There was a great deal of interest in sirtuin 1 in relation to aging and life span some years ago, very much overhyped as it turned out. Nothing of any practical use emerged from that research. Sirtuin 6 has a more robust effect on mouse life span, perhaps via improvement of mitochondrial function. Like all such exercises in metabolic manipulation that attempt to slow the progression of aging, targeting processes known to be involved in cellular responses to stress, it is likely that the beneficial effects diminish as species life span increases. A sirtuin with better results in mice remains unlikely to move the needle all that much on human life span.
Of the seven mammalian sirtuins, SIRT1-7, SIRT1, and SIRT6 protein levels increase upon dietary restriction and fasting in various mouse tissues and human cell lines. Interestingly, whole-body SIRT1 overexpression in mice leads to improvement in parameters reflecting healthspan, but not lifespan. Whereas whole-brain-specific SIRT1 overexpression did not affect lifespan and brain plasticity, hypothalamic SIRT1 overexpression delays aging. However, whole-body SIRT6 overexpression in mice background leads to a significant extension of male lifespan and healthspan, associated with inhibition of IGF-1 signaling.
Here, we show that overexpression of SIRT6, but not SIRT1, extends lifespan in C57BL/6JOlaHsd mice in both sexes. SIRT1 does not synergize with SIRT6 to further increase median or maximal survival. Overexpression of SIRT6 reduced the age-related metabolic decline in energy metabolism pathways and inhibited frailty by preserving hepatic NAD+ levels, gluconeogenesis capacity, and maintenance of normoglycemia, key markers of healthy aging. These results emphasize the potential of targeting SIRT6 for maintaining energy metabolism and reducing age-related frailty.