Evidence-Based Supplements for Healthspan: What Actually Works
After reviewing 100+ clinical trials from 2020-2025, most marketed "anti-aging" supplements have weak human evidence. A few affordable options show strong data: Creatine earns five stars (+1.37kg lean mass, possible lifespan extension), Vitamin D reduces mortality 6-7% (requires 3+ years), Omega-3 cuts heart attacks 28%. Resveratrol is overhyped garbage. NMN/NR raise NAD+ but lack longevity proof. This guide separates evidence from marketing.
The best longevity "supplement" remains: Resistance training 2x/week (27% mortality reduction) + Mediterranean diet (21% reduction) + 7-8 hours sleep + stress management + social connections (50% survival advantage).
These interventions are FREE or low-cost, have massive evidence, and dwarf the benefits of any supplement. Supplements should complement—never replace—foundational lifestyle interventions.
If you're not doing resistance training 2x/week, skip supplements and start there. ROI is 100x better.
Tier 1: Strong Evidence (Implement Now)
These supplements have strong human evidence from randomized controlled trials. Cost-effective. Worth considering for most people.
Dose: 3-5g/day
Evidence (Human Studies):
- Chilibeck 2017 meta-analysis: +1.37kg lean mass with resistance training
- Improved strength and physical function in older adults
- Animal studies: +9% mouse lifespan extension
- Cognitive benefits: improved memory in vegetarians/vegans
- Possibly neuroprotective against age-related cognitive decline
Mechanism: Increases phosphocreatine stores → enhanced ATP regeneration → improved muscle performance, strength, and recovery. May support mitochondrial function and cellular energy.
Timing: Daily, any time. No loading phase needed. With or without food.
Safety: Extremely well-tolerated. Myths about kidney damage debunked in healthy individuals. 30+ years of safety data.
Verdict:
#1 evidence-based supplement for aging. Criminally underrated. Resistance training + creatine is the longevity power couple.
Best for: Anyone doing resistance training (especially 50+). Vegetarians/vegans (dietary creatine from meat only).
Dose: 1,000-2,000 IU/day (target blood level 60-80 ng/mL)
Evidence (Human Studies):
- 2023 meta-analysis: 3+ years supplementation = 6-7% mortality reduction
- 2023 telomere study: 2,000 IU/day over 4 years slowed telomere shortening equivalent to preventing ~3 years biological aging
- CRITICAL: Benefits only seen with duration >3 years (not short-term)
- Impacts immune function, bone health, cardiovascular health, mood
- Most adults deficient (<30 ng/mL), especially in winter months
Mechanism: Vitamin D receptor expressed in nearly every tissue. Regulates 3% of human genome. Anti-inflammatory, immune-modulating, supports calcium absorption.
Timing: With meals containing fat (fat-soluble vitamin). Morning preferred (may affect sleep if taken evening).
Safety: Very safe at 1,000-2,000 IU/day. Test baseline (25-OH vitamin D), retest at 3 months to confirm target 60-80 ng/mL. Toxicity rare below 10,000 IU/day long-term.
Verdict:
One of the best-evidenced supplements. Requires 3+ years for mortality benefit—start now. Test, don't guess.
Best for: Nearly everyone. Deficiency widespread. Sun exposure insufficient/risky (skin cancer). Food sources inadequate.
Dose: 1-2g/day combined EPA+DHA (or 2-3 servings fatty fish/week)
Evidence (Human Studies):
- VITAL 2018: 840mg/day produced 28% fewer heart attacks, 50% fewer fatal MIs
- Ames 2018 PNAS: 2.5g/day fish oil slowed telomere shortening in older adults
- Combined with polyphenols: 3-fold increase glutathione peroxidase, 2-fold increase plasma antioxidant capacity
- Anti-inflammatory effects (reduce hs-CRP, IL-6)
- Brain health: some studies show cognitive benefits, others mixed
Mechanism: Incorporates into cell membranes → improves fluidity, reduces inflammation (competes with omega-6 for inflammatory pathways), supports cardiovascular health.
Timing: With meals containing fat. Triglyceride or phospholipid form preferred over ethyl ester (better absorption).
Safety: Safe at 1-2g/day. Minor GI upset possible. Choose molecularly distilled (removes mercury, PCBs). Check for rancidity (smell, taste).
