The Bidirectional Casual Relationships between Chronic Inflammation and Intrinsic Capacity Decline: Insights from Mendelian Randomization Analysis

INTRODUCTION: Intrinsic capacity, encompassing locomotion, vitality, cognition, psychology, and sensory function, is a critical determinant of healthy aging, yet its association with inflammatory markers remains poorly understood due to confounding factors in observational studies. We aimed to investigate the bidirectional causal relationships between chronic inflammation and intrinsic capacity decline by using Mendelian randomization (MR). METHODS: We conducted a bidirectional MR analysis using summary-level data from large-scale genome-wide association studies (GWAS). Genetic variants significantly associated with five inflammatory markers (C-reactive protein [CRP], interleukin-1 receptor antagonist [IL-1RA], interleukin-6 [IL-6], tumor necrosis factor-alpha [TNF-α], and white blood cell count [WBC]), and intrinsic capacity domains were used as instrumental variables. The inverse-variance weighted method was employed as the primary analysis, supplemented by sensitivity analyses such as MR-Egger, weighted median, and weighted mode methods. RESULTS: Higher CRP levels were negatively associated with anxiety, hand grip strength, malnutrition, and usual walking pace but positively associated with macular degeneration. Elevated IL-1RA levels were associated with reduced cognitive performance, while higher WBC levels were linked to decreased hand grip strength and usual walking pace. Better cognitive performance, hand grip strength, and the usual walking pace were associated with lower CRP and WBC levels. The robustness of these findings was confirmed by sensitivity analyses. CONCLUSION: Our study provides robust evidence for bidirectional causal relationships between chronic inflammation and intrinsic capacity decline, highlighting inflammation as a potential target for interventions to promote healthy aging. Future research is required to explore these relationships in more diverse populations and investigate therapeutic strategies to mitigate inflammation-related declines in intrinsic capacity.