Stimulation of RAS-dependent ROS signaling extends longevity by modulating a developmental program of global gene expression.

We show that elevation of mitochondrial superoxide generation increases Caenorhabditis elegans life span by enhancing a RAS-dependent ROS (reactive oxygen species) signaling pathway (RDRS) that controls the expression of half of the genome as well as animal composition and physiology. RDRS stimulation mimics a program of change in gene expression that is normally observed at the end of postembryonic development. We further show that RDRS is regulated by negative feedback from the superoxide dismutase 1 (SOD-1)-dependent conversion of superoxide into cytoplasmic hydrogen peroxide, which, in turn, acts on a redox-sensitive cysteine (C118) of RAS. Preventing C118 oxidation by replacement with serine, or mimicking oxidation by replacement with aspartic acid, leads to opposite changes in the expression of the same large set of genes that is affected when RDRS is stimulated by mitochondrial superoxide. The identities of these genes suggest that stimulation of the pathway extends life span by boosting turnover and repair while moderating damage from metabolic activity.

Antioxidants reveal an inverted U-shaped dose-response relationship between reactive oxygen species levels and the rate of aging in Caenorhabditis elegans.

Reactive oxygen species (ROS) are potentially toxic, but they are also signaling molecules that modulate aging. Recent observations that ROS can promote longevity have to be reconciled with the numerous claims about the benefits of antioxidants on lifespan. Here, three antioxidants [N-acetylcysteine (NAC), vitamin C, and resveratrol (RSV)] were tested on Caenorhabditis elegans mutants that alter drug uptake, mitochondrial function, and ROS metabolism. We observed that like pro-oxidants, antioxidants can both lengthen and shorten lifespan, dependent on concentration, genotypes, and conditions. The effects of antioxidants thus reveal an inverted U-shaped dose-response relationship between ROS levels and lifespan. In addition, we observed that RSV can act additively to both NAC and paraquat, to dramatically increase lifespan. This suggests that the effect of compounds that modulate ROS levels can be additive when their loci of action or mechanisms of action are sufficiently distinct.