A GWAS for late-life mortality in Drosophila identifies Diabetes and obesity regulated to regulate mortality and resilience.
Authors: Tyler Hilsabeck 1,2; Kenneth Wilson 1; Jennifer Beck 1,3; Christopher Nelson 1; Rachel Brem 1,2,4; Pankaj Kapahi 1,2
Affiliations: 1) Buck Institute, Novato, CA; 2) University of Southern California, Los Angeles, CA; 3) University of California, San Francisco, CA; 4) University of California, Berkeley, CA
Keywords: i. lifespan; a. stress responses
Variations in rate of aging in geneticaly heterogenious populations support the hypothesis that aging is at least partially genetically regulated. However, genetically identical individuals also vary in their time of death even when maintained in the same environment. We have observed in D. melanogaster that this variation is genotype dependent, as specific genotypes have characteristic survival curve shapes that are largely reproducible. We hypothesize that there is an underlying genetic component to this seemingly stochastic nature of lifespan curves. Typical aging studies reduce a strain’s lifespan down to a population-level value, such as mean or max lifespan. While these metrics can represent the trends in a population, they are unable to encapsulate the variation in the aging of individuals from the same distinct population. Instead, we used two values that characterize the logistic fit of a strain’s hazard ratio over its lifespan: the risk of initial mortality (α) and the rate of aging (β). To identify regulators of the rate of aging and stochasticity of lifespan, we performed a Genome-Wide Association Study (GWAS) of β for 160 different fly strains from the DGRP collection on two different diets late in life. This approach identified the candidate gene Diabetes and Obesity-Regulated (DOR), which has known roles in stress response, autophagy, and senescence, as having a role in the late-life mortality. DOR inhibition leads to a significant increase in late-life mortality that is preceded by a reduction in healthspan-related traits. Further, we’ve found that germline-specific inhibition is sufficient to shorten lifespan. We conclude that a decrease in expression of DOR, a conserved gene, compromises an organism’s resilience, leading to a decline in healthspan and increased mortality, providing a potential target for bolstering the decline seen in human aging.