2. Academic Validation
  3. Impaired ketogenesis in Leydig Cells drives testicular aging

Impaired ketogenesis in Leydig Cells drives testicular aging

  • Nat Commun. 2025 May 7;16(1):4224. doi: 10.1038/s41467-025-59591-8.
Congyuan Liu # 1 2,  Hao Peng # 1 2,  Jiajie Yu # 3,  Peng Luo # 4,  Chuanfeng Xiong 1 2,  Hong Chen 5 6,  Hang Fan 1 2,  Yuanchen Ma 1 2,  Wangsheng Ou 7,  Suyuan Zhang 1 2,  Cuifeng Yang 3,  Lerong Zhao 1 2,  Yuchen Zhang 1 2,  Xiaolu Guo 5 6,  Qiong Ke 1 2,  Tao Wang 1 2,  Chunhua Deng 3,  Weiqiang Li 1 2,  Andy Peng Xiang 8 9,  Kai Xia 10 11
Affiliations

Affiliations

  • 1 Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 2 National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 3 Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 4 Reproductive Medicine Center, The First Affiliated Hospital, Sun Yat-sen University, The Key Laboratory for Reproductive Medicine of Guangdong Province, Guangzhou, Guangdong, China.
  • 5 Center for Stem Cells Translational Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, Guangdong, China.
  • 6 Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
  • 7 State Key Laboratory of Ophthalmology, Zhong Shan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 8 Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China. xiangp@mail.sysu.edu.cn.
  • 9 National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China. xiangp@mail.sysu.edu.cn.
  • 10 Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China. xiak7@mail.sysu.edu.cn.
  • 11 National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China. xiak7@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 40328805 DOI: 10.1038/s41467-025-59591-8
Abstract

Testicular aging commonly leads to testosterone deficiency and impaired spermatogenesis, yet the underlying mechanisms remain elusive. Here, we show that Leydig cells are particularly vulnerable to aging processes in testis. Single-cell RNA Sequencing identifies the expression of Hmgcs2, the gene encoding rate-limiting enzyme of ketogenesis, decreases significantly in Leydig cells from aged mice. Additionally, the concentrations of ketone bodies β-hydroxybutyric acid and acetoacetic acid in young testes are substantially higher than that in serum, but significantly diminish in aged testes. Silencing of Hmgcs2 in young Leydig cells drives cell senescence and accelerated testicular aging. Mechanistically, β-hydroxybutyric acid upregulates the expression of Foxo3a by facilitating histone acetylation, thereby mitigating Leydig cells senescence and promoting testosterone production. Consistently, enhanced ketogenesis by genetic manipulation or oral β-hydroxybutyric acid supplementation alleviates Leydig cells senescence and ameliorates testicular aging in aged mice. These findings highlight defective ketogenesis as a pivotal factor in testicular aging, suggesting potential therapeutic avenues for addressing age-related testicular dysfunction.

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