Which supplements have the strongest evidence for extending lifespan or reducing age‑related disease risk?

Evidence-Based Supplements for Longevity

Omega-3 fatty acids (EPA+DHA) at 850–1,000 mg daily have the strongest mortality and cardiovascular benefit, reducing sudden cardiac death by 45% and total mortality by 15% in adults with established cardiovascular disease. 1, 2

Omega-3 Fatty Acids: The Most Robust Evidence

Cardiovascular Mortality Reduction

• For adults over 50 with documented coronary heart disease, prescribe 850–1,000 mg EPA+DHA daily, which reduces the composite endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke by 15% (RR 0.85; 95% CI 0.68–0.95) within 3–4 months. 1, 2
• The GISSI-Prevenzione trial demonstrated a 45% reduction in sudden cardiac death with this dose in post-MI patients, with effects appearing as early as 3 months. 1, 2
• In the GISSI-HF trial of older adults (mean age 67), this dose reduced total mortality with a hazard ratio of 0.91 (95% CI 0.833–0.998). 1

Primary Prevention Benefits

• Twice-weekly fatty fish consumption (or equivalent 250–500 mg EPA+DHA daily) reduces coronary heart disease mortality by 30% in women and sudden coronary death by 54% in men in prospective cohort studies. 3
• For hypertensive individuals, omega-3 supplementation provides a 7% relative risk reduction for cardiovascular disease (RR 0.93,95% CI 0.90–0.96), with stronger protective effects in those with hypertension. 1, 2

High-Dose EPA for High-Risk Patients

• For patients with elevated triglycerides (≥150 mg/dL) on statin therapy, 4 grams daily of pure EPA (icosapent ethyl) reduces fatal or nonfatal stroke by 38% and major cardiovascular events by 25%. 2, 3
• This high dose carries a 25% increased risk of atrial fibrillation, so assess AF risk before initiating. 2, 3

Cognitive Benefits

• Higher EPA+DHA intake (3.36 g daily achieving omega-3 index ≥4%) improves cognitive function at 12 and 30 months in older adults, with DHA contributing more than EPA to this effect. 3
• Women with greater habitual fish intake have reduced rates of death from Alzheimer's disease in prospective cohort data. 3

Dosing Algorithm

• General cardiovascular health: 500 mg EPA+DHA daily or two fatty fish meals weekly 3
• Documented coronary disease: 850–1,000 mg EPA+DHA daily 1, 2, 3
• Elevated triglycerides on statin: 4 g pure EPA daily (monitor for atrial fibrillation) 2, 3

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Vitamin D: Limited Longevity Evidence

What the Evidence Shows

• Vitamin D supplementation at 2,000 IU daily does NOT reduce cancer incidence (HR 0.96; 95% CI 0.88–1.06) or major cardiovascular events (HR 0.97; 95% CI 0.85–1.12) in the VITAL trial of 25,871 adults followed for 5.3 years. 4
• Death from any cause showed no benefit (HR 0.99; 95% CI 0.87–1.12). 4
• The U.S. Preventive Services Task Force found no evidence that vitamin D (with or without calcium) reduces cardiovascular disease, cancer, or all-cause mortality in community-dwelling adults. 1

When Vitamin D May Help

• For older adults with mild cognitive impairment or Alzheimer's disease, vitamin D supplementation may improve cognition, but this requires further study before routine recommendation. 5
• In combination with omega-3s and exercise, vitamin D 2,000 IU daily reduced odds of becoming pre-frail by 39% (OR 0.61; 95% CI 0.38–0.98) in robust older adults over 3 years, but only when all three interventions were combined—not individually. 6

Practical Recommendation

• Do not prescribe vitamin D for longevity or mortality reduction; the evidence does not support this use. 4
• Consider 600–800 IU daily for bone health in adults over 65, particularly when combined with calcium. 1, 7

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Calcium: No Longevity Benefit

• Calcium supplementation alone does not reduce fractures at any skeletal site in men, and high-quality trials show no mortality benefit. 7
• When combined with vitamin D, there is a modest reduction in fracture incidence, but this does not translate to longevity extension. 7
• Prioritize dietary calcium (1,200 mg daily from food sources) over supplements to avoid potential cardiovascular concerns and kidney stone risk associated with supplemental calcium. 7

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Multivitamins and Individual Vitamins: Insufficient Evidence

Vitamins A, C, E

• The U.S. Preventive Services Task Force found no evidence of beneficial effect on cardiovascular disease, cancer, or all-cause mortality for vitamins A, C, or E across 24 studies. 1
• Vitamin E at doses ≤400 IU daily had no effect on all-cause mortality in meta-analysis (mean age range 47–84 years). 1
• For older adults (>65 years), vitamin E at 200 IU daily may improve immune response and reduce infection risk, but this does not translate to proven longevity extension. 1

Multivitamins

• Daily low-dose multivitamin supplementation has been linked to reductions in cancer incidence and cataracts, especially among men, but the evidence is not consistent enough to recommend for longevity. 8

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Protein and Creatine for Sarcopenia

• Proper protein intake and creatine supplementation can mitigate sarcopenia in adults over 65, which indirectly supports healthy aging by maintaining autonomy in activities of daily living. 5
• Branched-chain amino acids and vitamin D may help in certain situations, but evidence is less robust. 5
• This addresses quality of life and functional independence rather than direct mortality reduction. 5

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Nutritional Oral Supplements (ONS) in Older Adults

• High-protein oral nutritional supplements (≥30 g protein, ≥400 kcal/day) reduce complications, hospital readmissions, and improve grip strength in malnourished older adults, but do not significantly reduce mortality. 1
• Meta-analyses of 62 trials showed reduced mortality only in subgroups of malnourished participants receiving ≥400 kcal/day, with inconsistent results overall. 1

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Critical Pitfalls to Avoid

• Do not recommend vitamin D or calcium for longevity—the highest-quality randomized trial (VITAL, 2019) definitively shows no mortality benefit. 4
• Do not prescribe high-dose omega-3 (≥4 g daily) without assessing atrial fibrillation risk, as this dose increases AF incidence by 25%. 2, 3
• Do not rely on multivitamins or individual vitamins (A, C, E) for mortality reduction—the evidence is insufficient or negative. 1
• Prioritize dietary sources of omega-3 (fatty fish twice weekly) over supplements when possible, as observational data show stronger mortality benefits from whole foods. 3

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Bottom Line: What to Prescribe

For proven longevity and mortality reduction, omega-3 fatty acids are the only supplement with robust, high-quality evidence. 1, 2, 3

• Adults with cardiovascular disease: 850–1,000 mg EPA+DHA daily 1, 2
• Healthy adults for primary prevention: 500 mg EPA+DHA daily or two fatty fish meals weekly 3
• High-risk patients with elevated triglycerides on statins: 4 g pure EPA daily (monitor for AF) 2, 3

All other supplements—including vitamin D, calcium, multivitamins, and individual vitamins—lack convincing evidence for extending lifespan or reducing age-related disease mortality in well-nourished populations. 1, 4