Symphony of regulated cell death: Unveiling therapeutic horizons in sarcopenia.

Abstract

Sarcopenia is a progressive musculoskeletal condition associated with aging, marked by a decline in muscle mass, strength, and performance. This condition not only compromises functional independence in older individuals but also contributes to escalating healthcare and economic burdens. Although the underlying mechanisms are complex and multifaceted, recent discoveries have emphasized the regulatory influence of multiple forms of programmed cell death-including apoptosis, ferroptosis, necroptosis, and pyroptosis-on skeletal muscle degeneration. These cell death pathways contribute to key pathological features such as muscle fiber loss, proteostasis imbalance, neuromuscular dysfunction, mitochondrial deficits, and persistent inflammation. This review synthesizes current understanding of the molecular underpinnings of regulated cell death (RCD) in sarcopenia and discusses emerging therapeutic interventions aimed at modulating these pathways. These include pharmacological agents (e.g., ferroptosis inhibitors, polyphenols), structured exercise programs (notably resistance), targeted nutritional support (e.g., amino acids, vitamin D), cell-based therapies, and gene-targeted strategies. Despite growing evidence supporting RCD as a viable therapeutic target, the interplay among different cell death modalities and the translation of mechanistic insights into clinical practice remain insufficiently understood. Advancing sarcopenia treatment will require integrated multi-omics analyses, identification of predictive biomarkers, and rigorously designed clinical studies to support personalized and effective therapeutic approaches.