The CISD2 gene, which is an evolutionarily conserved novel gene, encodes a transmembrane protein primarily associated with the mitochondrial outer membrane. Human CISD2 gene has been identified as the second causative gene associated with Wolfram syndrome (WFS; MIM 222300), which is an autosomal recessive neuro-degenerative disorder with premature death. WFS is highly variable in its clinical manifestations, which include Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness; thus, it is also known as the DIDMOAD syndrome. Importantly, the CISD2 gene is located within the candidate region on chromosome 4q where a genetic component for human longevity has been mapped. Previously we have shown that mouse Cisd2 deficiency shortens lifespan resulting in premature aging. Additionally, an age-dependent decrease in mouse Cisd2 expression has been detected during normal aging. Recently, we demonstrated that a persistent level of Cisd2 achieved by transgenic expression in mice extends their median and maximum lifespan without any apparent deleterious side effects. Cisd2 also ameliorates age-associated degeneration of the skin, skeletal muscles and neurons. Moreover, Cisd2 protects mitochondria from age-associated damage and functional decline as well as attenuating the age-associated reduction in whole-body energy metabolism. These results suggest that Cisd2 is a fundamentally important regulator of lifespan, and provide an experimental basis for exploring the candidacy of CISD2 in human longevity. Furthermore, any development of a therapy involving the CISD2 and anti-aging will, of course, directly benefit WFS2 sufferers too. Finally, I will discuss the molecular mechanism and recent findings for the regulatory roles of CISD2 in mammalian lifespan control.