Genetics of exceptional resilience and its variation; insights from the world's longest-lived animal - We all age and grow old. Age is the primary cause of disease and heath burden in today’s society. Thus understanding how to mitigate the shared mechanisms of the manifestation of age-related diseases will have significant impacts on healthcare and, more generally, quality of life. To understand how aging is mitigated with time, we can leverage cases in nature where organisms have evolved mechanisms that permit them to live exceptionally long lives – the inference being that aging also must be inhibited to support such extended lifespans. These natural experiments provide unique solutions to shared physiological constraints as occurring in humans. Here we detail the genome of the longest-living animal, the Ocean Quahog, Arctica islandica, and ask what genes and novel functions allow for the attainment of exceptional lifespan to over 500 years. We also capitalize on the differential selection on lifespan across different populations of the Quahog across an ecological cline, ranging from 35 to 507 years. This dynamic evolutionary selection on lifespan in this species permits both macroevolutionary comparisons of lifespan, but also fine detail population genetics of what local selective forces and genes may underlie this shift. Our central hypothesis is that factors associating with exceptional longevity- -in even distantly related animals such as the Ocean quahog--will have core physiological similarities that will inform of mechanisms that can be altered to extend lifespan and healthspan. In Aim 1, we first propose to look at patterns of selection across the genome in comparison with lifespan variation among bivalve species as well as within different populations of A. islandica. As the distance between bivalves and more commonly used model animals is quite large, the orthology of genes is often hard to pin down, in Aim 2 we will assess conservation and homology of genes across the A. islandica genome though structural mapping. This will provide the codex of gene conservation and potential novelty within this large family of animals. To provide context for changes we observe associating with lifespan, we will use the evolutionarily defined genesets from A. islandica to refine human GWAS data for humans that live at the fringes of expected limits. Lastly in Aim 3, we look to functional changes in proteostatic mechanisms functioning within A. islandica. We will assess variation and function of small chaperone proteins in Arctica and ask if particular variants are sufficient to impart proteostatic resiliency in experimental models in Drosophila and zebrafish of aging and lifespan regulation. Lastly, we have evidence of specific variants of metabolic regulator, gapdh, shared across animals with exceptional longevity, including Arctica islandica. We will ask if these variants are sufficient to render proteostatic resiliency, as well as to extend healthspan and lifespan of Drosophila and zebrafish strains. Together, these aims will provide essential window into understanding the core principles and factors that underlie capacity for exceptional long life, and the heath implication that follow.
