The testes manufacture testosterone, generally important to long-term health. Further, germ cells resident in the testes manufacture sperm. This process of spermatogenesis is necessary for reproduction. Both of these functions decline with age. As is the case for near all outcomes of degenerative aging, the research community has yet to construct a clear model of cause and effect that reaches from the known root causes of aging to declining function in the tests. Cellular biochemistry is complex and incompletely mapped, and aging is a further complexity imposed upon those systems, not just as the level of individual cells, but also at the level of tissues containing enormous numbers of interacting cells of different types. It is a challenging task.
Researchers regularly uncover intermediary mechanisms in aging that appear important. Not a root cause and not a final outcome, but something in the middle layer of complex interactions that is influential enough on the progression of disease or loss of function to be worthy of note. Today's open access paper is an example of the type, in which researchers observe that loss of the capacity for ketogenesis in Leydig cells in the testes that are responsible for the production of testosterone appears important in the functional decline of the testes. This may be a target for the development of drugs to slow some of the more important age-related deterioration that takes place in this organ, though it seems that β-hydroxybutyric acid supplementation works well enough.
Impaired ketogenesis in Leydig Cells drives testicular aging
Testicular aging is characterized by a reduction in testosterone, which is linked to various male reproductive disorders and a diminished quality of life in the elderly. Currently, testosterone replacement therapy (TRT) serves as the primary intervention for alleviating symptoms associated with testicular aging. However, TRT is accompanied by notable adverse effects. Moreover, TRT fails to mimic the physiological secretion patterns of testosterone and can negatively impact spermatogenesis. Consequently, there is a pressing need to explore novel therapeutic strategies for addressing testicular aging.
Aging testes undergo profound alterations in both germ cells and somatic cells, leading to reduced functionality. Previous studies have shown that testicular aging is marked by a decline in the number of spermatogonia and spermatocytes, as well as the accumulation of DNA damage and mutations within germline cells. As the primary cells producing testosterone, Leydig cells (LCs) play a crucial role in spermatogenesis and male fertility. LCs are thought to be vulnerable to age-related damage, primarily due to oxidative stress induced by reactive oxygen species (ROS).
In this study, we characterize testicular aging by detecting the senescence marker senescence-associated β-galactosidase (SA-β-gal), identifying that LCs are the most susceptible cells to aging in the testis. Single-cell transcriptomics reveals a significant downregulation of 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2), which encodes the rate-limiting enzyme in ketogenesis, in aged LCs. Moreover, silence of Hmgcs2 in young LCs impairs ketogenesis, causing premature senescence and accelerating testicular aging. Mechanistically, β-hydroxybutyric acid (BHB), a ketogenic product and inhibitor of histone deacetylase 1 (HDAC1), promotes Foxo3a expression by enhancing histone acetylation, thereby alleviating LCs senescence and improving steroidogenic function.
In vivo studies further demonstrate that enhancing ketogenesis via Hmgcs2 overexpression or BHB supplementation reduces LCs senescence and improves testicular function in aged mice.
View the full article at FightAging
