The Lactate Nexus: A Molecular Bridge Linking Physical Activity, Sleep, and Cognitive Enhancement
Alimjan Ablitip, Kefeng Zheng, Hao Ding, Yicong Cui, Xindong Ma, Yanwei You
Abstract
Physical activity (PA) and quality sleep are essential for cognitive health, providing synergistic protection against age-related cognitive decline. However, the shared molecular pathways that explain their combined and interactive benefits remain poorly understood. This review suggests that lactate, long dismissed as a metabolic waste product, is a unifying mechanism. We introduce the "Lactate Nexus", a conceptual framework that proposes lactate functions as a key signalling molecule, mechanistically linking the pro-cognitive effects of both daytime exercise and nighttime sleep. We begin by outlining lactate's evolving role-from an energy substrate shuttled from astrocytes to neurons (the Astrocyte-Neuron Lactate Shuttle) to a pleiotropic signal. As a signal, lactate influences neuroplasticity via NMDA receptors, neuroinflammation via the HCAR1 receptor, and gene expression through the epigenetic modification of histone lactylation. We then compile evidence demonstrating how PA provides a substantial lactate signal that activates these pathways and primes the brain's metabolic infrastructure. Crucially, we integrate this with proof that lactate levels naturally increase during slow-wave sleep to support memory consolidation and glymphatic clearance. The "Lactate Nexus" framework offers a comprehensive molecular explanation for the synergy between PA and sleep, positioning lactate as a key signalling mediator and a promising biomarker and therapeutic target for fostering lifelong cognitive resilience.