2. Academic Validation
  3. Exercise-induced β-hydroxybutyrate contributes to cognitive improvement in aging mice

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

  • J Sport Health Sci. 2025 Dec 18:101113. doi: 10.1016/j.jshs.2025.101113.
Lian Wang 1,  Liwei Mao 1,  Danlin Zhu 2,  Ke Li 2,  Haoyang Gao 2,  Muge Zhou 3,  Jiabin Wu 2,  Dan Yang 2,  Ze Wang 2,  Wenhong Wang 4,  Yifan Guo 5,  Yingying Xu 6,  Peijie Chen 7,  Weihua Xiao 8
Affiliations

Affiliations

  • 1 Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
  • 2 Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China.
  • 3 Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; Rehabilitation Center, Children's Hospital of Fudan University, Shanghai 201102, China.
  • 4 Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; Research Institute for Biology and Medicine, Hunan University of Medicine, Huaihua 418000, China.
  • 5 Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; School of Elderly Care Services and Management, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 6 Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; Department of Physical Education, Henan Sport University, Zhengzhou 450044, China.
  • 7 Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China. Electronic address: [email protected].
  • 8 Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China. Electronic address: [email protected].
PMID: 41421649 DOI: 10.1016/j.jshs.2025.101113
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.

Keywords

BDH1; Exercise; GPR109A; PPARγ; β-hydroxybutyrate.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
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  • HY-16578
    99.98%, PPARγ Antagonist