While much the history of work on sirtuins is one of disappointing results, the majority of that work involved SIRT1. Both SIRT3 and SIRT6 may be more interesting, based on animal studies conducted since the SIRT1 era. SIRT3 localizes to the mitochondria, and mitochondrial function is important in the context of aging. Researchers have shown that SIRT3 upregulation in mice improves hematopoietic stem cell function. SIRT6 upregulation, however, has been shown to modestly extend life in mice, there is a larger body of work surrounding its effects on metabolism than is the case for SIRT3, and at least one group is attempting to produce therapies based on targeting SIRT6.
A good review paper on SIRT6 in aging, inflammation, and cancer was published earlier this year. As a companion piece to that review, today's paper has the theme of aging and inflammation in common, but also touches on cardiovascular disease. The role of the more promising sirtuins in aging is interesting, but it is worth bearing in mind that these may turn out to be approaches that move the needle on life span to a greater degree in short-lived species than in long-lived species. This is true of many of the demonstrated ways to adjust metabolism to modestly slow aging, as they tend converge on a few specific mechanisms of action, such as increasing efficiency of autophagy. Of all the sirtuins, SIRT6 seems the least likely to fall into this category, given that it is known to influence cellular senescence, transposon activation, and DNA repair, rather than the more usual package of stress response mechanisms.
Sirtuins, comprising a group of evolutionarily conserved nicotinamide adenine dinucleotide (NAD+)-dependent proteins, beneficially regulate lifespan and cellular senescence. In mammalian cells, seven different sirtuin proteins have been identified (SIRT1-7). SIRT1 and SIRT2 are present in both the nucleus and cytoplasm; SIRT3, SIRT4 and SIRT5 are exclusively found in mitochondria, and SIRT6 and SIRT7 are thought to be located in the nucleus. Notably, in response to stress, SIRT6 localizes to cytoplasmic stress granules, suggesting that SIRT6 is not exclusively a nuclear protein. Sirtuins are involved in a broad range of physiological processes, including genome stability, energy metabolism, aging, tumorigenesis, and cardiovascular biology, via their regulation of key protein activities.
Among sirtuin family members, sirtuin 6 (SIRT6) is of particular interest and has gained more attention due to its distinctive enzymatic activities; for example, SIRT6 catalyzes deacetylation and mono-ADP-ribosylation and exhibits long-chain fatty acid (FA) deacylase activity. These enzymatic activities indicate that SIRT6 is closely related to cellular biological processes, such as DNA repair, genome stability, inflammation, and metabolic homeostasis. Studies have revealed that dysregulation of SIRT6 activity leads to the onset and development of many diseases, including but not limited to metabolic diseases, cardiovascular diseases (CVDs), cancers, and neurodegenerative diseases.
The essential roles of SIRT6 in regulating chromatin and nuclear-cytoplasmic signaling pathways important for cellular homeostasis have been well characterized. In terms of genome stability, SIRT6 enhances DNA repair and maintains telomere integrity by regulating DNA repair and chromatin-associated factors, such as PARP1, DDB2, SNF2H and WRN. With respect to cellular metabolism, SIRT6 regulates multiple metabolic processes, including glycolysis, gluconeogenesis, insulin secretion, lipid synthesis, lipolysis, and thermogenesis, mainly by regulating the multiple transcriptional activities of HIF1α, FOXO proteins, and the PPAR family of transcription factors.
In addition, SIRT6 maintains an appropriate inflammatory response by regulating the TNF-α and NF-κB signaling pathways. These functions can influence cellular senescence and aging-related diseases, including CVDs, cancer, and neurodegenerative diseases. Therefore, studying the biological functions of SIRT6 in different diseases is valuable and helpful for the identification of highly specific SIRT6 cellular targets. With a deeper understanding of SIRT6, certain SIRT6 regulatory compounds have been identified, offering novel and promising therapeutic options for aging-related diseases.