Lian Wang, Liwei Mao, Danlin Zhu, Ke Li, Haoyang Gao, Muge Zhou, Jiabin Wu, Dan Yang, Ze Wang, Wenhong Wang, Yifan Guo, Yingying Xu, Peijie Chen, Weihua Xiao
• Aerobic exercise elevated circulating β-hydroxybutyrate (β-HB) levels and improved cognitive performance in aging mice. • Loss of 3-hydroxybutyrate dehydrogenase 1 (BDH1) impaired endogenous β-HB production and attenuated exercise-induced cognitive benefits. • Exogenous β-HB mimicked exercise effects in wild-type mice but showed limited efficacy in BDH1-deficient mice. • Activation of the β-HB/G protein-coupled receptor 109A–peroxisome proliferator-activated receptor gamma (GPR109A–PPARγ) axis promoted antioxidant and anti-inflammatory responses that support cognitive function in aging. 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. 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. 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. 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.