Lactylation: Unlocking the regulatory code of exercise-mediated anti-aging.

Abstract

Aging is a complex biological process characterized by the loss of metabolic homeostasis, epigenetic drift, and systemic functional decline. Although exercise is widely recognized as a potent non-pharmacological intervention for aging, the mechanisms by which it translates transient metabolic fluctuations into long-term systemic adaptations remain incompletely understood. During physical activity, skeletal muscle exhibits significantly enhanced glycolytic flux, leading to the accumulation of lactate. This key metabolite is dynamically distributed across tissues via monocarboxylate transporters, acting as a pivotal signaling hub that links exercise load to systemic metabolic remodeling. The discovery of lysine lactylation (Kla) has redefined the biological significance of lactate, identifying it as a signaling molecule that functions as a molecular interface between cellular metabolic states and epigenetic regulation.Here, we systematically review the core "Exercise-Lactate-Kla" regulatory axis. We elucidate how exercise-induced lactylation retards the aging process at the molecular level by orchestrating mitochondrial quality control, maintaining immune homeostasis, promoting stem cell regeneration, and suppressing the senescence-associated secretory phenotype (SASP). Furthermore, we provide a comprehensive analysis of the cross-organ anti-aging effects of this axis across multiple physiological domains, including the neurological, cardiovascular, musculoskeletal, and metabolic systems. Concurrently, this review systematically evaluates existing research using a three-tier evidence grading framework, clarifying the differences in evidence strength across various mechanisms and identifying core causal gaps. This provides a novel theoretical framework for understanding the "metabolism-epigenetics" coupling mechanism by which exercise delays aging, and establishes a scientific foundation for formulating precise exercise prescriptions and developing lactylation-targeted anti-aging strategies in the future.