Exercise-induced β-hydroxybutyrate contributes to cognitive improvement in aging mice.

Journal of sport and health science 2025

Wang L, Mao L, Zhu D, Li K, Gao H, Zhou M, Wu J, Yang D, Wang Z, Wang W, Guo Y, Xu Y, Chen P, Xiao W

Abstract

BACKGROUND: Aging is a major contributor to cognitive decline and neurodegeneration, yet effective interventions to counteract aging-related neuronal dysfunction remain limited. β-hydroxybutyrate (β-HB), a ketone body elevated during fasting or aerobic exercise, functions as both an energy substrate and a signaling metabolite. METHODS: We assessed the effects of exercise-induced and exogenously supplemented β-HB on cognitive performance in aging mice. To examine the role of endogenous β-HB metabolism, we used 3-hydroxybutyrate dehydrogenase 1 (BDH1) knockout mice. In vitro, we investigated the impact of G protein-coupled receptor 109A (GPR109A) knockdown on β-HB-mediated activation of peroxisome proliferator-activated receptor gamma (PPARγ) and downstream pathways. RESULTS: Exercise elevated circulating β-HB levels and improved cognitive outcomes in aging mice. Exogenous β-HB supplementation mimicked these benefits. Loss of BDH1 impaired endogenous β-HB production and attenuated both exercise- and β-HB-induced cognitive improvements. In vitro, GPR109A knockdown suppressed β-HB-driven activation of PPARγ and downstream neuroprotective pathways linked to inflammation and oxidative stress. CONCLUSION: These findings identify the β-HB/GPR109A-PPARγ axis as a key mediator of exercise-induced cognitive enhancement in aging. β-HB emerges as a potential therapeutic candidate to mitigate brain aging and cognitive decline.

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