What actually works for extending healthspan. Compiled from peer-reviewed research, NIA ITP trials, and clinical studies.
Last updated: March 30, 2026 · Sources: NEJM, Cell, NIA ITP, PEARL Trial, Journal of Gerontology, GeroScience
Ranked by evidence quality. Only interventions with human trial data included.
Most validated lifespan-extending compound in mammals. 20-year NIA ITP record. +15-20% lifespan in mice across sexes. PEARL trial: weekly 10mg showed lean mass gain in women.
Beyond weight loss: cardiovascular mortality -20% (SELECT trial, 2024). Emerging neurological protection data. FDA removed HRT black box warning — signals regulatory shift toward proactive longevity.
+13.6% lifespan in male mice (NIA ITP 2025 review). Cardiovascular + renal + metabolic benefits. Originally diabetes drugs — now recognized as geroprotective agents.
TAME trial underway (N=3,000). Anti-aging effects in non-human primates (2024 Cell study). David Sinclair protocol: 800mg/day. Suppresses mTOR + activates AMPK.
Sinclair protocol: 1g NMN/day. NAD+ levels decline ~50% by age 50. Small human trials show improved insulin sensitivity, muscle function. No long-term human lifespan data yet.
Target senescent cells ("zombie cells"). Fisetin showed 25-30% extension in mice. Mayo Clinic human trials underway. Food sources: strawberries (fisetin), onions (quercetin).
Partial reprogramming using Yamanaka factors. Retro Biosciences ER-100: first human trials starting 2026. Could reverse cellular aging. Most transformative if it works at scale.
+36.6% median lifespan in mice — better than either alone. Supports multi-pathway targeting thesis. Human combo trials not yet designed. The most powerful known combination in ITP data.
CNN/Lancet meta-analysis (Jan 2026): optimal lifestyle combination adds 9.35 years of lifespan AND 9.46 years of healthspan.
The greatest longevity gain — 9.35 years — came from combining 42-103 min/day exercise + 7-8 hours sleep. Neither alone was nearly as effective. The combination effect is multiplicative, not additive. (CNN/Lancet, January 2026)
| Intervention | Evidence | Mechanism | Practical Protocol |
|---|---|---|---|
| Exercise (Zone 2 + Strength) | ⭐⭐⭐⭐⭐ Strongest | Mitochondrial biogenesis, mTOR modulation, insulin sensitivity, HRV improvement | 150 min/wk Zone 2 cardio + 2x/wk resistance training. VO2max most predictive of longevity. |
| Sleep (7-8 hours, consistent) | ⭐⭐⭐⭐⭐ Strongest | Glymphatic clearance (amyloid), hormonal reset, DNA repair, immune function | Same bedtime ±30 min. Dark/cool room. Caffeine cutoff 12pm. Track HRV for sleep quality. |
| Time-Restricted Eating (16:8) | ⭐⭐⭐⭐ Strong | Autophagy activation, insulin sensitivity, circadian rhythm alignment | Eat within 8-10 hour window. Skip breakfast or dinner. 3-day extended fast 2x/year. |
| Cold Exposure | ⭐⭐⭐ Moderate | Brown fat activation, mitochondrial density, norepinephrine release, vagal tone | 2-3 min cold shower or 11 min/week cold immersion (Huberman protocol). Post-exercise. |
| Heat Therapy (Sauna) | ⭐⭐⭐⭐ Strong | Heat shock proteins, cardiovascular stress adaptation, mitochondrial function | 4x/week, 20 min at 80°C+. Finnish cohort: 40% lower cardiovascular mortality at 4x/week. |
| Social Connection | ⭐⭐⭐⭐⭐ Strongest | HPA axis modulation, inflammation reduction, purpose/meaning → epigenetic effects | Often underrated. Isolated individuals have 26% higher mortality risk. Quality > quantity. |
| Stress Management | ⭐⭐⭐⭐ Strong | Cortisol reduction, telomere preservation, inflammatory cytokine regulation | HRV tracking (Oura/WHOOP). Identify what tanks your HRV (alcohol, late meals, screen time). |
What to track if you're serious about longevity optimization.
