A lot of work has gone into better understanding the roles of sirtuin 1 (SIRT1) in aging, ultimately something of a dead end, not a large enough influence on relevant areas of cellular biochemistry to produce viable treatments to slow aging. Sirtuin 6 (SIRT6), on the other hand is less well explored, but somewhat more interesting, even though it is likely still only a path towards therapies that can do not more than modestly slow aging over time. Overexpression of SIRT6 extends life in mice. One of the possible mechanisms for that extension of life is promotion of DNA repair, and a startup biotech company is working on a SIRT6 gene therapy aimed at improving DNA repair in inherited DNA repair deficiency conditions. Nonetheless, what is presently known about SIRT6 is much less than we'd like to know, as noted in this review paper.
SIRT6 has a range of post-translational modification (PTM) capabilities and is widely involved in aging, immunity, and cancer regulation. SIRT6 is a longevity protein that prevents cells, tissues, organs, and the body from aging. Although the mechanisms underlying these effects are diverse, they all involve resistance of aging by promoting of DNA damage repair, maintaining of the normal telomere structure of chromosomes, regulating of glucose and NAD+ metabolic balance, and by regulating of the senescence-associated secretory phenotype (SASP). SIRT6 can also affect the differentiation and function of immune cells by regulating PTM affecting cells or the immunometabolism. However, the role of SIRT6 in immune regulation is complex.
Although most studies have shown SIRT6 to have anti-inflammatory activity, there is no lack of evidence regarding its pro-inflammatory potential. There has been insufficient research on how SIRT6 affects inflammation by regulating immune cells; SIRT6 has rarely been studied in many immune cells including granulocytes, monocytes, B cells, natural killer (NK) cells, and NKT cells. However, according to the recent research, the SIRT6-PTM or immunometabolism axes represent new directions with research potential.
The role of SIRT6 in cancer development is complex. SIRT6 shows differential expression in cancer tissues compared with normal tissues; its expression levels may also vary among different cancers, at different stages of the same cancer, and in different cell lines of the same tumor type. It also has both positive and negative effects on the regulation of cancer. Few studies have analyzed whether SIRT6 could achieve anti-cancer effects via regulation of immune cell function. This could represent a new direction for future research. For example, it may be possible to adjust the polarization of macrophages through SIRT6 to affect tumor progression.
Taken together, these findings indicate that SIRT6 will serve as an important target candidate for regulating immunosenescence and immune cell function. Drugs designed to target SIRT6 will also make an important contribution to the fight against chronic inflammation and cancer. SIRT6, as an important regulator throughout immunosenescence, inflammaging, and cancer, is a potential target for the regulation of the immune system.