The mitochondrial side of frailty

Purpose of review. Frailty, a prevalent geriatric condition marked by reduced physiological reserve and greater vulnerability to stressors, is increasingly linked to mitochondrial dysfunction. This review summarizes current evidence on mitochondrial quality control, bioenergetics, and signaling in frailty, with emphasis on biomarker discovery and translational potential. Recent findings. Preclinical and human studies have shown that impaired mitochondrial biogenesis, altered dynamics, and defective mitophagy contribute to frailty, sarcopenia, and immune dysregulation. Frail older adults exhibit reduced mitochondrial DNA content, diminished mitochondrial respiratory capacity, elevated reactive oxygen species generation, and distinctive metabolomic changes. Potential biomarkers include mitochondria-derived vesicles, circulating metabolites, and measures of peripheral blood mononuclear cell respiration, which may enable early detection of functional decline. Multivariate profiling approaches have identified sex-specific and shared molecular signatures converging on mitochondrial pathways. Interventions promoting mitochondrial health, including resistance training and targeted immunomodulation, hold promise in slowing frailty progression. Summary. Mitochondrial dysfunction lies at the intersection of musculoskeletal, metabolic, and immune changes underpinning frailty. While integrative biomarker panels have defined metabolic signatures, early diagnosis and personalized therapies remain unmet needs. Longitudinal studies are required to establish causality, refine biomarker utility, and guide precision medicine strategies to preserve mitochondrial function, extend healthspan, and improve quality of life in aging populations.