Instalab ResearchAnimal studies once suggested antioxidants like vitamin E and vitamin C could extend lifespan by reducing oxidative damage. However, large randomized human trials have consistently shown no significant lifespan extension. Some even found increased risks of disease with high-dose supplementation. The conclusion from trustworthy human data is clear: antioxidant pills do not slow aging, even though antioxidant-rich diets remain beneficial for overall health.
Caloric restriction (CR) is the most robustly validated intervention for extending lifespan in animals, including rodents and primates. In humans, we lack definitive lifespan data, but smaller clinical studies confirm CR improves metabolic health and markers of aging. The search for CR mimetics has led to drugs like metformin and rapamycin.
Metformin: The Targeting Aging with Metformin (TAME) trial is designed to test whether metformin can reduce the onset of multiple age-related diseases in humans. Epidemiological data already suggest metformin users with type 2 diabetes live longer and have lower cardiovascular and cancer mortality compared to non-users. However, direct statistically significant evidence of lifespan extension in non-diabetic humans is not yet available.
Rapamycin: In animal models, rapamycin robustly extends lifespan by 10–15% in mice. Human studies are limited but show rapamycin analogues improve immune function in older adults. No statistically significant human data yet confirm lifespan extension, but trials are ongoing.
Declining NAD+ levels with age contribute to metabolic dysfunction. Supplementing with precursors like nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) aims to restore these levels.
NMN: In a 10-week randomized, placebo-controlled trial of overweight postmenopausal women with prediabetes, NMN improved muscle insulin sensitivity significantly (p < 0.05), though NAD+ levels in muscle did not increase. Another 60-day multicenter, double-blind trial in 80 healthy adults found NMN raised blood NAD+ concentrations (p ≤ 0.001), improved six-minute walking distance (p < 0.01), and prevented an increase in biological age compared to placebo (p < 0.05). No serious side effects were observed. While these are promising functional results, evidence of actual lifespan extension in humans is still absent.
NR: Early human trials show NR raises NAD+ levels, but statistically significant improvements in aging biomarkers remain less clear compared to NMN. More clinical data is required.
Spermidine induces autophagy and extends lifespan in yeast, worms, flies, and mice, with robust statistical support in animal research. In humans, observational studies suggest higher dietary spermidine intake correlates with reduced cardiovascular disease risk. However, randomized clinical trials of spermidine supplementation in humans are still limited, so current evidence does not yet confirm causation or quantify lifespan benefits.
Vitamin D has been tested in very large randomized controlled trials. Results show outcomes for disease-specific endpoints and some data indicates supplementation may modestly reduce all-cause mortality. Two ongoing mega-trials, each with over 5,000 participants, are designed to directly evaluate mortality reduction. These studies are statistically powered to detect small but meaningful effects. Until final results are published, vitamin D remains promising but unproven as a longevity agent.
Fish oil and omega-3 fatty acids are beneficial for heart health but have not shown statistically significant effects on lifespan in rigorous human trials. Resveratrol, once highly publicized, improves health and survival in certain animal models but fails to consistently demonstrate benefits in humans. Curcumin and other herbal extracts remain in early stages with no large, statistically significant clinical outcomes.
When animal and human research are clearly separated, only a few supplements currently stand out with statistically significant human clinical trial data relevant to aging. NMN has the strongest human evidence so far, with improvements in NAD+ levels, muscle function, walking performance, and biological age markers. Metformin and rapamycin analogues are supported by strong animal data and mechanistic plausibility, but human lifespan results are pending. For now, evidence-based lifestyle choices like diet, exercise, and metabolic health management remain the most reliable tools for extending healthspan.
