Leydig cells are particularly vulnerable to testis ageing, new preclinical data in Nature Communications have shown. The pivotal factor in this process is ketogenesis, impairment of which drives testicular ageing and enhancement ameliorates it. These observations have implications for men’s reproductive health.

Histological and functional analyses of testes from young (2-month-old) and aged (24-month-old) mice showed considerable testicular ageing in aged mice. β-galactosidase — a marker of cellular senescence — staining revealed that senescence increased with age and was associated with Leydig cells. A Leydig cell senescence signature was discovered using single-cell RNA sequencing. Gene set enrichment analysis revealed that upregulated genes associated with increased age were related to inflammation and downregulated genes were related to metabolism. Specifically, differential gene expression analysis showed that Hmgcs2 — which encodes the rate-limiting enzyme for ketogenesis — was most substantially downregulated, and immunofluorescence revealed a considerable reduction in HMGCS2 expression in aged mice. Assessment of intratesticular ketone bodies showed that acetoacetic acid and β-hydroxybutyric acid concentrations were diminished in aged testes.