Because our earlier work on Sirt6-LKO mice did not observe liver cancer formation up to 13 months of age although they all developed fatty liver (Kim et al, 2010), we first divided Sirt6-LKO mice into several cohorts for the development of spontaneous liver cancer in aging mice; chemically induced tumorigenesis after treating with DEN; and obesity-induced tumorigenesis by crossing with ob/ob mutant mice (Fig. 1A). Here, SIRT6 is linked to obesity due to melanocortin 4 receptor deficiency.