Modulation of immune function by activators of the peroxisome proliferator-activated receptor Alpha in aging

Oxidative stress contributes to a number of biological alterations in aging, including important parameters of immune function. This dissertation demonstrates that the redox-regulated transcription factor NF-kappaB becomes activated in cells that comprise the spleen and secondary lymphoid organs of aged experimental mice. NF-kappaB transcriptionally regulates genes encoding products capable of exerting inflammatory effects that are detrimental to immunocompetence, perpetuate the pro-oxidant state, and contribute to disease in aging. Since NF-kappaB can be activated in response to stimulation with reactive oxygen species, regimens that exert an antioxidant effect should ameliorate NF-kappaB activity and reduce the expression of NF-kappaB regulated genes. Aged mice were provided dietary supplementation with the antioxidant vitamin E or with specific activators of PPAR-alpha;, including dehydroepiandrosterone-3?-sulfate (DHEAS) or WY-14,643. Activators of PPAR-alpha; may modulate cellular redox state through the transcriptional upregulation of antioxidant and fatty acid-catabolizing enzymes. Supplementation of aged mice with these agents reduced splenic NF-kappaB activity and inflammatory cytokine production to levels seen in young mice and reduced tissue levels of oxidative damage, implicating excesses in oxidative stress as etiologic for the aged phenotype. The capacity of PPAR-apha activation to function in a manner similar to vitamin E suggested that the activation of PPAR-alpha does exert a cellular antioxidant effect and that appropriate regulation of the PPAR-alpha system may be essential to maintenance of redox balance in aging. With PPAR-alpha knockout mice, a functional PPAR-alpha was required for the beneficial effects of DHEAS or WY-14,643 in aging or under conditions of redox imbalance induced by feeding a vitamin E-deficient diet. PPAR-alpha -/- mice also showed indices of oxidative stress at an earlier age than PPAR-alpha +/+ mice, supportive of the essential role for PPAR-alpha; in the maintenance of redox balance. Furthermore, reduced expression of PPAR-alpha; in the spleen is another consequence of aging, a finding suggesting that age-associated alterations in the PPAR-alpha; system may contribute to the immunosenecent phenotype as well as to a number of disease states.