ABSTRACT Background: Although obesity and frailty interrelationship remains debated, it is biologically plausible that obesity accelerates frailty through chronic inflammation, insulin resistance, and oxidative stress; however, observational evidence is limited by confounding and reverse causality. Mendelian randomization leverages genetic variants as instrumental variables to strengthen causal inference and help clarify the directionality of the obesity–frailty relationship. Objectives: This study aims to investigate the bidirectional causal relationship between obesity and frailty using a two-sample Mendelian randomization (MR) approach. Recognizing the potential interplay between these conditions, where obesity may contribute to frailty and vice versa, we seek to clarify the causality and magnitude of their association, addressing critical gaps in the current understanding of these interlinked health challenges. Methods: We utilized genome-wide association study (GWAS) data from 638,236 individuals, with obesity and frailty data sourced from the UK Biobank (GWAS ID: Ukb-b-15541) and the European Bioinformatics Institute (GWAS ID: Ebi-a-GCST90020053), respectively. A total of 94 single-nucleotide polymorphisms were selected as instrumental variables for both traits following stringent statistical screening criteria. MR analyses were conducted using multiple approaches to ensure the robustness and consistency of causal estimates. Results: The findings reveal a significant bidirectional causal relationship between obesity and frailty. Genetic liability to obesity was associated with an increased risk of frailty, while genetic predisposition to frailty was also linked to a higher likelihood of obesity. These results suggest a reinforcing feedback loop between the two conditions. Sensitivity analyses further supported these findings, demonstrating minimal evidence of heterogeneity or pleiotropy. Conclusion: This study provides robust evidence for a bidirectional causal relationship between obesity and frailty, emphasizing the importance of integrated clinical and public health interventions addressing both conditions. The findings highlight the potential for targeted strategies to mitigate frailty risks by managing obesity and vice versa, offering valuable insights for promoting healthier aging.
Ji et al. (Wed,) studied this question.