Separating the Effects of Adiposity Across Different Life Stages on Human Longevity and Aging.

Abstract

To investigate the independent effects of body weight at different life stages on human longevity and aging. A life course Mendelian randomization (MR) framework was used to explore the relationships between birth weight, childhood body mass index (BMI), adulthood BMI, and aging-related outcomes: parental lifespan, life expectancy, intrinsic epigenetic age acceleration (IEAA), facial aging (FA), and frailty index. Univariable MR was used to assess the overall effects, whereas multivariable MR distinguished the independent effects. The study data was analyzed from April 11 to October 15, 2024. Univariable MR results found that genetically predicted 1-SD increase in childhood BMI was causally associated with a 0.115-year reduction in parental lifespan (95% CI, -0.179 to -0.132 years), lower odds of longevity (90^th percentile: odds ratio, 0.75; 95% CI, 0.60-0.94), and higher levels of IEAA (β = 0.387; 95% CI, 0.149 to 0.625), FA (β = 0.028; 95% CI, 0.002 to 0.054), and frailty index (β = 0.083; 95% CI, 0.048 to 0.118). The effects of childhood BMI on these outcomes remained significant after adjusting for birth weight and adulthood BMI (parental lifespan β = -0.115; longevity 90^th odds ratio, 0.77; IEAA β = 0.272; FI β = 0.099), with the exception of FA. These findings remained robust across multiple sensitivity analyses, including MR-Egger and weighted median methods. This study highlights the enduring influence of childhood BMI on aging and longevity outcomes, emphasizing the critical role of early-life adiposity in shaping long-term health trajectories.