Inhibition of Respiration Extends C. elegans Life Span via Reactive Oxygen Species that Increase HIF-1 Activity

SummaryA mild inhibition of mitochondrial respiration extends the life span of many organisms, including yeast, worms, flies, and mice [1, 2, 3, 4, 5, 6, 7, 8, 9 and 10], but the underlying mechanism is unknown. One environmental condition that reduces rates of respiration is hypoxia (low oxygen). Thus, it is possible that mechanisms that sense oxygen play a role in the longevity response to reduced respiration. The hypoxia-inducible factor HIF-1 is a highly conserved transcription factor that activates genes that promote survival during hypoxia [11 and 12]. In this study, we show that inhibition of respiration in C. elegans can promote longevity by activating HIF-1. Through genome-wide screening, we found that RNA interference (RNAi) knockdown of many genes encoding respiratory-chain components induced hif-1-dependent transcription. Moreover, HIF-1 was required for the extended life spans of clk-1 and isp-1 mutants, which have reduced rates of respiration [ 1, 4 and 13]. Inhibiting respiration appears to activate HIF-1 by elevating the level of reactive oxygen species (ROS). We found that ROS are increased in respiration mutants and that mild increases in ROS can stimulate HIF-1 to activate gene expression and promote longevity. In this way, HIF-1 appears to link respiratory stress in the mitochondria to a nuclear transcriptional response that promotes longevity.

► Reduced mitochondrial respiration extends life span in many species ► Inhibition of mitochondrial respiration increases HIF-1 activity in C. elegans ► HIF-1 is required for the longevity caused by mutations that inhibit respiration ► Inhibiting respiration appears to activate HIF-1 via reactive oxygen species