MANIPULATION OF BASAL GANGLIA AGING BY DIET AND DOPAMINE

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This study will examine manipulations of basal ganglia aging in rodents with an emphasis on transcriptional changes in GFAP, an intermediate filament of astrocytes that shows a general increase in prevalence during aging. Besides GFAP, other astrocyte markers of aging (apoE and apoJ) also increase in response to lesioning, which suggests the hypothesis that some spontaneous aging changes represent responses of astrocytes to the same stimuli as in acute responses to lesions. As a rationale for these studies on the manipulation of aging, chronic diet restriction (DR) reduced the age-related loss of striatal dopaminergic D2-receptors, while the DA agonist pergolide (PERG) reduced the loss of nigrostriatal terminals. Moreover, DR attenuated age-related increase of astrocyte GFAP mRNA in the striatum (preliminary data), as we have found in hippocampus and hypothalamus. We hypothesize that manipulation of aging in the basal ganglia by chronic DR or PERG share common mechanisms by attenuating oxidative damage that stimulates glial hyperactivity. In particular, we will examine how DR and PERG influence age changes in glia to test the hypothesis that activated microglia increase production of TGF-Beta1 and other cytokines that, in turn, activate astrocytes to increase production of GFAP and apoJ (clusterin). We will also examine the D2-receptor mRNA, a neuronal marker which decreases during aging. Oxidative damage will be directly assayed in proteins and lipids. We will also examine transcriptional mechanisms in the responses of GFAP to lesions and aging. These studies probe mechanisms in basal gangliar aging that bear on changes in motor functions during normal aging and changes that may increase the risk of catastrophic loss of substantia nigra neurons that lead to Parkinson disease (PD).