Dietary restriction and proteasome-mediated protein degradation in the aging CNS

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DESCRIPTION (provided by applicant): The proteasome is an intracellular protease that is responsible for a significant amount of intracellular proteolysis. Inhibition of the proteasome-proteolytic pathway is thought to occur as a part of normal aging in most tissues. Proteasome inhibition likely contributes to numerous age-related alterations in the proteome, and thereby promotes a variety of cell disturbances during aging, although the lack of rigorous biochemical and proteomic analysis has made such estimations largely hypothetical and theoretical. Dietary restriction (DR) increases average and maximal lifespan in mammals, and suppresses a variety of deleterious age-related alterations at both the cellular and systems level. Our data suggests that DR ameliorates age-related impairments in proteasome function within the central nervous system (CNS). The focus of this proposal is to test the hypothesis that DR ameliorates age-related impairments in proteasome function in the CNS, as the result of direct effects on the proteasome complex. Additionally, we hypothesize that this preservation of proteolysis by DR contributes to maintenance of the proteome and inhibition of cellular disturbances during aging of the CNS. The specific aims are as follows: (1) to test the hypothesis that DR alters age-related alterations in the biogenesis, composition, and oxidation of proteasome complexes in selective regions of the CNS; (2) to test the hypothesis that DR alters age-related changes in proteasome function in selective regions of the CNS; (3) to identify which proteins in the CNS exhibit decreased degradation following proteasome inhibition; (4) to test the hypothesis that DR ameliorates age-related elevations in key proteasome substrates within the CNS. Together, these data will significantly contribute to our understanding of the molecular basis for DR-induced effects in the CNS, and contribute to our understanding of how DR ameliorates age-related impairments in proteasome function in the CNS. Additionally, these data will contribute to our understanding of how proteasome inhibition promotes disruptions in the proteome, and ultimately contributes to cellular dysfunction in the CNS. Such data may not only be important to our understanding of aging in the CNS, but may identify novel therapeutic targets for aging and age-related diseases of the CNS.