Impaired ketogenesis in Leydig Cells drives testicular aging

Congyuan Liu, Hao Peng, Jiajie Yu, Peng Luo, Chuanfeng Xiong, Hong Chen, Hang Fan, Yuanchen Ma, Wangsheng Ou, Suyuan Zhang, Cuifeng Yang, Lerong Zhao, Yuchen Zhang, Xiaolu Guo, Qiong Ke, Tao Wang, Chunhua Deng, Weiqiang Li, Andy Peng Xiang () and Kai Xia ()
Additional contact information
Congyuan Liu: Sun Yat-sen University
Hao Peng: Sun Yat-sen University
Jiajie Yu: Sun Yat-sen University
Peng Luo: Sun Yat-sen University, The Key Laboratory for Reproductive Medicine of Guangdong Province
Chuanfeng Xiong: Sun Yat-sen University
Hong Chen: Shenzhen Qianhai Shekou Free Trade Zone Hospital
Hang Fan: Sun Yat-sen University
Yuanchen Ma: Sun Yat-sen University
Wangsheng Ou: Sun Yat-sen University
Suyuan Zhang: Sun Yat-sen University
Cuifeng Yang: Sun Yat-sen University
Lerong Zhao: Sun Yat-sen University
Yuchen Zhang: Sun Yat-sen University
Xiaolu Guo: Shenzhen Qianhai Shekou Free Trade Zone Hospital
Qiong Ke: Sun Yat-sen University
Tao Wang: Sun Yat-sen University
Chunhua Deng: Sun Yat-sen University
Weiqiang Li: Sun Yat-sen University
Andy Peng Xiang: Sun Yat-sen University
Kai Xia: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59591-8

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