Verdict:
Solid cardiovascular benefits. Food sources ideal (fatty fish 2-3x/week), but supplements effective if fish intake inadequate.
Best for: Those not eating fatty fish 2-3x/week. Cardiovascular disease prevention. Possibly brain health.
Dose: Men 400-420mg/day, Women 310-320mg/day FROM FOOD
Evidence (Human Studies):
- Meta-analysis of 1.17 million participants: dietary magnesium = 13% lower all-cause mortality
- CRITICAL FINDING: Supplemental magnesium showed NO mortality benefit
- Involved in 300+ enzymatic reactions, ATP production, DNA repair
- Deficiency common (50% of Americans), but supplementation doesn't replicate food benefits
Mechanism: Cofactor for energy production, protein synthesis, nerve function, blood pressure regulation. Food sources provide bioavailable forms with cofactors supplements lack.
Food Sources: Dark leafy greens (spinach, chard), nuts (almonds, cashews), seeds (pumpkin, sunflower), whole grains, dark chocolate, legumes, avocados
Timing: Multiple food sources throughout day. Magnesium-rich foods at each meal.
Safety: From food: extremely safe. Supplemental magnesium: can cause diarrhea (osmotic effect). Not recommended based on evidence.
Verdict:
Strong evidence requiring FOOD sources, not pills. This is why diet quality matters—you can't supplement your way out of poor nutrition.
Best for: Everyone. Prioritize magnesium-rich whole foods. Skip the supplement aisle.
Tier 2: Moderate Evidence (Consider After Tier 1)
These supplements show promising but limited human evidence. More expensive. Consider after optimizing Tier 1 foundations.
Dose: CoQ10 100-200mg/day + Selenium 200mcg/day
Evidence:
- KiSEL-10 Study: 50% reduction in cardiovascular mortality at 12-year follow-up
- Elderly Swedish population (low baseline selenium levels)
- CoQ10 declines with age and statin use
- Some studies show improved heart function in heart failure patients
- Mixed results in general population without deficiency
CoQ10 mechanism: Mitochondrial electron transport chain component. Antioxidant. Declines with age and statin medications.
Selenium mechanism: Component of glutathione peroxidase (antioxidant enzyme). Thyroid hormone metabolism.
Verdict:
Impressive long-term data from KiSEL-10, but single study in specific population. Moderate evidence. Consider if 70+, on statins, or low selenium region.
Safety: Generally safe. Selenium toxicity possible >400mcg/day long-term. CoQ10 well-tolerated.
Dose: NMN 250-1,000mg/day OR NR 300-500mg/day
Evidence:
- Reliably raises NAD+ levels in humans (proven)
- Yi 2023: 600mg NMN improved 6-minute walk, stabilized biological age
- Long-term healthspan benefits remain UNPROVEN in humans
- Promising animal studies (mice), but human trials short-term
- No mortality data, no long-term disease prevention data
Mechanism: NAD+ precursors → boost cellular NAD+ → support sirtuins, DNA repair, mitochondrial function. NAD+ declines with age.
Verdict:
Raises NAD+ consistently, but do higher NAD+ levels translate to healthspan benefits in humans? Unknown. Expensive for uncertain benefit.
Safety: Short-term studies show good safety profile. Long-term unknown. Quality varies widely between brands.
Consider if: Wealthy biohackers, bleeding-edge adopters. Wait for more human longevity data if budget-conscious.
Dose: Dasatinib 100mg + Quercetin 1,000mg for 3 consecutive days monthly
Evidence:
- Hickson 2019: reduced senescent cells in diabetic kidney disease
- Justice 2019: improved physical function in idiopathic pulmonary fibrosis
- Promising pilot studies in specific disease states
- NO general population longevity trials completed yet
- Theory strong, human data extremely limited
Mechanism: Senolytic drugs selectively kill senescent 'zombie' cells that accumulate with age and secrete inflammatory factors (SASP).
Verdict:
James Kirkland's research exciting, but human trials just beginning. Too early for general population use. Watch this space—2025-2030 will bring clarity.
Safety: Dasatinib is cancer chemotherapy drug (off-label use). Requires medical supervision. Not for DIY experimentation.
Consider if: Under physician supervision for specific conditions. Wait for completed trials for general longevity use.
