Myokines as molecular mediators of the muscle-brain axis: Mechanisms linking sarcopenia to cognitive decline and implications for preventive strategies in ageing - A narrative review.
TL;DR
Convergent preclinical and emerging human evidence supports the PGC-1α/FNDC5/BDNF pathway as a central mediator of exercise-induced neuroprotection, while chronic IL-6 elevation and IGF-1 decline emerge as bidirectional drivers of muscle and brain ageing.
Abstract
Sarcopenia and cognitive decline frequently co-occur in older adults, and growing evidence indicates that these conditions share a common biological substrate centred on the muscle-brain axis. In this narrative review we synthesise contemporary mechanistic and translational evidence on how skeletal muscle communicates with the ageing brain through myokines and exerkines - including irisin/FNDC5, brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), cathepsin B, and growth differentiation factor-15 (GDF-15) - and how progressive sarcopenia disrupts this signalling to accelerate cognitive impairment. Database searches in PubMed, Scopus and Web of Science (2000-2026) identified 147 records, of which 68 primary studies and reviews were synthesised under three thematic pillars: (i) the molecular biology of the muscle-brain axis in ageing; (ii) shared pathophysiological mechanisms - mitochondrial dysfunction, neuromuscular junction (NMJ) instability, inflammaging and anabolic resistance - linking sarcopenia to cognitive decline; and (iii) preventive strategies that operate through this axis. Convergent preclinical and emerging human evidence supports the PGC-1α/FNDC5/BDNF pathway as a central mediator of exercise-induced neuroprotection, while chronic IL-6 elevation and IGF-1 decline emerge as bidirectional drivers of muscle and brain ageing. Multicomponent exercise, optimised protein/leucine intake, lecithin and probiotic interventions, repetitive transcranial magnetic stimulation, and pharmacological modulation of AMPK/PGC-1α/SIRT1 signalling all show capacity to reshape the myokine secretome and preserve cognition, though evidence levels vary substantially across intervention categories. We highlight key knowledge gaps - including a translational gap between rodent and human evidence, the absence of validated myokine biomarker panels, and the need for standardised assay protocols - and outline an integrative model to guide future biogerontological research and preventive trials.