What interventions have been associated with increased longevity and have they been shown to work in humans?
Studies of yeast, worms, flies, rodents, and mammals have demonstrated that caloric restriction (CR; 30%–40% reduction in daily energy intake) increases mean (i.e., average life expectancy) and maximal life span. Interestingly, generating a negative energy balance in rodents through increased energy expenditure (exercise) results in similar improvements in mean life span as CR but does not increase maximal life span. Studies in humans have suggested that CR produces physiologic, metabolic, and hormonal effects that parallel many of the positive effects found in other species. CR intervention trials with durations of 6 months to 2 years in healthy adults found that CR led to improvements in cardiometabolic risk and did not adversely affect quality of life.
Dietary composition also plays a role in longevity. A large meta-analysis of data from the Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES), including 400,000 elderly participants, found that adherence to a healthy diet (limited saturated fats, mono- and disaccharides, and cholesterol; 6%–10% of energy intake from polyunsaturated fatty acids [PUFAs] and 10%–15% from protein; and intake of > 25 g/day of fiber and > 400 g/day of fruits and vegetables), was associated with increased life expectancy. Although prolonged dietary intervention trials for longevity typically study biomarkers of longevity rather than actual lifespan, most of the evidence shows that prolonged adherence to similar diets (e.g., Mediterranean) with or without caloric restriction have led to improved indices of insulin sensitivity, oxidative stress, and other CVD risk factors. A 5-year primary prevention trial in older adults at high CVD risk showed that consumption of Mediterranean-style diets led to a decrease in incident CVD, type 2 diabetes, peripheral artery disease and atrial fibrillation in men and women.
It is estimated that one quarter to one third of the variance in life expectancy in humans is explained by genetic factors. Large-scale collaborations are studying different populations to define biomarkers or genes associated with longevity in humans. Variants of two genes, APOE (apolipoprotein E) and FOXO3A (forkhead box O3A), have been consistently shown to be associated with longevity. APOE is a major carrier of cholesterol and aids in lipid transport and injury repair in the brain. The FOXO3A gene is involved in the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway and may influence longevity via its effects on oxidative stress and insulin sensitivity.