Tier 3: Weak/Experimental Evidence (Wait or Skip)
These supplements either lack human longevity data, show inconsistent results, or are overhyped relative to evidence. Most should be skipped.
Dose: 500-1,000mg/day (off-label, prescription required)
Evidence:
- TAME trial (Targeting Aging with Metformin): FDA-approved 2015, STILL NOT STARTED as of 2025
- Observational data in diabetics: possible longevity benefit
- Diabetes Prevention Program: lifestyle changes 2x more effective than metformin (58% vs 31% diabetes prevention)
- May blunt exercise adaptations (interference with mitochondrial adaptations)
- Depletes B12 (requires monitoring)
Mechanism: AMPK activation, mTOR inhibition, improves insulin sensitivity. Mitochondrial complex I inhibitor.
Verdict:
Strong theory, but human longevity trial hasn't materialized despite 10 years. Lifestyle interventions superior for healthy individuals. May interfere with exercise benefits.
Safety: Generally safe in diabetics. Lactic acidosis risk (rare). GI upset common. B12 monitoring required.
Consider if: Pre-diabetic or diabetic (established indication). Healthy individuals: wait for TAME trial results before off-label use.
Dose: 5-7mg once weekly (off-label, prescription required)
Evidence:
- Exceptional animal data: 9-14% mouse lifespan extension (most robust animal longevity drug)
- FDA-approved immunosuppressant (organ transplant)
- Human longevity trials: NONE completed
- Dog Aging Project testing rapamycin in companion dogs (results pending)
- Small human trials for aging markers (ongoing)
Mechanism: mTOR inhibition → autophagy activation, reduced protein synthesis, metabolic shifts mimicking caloric restriction.
Verdict:
Best animal longevity data of any drug. Human longevity evidence: zero. Immunosuppressant side effects concerning for healthy individuals.
Safety: Immunosuppression (increased infection risk), mouth sores, elevated cholesterol, impaired wound healing. Requires medical monitoring.
Consider if: Clinical trial participation. Not for general use until human data available. High-risk biohackers only.
Evidence:
- 150+ trials conducted. Consistent finding: very low bioavailability (<1%)
- Some studies show blocked exercise benefits (interferes with mitochondrial adaptations)
- Red wine polyphenols have benefits, but NOT due to resveratrol specifically
- Initial excitement based on misinterpreted rodent studies (doses impossibly high in humans)
Mechanism: Theoretically activates sirtuins. Reality: doesn't reach tissues at meaningful concentrations in humans.
Verdict:
Most overhyped longevity supplement. Skip entirely. If drinking red wine, benefits come from alcohol's hormetic effects + other polyphenols, NOT resveratrol.
Safety: Safe because it doesn't do anything (too poorly absorbed).
Complete waste of money. 15+ years of research failed to show human benefits.
Budget-Optimized Supplement Strategy
- Creatine 3-5g/day: $10-15/month
- Vitamin D 1,000-2,000 IU/day: $5-10/month
- Omega-3 1-2g/day: $10-30/month (OR eat fatty fish 2-3x/week)
- Magnesium-rich diet: $0 (from whole foods)
- • CoQ10 100-200mg/day if 70+ or on statins
- • Consider if cardiovascular disease family history
- ❌ Resveratrol (waste of money)
- ❌ Expensive 'longevity' blends (unproven ingredients)
- ❌ Anything promising miracles
- ❌ Proprietary blends (can't verify doses)
The best longevity 'supplement' remains: resistance training + adequate protein + good sleep + stress management + social connections. Supplements are 10% of the equation.
Testing: Don't Guess, Test
Don't supplement blindly. Test baseline levels, supplement to optimize, retest to confirm target ranges achieved.
Optimal: 60-80 ng/mL
Frequency: Baseline, retest 3 months after starting supplementation, then annually
$30-50Optimal: >8% (target 8-12%)
Frequency: Baseline, retest 3-4 months after starting, then annually
$50-100Optimal: 6.0-6.5 mg/dL
Frequency: If symptoms suggest deficiency (muscle cramps, fatigue). Otherwise focus on dietary intake.
$40-60Serum magnesium unreliable (only 1% of total body magnesium in blood). RBC magnesium better indicator.
