Understanding how mitochondria influence and regulate the aging process is one of the most important problems in contemporary biology. Our previous results demonstrated that the mitochondrial ETC is required during larval development to set the rates of aging and physiological states of the worm. We propose to expand these findings to ask in which tissues this pathway is required to function to set the rates of aging and physiology. Our hypothesis is that the mitochondrial activity in specific tissues is important for the regulation of the aging process. We propose three different approaches to modulate ETC activity in a tissue specific manner.
In Specific Aim I, we propose to express tissue specific ETC dsRNA to inactivate members of the ETC and ATP synthase, identified in our earlier studies, to test whether longevity, stress resistance or rates of development and physiology were altered. Alteration of one of these phenotypes by ETC dsRNA expression in a particular tissue would allow us to conclude that the mitochondria of that tissue play an important role in regulating longevity, stress resistance and rates of development and other physiological processes.
In Specific Aim II, we propose to activate ETC function within specific tissues by tissue specific expression of ucp1. Tissue specific expression of ucp1 resulting in animals with shorter life spans and reduced resistance to stress will allow us to conclude that ETC activity in specific tissues of the worm plays an important role in life span determination and stress resistance.
In Specific Aim III, we will determine which tissues require normal levels of mev-1 activity for normal longevity and stress resistance. Using tissue specific promoters, we will restore wild type mev-1 message to mev-1(kn1) mutant animals. Complementation of mev-1(kn1) mutant defects by tissue specific expression of wild type mev-1 will allow us to identify the tissues in which mev-1 is required to regulate longevity and stress resistance.
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