ALTERATIONS IN OXIDATIVE STRESS RESPONSE WITH HUMAN AGING

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): While it is generally accepted that mammalian aging is associated with a reduced ability to cope with environmental stresses, experimental evidence linking a decline in stress tolerance to alterations in specific pathways known to be involved in regulating stress responsiveness has been lacking. The extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (Pl3-kinase)/Akt signaling pathways play important roles in promoting cell survival following oxidant injury in human and rodent ceils. We hypothesize that human aging is associated with a decline in the ability of cells to activate these host responses to acute oxidant injury, and that this in turn contributes to a reduced tolerance to oxidative insults. We will test this hypothesis using human CD4+ T cells obtained from young adult (25-40 years of age) and elderly (>70 years old) donors. The specific aims are: 1. To examine relative levels of ERK and Akt activation in hydrogen peroxide-treated CD4+ T cells derived from young versus elderly donors. 2. To examine survival of young versus aged CD4+ T cell populations treated with hydrogen peroxide, and investigate the relationship between survival and ERK and Akt activation. 3. To examine basal differences and hydrogen peroxide-induced changes in the global patterns of gene expression in CD4+ T cells of young and elderly donors using cDNA arrays. Oxidative damage is believed to be an important factor in normal aging, as well as age-related diseases in humans. Better understanding of how the response to oxidative stress is altered with aging could lead to strategies to boost this response in the elderly, and thereby improve stress tolerance.