Impaired ketogenesis in Leydig Cells drives testicular aging
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, th...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59591-8 |
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| author | 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 Kai Xia |
| author_facet | 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 Kai Xia |
| author_sort | Congyuan Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ccb69b59b02f4df1a3e966d6545a55b0 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ccb69b59b02f4df1a3e966d6545a55b02025-08-20T01:49:48ZengNature PortfolioNature Communications2041-17232025-05-0116111910.1038/s41467-025-59591-8Impaired ketogenesis in Leydig Cells drives testicular agingCongyuan Liu0Hao Peng1Jiajie Yu2Peng Luo3Chuanfeng Xiong4Hong Chen5Hang Fan6Yuanchen Ma7Wangsheng Ou8Suyuan Zhang9Cuifeng Yang10Lerong Zhao11Yuchen Zhang12Xiaolu Guo13Qiong Ke14Tao Wang15Chunhua Deng16Weiqiang Li17Andy Peng Xiang18Kai Xia19Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityDepartment of Urology and Andrology, The First Affiliated Hospital, Sun Yat-sen UniversityReproductive Medicine Center, The First Affiliated Hospital, Sun Yat-sen University, The Key Laboratory for Reproductive Medicine of Guangdong ProvinceCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityCenter for Stem Cells Translational Medicine, Shenzhen Qianhai Shekou Free Trade Zone HospitalCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityState Key Laboratory of Ophthalmology, Zhong Shan Ophthalmic Center, Sun Yat-sen UniversityCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityDepartment of Urology and Andrology, The First Affiliated Hospital, Sun Yat-sen UniversityCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityCenter for Stem Cells Translational Medicine, Shenzhen Qianhai Shekou Free Trade Zone HospitalCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityDepartment of Urology and Andrology, The First Affiliated Hospital, Sun Yat-sen UniversityCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen UniversityAbstract 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.https://doi.org/10.1038/s41467-025-59591-8 |
| spellingShingle | 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 Kai Xia Impaired ketogenesis in Leydig Cells drives testicular aging Nature Communications |
| title | Impaired ketogenesis in Leydig Cells drives testicular aging |
| title_full | Impaired ketogenesis in Leydig Cells drives testicular aging |
| title_fullStr | Impaired ketogenesis in Leydig Cells drives testicular aging |
| title_full_unstemmed | Impaired ketogenesis in Leydig Cells drives testicular aging |
| title_short | Impaired ketogenesis in Leydig Cells drives testicular aging |
| title_sort | impaired ketogenesis in leydig cells drives testicular aging |
| url | https://doi.org/10.1038/s41467-025-59591-8 |
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