Association between Circulating Antioxidants and Longevity: Insight from Mendelian Randomization Study

BACKGROUND: Antioxidants attracted long-standing attention as promising preventive agents worldwide. Previous observational studies have reported that circulating antioxidants are associated with reduced mortality; however, randomized clinical trials indicate neutral or harmful impacts. The association of long-term circulating antioxidant exposure with longevity is still unclear. OBJECTIVES: We aim to determine whether long-term circulating antioxidant exposure is causally associated with longevity in the general population using the two-sample Mendelian randomization (MR) design. METHODS: Genetic instruments for circulating antioxidants (ascorbate, lycopene, selenium, beta-carotene, and retinol) and antioxidant metabolites (ascorbate, alpha-tocopherol, gamma-tocopherol, and retinol) were identified from the largest up-to-date genome-wide association studies (GWASs). Summary statistics of these instruments with individual survival to the 90(th) vs. 60(th) percentile age (11,262 cases and 25,483 controls) and parental lifespan (N = 1,012,240 individuals) were extracted. The causal effect was estimated using the inverse-variance weighted method in the main analysis and complemented by multiple sensitivity analyses to test the robustness of results. RESULTS: We found that genetically determined higher concentration of circulating retinol (vitamin A) metabolite was casually associated with a higher odds of longevity (OR, 1.07; 95% CI, 1.02–1.13; P < 0.01) and increased parental lifespan (lifespan years per 10-fold increase: 0.17; 95% CI, 0.07–0.27; P < 0.01). Present evidence did not support a causal impact of circulating ascorbate (vitamin C), tocopherol (vitamin E), lycopene, selenium or beta-carotene on life expectancy. No evidence was identified to show the pleiotropic effects had biased the results. CONCLUSIONS: Long-term higher exposure to retinol metabolite is causally associated with longevity in the general population. Future MR analyses could assess the current findings further by utilizing additional genetic variants and greater samples from large-scale GWASs.