Mitochondrial longevity pathways

Production of reactive oxygen species (ROS) is a tightly regulated process, and increased levels of ROS within mitochondria are the principal trigger not only for mitochondrial dysfunctions but, more in general, for the diseases associated with aging, thus representing a powerful signaling molecules. One of the key regulators of ROS production, mitochondrial dysfunction, and aging is the 66-kDa isoform of the growth factor adapter shc (p66shc) that is activated by stress and generates ROS within the mitochondria, driving cells to apoptosis. Accordingly, p66shc knockout animals are one of the best characterized genetic model of longevity.On the other hand, caloric restriction is the only non-genetic mechanism that is shown to increase life span. Several studies have revealed a complex network of signaling pathways modulated by nutrients, such as IGF-1, TOR, sirtuins, AMP kinase, and PGC-1α that are connected and converge to inhibit oxidative stresses within the mitochondria. Animal models in which components of these signaling pathways are induced or silenced present a general phenotype characterized by the deceleration of the aging process. This review will summarize the main findings in the process that link mitochondria to longevity and the connections between the different signaling molecules involved in this intriguing relationship.

Research Highlights
► Mitochondrial ROS are potent signal molecules able to regulate the aging process.
► ROS production within mitochondria is regulated by intracellular signaling cascades.
► The life span determinant p66shc triggers ROS production within mitochondria.
► Other signaling cascades (e.g., IGF-1) converge on ROS production to control aging.