Immune cell contributions to sarcopenia: Evidence from genetic analyses

Recent evidence suggests a potential role of immune cell activity in the development of sarcopenia, but the causal relationship remains unclear. To address this, we conducted a bidirectional 2-sample Mendelian randomization (MR) analysis to evaluate whether immune cell traits causally influence sarcopenia. Genetic instruments for 731 immune cell traits were derived from a cohort of 3757 individuals of European ancestry, and sarcopenia-related data (including hand grip strength, appendicular lean mass, and walking pace-) were obtained from large-scale genome-wide association studies of European populations. Causal effects were estimated using inverse-variance weighted and weighted median MR, with MR-Egger regression applied for sensitivity analyses. Our results identified several immune cell traits with significant causal effects on sarcopenia. Increased expression of human leukocyte antigen-DR on plasmacytoid and total conventional dendritic cells, as well as human leukocyte antigen-DR on cluster of differentiation 33- myeloid cells, was associated with lower appendicular lean mass, slower walking pace, and higher risk of low hand grip strength. Conversely, certain lymphoid cell traits, including higher numbers of specific T and B cell subsets, were associated with protective effects against sarcopenia. Reverse MR analyses indicated no strong causal effects of sarcopenia traits on immune cell profiles. These findings provide robust genetic evidence supporting a causal link between immune cell composition and sarcopenia, highlighting myeloid cells as potential contributors to sarcopenia development, while lymphoid cells may exert protective effects. This insight advances our understanding of sarcopenia pathophysiology and may inform future preventive and therapeutic strategies.