Sirtuin 6 Overexpression Reverses Age-Related Structural Changes in Nuclear DNA in Liver Cells
The expression of genes from nuclear DNA is determined by the structure of nuclear DNA, meaning which regions are spooled and inaccessible versus which regions are unspooled and accessible to transcription machinery. This is visible as the structure of chromatin in the cell nucleus, where chromatin is the name given to the complex structures formed by nuclear DNA and its supporting molecules such as histones. Epigenetic mechanisms control DNA structure by adding and removing decorations to DNA and histones, and this control changes with age in ways that are ultimately detrimental. A range of potential approaches to treatments for aging revolve around the question of whether there are safe enough, effective enough ways to change this epigenetic landscape to make the structure of DNA more youthful in nature, and thus gene expression and cell behavior also more youthful in nature. The most well developed example is partial reprogramming, but it is not the only one.
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. Our multi-omics approach, combining ATAC-seq, methylome, and RNA-seq shows that aging leads to increased chromatin accessibility in the male murine liver, accompanied by upregulation of inflammation and downregulation of metabolic pathways.
Remarkably, SIRT6 overexpression reverses these changes in chromatin structure, reducing inflammation and enhancing metabolic function. Notably, ETS family members and liver-enriched transcription factors are enriched in regions with increased and reduced accessibility during aging, respectively. ChIP-seq shows 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 male mice demonstrates that SIRT6 not only slows age-related chromatin changes but can also reverse them, rejuvenating chromatin accessibility to a youthful state.