From Genes to Longevity: Identifying Modifiable Risk Factors That Accelerate or Delay Aging

Background With global aging, slowing aging is an urgent priority. While inevitable, aging rate may be modifiable by various environmental factors. This study aims to identify modifiable factors that have causal associations with aging. This can inform strategies to extend healthspan and mitigate the societal burden of aging. Methods and Design We evaluated 57 potentially modifiable risk factors for their associations with aging by using a two-sample bidirectional Mendelian randomization (MR) framework from Genome-wide association studies of 2,913 to 1,405,995 individuals who were predominantly of European descent. MR analyses were primarily conducted using the inverse-variance-weighted method, followed by various sensitivity analyses. Results Among 57 potentially risk factors, we identified ferritin, transferrin saturation, the initial stage of smoking, body mass index and systolic blood pressure as key factors that significantly contribute to accelerated aging. Primarily, ferritin exhibits a noteworthy impact on GrimAge acceleration (β [SE] per 1-SD increase: 0.646 [0.101] year), PhenoAge acceleration (per 1-SD increase: 0.565 [0.138] year), and telomere length (per 1-SD increase: -0.570 [0.169] year). Moderate indicators include leisure screen time, osteoarthritis and daily cigarette consumption. Meanwhile, educational attainment was identified as an effective factor in slowing the aging process. Sensitivity analyses corroborated the robustness of these causal associations. Conclusion The study provides unique quantitative insights into modifiable causal risk factors for aging. Our findings underscore valuable intervention targets capable of slowing biological aging and fostering healthy longevity - an indispensable reference for public health strategies and relevant clinical scenarios.