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.

Polydatin Attenuates Cisplatin-Induced Acute Kidney Injury via SIRT6-Mediated Autophagy Activation

“…First, we evaluated the effects of different doses of PD (20 μM, 40 μM, and 80 μM) on the autophagy flux in CP-treated HK-2 cells. WB results showed that, compared with the control, CP (20 μM) significantly induced the increase of LC3 II and p62 expression (Figures 3(a Increasing evidence shows that SIRT6-mediated autophagy has a positive effect on cell survival [31]. To confirm whether SIRT6 is involved in the cytoprotective effect of PD against CP, the CP-induced HK-2 cells were treated with PD combined with or without OSS-128167, an inhibitor of SIRT6, to evaluate the relationship between SIRT6 and autophagy flux.…”

“…It has been widely reported the role of energy signaling pathways mediated by mTOR, AMPK, and NAD + metabolism in the regulation of autophagy in CP nephrotoxicity [1]. Sirtuin 6 (SIRT6) belongs to NAD + -dependent deacetylase, which is widely expressed in mammalian organs, and regulates multiple biological processes, including inflammatory response, oxidative stress, telomere homeostasis, and autophagy [31]. The protective effect of SIRT6 activating autophagy has been proved in different organ injuries, including I/R injury [39][40][41], diabetes [42][43][44][45], and sepsis [19,46,47].…”

“…Sirtuin 6 (SIRT6) belongs to a nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase, which plays a protective role in different organ injuries by regulating autophagy [31]. Overexpression of SIRT6 can alleviate CP-AKI [32], but the relationship between SIRT6 and autophagy in CP-AKI remains a mystery.…”

Translation of Cellular Senescence to Novel Therapeutics: Insights From Alternative Tools and Models

“…A recent statistical report released by the American Heart Association (AHA) and National Institutes of Health (NIH) showed that cardiovascular disease (CVD) has a higher incidence than other common diseases, even more than the combination of lung diseases and cancer ( Bozaykut et al, 2020a ; Virani et al, 2020 ; Li et al, 2021 ). Older people are prone to develop any kind of CVD (heart failure, hypertension, stroke, coronary heart disease) and aging has been proposed to be the main risk ( Rodgers et al, 2019 ).…”

Mitochondrial Sirtuins in Chronic Degenerative Diseases: New Metabolic Targets in Colorectal Cancer

“…Multiple SIRT6 pathways are related to senescence, oxidative stress and inflammation. SIRT6 counters oxidative stress by inhibiting c-Jun, Notch1 and Notch4 transcription and protein kinase B (AKT) phosphorylation via metal regulatory transcription factor 1 (MTF1) and BRG1-associated factor 170 (BAF-170) recruitment, resulting in the downregulation of inflammatory cytokines expression [ 28 ]. SIRT7 regulates stem cell senescence and heterochromatin stabilization; its deficiency accelerates the aging process while its activity displays a beneficial role [ 29 ].…”