ArticleNature communications2025
Impaired ketogenesis in Leydig Cells drives testicular aging.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Article
- Testicular ageing as a central hallmark of male senescence: characteristics, molecular mechanisms and emerging therapeutic strategies.Annals of medicine · 2026Review
- Platelet-Derived Growth Factor Receptor Alpha in Male Reproductive Health and Oxidative Stress: Stromal Homeostasis, Injury, and Research Perspectives.Antioxidants (Basel, Switzerland) · 2026Review
- Polystyrene microplastics impair sheep spermatogenesis by disrupting rumen microbiota-derived butyrate signaling.Journal of animal science and biotechnology · 2026Article
- Article
- Effects of dietary supplementation with polyphenolic extracts from Lasia spinosa Thw. roots on reproductive performance in Guangxi Ma Roosters.Poultry science · 2026Article
- LIPUS promotes stem leydig cells proliferation by up-regulating Wnt5a expression and delays male aging.Scientific reports · 2026Article
- Quercetin upregulates steroid hormone biosynthesis to enhance reproductive performance in roosters.Poultry science · 2026Article
- Effect of Vitamin K Supplementation on Testosterone Production in a Rat Model of Late-Onset Hypogonadism.Foods (Basel, Switzerland) · 2026Article
- Review
- Review
- Bioactive Peptide C248 of PRDX4 Ameliorates the Function of Testicular Leydig Cells via Mitochondrial Protection.Antioxidants (Basel, Switzerland) · 2025Article
- ucOCN Promotes Testosterone Synthesis via the PKA-MAPK/ERK-CREB Signaling Pathway in Porcine Leydig Cells.Cells · 2025Article
- Testosterone and Obesity in an Aging Society.Biomolecules · 2025Review
- Aging-TCA: a cross-species single-cell transcriptomic atlas for studying testicular aging.BMC genomics · 2025Article
- Review
- Research Progress on the Interaction Between SIRT1 and Mitochondrial Biochemistry in the Aging of the Reproductive System.Biology · 2025Review
Corrections and comments
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Authors and funding
20 authors.
Funding
No grant is acknowledged in the PubMed record.
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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