Mendelian randomization supports causality between overweight status and accelerated aging.

It is reported that overweight may lead to accelerated aging. However, there is still a lack of evidence on the causal effect of overweight and aging. We collected genetic variants associated with overweight, age proxy indicators (telomere length, frailty index and facial aging), etc., from genome-wide association studies datasets. Then we performed MR analyses to explore associations between overweight and age proxy indicators. MR analyses were primarily conducted using the inverse variance weighted method, followed by various sensitivity and validation analyses. MR analyses indicated that there were significant associations of overweight on telomere length, frailty index, and facial aging (β = -0.018, 95% CI = -0.033 to -0.003, p = 0.0162; β = 0.055, 95% CI = 0.030-0.079, p < 0.0001; β = 0.029, 95% CI = 0.013-0.046, p = 0.0005 respectively). Overweight also had a significant negative causality with longevity expectancy (90th survival percentile, β = -0.220, 95% CI = -0.323 to -0.118, p < 0.0001; 99th survival percentile, β = -0.389, 95% CI = -0.652 to -0.126, p = 0.0038). Moreover, the findings tend to favor causal links between body fat mass/body fat percentage on aging proxy indicators, but not body fat-free mass. This study provides evidence of the causality between overweight and accelerated aging (telomere length decreased, frailty index increased, facial aging increased) and lower longevity expectancy. Accordingly, the potential significance of weight control and treatment of overweight in combating accelerated aging need to be emphasized.