Identification of a gene expression pattern associated with frailty and related to senescence

Frailty is a geriatric syndrome that represents a state of vulnerability with increased risk of negative health outcomes and the molecular mechanisms underlying frailty remain poorly understood. In our study, we performed a transcriptomic analysis of robust and frail community-dwelling individuals and we identified the differential expression of 35 transcripts associated with frailty based on Timed Up and Go, Gait Speed and Tilburg frailty indicator scales. Seven candidates were validated in two independent cohorts and also showed a differential expression pattern in serially passaged human primary fibroblasts and myoblasts. Their expression was partially restored after intervention of frail individuals with physical activity. Additional analyses revealed the expression of a 3-gene pattern, i.e. increased EGR1 and reduced DDX11L1 and miR454, associated with frail individuals and with clinical parameters related to frailty such as polypharmacy and multimorbidity. Loss and gain of EGR1, DDX11L1 and miR454 function experiments in fibroblasts showed they regulate cell proliferation and senescence. In addition, they modulate senescence-related downstream pathways. In conclusion, our results identify a pattern of genes whose altered expression is related to frailty and highlight senescence-associated pathways driven by EGR1, DDX11L1 and miR454 as potential biomarkers and players in the physiopathology of frailty.