Obesity is a causal risk factor for the development of age-related disease conditions, which includes Type 2 diabetes mellitus, cardiovascular disease, and dementia. In genome-wide association studies, genetic variation in FTO is strongly associated with obesity and has been described across different ethnic backgrounds and life stages. To date, much work has been devoted on determining the biological mechanisms via which FTO affects body weight regulation and ultimately contributes to age-related cardiometabolic and brain disease. The main hypotheses of the involved biological mechanisms include the involvement of FTO in habitual food intake and energy expenditure. In this narrative review, our overall aim is to provide an overview on how FTO gene variants could increase the risk of developing age-related disease conditions. Specifically, we will discuss the state of the literature based on the different hypotheses how FTO regulates body weight and ultimately contributes to cardiometabolic disease and brain disease.