Restoration of circadian rhythm as novel targets against sarcopenia

ABSTRACT: Sarcopenia, characterized by the age-related decline in skeletal muscle mass, strength, and function, is associated with high healthcare costs and significant health risks, including falls, fractures, functional decline, and mortality. Despite its prevalence and extensive research, there are currently no Food and Drug Administration (FDA)-approved drugs to modify its course, likely due to an incomplete understanding of its underlying mechanisms. Recent evidence highlights two key factors in sarcopenia development: (1) Disrupted circadian rhythms affecting pathways such as protein remodeling, insulin resistance, and mitochondrial function; (2) systemic chronic low-grade inflammation (SCLGI). This review focuses on circadian rhythm regulators implicated in skeletal muscle deterioration, examining their roles, potential interactions, and the impact of circadian disruption on sarcopenia progression. Additionally, we explore how clock genes reciprocally influence the inflammatory profile, which is crucial for developing treatment strategies to mitigate the detrimental effects of sarcopenia. We also examine factors that influence the clock and have the potential to restore circadian rhythm mechanisms that are deregulated in sarcopenia. Drawing from these insights, strategies aimed at restoring circadian synchrony and resolving inflammation are proposed as a novel therapeutic approach to effectively mitigate the manifestations of sarcopenia.