The lactate shuttle in ageing: a metabolic bridge between muscle fatigue and brain resilience

Traditionally, lactate was considered a glycolytic byproduct that causes muscle fatigue, but now its biological role is undergoing a significant paradigm shift. Emerging evidence suggests that lactate acts as an inter-organ metabolic and signaling mediator linking exercise-induced peripheral metabolic stress to central nervous system adaptation. This review explores how exercise drives lactate pulses and delivers them to the brain through the circulatory system and blood-brain barrier (BBB). Lactate has a dual function in the brain, serving not only as the preferred energy substrate for active neurons but also as a core signaling molecule. Through pathways involving G protein coupled receptor 81 (GPR81) and histone lactylation, lactate regulates neuroplasticity, cerebrovascular function, neuroinflammation, and antioxidant defense, thereby establishing cognitive resilience. During aging, multiple components of this proposed lactate signaling axis may become compromised, including skeletal muscle lactate production, circulatory and blood-brain barrier transport, and cellular responsiveness within the brain. Such multi-level impairment may contribute to neuromuscular co-aging and may increase vulnerability to neurodegenerative disorders, including Alzheimer's disease. Ultimately, we explored the translational potential of restoring the lactate signaling axis through multimodal strategies to promote healthy aging, including precise exercise prescriptions, GPR81 targeted therapy, metabolic interventions, and biomarker development. This review aims to combine metabolic science with evidence of neuroaging, providing a new theoretical framework for determining the primacy of exercise-driven brain health and advancing anti-aging interventions.