TruDiagnostic TruAge Complete: measures biological age via DNA methylation. SYMPHONYAge report breaks down aging by organ system. The most predictive biomarker for future health outcomes.
Single strongest predictor of longevity in healthy adults. Each 1-MET increase in fitness = 13% reduction in all-cause mortality. Target: above 75th percentile for your age.
Proxy for autonomic nervous system health and recovery. Track with Oura Ring or WHOOP. Higher baseline HRV = better recovery, lower inflammation. Most responsive to lifestyle inputs.
Better cardiovascular risk marker than LDL. Target: <70 mg/dL (aggressive prevention). Standard labs often miss elevated ApoB. Peter Attia's top biomarker recommendation.
Metabolic dysfunction drives accelerated aging via AGEs, inflammation, and mitochondrial damage. HOMA-IR <1.5 ideal. CGM (Levels Health) gives real-time glucose data.
Grip strength predicts all-cause mortality better than blood pressure in many studies. Gait speed <0.8 m/s = high risk. Both test musculoskeletal aging with zero cost.
Findings that shifted the scientific consensus.
48-week RCT: weekly 10mg rapamycin improved lean mass (6% gain) and reduced pain in women. Low-dose intermittent dosing appears to preserve benefits while reducing immunosuppression risk. Game-changer for off-label longevity use.
Source: Aging journal, 2025 · PEARL Trial · N=12054 molecules tested across 20 years. Rapamycin + acarbose produced 36.6% median lifespan extension — the highest ever recorded in the ITP. Confirms multi-pathway targeting is the future of longevity medicine.
Source: Journal of Gerontology, 2025 · 3 independent sitesBeyond metabolic effects: new data shows semaglutide reduces neuroinflammation markers. Case series showing cognitive improvement in early Alzheimer's patients. SELECT trial cardiovascular data: -20% major cardiac events.
Source: SELECT Trial 2024 · N=17,604 · Nature Medicine 2025Largest meta-analysis to date. Optimal combination: 42-103 min/day exercise + 7-8 hours sleep + healthy diet adds both lifespan AND healthspan by 9+ years. No drug achieves this. Lifestyle remains the most powerful intervention.
Source: Lancet / CNN Health, January 2026 · Meta-analysis of 20+ studiesThe field is moving from "fixing aging" (molecular targets, single drugs) to "preserving biological coordination" (systems-level understanding of how aging disrupts cellular communication). Next breakthrough may be architectural, not pharmaceutical.
Source: EurekAlert / Targeting Longevity 2026 ConferenceWhat to do if you're starting from zero. Ranked by evidence-to-cost ratio.
1. Exercise: 150 min Zone 2 + 2x strength/week → biggest ROI of anything on this list
2. Sleep: 7-8 hours, consistent schedule → synergistic with exercise
3. Diet: Protein 1.6g/kg BW + minimize ultra-processed + time-restricted eating window
4. Stress/HRV: Track with free WHOOP trial or Oura, identify what tanks your HRV
• Vitamin D3 + K2: Most people deficient. 4,000-8,000 IU D3 + 100mcg K2-MK7
• Omega-3 (EPA/DHA): 2-4g/day from fish oil. Anti-inflammatory, cardiovascular, brain
• Magnesium glycinate: Most people deficient. Sleep, HRV, muscle function
• Creatine: 5g/day. Muscle mass, cognitive function, emerging longevity data
• NMN 500-1000mg/day: NAD+ precursor. Moderate evidence. Morning with resveratrol.
• Rapamycin (off-label): Find longevity-focused physician. Weekly low-dose protocol.
• Epigenetic age test: TruDiagnostic ~$299. Know your biological age baseline.
• ApoB + Lp(a) bloodwork: Know your cardiovascular risk profile precisely.