Investigating the contribution of AMPK regulation to physiology and lifespan in C. elegans

Life expectancy increased dramatically during the 20th century and gave rise to a variety of age-related diseases which affect modern society. Recent studies investigating the relationship between energy homeostasis and longevity imply that nutrient-sensing pathways are important for determining lifespan. AMP-activated protein kinase (AMPK) is a key metabolic regulator which responds to changes in the AMP:ATP ratio within cells, promoting a metabolic shift towards increased catabolism and autophagy during a low-energy state to promote restoration of cellular energy supply. AMPK is a heterotrimeric protein consisting of α catalytic, β linker and γ regulatory subunits. AMP binds to specific, evolutionary conserved residues in the γ subunit, initiating a conformational change across the kinase and allosterically regulating its activity.Previous work in the nematode worm Caenorhabditis elegans has demonstrated that AMP-sensitivity is important for AMPK-mediated contributions to longevity. Here, I use this genetic model to further explore the functional roles of AMPKγ and investigate the relationship between AMP binding, physiology, and lifespan more closely. C. elegans are unusual because they have five different AMPKγ subunits which are believed have different abilities to bind AMP. Using C. elegans, I create two alternative models of AMPK function, believed to be AMP-sensitive and AMP-insensitive. Through investigations into AMPK activation, I show that an aakg-1; aakg-2; aakg-3 knockout is unable to respond normally to AMP, which may contribute to substantial shortening of lifespan. Additionally, I have also found that the sensitivity of AMPKγ to AMP is important for stress resistance, fecundity, and dauer.Taken together, my analysis shows that alternative modes of AMPK activation affect several aspects of worm physiology, suggesting that AMPKγ holds potential pharmacological relevance, which in some cases can be separated from AMPKα.