns.", "keyStudies": [ { "ref": "Solis et al., eLife 2018", "finding": "Extended worm lifespan even started late; of 21 compounds, only minocycline worked in old worms", "url": "https://doi.org/10.7554/eLife.40314" } ], "effect": "Lifespan extension in C. elegans (incl. late-life)", "human": "No human longevity data", "safety": "Dizziness, photosensitivity, pigmentation, rare drug-induced lupus; chronic use disrupts microbiome", "dose": "100-200 mg/day (antibiotic)", "status": "FDA-approved (antibiotic); experimental", "accessibility": "rx", "caveats": "Worm-only lifespan data; antibiotic resistance/microbiome harm limit chronic use", "sources": [ "https://doi.org/10.7554/eLife.40314" ], "evi": 36, "hum": 12, "imp": 38, "safe": 55, "overall": 34, "tier": "D", "rank": 124 }, { "id": "senolytic-vaccine", "name": "Senolytic Vaccine", "aka": "Anti-GPNMB vaccine", "category": "frontier", "klass": "Immunotherapy vs senescent cells", "mechanism": "Vaccination against a senescent-cell antigen (GPNMB) directs the immune system to clear senescent cells", "hallmarks": [ "Cellular senescence", "Chronic inflammation", "Altered intercellular communication" ], "evidenceType": "animal-other", "evidence": "A 2021 study showed an anti-GPNMB vaccine cleared senescent cells, reduced atherosclerotic plaque, and extended lifespan in progeroid mice. Entirely in mice; a human vaccine is in development with autoimmunity as a key theoretical risk.", "keyStudies": [ { "ref": "Suda/Minamino, Nature Aging 2021", "finding": "Vaccine reduced senescence/plaque, extended progeroid mouse lifespan", "url": "https://www.nature.com/articles/s43587-021-00151-2" } ], "effect": "Mouse: reduced senescence/plaque, extended progeroid lifespan; no human data", "human": "No human trials yet", "safety": "Theoretical autoimmunity (GPNMB not senescence-exclusive); untested in humans", "dose": "Experimental (peptide vaccine in mice)", "status": "Preclinical; human development underway", "accessibility": "experimental", "caveats": "Entirely preclinical; antigen specificity/autoimmune risk must be resolved", "sources": [ "https://www.nature.com/articles/s43587-021-00151-2" ], "evi": 40, "hum": 8, "imp": 60, "safe": 35, "overall": 34, "tier": "D", "rank": 125 }, { "id": "nk-cell-rejuvenation", "name": "NK / Immune Cell Rejuvenation", "aka": "Adoptive NK cell senotherapy", "category": "frontier", "klass": "Adoptive immune-cell therapy", "mechanism": "Expanded/engineered NK cells are infused to eliminate senescent cells and restore immune surveillance", "hallmarks": [ "Cellular senescence", "Altered intercellular communication", "Chronic inflammation" ], "evidenceType": "mechanistic", "evidence": "NK cells naturally clear senescent cells, supporting adoptive NK therapy as 'senotherapy'. Evidence for the aging application is mechanistic/early proof-of-concept; NK therapy is clinically advanced in oncology, but no controlled trials show anti-aging benefit.", "keyStudies": [ { "ref": "Immunity & Ageing 2024 review", "finding": "Frames adoptive NK therapy as senescent-cell-clearing senotherapy", "url": "https://immunityageing.biomedcentral.com/articles/10.1186/s12979-024-00451-2" } ], "effect": "Preclinical senescent-cell clearance; no demonstrated human aging effect", "human": "Proven in oncology; aging use mechanistic/early only", "safety": "Oncology NK therapy generally tolerable; aging-specific safety untested", "dose": "Experimental for aging", "status": "Established in cancer; anti-aging preclinical", "accessibility": "experimental", "caveats": "No controlled human aging evidence; benefit inferred from senescent-cell biology", "sources": [ "https://immunityageing.biomedcentral.com/articles/10.1186/s12979-024-00451-2" ], "evi": 24, "hum": 20, "imp": 50, "safe": 50, "overall": 34, "tier": "D", "rank": 126 }, { "id": "nad-iv", "name": "NAD+ IV Therapy", "aka": "Intravenous NAD+ infusion", "category": "nad", "klass": "IV NAD+", "mechanism": "Infuses NAD+ directly, though it is largely degraded to precursors before cellular uptake", "hallmarks": [ "Deregulated nutrient sensing", "Mitochondrial dysfunction", "Altered intercellular communication" ], "evidenceType": "human-cohort", "evidence": "Despite aggressive clinic marketing, controlled efficacy evidence for IV NAD+ in aging is essentially absent — systematic reviews find no eligible outcome trials. Tolerable short-term but benefits are anecdotal; expensive and