Mutagenic Screen for Longevity Genes in Mice

Mark Mayford, Ph.D. Scripps Research Institute Contact Dr. Mayford

Generalized aging at the cellular level is thought to arise from the accumulation of damage to protein and nucleic acids that eventually results in the impairment of normal cellular function or transformation of the cells to a cancerous form of growth. How does this damage occur? One hypothesis that is consistent with invertebrate genetic studies as well as with comparative studies of longevity across species is the “free radical theory of aging”. According to this view, it is the oxidative damage to proteins, lipids and DNA caused by free radicals produced during normal metabolic activity that eventually leads to impaired cellular function and aging. Genetic screens in invertebrates such as Drosophila have been successful in identifying mutant animals with up to a twofold increase in longevity and these animals often show increased resistance to oxidative stress. However much less is known about aging in mammals. We propose to employ genetic screens in the mouse to identify mutant animals with increased resistance to or decreased production of free radicals. Mutant animals identified on the basis of altered free radical response will then be analyzed in aging studies to determine whether they show a delay in the onset of various age related disorders and an increase in longevity. The results should provide a test of the free radical theory of aging in mammals and potential therapeutic targets for the numerous age related disorders thought to involve free radical induced cellular damage.