Molecular analysis of the role of mitochondria in aging and lengevity

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Title: Molecular analysis of the role of mitochondria in aging and lengevity
Author: Kashyap B Choksi
Abstract: The Free Radical Theory of Aging states that there is an increase in reactive oxygen species (ROS ) production with aging leading to increase in tissue dysfunction . Mitochondria are the major source of ROS , which damages essential macromolecules by oxidative modification and may lead to mitochondrial dysfunction . Accumulation of oxidative damage caused by ROS has been implicated as a major causal factor in the age -associated decline in tissue function and implicated in many age -associated diseases and sarcopenia . Mitochondrial electron transport chain (ETC ) complexes I and III are the principle sites of ROS production , and oxidative modifications to their complex subunits inhibit their in vitro activity . Therefore , we hypothesize that mitochondrial complex subunits are primary targets for oxidative damage which may impair their structure /function leading to mitochondrial dysfunction associated with aging . \r \n In addition , numerous studies have identified long -lived mutant mice (i .e . , Ames dwarf mice ) that suggest that their longevity correlates with oxidative stress resistance . It has not yet been determined whether the mutant mice have inherently lower levels of ROS and whether there are changes in the electron transport chain function compared to wild -type . Therefore , we hypothesize that the dwarf mice have lower levels of ROS -generated lipid peroxidation markers and there are age -related changes in ETC function from tissues of dwarf and wild -type that may play a role in longevity . \r \n In our studies , we have developed a novel methodology for detecting oxidative modification markers using bovine heart mitochondria . In addition , we found that in various mouse tissues ETC proteins are specifically targeted for oxidation and in most cases increased oxidative modifications with aging correlate with decreased enzymatic activities . Thus , we propose that the specificity of the oxidative modification may play a key role in predicting the consequences of ROS -mediate damage . The results from long -lived Ames dwarf mice show that they have lower levels of ROS markers suggesting delayed aging characteristics and except for kidney very little changes in ETC function are noted . Therefore , our studies provide important insight into physiological effects of oxidative modifications on mitochondrial function as well as role of oxidative stress markers in aging and longevity .
URI: http : / /hdl .handle .net /2152 .3 /226
Date: 2007-10-10


Molecular analysis of the role of mitochondria in aging and lengevity. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /226 .

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