FOXO3 and metabolic disease: Interestingly, it has been observed how SIRT1 can regulate the expression of other anti-aging genes such as Klotho, p66Shc (longevity protein) and Forkhead box proteins (FOXO1/FOXO3a) and how various adverse environmental effects such as unhealthy diets can inactivate the SIRT1 gene which in turn could play a key role in the development of metabolic diseases and premature aging in individuals (Martins, 2016; Martins, 2017).