Skeletal Muscle – Brain Crosstalk in Cognitive Aging and Dementia: Physiological Roles of Myokines and Lactate Signalling

ABSTRACT Aging is accompanied by progressive cognitive decline and an increasing burden of dementia. While physical activity is one of the most effective non-pharmacological strategies for preserving cognitive health, the biological mechanisms underlying its neuroprotective effects remain incompletely understood. In recent years, skeletal muscle has emerged as an active endocrine organ that communicates with the brain through the release of myokines and metabolites during exercise. This muscle–brain crosstalk provides a mechanistic framework linking muscle activity to brain plasticity and cognitive resilience.This clinical and translational narrative review synthesizes experimental and translational evidence on skeletal muscle–brain communication in cognitive aging and dementia, with a specific focus on irisin (FNDC5), brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and lactate signalling. Exercise-induced irisin enhances hippocampal BDNF expression and synaptic plasticity, while acute muscle-derived IL- 6 exerts anti-inflammatory effects that contrast with the chronic inflammatory state of aging. Lactate, once considered a metabolic by-product, is now recognized as a key signalling molecule that supports neuronal metabolism, memory formation, and epigenetic regulation through lactylation.Aging disrupts these beneficial signalling pathways through sarcopenia, metabolic dysfunction, and chronic low-grade inflammation, thereby increasing vulnerability to cognitive decline and dementia. Evidence from animal models, observational studies, and exercise interventions in older adults supports a causal link between skeletal muscle health and cognitive outcomes.By integrating molecular mechanisms with clinical observations, this review highlights skeletal muscle as a modifiable determinant of brain aging. Preserving muscle health through targeted exercise emerges as a physiologically grounded strategy for promoting cognitive resilience and reducing dementia risk.