Insoluble protein carbonyl: A critical determinant for mammalian longevity

University Of Texas Hlth Science Center, San Antonio TX

Investigators

Abstract

DESCRIPTION (provided by applicant): It is now well documented in literature that post-translational changes in protein, particularly protein carbonylation, occur with increasing age in animals ranging from invertebrates, e.g., yeast and Drosophila, to humans. Carbonylated proteins accumulate over time to form high molecular weight insoluble aggregates if they are escaped degradation by the proteasome. Accumulation of insoluble aggregates has been shown to be extremely toxic to cells and to be associated with several age-related diseases, especially neurodegenerative diseases. Recent work in my laboratory on various short- (lab mouse, wild caught mouse, rat) and long-lived (naked mole rat, bat and marmoset) mammal species including inbred ad libitum and dietary (DR) restricted young and old C57BL/6 mice has shown for the first time an unexpected generalized observation that long- lived species have low level of insoluble cellular protein carbonyl than short-lived species. This data strongly suggests that long lifespan species seems to have better ability to attenuate accumulation of insoluble protein carbonyl than short-lived species. Since carbonylated proteins in general are marked for proteolysis by the proteasome, we speculated that active proteasomal function might be one of the defense machineries used by long-lived species to maintain good quality of proteins. Our preliminary study with rodent species found a direct association between active proteasomal function and increased longevity. Taken these together, the proposed research would expand these intriguing initial observations to evaluate the general hypothesis that long-lived species exhibit reduced accumulation of insoluble protein carbonyl and maintain cell viability via activation of proteasomal machinery. In this proposal, we would like to use variety of non-traditional short- and long-lived species fibroblast cells to test the hypothesis. This project represents the first study to critically evaluate the crosstalk between protein carbonylation and proteasomal function which play a critical role in protecting cells from protein toxicity across a broad range of mammals. These data will allow us to determine if reduced protein toxicity is a common/public mechanism used by evolutionary processes to increase longevity. This proposal will test the hypothesis by pursuing the following specific aims. Specific Aim 1. To test the hypothesis that efficient response of proteasomal function, reduction in insoluble protein carbonyl and restoring cell viability are common traits for fibroblast cells of long-lived species n response to oxidative stress. Specific Aim 2. To test the hypothesis that inactivation of proteasomal function initiates accumulation of insoluble protein carbonyl which lead to increase cell death in fibroblast of long-lived species.