Studies on the lifespan extension by low levels of reactive oxygen species in C. elegans

Abstract

For the last two decades, many molecules and pathways that regulate life span in various organisms have been identified. Among these, reduced mitochondrial respiration has been shown to extend the lifespan of various species including C. elegans, Drosophila and mice. Although several recent studies identified genes that are required for this lifespan extension, underlying molecular mechanism are still poorly understood. Our group previously proposed that the inhibition of the respiration lengthens the lifespan of C. elegans through increasing the level of reactive oxygen species (ROS). We showed that the elevated ROS stabilize hypoxia inducible factor (HIF-1), a longevity-promoting transcription factor required for the responses to low oxygen conditions. Our findings challenged the oxidative stress theory of aging that reactive oxygen species (ROS) are byproducts of mitochondrial respiration and main determinants of aging through damaging molecules such as - DNA, proteins and lipids. In this thesis, I focused on further elucidation of the molecular mechanisms by which ROS promote the long lifespan of C. elegans. First, since dietary restriction is a well known evolutionarily conserved longevity mechanism, therefore I examined whether ROS treatment mimicked dietary restriction by reducing the feeding of C. elegans and found that it did not. Second, I tested whether the ROS treatment increased lifespan by enhancing innate immune response and found that it did not. I examined which longevity genes are required for the ROS- induced lifespan extension by using mutations in hsf-1/heat shock factor 1, aak-2/AMP kinase, and sir-2.1/sirtuin. I found that aak-2 is required for this lifespan extension similar to hif-1. Since mice with reduced respiration mutation live long as well as C. elegans, it will be important to examine how inhibition of mitochondrial respiration increases lifespan and I believe my study will shed light on elucidating the molecular mechanisms.