Type 2 diabetes (T2D) is associated with insulin resistance in target tissues including the β-cell, leading to significant β-cell loss and secretory dysfunction. T2D is also associated with aging, and the underlying mechanisms that increase susceptibility of an individual to develop the disease implicate epigenetics: interactions between susceptible loci and the environment. In this review, we discuss the effects of aging on β-cell function and adaptation, besides the significance of mitochondria in islet bioenergetics and epigenome. We highlight three important modulators of the islet epigenome, namely: metabolites, hormones, and the nutritional state. Unraveling the signaling pathways that regulate the islet epigenome during aging will help to better understand the development of disease progression and to design novel therapies for diabetes prevention.