Alternative mitochondrial fuel extends life span

Abstract

In this issue of Cell Metabolism, Ristow and colleagues (Zarse et al., 2012) elucidate a conserved mechanism through which reduced insulin-IGF1 signaling activates an AMP-kinase-driven metabolic shift toward oxidative proline metabolism. This, in turn, produces an adaptive mitochondrial ROS signal that extends worm life span. These findings further bolster the concept of mitohormesis as a critical component of conserved aging and longevity pathways.

Figure 1

Proposed model for mitohormesis in response to reduced insulin/IGF1-signaling.A. In C. elegans and mice (MEFs), impaired insulin/IGF1-signaling reduces glucose uptake, ultimately increasing the cellular AMP/ATP ratio. This energy-stress signal activates AMP kinase, which engages a transcriptional “metabolic shift program” that includes induction of mitochondrial proline oxidase. This shift in metabolism generates mitochondrial ROS that initiate an adaptive ROSsignaling pathway. B. The adaptive mitochondrial ROS signal, through PMK-1 (p38) and SKN-1 (NRF2), activates a protective transcriptional “stress response program.” This involves increased expression of SOD and catalase (CAT), which detoxify ROS and improve cellular stress resistance to ultimately help to extend C. elegans lifespan.