SUPPRESSION OF SHC ADAPTOR PROTEIN AS A PHARMACOLOGICAL INTERVENTION TO AMELIORATE AGE-STRESS

摘要

Advanced glycation end products have pathogenic implications towards diabetes, liver diseases and various other neurodegenerative diseases. In particular vascular complications that arise due to diabetes involves neuropathy, nephropathy, retinopathy and vitreopathy that lead to renal diseases and blindness. AGEs are endogenous products created by maillard reaction and several pathways including the glyoxalase I and aldo keto reductases are involved with detoxification of the AGEs. A recent study showed less circulating and tissue AGEs in p66Shc knockout mice compared to WT mice. A candidate genetic screen for worm orthologs of human genes associated with diabetic complications identified C. elegans SHC-1 as a strong modulator of pathogenic phenotypes in glod-4 mutants (C. elegans model lacking a functional glyoxalase gene). These glod-4 mutants maintain elevated AGEs, sensitivity to touch, and decreased lifespan. However RNAi against the Caenorhabditis elegans shc-1 gene and Acarbose and Idebenone discovered as SHC protein binders increases the lifespan of these glod-4 mutants. Thus we hypothesize that inhibition of SHC-1 may play an indispensable role in preventing AGE accumulation and AGE-stress. Thus in this study we propose to establish the mechanism by which shc modulates AGE accumulation and lifespan in C. elegans. Further we will Study SHC inhibitors (and or diets that modulate SHC) as pharmacological intervention to ameliorate AGE-stress and increase healthspan and lifespan.