An altered balance of dietary amino acids has been shown to modulate lifespan in several model systems. But the mechanisms through which these effects occur are still relatively unknown. The goal of this proposal is to explore the relationshi between amino acid breakdown and lifespan extension in C. elegans worms. We hypothesize that several amino acids including threonine, isoleucine, and valine increase lifespan in C. elegans by increasing succinyl-CoA and acetyl-CoA levels and the increased acetyl-CoA levels will increase histone acetylation by CREB-binding protein-1 (CBP-1) histone acetyltransferase.
The specific aims for this investigation are to first determine the lifespan of worms individually administered each of the 20 amino acids and to determine the signaling pathways that are activated to extend lifespan. The amino acid breakdown products responsible for lifespan extension will subsequently be identified. Next, it will be determined if acetyl-CoA activation of the histone acetyltransferase CREB binding protein-1 (CBP-1) is involved in this process. Lastly, acetyl-CoA and succinyl-CoA levels will be measured following addition of several amino acids and knockdown of acetyl-CoA generating enzymes to determine if acetyl-CoA or succinyl- CoA levels positively correlate with lifespan. This research program is novel because it combines biochemical metabolism and genetic analysis to study aging. Mitochondrial bioenergetics plays a very important role in determining the rate of aging and the onset of aging related diseases. Our research laboratory focuses on mitochondrial analysis of C. elegans aging. The researchers who make up the project team for this two year investigation consist of the PI, one second year Ph.D. student and one fourth year Ph.D. student. The project will provide an important component of the Ph.D. training program for the two graduate students. The proposed work is innovative because it has the possibility to induce a paradigm shift in our understanding of the molecular mechanisms of how metabolism of amino acids is linked to longevity. Our results will answer three very important questions at the intersections of the fields of metabolism and aging. First, the molecular pathways leading to amino acid-induced lifespan extension will be established. Second, it will be determined if the TCA cycle metabolites acetyl-CoA and succinyl-CoA play a role in metabolite-induced lifespan extension. And third, a role for CBP-1 in amino acid induced lifespan extension will be tested. These experiments will lay the groundwork for metabolite-based therapies for human aging-related disorders.
The goal of our research is to elucidate the individual amino acids that extend lifespan and the amino acid breakdown products and signaling pathways necessary for lifespan extension. We will use C. elegans nematode worms in our studies, since they provide a powerful genetic system and only live for approximately three weeks. Once it is known which amino acids and breakdown products extend lifespan, we will be able to develop a cocktail of these metabolites to increase healthspan and delay aging-associated disorders.
|Edwards, Clare; Canfield, John; Copes, Neil et al. (2014) D-beta-hydroxybutyrate extends lifespan in C. elegans. Aging (Albany NY) 6:621-44|