Figure 1. A model for lifespan extension by mild inhibition of mitochondrial respiration in C. elegans. Mild reduction in mitochondrial respiration leads to the increase in reactive oxygen species (ROS) production and triggers mitochondrial unfolded protein response (UPRmito). The increased ROS either by reducing mitochondrial respiration or by pro-oxidant treatment promotes longevity at least in part by increasing the activity of hypoxia-inducible factor 1 (HIF-1). EGL-9 (HIF prolyl hydroxylase) and VHL-1 (von Hippel Lindau 1, E3 ubiquitin ligase) affect longevity perhaps through down-regulating HIF-1 (note that this part is currently inconclusive and therefore is shown with a dashed line.). UPRmito caused by impaired mitochondrial respiration extends lifespan through unidentified endocrine signals that relay the longevity response among different tissues.