Persistent fatigue is often dismissed as an inevitable consequence of getting older, but understanding its biological roots could open doors to targeted interventions that meaningfully extend functional healthspan. This narrative review tackles a surprisingly underexplored question: which of the recognized hallmarks of biological aging are most tightly linked to the fatigue that accumulates across the lifespan?
Drawing on 30 studies published between 2005 and 2024, the majority involving community-dwelling older adults, the review identified mitochondrial dysfunction and chronic low-grade inflammation as the two hallmarks most consistently associated with both subjective fatigue and objective muscle fatigability. Mitochondrial dysfunction appears to drive fatigue partly through impaired electron transport chain efficiency and a premature shift toward anaerobic metabolism under exertion. Inflammatory mediators — particularly interleukin-6 and C-reactive protein — seem to act through central nervous system pathways and persistent subclinical systemic inflammation rather than peripheral muscle mechanisms alone. Notably, 63% of included studies were cross-sectional, limiting causal inference, and no evidence linking other hallmarks — such as cellular senescence, epigenetic alterations, or stem cell exhaustion — to fatigue was found, though the authors acknowledge this may reflect a research gap rather than a true absence of effect.
This synthesis is valuable but comes with meaningful caveats. The preponderance of cross-sectional designs means the directionality of these associations remains unresolved — fatigue itself may accelerate mitochondrial decline through physical inactivity, creating a bidirectional feedback loop. The focus on community-dwelling subjects, while appropriate for isolating age-related rather than disease-related fatigue, also means findings may not translate to frailer populations. Practically, the mitochondrial and inflammatory pathways identified here overlap substantially with mechanisms already being targeted by lifestyle interventions — aerobic training, caloric restriction mimetics, and anti-inflammatory dietary patterns — lending those approaches additional mechanistic rationale. This review is best characterized as confirmatory and consolidating rather than paradigm-shifting, but its structured framing of fatigue within the hallmarks-of-aging model provides a useful scaffold for future longitudinal and interventional research.
