Grant: Operating Grant

It has been observed that aging, which is the main risk factor for many diseases, is systematically accompanied by increased production of reactive oxygen species (also called free radicals), which are molecules that can be toxic at high concentration. It has therefore been suggested that these free radicals might be the cause of aging, and people have tried to combat their production or their effects with so-called anti-oxidants, although the efficacy of anti-oxidants in slowing down aging has never been clearly demonstrated. Recently, we and others have shown through genetic experiments in animals that free radicals are almost certainly not the cause of aging. It remains very important however to explain why increased free radical production accompanies aging. For this we are proposing to use a model animal, the nematode Caenorhabditis elegans, and to study several long-lived mutants that we have previously identified. These mutants have dysfunctional mitochondria, which are the energy producing parts of the cell and are the main site of free radical production. We have found that these mutant mitochondria generate high levels of free radicals, yet age slowly and are protected from free radical toxicity. We hypothesize that free radicals can function as a cellular stress signal that induces a protective response. This hypothesis suggests that aging is accompanied by increased free radical production because, with time, the organism sustains ever greater stresses due to aging. We will try to understand the mechanisms that link mitochondrial function, free radical production, protection from free radical toxicity, and aging in the mutant animals. Understanding these links should shed light on these processes in non-mutant animals and in people. We believe that our results could help to understand the nature of the aging process and when and why antioxidants could, or would not, be beneficial.