The First Molecule Able To Activate Anti-Aging Target Sirtuin 6

Lombard, David B., and Richard A. Miller. "Ageing: Sorting out the sirtuins." Nature 483.7388 (2012): 166-167.

Sirtuins are a class of proteins that gained celebrity status as the supposed targets of the life-extension compound derived from red wine, resveratrol. However some more recent publications have casted doubt on the mechanism by which resveratrol lengthens lifespan. In fact, even the relationship between the sirtuins and aging has been called into question.  

Yeast has five sirtuin genes (the best known and first one discovered was Sir-2), the roundworm C. elegans has four sirtuin genes (Sir-2.1 to Sir-2.4), fruit flies have five sirtuin genes (including dSir2), and mammals like ourselves have seven sirtuin genes (Sirt-1 to Sirt-7). The different sirtuin genes within an organism have differences in their function and localization within the cell. Hence it is important to specify which sirtuin gene one is talking about. Sirt-1 and the most closely related sirtuin genes (homologs) Sir2 (yeast), dSir2 (fruit flies), and Sir2.1 (roundworm) have received the most attention in the aging research field.     

Placing extra copies of Sir2 into the genome of yeast extends lifespan (Longo et al., 2012). This lifespan extension is correlated with a decreased accumulation of circular DNA fragments inside the nucleus of the aging yeast cell. Interestingly, such circular fragments do not accumulate in the nucleus of other species and may thus represent a yeast-specific mechanism of aging (a so called private mechanism of aging). Several studies have suggested that placing extra copies of the dSir2/Sir2.1 gene in the genome of fruit flies or C. elegans also extends its lifespan but a more recent large study failed to find lifespan extension and concluded that the original results were caused by experimental artifacts (Burnett et al., 2011).

Sirt 6 and mice

Male mice that overexpress Sirt-6 have longer lifespans and are protected from obesity-induced metabolic abnormalities. Conversely, mice that lack Sirt-6 only live 4-5 weeks and show aging-associated phenotypes such as an abnormal low level of a certain type of white blood cell (= lymphopenia), loss of fat under the skin (= subcutaneous fat), and severely low levels of blood sugar (= hypoglycemia) (Nakagawa and Guarente, 2011; Tasselli et al., 2016).  

In a new paper published in the prestigious journal Angewandte Chemie International Edition researchers succeeded in developing the first class of synthetic molecules that activates the SIRT-6 protein. While it was previously found that fatty acids could weakly activate SIRT-6, no SIRT-6 activators were known that exhibited ‘drug-like properties’. This discovery could potentially lead to a new class of anti-aging drugs. 

Main reference

You W et al. (2017). Structural basis of sirtuin 6 activation by synthetic small molecules. Angew Chem Int Ed 56: 1007-1011.  

References

Burnett C et al. (2011). Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477: 482-485.

Longo VD et al. (2012). Replicative and chronological aging in Saccharomyces cerevisiae. Cell Metab 16(1): 18-31. 

Nakagawa T, Guarente L (2011). Sirtuins at a glance. J Cell Sci 124: 833-838. 

Tasselli L et al. (2016). SIRT6: Novel mechanisms and links to aging and disease. Trends Endocrinol Metab [Epub ahead of print].