Causal Associations of Cognitive Reserve and Hierarchical Aging-Related Outcomes: A Two-Sample Mendelian Randomization Study.

Purpose Two-sample Mendelian randomization methods were used to explore the causal effects of cognitive reserve proxies, such as educational attainment, occupational attainment, and physical activity (PA), on biological (leukocyte telomere length), phenotypic (sarcopenia-related features), and functional (frailty index and cognitive performance) aging levels.Results Educational attainment had a potential protective effect on the telomere length (beta = 0.10, 95% CI: 0.08-0.11), sarcopenia-related features (beta = 0.04-0.24, 95% CI: 0.02-0.27), frailty risk (beta = -0.31, 95% CI: -0.33 to -0.28), cognitive performance (beta = 0.77, 95% CI: 0.75-0.80). Occupational attainment was causally related with sarcopenia-related features (beta = 0.07-0.10, 95% CI: 0.05-0.14), and cognitive performance (beta = 0.30, 95% CI: 0.24-0.36). Device-measured PA was potentially associated with one sarcopenia-related feature (beta = 0.14, 95% CI: 0.03-0.25).Conclusions Our findings support the potential causality of educational attainment on biological, phenotypic, and functional aging outcomes, of occupational attainment on phenotypic and functional aging-related outcomes, and of PA on phenotypic aging-related outcomes.