Optimal: >400 pg/mL
Frequency: Every 6-12 months if taking metformin
$20-40Supplement Quality: Why It Matters
- FDA doesn't regulate supplements like drugs—no pre-market approval required
- Studies find 25-50% of supplements don't contain labeled amounts
- Contamination with heavy metals, pesticides, unlabeled ingredients common
- Proprietary blends hide actual ingredient doses
- Cheap supplements often use poor bioavailability forms
Third-party testing certifications
Look for: USP Verified, NSF Certified for Sport, ConsumerLab.com approval, Informed Choice/Sport
Reputable brands with transparency
Brands that publish Certificate of Analysis (COA), use third-party testing, transparent about sourcing
Bioavailable forms
Magnesium glycinate > magnesium oxide. Methylcobalamin/adenosylcobalamin > cyanocobalamin (B12). Vitamin D3 > D2.
Avoid proprietary blends
If label says 'Proprietary Blend 500mg' without listing individual doses, skip it. Can't verify effective doses.
Thorne, Pure Encapsulations, Life Extension, Jarrow, NOW Foods (NSF certified products), Designs for Health. Not exhaustive—verify third-party testing.
Supplement Timing Optimization
Timing: Morning with breakfast (fat-containing meal)
Why: Fat-soluble vitamin requires dietary fat for absorption. Morning dosing may reduce sleep interference.
Timing: With largest meal of the day
Why: Maximizes absorption with dietary fat. Reduces fishy burps (freeze capsules if persistent).
Timing: Anytime, daily (consistency matters)
Why: Loading saturation, not acute effects. With or without food fine. Some take post-workout with carbs/protein.
Timing: Evening with dinner
Why: May have mild relaxing effect. Avoid large doses at once (GI upset). Split if >300mg.
Timing: With breakfast or lunch (fat-containing)
Why: Fat-soluble. Ubiquinol form (reduced) may absorb better than ubiquinone (oxidized).
Common Supplement Mistakes to Avoid
Reality:
Most vitamins/minerals have U-shaped curves. Excess doesn't help, may harm. Water-soluble vitamins (B, C) mostly excreted, fat-soluble (A, D, E, K) can accumulate.
Fix: Follow evidence-based doses. Test levels when possible. More is not better.
Reality:
You might already be optimal. Vitamin D, B12, magnesium vary widely between individuals. Testing prevents unnecessary supplementation.
Fix: Test vitamin D, omega-3 index, RBC magnesium before starting. Retest to confirm optimization.
Reality:
Vitamin D mortality benefits require 3+ years. Creatine muscle benefits take 4-8 weeks. Supplements are slow, subtle interventions.
Fix: Set realistic expectations. Measure objectively (biomarkers, functional tests). Give interventions adequate time (months to years).
Reality:
Supplement industry is $50+ billion with massive marketing budgets. Most marketed benefits lack human evidence.
Fix: Demand human RCT evidence. Ignore testimonials, influencer marketing. Stick to Tier 1 supplements with strong evidence.
Reality:
Magnesium supplement doesn't work—food sources do. Whole foods provide nutrients in bioavailable forms with cofactors supplements lack.
Fix: Supplements complement, don't replace, quality nutrition. Mediterranean diet + strategic supplementation (vitamin D, omega-3 if needed) beats poor diet + mega-supplements.
The Bottom Line
Most supplements marketed for longevity lack strong human evidence. A few exceptions exist.
Tier 1 priorities: Creatine (★★★★★), Vitamin D (★★★★★), Omega-3 (★★★★☆), dietary magnesium (★★★★★). Total cost: $25-55/month.
Vitamin D requires 3+ years for mortality benefit. Test baseline (25-OH), target 60-80 ng/mL, retest to confirm.
Magnesium paradox: Dietary magnesium reduces mortality 13%, but supplemental magnesium shows NO benefit. Food sources only.
Skip entirely: Resveratrol (overhyped, poor bioavailability), expensive longevity blends (unproven), proprietary blends (can't verify doses).
Experimental tier: NMN/NR raise NAD+ but lack longevity proof. Rapamycin has best animal data but zero human longevity trials. Senolytics promising but early.
Reality check: Resistance training 2x/week (27% mortality reduction) + Mediterranean diet (21% reduction) beats any supplement. Supplements are 10% of the equation.
Demand human RCT evidence. Ignore marketing hype. Start with lifestyle, add strategic supplementation. Test, don't guess.