Histone Deacetylase 9 Gene Deletion Ameliorates Aging-Related Adipose Tissue Senescence and Mitochondrial Dysfunction in Mice.

Abstract

Cellular senescence and mitochondrial dysfunction are prevalent in adipose tissues and disrupt metabolic homeostasis during aging, but the mechanisms are poorly understood. Here, we investigated the role of histone deacetylase 9 (HDAC9), an epigenetic regulator of adipogenic differentiation, in aging-related adipose tissue senescence and mitochondrial dysfunction. HDAC9 expression correlated positively with age in mouse adipose tissues. Compared to age-matched wild-type (WT) mice, Hdac9 knockout (KO) mice gained less weight and had reduced fat mass during aging, in conjunction with reduced senescence-associated beta-galactosidase (SABG) staining and expression of senescence markers in adipose tissues. Additionally, preadipocytes isolated from Hdac9 KO mice exhibited reduced baseline and stress-induced senescence compared to WT mice. Mechanistically, HDAC9 gene deletion resulted in coordinated upregulation of mitochondria-associated genes, in association with increased mitochondrial DNA content and adipose tissue mitochondrial oxygen consumption parameters (e.g., increased basal respiration, proton leak). Furthermore, thiosulfate sulfurtransferase (TST), whose downregulation is associated with mitochondrial dysfunction, was reduced in adipose tissues of aging mice and upregulated by HDAC9 gene deletion. Finally, silencing TST in preadipocytes upregulated expression of senescence markers and increased SABG staining. We conclude that deletion of HDAC9 ameliorates the development of adipose tissue senescence and mitochondrial dysfunction with aging, at least in part via upregulation of TST, suggesting that targeting HDAC9 may be a promising strategy to maintain healthy adipose tissue during aging.