Ageing Fatigue Subtypes: A Mechanism-Based Nomenclature and Translational Research Framework

Fatigue is among the most prevalent and functionally limiting symptoms in older adults, affecting an estimated 15–45% of community-dwelling individuals aged 65 and above. Despite its prevalence, fatigue in ageing remains defined by subjective report and assessed by instruments that are mechanism-agnostic, creating a fundamental barrier to therapeutic development. No validated biological taxonomy of ageing-related fatigue currently exists. This paper proposes a mechanism-based working nomenclature for fatigue subtypes in ageing, maps each subtype to its dominant biological pathway, candidate biomarkers, and clinical outcome assessment (COA) limitations, and identifies repurposable therapeutic candidates and evidence gaps. Five mechanistically distinct fatigue subtypes are proposed: OxFatigue (mitochondrial dysfunction/NAD⁺ depletion), ImmuneFatigue (chronic low-grade inflammation/SASP), NeuroFatigue (neuroinflammaging/microglial priming), TryptoFatigue (IDO1-driven tryptophan-kynurenine pathway activation), and GlycoFatigue (insulin resistance of energy metabolism/mTOR–AMPK dysregulation). A sixth composite subtype, MetaFatigue, is proposed for convergent multi-pathway states in advanced frailty. Each subtype carries distinct biomarker signatures and maps to pathway-matched repurposing candidates. A mechanism-based nomenclature for ageing fatigue is the necessary precondition for biomarker-enriched clinical trials and precision geroscience. This framework provides a testable platform for subtype validation and creates a translational bridge to rare inherited metabolic diseases sharing convergent pathway biology. CortexBio Pillar: Metabolic Mosaic. Project code: CB-FATIGUE-AGEING-01. SANRA compliance: 12/12. Scientific priority date: 18 June 2026.