Identification of Key Genes and Pathways Associated with Frailty and Exercise Effects Using a Network and Evolutionary Approach

Background: Frailty is an aging-associated syndrome involving a loss of physiological reserve and function, with decreased ability to recover from physical and psychosocial stress. However, the etiology and pathogenesis of frailty remain largely unknown. Aim: This study aimed to investigate key genes involved in frailty pathogenesis, exercise effects, and their contributions. Methods: We performed a weighted gene co-expression network analysis using a microarray dataset. By using the positive selection (PS), human accelerated region (HAR), and aging gene sets, we identified key genes for frailty and exercise-related genes. Results: We identified magenta and pink modules that have the most significant enrichments for the evolutionally elaborated genes. A functional enrichment analysis (FEA) revealed that genes related to redox-process regulation and extracellular-matrix organization were enriched in magenta and pink modules, respectively. We observed that six of the evolutionarily imprinted genes in the modules (MEOX2, PLCB4, LPAR6, SH3KBP1, APP and SPON1) were highly connected and showed signs of hub properties, which might play crucial roles in frailty- and exercise-related mechanisms. Conclusions: Further investigation into the functions of the identified modules and their member genes could aid in identifying diagnostic biomarkers and therapeutic targets for frailty.