A role for the CISD2 gene in lifespan control and human disease.

CISD2, the causative gene for Wolfram syndrome 2 (WFS2), is an evolutionarily conserved novel gene. Recently, we have demonstrated that CISD2 is involved in mammalian lifespan control; this work also establishes WFS2 as a mitochondria-mediated disorder and effectively links CISD2 gene function, mitochondrial integrity, and aging in mammals. In wild-type mice, the expression levels of CISD2 decrease in an age-dependent manner during the naturally aging process; this correlates with mitochondrial breakdown and parallels the development of an aged phenotype. Future work will examine how the CISD2 knockout mouse helps us to understand WFS2 pathogenesis, as well as exploring the potential effects of increased CISD2 expression. In addition, it will be of great interest to compare gene activity and/or protein function between normal human populations and long-lived centenarian groups. Together, human and mouse genetic studies should provide evidence as to whether CISD2 is a "master gene" for extreme old age.