Fatigue, muscle fatigability, and the Hallmarks of Aging: a narrative review

BACKGROUND: Fatigue is a common symptom in the general population, and its prevalence increases with advancing age, suggesting that it may represent an age-related condition. However, the underlying pathophysiological mechanisms of fatigue during aging remain poorly understood, limiting the identification of potential therapeutic targets. This review summarises current evidence on the associations between the main biological drivers of ageing and both self-perceived fatigue and muscle fatigability. METHODS: Broad search terms related to fatigue and the hallmarks of ageing were combined. Studies using any study design were included if they involved human participants and reported associations between fatigue and biomarkers of ageing. Studies were excluded if they focused solely on patients with specific diseases or if fatigue was embedded within specific symptom clusters. RESULTS: Thirty studies were included; they were published between 2005 and 2024. Most studies (83%) involved community-dwelling subjects; 63% were cross-sectional. Mitochondrial dysfunction(definition) and chronic inflammation showed the strongest associations with self-perceived fatigue and, to a lesser extent, muscle fatigability. Mitochondrial dysfunction may contribute via impaired electron transport and early anaerobic metabolism, while inflammatory markers (e.g., interleukin-6, C-reactive protein) may act via central nervous system pathways and persistent subclinical systemic inflammation. We found no evidence linking epigenetic alterations, proteostasis(definition) dysfunction, and impaired macroautophagy to fatigue. Other hallmarks show limited evidence. CONCLUSIONS: Despite its clinical relevance, the interplay between the biological drivers of ageing and the fatigue is still poorly understood, although current findings suggest a role for mitochondrial dysfunction and chronic inflammation. Further investigations may help identify potential pathways for treating fatigue.