Sirtuins are a family of conserved enzymes which have in common a deacetylase domain and a dependency for NAD+ as co-substrate. The silent information regulator 2 (Sir2) from yeast Saccharomyces cerevisiae, when overexpressed resulted in lifespan extension. Several mammalian Sirtuin family members are able to improve healthspan however, only SIRT6 was proved able to extent lifespan. The mechanisms behind life span extension is unclear but hypothesized to be due to SIRT6 capacity to maintain genomic stability, improve insulin signalling and reduce tumorigenesis. In order to address these issues we used a mouse model were SIRT6 is physiologically overexpressed. Our data indicate that SIRT6 improve insulin sensitivity in skeletal muscle and liver protecting against diet-induced T2DM and, in the cancer context, SIRT6 suppresses cancer stem cells diminishing in vitro and in vivo tumorigenesis.