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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, a comprehensive analysis of senescence landscapes in mice testes during aging revealed that the Leydig cells (LCs) are particularly vulnerable to aging processes. Single-cell RNA sequencing identified the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme of ketogenesis, decreased significantly in LCs from aged mice. Additionally, the concentrations of ketone bodies β-hydroxybutyric acid (BHB) and acetoacetic acid (AcAc) in the young testes were substantially higher than that in serum, but significantly diminished in aged testes. Silencing of Hmgcs2 in young LCs resulted in decreased ketone body production, which in turn drove LCs senescence and accelerated testicular aging. Mechanistically, BHB acted as an endogenous inhibitor of histone deacetylase 1 to upregulate the expression of Foxo3a by promoting histone acetylation, thereby mitigating LCs senescence and promoting testosterone production. Consistently, enhanced ketogenesis by genetic manipulation or oral BHB supplementation alleviated LCs senescence and ameliorated testicular aging in aged mice. These findings highlight defective ketogenesis as a pivotal factor in testicular aging, suggesting novel therapeutic avenues for addressing age-related testicular dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE287203 | GEO | 2025/03/27

REPOSITORIES: GEO

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Project description:Beta-hydroxybutyrate (BHB) is a ketone body synthesized during fasting or strenuous exercise. Our previous study demonstrated that a cyclic ketogenic diet (KD), which induces BHB levels similar to fasting every other week, reduces midlife mortality and improves memory in aging mice. BHB actively regulates gene expression and inflammatory activation through non-energetic signaling pathways. Neither of these activities has been well-characterized in the brain and they may represent mechanisms by which BHB affects brain function during aging. First, we analyzed hepatic gene expression in an aging KD-treated mouse cohort using bulk RNA-seq. In addition to the downregulation of TOR pathway activity, cyclic KD reduces inflammatory gene expression in the liver. We observed via flow cytometry that KD also modulates age-related systemic T cell functions. Next, we investigated whether BHB affects brain cells transcriptionallyin vitro. Gene expression analysis in primary human brain cells (microglia, astrocytes, neurons) using RNA-seq shows that BHB causes a mild level of inflammation in all three cell types. However, BHB inhibits the more pronounced LPS-induced inflammatory gene activation in microglia. Furthermore, we confirmed that BHB similarly reduces LPS-induced inflammation in primary mouse microglia and bone marrow-derived macrophages (BMDMs). BHB is recognized as an inhibitor of histone deacetylase (HDAC), an inhibitor of NLRP3 inflammasome, and an agonist of the GPCR Hcar2. Nevertheless, in microglia, BHB's anti-inflammatory effects are independent of these known mechanisms. Finally, we examined the brain gene expression of 12-month-old male mice fed with one-week and one-year cyclic KD. While a one-week KD increases inflammatory signaling, a one-year cyclic KD reduces neuroinflammation induced by aging. In summary, our findings demonstrate that BHB mitigates the microglial response to inflammatory stimuli, like LPS, possibly leading to decreased chronic inflammation in the brain after long-term KD treatment in aging mice.

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Impaired ketogenesis in Leydig Cells drives testicular aging

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