A team led by Sun Yat-sen University demonstrates that the ketogenesis enzyme HMGCS2 in Leydig cells generates β-hydroxybutyrate to epigenetically boost FOXO3a and delay cellular senescence, preserving testosterone output and testicular function.
Key points
Single-cell RNA-seq of young vs. aged mouse testes reveals Hmgcs2 downregulation in senescent Leydig cells.
Pharmacological inhibition or genetic knockout of HMGCS2 in Leydig cells reduces ketone bodies, induces p21-driven senescence, and impairs testosterone synthesis.
β-Hydroxybutyrate supplementation or Hmgcs2 overexpression restores H3K9 acetylation via HDAC1 inhibition, upregulates FOXO3a, and mitigates testicular aging.
Why it matters:
Identifying ketogenesis in Leydig cells as a key anti-aging pathway unveils a novel target for therapies to preserve male reproductive function during aging.
Q&A
What is ketogenesis in Leydig cells?
How does β-hydroxybutyrate prevent cell senescence?
Why target HMGCS2 for testicular aging?
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Academy
Ketogenesis in Leydig Cells and Testicular Aging
Overview
The testis contains multiple cell types, including Leydig cells, which produce testosterone essential for male reproductive function. Recent research uncovers that Leydig cells also carry out a form of ketogenesis—a process usually limited to the liver—producing local ketone bodies that support cell health and delay aging.
What Is Ketogenesis?
Ketogenesis is the biochemical pathway in which fatty acids are converted into ketone bodies: acetoacetate (AcAc), β-hydroxybutyrate (BHB), and acetone. The liver classically performs ketogenesis during fasting states to supply alternative energy fuels for brain and muscle. Key enzymes in this pathway include:
- Acat1 (Acetyl-CoA acetyltransferase): Combines two acetyl-CoA molecules to produce acetoacetyl-CoA.
- Hmgcs2 (3-Hydroxy-3-methylglutaryl-CoA synthase 2): Catalyzes acetoacetyl-CoA conversion into HMG-CoA; rate-limiting step.
- Hmgcl (HMG-CoA lyase): Splits HMG-CoA to generate acetoacetate.
- Bdh1 (β-hydroxybutyrate dehydrogenase): Converts acetoacetate to β-hydroxybutyrate.
Leydig Cells and Local Ketogenesis
In the aging testis, Leydig cells show reduced expression of Hmgcs2, leading to diminished intratesticular levels of BHB and AcAc. This local shortage of ketone bodies accelerates cellular senescence marked by:
- Upregulation of p21 and Cxcl10, hallmark senescence markers.
- Accumulation of senescence-associated β-galactosidase (SA-β-gal) positivity.
- Decline in testosterone synthesis capacity.
Mechanism of Protection by β-Hydroxybutyrate
Supplementing aged or HMGCS2-deficient Leydig cells with BHB reverses senescence by acting as an endogenous inhibitor of histone deacetylase 1 (HDAC1). This increases histone H3K9 acetylation at promoters of longevity genes such as FOXO3a, enhancing antioxidant defenses and DNA repair functions. In contrast, acetoacetate does not confer this epigenetic benefit in Leydig cells.
Therapeutic Implications for Testicular Aging
Enhancing ketogenesis—via genetic overexpression of Hmgcs2 or dietary BHB supplementation—restores local ketone levels, reduces Leydig cell senescence, and preserves testosterone and spermatogenesis in aged mice. This approach suggests a noninvasive strategy to combat age-related male hypogonadism and maintain fertility.
Key Takeaways
- Local ketone production in Leydig cells is critical for delaying testicular aging.
- β-Hydroxybutyrate mediates epigenetic reprogramming through HDAC1 inhibition and H3K9 acetylation.
- Targeting HMGCS2 or dietary ketone supplementation may represent novel therapies for age-related testosterone decline.
