SIRT6 in Senescence and Aging-Related Cardiovascular Diseases

Abstract

SIRT6 belongs to the nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylases and has established diverse roles in aging, metabolism and disease. Its function is similar to the Silent Information Regulator 2 (SIR2), which prolongs lifespan and regulates genomic stability, telomere integrity, transcription, and DNA repair. It has been demonstrated that increasing the sirtuin level through genetic manipulation extends the lifespan of yeast, nematodes and flies. Deficiency of SIRT6 induces chronic inflammation, autophagy disorder and telomere instability. Also, these cellular processes can lead to the occurrence and progression of cardiovascular diseases (CVDs), such as atherosclerosis, hypertrophic cardiomyopathy and heart failure. Herein, we discuss the implications of SIRT6 regulates multiple cellular processes in cell senescence and aging-related CVDs, and we summarize clinical application of SIRT6 agonists and possible therapeutic interventions in aging-related CVDs.

Keywords: SIRT6; autophagy; cardiovascular diseases; oxidative stress; senescence.

FIGURE 1

Domain architecture, subcellular localization, and enzymatic activity of human sirtuin family of Class III NAD⁺-dependent histone deacetylases. Schematics represent the domain structure of human sirtuins. Amino acid positions are noted above each schematic. The domains are represented in different colors. Adapted from UniProt Universal Protein Resource Database.

FIGURE 2

Model for the function of SIRT6 in age-related cellular events. SIRT6 directly binds to Mtf1 to promote the expression of metallothionein Mt1 and Mt2. SIRT6 recruits BAF170 and RNA polymerase II to promote the expression of Nrf2 and downstream genes to participate in antioxidant stress. SIRT6 inhibits the activity of c-JUN, the transcription of Notch1 and Notch4 signals and the phosphorylation of Akt signal via epigenetic regulation. These upregulate the expression of pro-inflammatory cytokines IL-1 β, IL-6, and TNF-α and downregulate anti-inflammatory cytokines IL-10 to attenuates the effect of inflammation. SIRT6 inhibites the activity of Akt-mTOR pathway thus promotes FOXO3-dependent autophagy. Both single and double strand break trigger the recruitment of SIRT6 and activation of PARP1 at the damage sites and promote PARP1 mediated DNA repair. SIRT6 also recruits repair factors 53BP1, BRCA1, and RPA at double-strand breakpoint for damage repair. SIRT6 recruits and interacts with CHD4 to render the relaxation of chromatin required for DNA repair. And CHD4 replaces HP1 in histone H3K9 further promoting homologous recombination. SIRT6 binds to and deacetylate CtIP to promote terminal excision. SIRT6 keeps the low physiological level of H3K9 acetylation and preserves the telomere position effect to maintain normal function of telomere.