Biomarkers and Early Mechanisms of Sarcopenia: Central Roles of Mitochondrial Dysfunction, Inflammaging, Cellular Senescence, and Neuromuscular Degeneration

Sarcopenia is a progressive age-related skeletal muscle disorder characterized by the loss of muscle mass, strength, and physical performance, leading to frailty, disability, and increased mortality. Although its clinical consequences are well recognized, the underlying biological mechanisms remain incompletely understood, limiting the development of early diagnostic strategies and targeted therapies. Increasing evidence indicates that sarcopenia results from complex interactions among mitochondrial dysfunction, chronic low-grade inflammation (inflammaging), cellular senescence, neuromuscular junction degeneration, and anabolic resistance. The present review critically summarizes the current evidence on the principal circulating and molecular biomarkers associated with these interconnected mechanisms. Mitochondrial dysfunction appears to represent an early upstream event that promotes excessive reactive oxygen species production, defective mitophagy, inflammatory activation, and cellular senescence. Chronic inflammation, mediated primarily through IL-6 and TNF-α, further accelerates muscle catabolism and regenerative failure, whereas senescence-associated pathways impair satellite cell function and muscle repair. Neuromuscular degeneration and anabolic resistance further contribute to progressive muscle atrophy and functional decline. Among the candidate biomarkers, GDF-15, FGF-21, IL-6, TNF-α, CAF22, p16INK4a, p21/CDKN1A, IGF-1, and myostatin appear particularly promising for characterizing the biological heterogeneity of sarcopenia. However, no single biomarker currently demonstrates sufficient diagnostic accuracy for routine clinical use. Instead, integrated multi-biomarker approaches combining mitochondrial, inflammatory, senescence-associated, neuromuscular, and anabolic markers may improve early diagnosis, risk stratification, and personalized therapeutic strategies. Future prospective longitudinal studies are required to validate these biomarkers and facilitate their translation into clinical practice.