Genetic insights into aging: Obesity’s impact on frailty risk uncovered

Frailty is an age-associated condition characterized by a state of vulnerability that compromises the quality of life and independence of older adults. To date, no studies have employed Mendelian randomization (MR) to investigate the causal relationship between obesity and frailty risk. Therefore, this study utilized a two-sample MR approach to elucidate the potential causal link between obesity and frailty. A two-sample MR analysis was conducted to assess the causal relationship between body mass index (BMI) or waist circumference and frailty. Independent genetic variants associated with obesity and frailty were selected as instrumental variables (IVs). MR analyses were primarily performed using inverse variance weighting, MR-Egger, weighted median, simple, and weighted models. In addition, the Mendelian Randomization Pleiotropy RESidual Sum and Outlier framework was applied to assess horizontal pleiotropy and to identify potential outlier variants. Through a rigorous and meticulous screening process, we identified 68 and 41 single nucleotide polymorphisms as IVs for BMI and waist circumference, respectively. Our analyses uncovered a significant positive causal association with frailty for both BMI (β = 0.1283, SE = 0.0255, P = 5.2589e-07) and waist circumference (β = 0.1340, SE = 0.0357, P = .0001). Cochran Q-test indicated the presence of heterogeneity among the IV estimates attributable to individual variant effects in both analyses (Q = 153.8575, P < 8.753493e-09; Q = 111.1552, P < 7.432416e-09). Besides, no significant pleiotropy was detected for the association of BMI, waist circumference and with frailty (intercept = 0.002609868, P = .2054007; intercept = 0.003445858; P = .7968586). The Mendelian Randomization Pleiotropy RESidual Sum and Outlier analysis identified no outliers for either exposure, and thus no single nucleotide polymorphisms were excluded. This study substantiates the significant association between obesity and an elevated risk of frailty, thereby offering a robust theoretical foundation for policymakers to institute more stringent weight management strategies.