SIRT6 Overexpression Counteracts Chromatin Aging [RNA-Seq]

Aging is associated with detrimental changes in chromatin structure and gene expression, contributing to inflammation, metabolic decline and tissue dysfunction. SIRT6, a histone deacetylase, plays a key role in maintaining chromatin integrity and promoting longevity. Here, we show that aging leads to increased chromatin accessibility in the murine liver, accompanied by upregulation of inflammation and downregulation of metabolic pathways. Remarkably, SIRT6 overexpression reversed these changes, reducing inflammation and enhancing metabolic function. Notably, ETS family members were enriched in regions with increased accessibility during aging, while liver-enriched transcription factors (LETFs) were enriched in regions with reduced accessibility. ChIP-seq analyses of H3K9ac and H3K56ac binding showed that H3K9ac, but not H3K56ac, is associated with increased accessibility during aging, and that SIRT6 can reverse this effect. Furthermore, AAV-mediated SIRT6 overexpression in aged mice demonstrated that SIRT6 not only slows age-related chromatin changes but can also reverse them, rejuvenating chromatin accessibility to a youthful state.