clinic-administered.", "keyStudies": [ { "ref": "Systematic review 2026", "finding": "No eligible outcome trials of IV/IM NAD+ for anti-aging", "url": "https://www.sciencedirect.com/science/article/pii/S1568163726000498" } ], "effect": "Unproven; no controlled outcome data", "human": "Only small tolerability/PK studies", "safety": "Infusion reactions (flushing, nausea, chest discomfort) if fast; unregulated clinic quality", "dose": "~250-1000 mg per slow infusion", "status": "Off-label wellness service", "accessibility": "clinic-only", "caveats": "High-cost, heavily-hyped with no controlled efficacy evidence and questionable bioavailability", "sources": [ "https://www.sciencedirect.com/science/article/pii/S1568163726000498" ], "evi": 28, "hum": 25, "imp": 28, "safe": 55, "overall": 33, "tier": "D", "rank": 127 }, { "id": "exosome-therapy", "name": "Exosome Therapy", "aka": "Extracellular vesicle therapy", "category": "frontier", "klass": "Cell-derived nanovesicle therapy", "mechanism": "MSC-derived exosomes deliver regenerative miRNA/protein cargo to modulate inflammation and repair", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation", "Mitochondrial dysfunction" ], "evidenceType": "human-other", "evidence": "Preclinical and early human data suggest possible benefit for skin/hair, but human evidence is limited to small heterogeneous cosmetic studies. No exosome product is FDA-approved, the FDA has warned against marketed products, and manufacturing/standardization is unsolved.", "keyStudies": [ { "ref": "Systematic review 2025", "finding": "Preliminary dermatologic benefit; small/heterogeneous studies", "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12736761/" }, { "ref": "FDA warnings 2024-25", "finding": "Exosome products deemed unapproved", "url": "https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/consumer-alert-regenerative-medicine-products-including-stem-cells-and-exosomes" } ], "effect": "Possible modest dermatologic benefit; systemic/aging effects unproven", "human": "Only small cosmetic studies; no rigorous systemic aging evidence", "safety": "Unregulated products risk contamination/infection; FDA-flagged", "dose": "No standardized dose", "status": "Not FDA-approved; widely sold illegitimately", "accessibility": "experimental", "caveats": "Manufacturing unstandardized, market largely unregulated; systemic anti-aging claims unsupported", "sources": [ "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12736761/", "https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/consumer-alert-regenerative-medicine-products-including-stem-cells-and-exosomes" ], "evi": 30, "hum": 30, "imp": 32, "safe": 45, "overall": 33, "tier": "D", "rank": 128 }, { "id": "mots-c", "name": "MOTS-c", "aka": "Mitochondrial-derived peptide", "category": "hormone", "klass": "Mitochondrial-derived peptide", "mechanism": "Exercise/stress-induced peptide acting via AMPK; regulates metabolic stress-response genes", "hallmarks": [ "Mitochondrial dysfunction", "Deregulated nutrient sensing", "Altered intercellular communication" ], "evidenceType": "animal-other", "evidence": "An endogenous mitochondrial peptide that rises with exercise and declines with age; in mice late-life intermittent dosing improves physical capacity and healthspan. Essentially no controlled human efficacy trials and no human lifespan data; all human relevance is extrapolated.", "keyStudies": [ { "ref": "Reynolds et al., Nat Commun 2021", "finding": "Late-life MOTS-c increased physical capacity/healthspan in mice", "url": "https://doi.org/10.1038/s41467-020-20790-0" } ], "effect": "Robust metabolic/healthspan 'exercise-mimetic' effects in mice; human effect unknown", "human": "No controlled human efficacy trials", "safety": "No human safety dataset; gray-market injectable purity unknown", "dose": "No validated human dose", "status": "Research compound; not approved", "accessibility": "experimental", "caveats": "Promising mouse biology does not equal proven human benefit; sold ahead of evidence", "sources": [ "https://doi.org/10.1038/s41467-020-20790-0" ], "evi": 36, "hum": 12, "imp": 48, "safe": 40, "overall": 33, "tier": "D", "rank": 129 }, { "id": "grounding-earthing", "name": "Grounding / Earthing", "aka": "Earthing mats/sheets", "category": "therapy", "klass": "Electrophysiological contact (unproven)", "mechanism": "Hypothesized transfer of Earth's electrons via skin contact to reduce