Mitochondrial complex I: a central regulator of the aging process.

Mitochondria are considered major regulators of longevity, although their exact role in aging is not fully understood. Data from different laboratories show a negative correlation between reactive oxygen species (ROS) generated by complex I and lifespan. This suggests that complex I has a central role in the regulation of longevity. Here, we review data that both support and refute the role of complex I as a pacemaker of aging. We include data from our laboratory, where we have manipulated ROS production by the electron transport chain (ETC) in Drosophila melanogaster. The bypass of complex I increases the lifespan of the fruit fly, but it is not clear if this is caused by a reduction in ROS or by a change in the NAD+ to NADH ratio. We propose that complex I regulates aging through at least two mechanisms: (1) an ROS-dependent mechanism that leads to mitochondrial DNA damage and (2) an ROS-independent mechanism through the control of the NAD+ to NADH ratio. Control of the relative levels of NAD+ and NADH would allow the regulation of (1) glyco- and (2) lipoxidative-damage and (3) the activation of sirtuins.