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

  • Keller, Jeff (PI)

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Description

The proteasome is an intracellular protease that is responsible for a significant amount of intracellular proteolysis, in particular the degradation of short-lived proteins. Inhibition of the proteasome-proteolytic pathway appears 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 the 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 central hypothesis that DR ameliorates agerelated impairments in proteasome function in the CNS, as the result of direct effects on the proteasome complex. Additionally, we hypothesize that this preservation of proteasome-mediated protein degradation by DR contributes to the maintentenance of the proteome and thereby inhibits cellular disturbances during the aging of the CNS. Specifically we hypothesize that the maintenance of the proteome in DR is mediated by preventing the accumulation of key proteasome substrates, derived as the result of proteasome impairment in the aging CNS, as well as by ameliorating the wide spread impairment in protein synthesis which occurs as the result of proteasome inhibition. 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 impairments in proteasome function promote disruptions in the proteome, and ultimately contribute to cellular dysfunction in the CNS. The specific aims for testing these hypotheses 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 test the hypothesis that proteasome inhibition promotes the accumulation of specific proteins while concominantly decreasing overall protein synthesis in the CNS; (4) to test the hypothesis that DR ameliorates age-related proteome alterations induced by proteasome inhibition in the CNS. Taken together, these data will not only advance our understanding of aging in the CNS, but may have important implications for identifying potential therapeutic targets for aging and age-related disorders of the CNS.
StatusFinished
Effective start/end date9/1/0712/24/07

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