inflammation (mechanism unestablished)", "hallmarks": [ "Chronic inflammation" ], "evidenceType": "mechanistic", "evidence": "A few low-quality studies report sleep/pain/inflammation improvements, but the field is dominated by tiny samples, poor blinding and commercial conflicts. Mainstream reviewers consider the evidence too weak to support health claims; no rigorous replication.", "keyStudies": [ { "ref": "Cleveland Clinic review 2022", "finding": "Evidence sparse, low-quality, insufficient to recommend", "url": "https://health.clevelandclinic.org/earthing" } ], "effect": "Claimed sleep/pain/inflammation benefits; not reliably demonstrated", "human": "Small low-quality studies; effect likely placebo", "safety": "Low physical risk; main risk is overhyped claims/opportunity cost", "dose": "Skin contact with ground / grounding products", "status": "Marketed wellness product; not medically recognized", "accessibility": "otc", "caveats": "Weakest evidence base in this set; claims rest on poor-quality, conflicted studies", "sources": [ "https://health.clevelandclinic.org/earthing" ], "evi": 22, "hum": 25, "imp": 20, "safe": 70, "overall": 32, "tier": "D", "rank": 130 }, { "id": "follistatin-gene-therapy", "name": "Follistatin Gene Therapy", "aka": "FST gene therapy", "category": "frontier", "klass": "Myostatin-pathway gene therapy", "mechanism": "Delivering follistatin inhibits myostatin/activin signaling, increasing muscle and reducing fat", "hallmarks": [ "Stem cell exhaustion", "Deregulated nutrient sensing", "Altered intercellular communication" ], "evidenceType": "animal-other", "evidence": "Follistatin overexpression robustly increases muscle mass in animals. Human evidence is very weak — Minicircle's plasmid trial reports small, unpublished, offshore, self-pay results; no controlled efficacy or longevity data.", "keyStudies": [ { "ref": "Minicircle trial (company-reported)", "finding": "~2 lb fat-free mass gain, minor LDL rise (unpublished)", "url": "https://clinicaltrials.gov/study/NCT06411366" } ], "effect": "Mouse: large muscle gains; human: small company-reported changes", "human": "Only an unregulated, unpublished offshore study", "safety": "Reported mild LDL increase; off-target risks of chronic myostatin inhibition unknown; gene-therapy risks", "dose": "Offshore plasmid (~$25,000)", "status": "Not approved; unregulated clinics", "accessibility": "experimental", "caveats": "Human data unpublished, uncontrolled and commercially conflicted; longevity benefit speculative", "sources": [ "https://clinicaltrials.gov/study/NCT06411366" ], "evi": 28, "hum": 18, "imp": 45, "safe": 38, "overall": 31, "tier": "D", "rank": 131 }, { "id": "epitalon", "name": "Epitalon", "aka": "Epithalon, epithalamin (AEDG)", "category": "hormone", "klass": "Synthetic pineal tetrapeptide", "mechanism": "Claimed telomerase activation and normalized melatonin/circadian function", "hallmarks": [ "Telomere attrition", "Epigenetic alterations", "Altered intercellular communication" ], "evidenceType": "in-vitro", "evidence": "Cell-culture work reports telomerase activation and rodent studies report lifespan effects, but human evidence is limited to small open-label/case series and the unreplicated Russian mortality program. Telomerase activation also carries a theoretical cancer concern.", "keyStudies": [ { "ref": "Khavinson et al., Bull Exp Biol Med 2003", "finding": "Activated telomerase, extended fibroblast replicative capacity in vitro", "url": "https://pubmed.ncbi.nlm.nih.gov/12937682/" } ], "effect": "In-vitro telomerase/telomere effects and rodent claims; human longevity unproven", "human": "Only small open-label case series; very LOW quality", "safety": "Reported well tolerated; long-term unknown; theoretical oncogenic concern; gray-market purity", "dose": "5-10 mg/day SC in short courses", "status": "Not approved; unregulated peptide", "accessibility": "experimental", "caveats": "Heavily marketed 'telomere' peptide whose human evidence is essentially anecdotal/Russian-only", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/12937682/" ], "evi": 26, "hum": 15, "imp": 40, "safe": 45, "overall": 30, "tier": "D", "rank": 132 }, { "id": "foxo4-dri", "name": "FOXO4-DRI peptide", "aka": "FOXO4-D-Retro-Inverso, Proxofim", "category": "senolytic", "klass": "Interfering peptide", "mechanism": "Disrupts FOXO4-p53 binding, triggering apoptosis selectively in senescent cells", "hallmarks": [ "Cellular senescence", "Genomic instability", "Altered intercellular communication" ], "evidenceType": "animal-other", "evidence": "Based largely on a single 2017 paper showing senescent-cell clearance and partial restoration of function in aged/progeroid mice. No human trials, limited independent in-vivo replication, yet heavily marketed in the gray-market peptide space.", "keyStudies": [ { "ref": "Baar et al., Cell 2017", "finding": "Cleared senescent cells, restored fur/renal function in aged mice", "url": "https://www.cell.com/cell/fulltext/S0092-8674(17)30293-3" } ], "effect": "Mouse healthspan signals from limited studies; no human effect", "human": "None; no registered trials", "safety": "Unknown in humans; unregulated peptide purity concerns", "dose": "No validated human dose", "status": "Experimental; gray-market peptide", "accessibility": "experimental", "caveats": "Rests on one 2017 study; sold to consumers far ahead of human evidence", "sources": [ "https://www.cell.com/cell/fulltext/S0092-8674(17)30293-3" ], "evi": 28, "hum": 8, "imp": 45, "safe": 30, "overall": 27, "tier": "D", "rank": 133 }, { "id": "bpc-157", "name": "BPC-157", "aka": "Body Protection Compound-157", "category": "hormone", "klass": "Synthetic pentadecapeptide", "mechanism": "Proposed pro-angiogenic/cytoprotective effects (VEGFR2/NO) promoting tendon/gut/tissue healing", "hallmarks": [ "Altered intercellular communication", "Chronic inflammation" ], "evidenceType": "animal-other", "evidence": "Extensive rodent literature suggests accelerated tendon/gut healing, but the human evidence base is essentially absent — no completed published RCTs. The FDA placed BPC-157 on its 503A Category 2 (significant-risk) list in 2023, then removed it in April 2026 pending an advisory-committee review (still NOT FDA-approved); its pro-angiogenic mechanism raises a theoretical tumor concern.", "keyStudies": [ { "ref": "Sikiric et al. (rodent studies)", "finding": "Accelerated tendon/muscle/GI healing in rats" }, { "ref": "FDA 503A bulk-substances list", "finding": "Category 2 (significant safety risk) 2023; removed April 2026 pending review, still not approved", "url": "https://www.fda.gov/drugs/human-drug-compounding/certain-bulk-drug-substances-use-compounding-may-present-significant-safety-risks" } ], "effect": "Robust tissue-healing in rodents; no established human efficacy", "human": "No published human RCTs; widespread off-label/gray-market use", "safety": "No adequate human safety data; FDA-flagged over impurity/immunogenicity (Category 2 2023-26, since de-listed but still unapproved); theoretical cancer concern", "dose": "Self-administered ~250-500 mcg/day (unvalidated)", "status": "Not approved; FDA 'do not compound' Category 2", "accessibility": "experimental", "caveats": "Popular 'healing peptide' with NO human trial evidence and explicit FDA safety concerns", "sources": [ "https://www.fda.gov/drugs/human-drug-compounding/certain-bulk-drug-substances-use-compounding-may-present-significant-safety-risks" ], "evi": 28, "hum": 12, "imp": 35, "safe": 38, "overall": 27, "tier": "D", "rank": 134 }, { "id": "piperlongumine", "name": "Piperlongumine", "aka": "Piplartine", "category": "senolytic", "klass": "Natural alkaloid (long pepper)", "mechanism": "Degrades OXR1 selectively in senescent cells, raising ROS to trigger apoptosis", "hallmarks": [ "Cellular senescence", "Mitochondrial dysfunction" ], "evidenceType": "in-vitro", "evidence": "Senolytic activity is established essentially only in cell culture; no lifespan or controlled human studies. Most interest is mechanistic and as a scaffold for analogs.", "keyStudies": [ { "ref": "Wang et al., Aging (Albany NY) 2016", "finding": "Identified piperlongumine as a senolytic; killed senescent fibroblasts in vitro via ROS-independent apoptosis", "url": "https://pubmed.ncbi.nlm.nih.gov/27913811/" } ], "effect": "In-vitro senolysis; no in-vivo healthspan data", "human": "No human aging data", "safety": "Limited human safety data; reactive scaffold (its senolysis is ROS-independent, though piperlongumine is pro-oxidant in cancer settings)", "dose": "No established protocol", "status": "Research compound", "accessibility": "experimental", "caveats": "In-vitro only; unproven safety, no lifespan data", "sources": [ "https://pubmed.ncbi.nlm.nih.gov/27913811/" ], "evi": 24, "hum": 8, "imp": 40, "safe": 40, "overall": 26, "tier": "D", "rank": 135 } ] }