Genome-wide analysis reveals distinct genetic mechanisms of diet-dependent lifespan and healthspan inD. melanogaster

Abstract

27Dietary restriction (DR) robustly extends lifespan and delays age-related diseases across 28species. An underlying assumption in aging research has been that DR mimetics extend both 29 lifespan and healthspan jointly, though this has not been rigorously tested in different genetic 30 backgrounds. Furthermore, nutrient response genes important for lifespan or healthspan 31 extension remain underexplored, especially in natural populations. To address these gaps, we 32 utilized over 150 DGRP strains to measure nutrient-dependent changes in lifespan and age-33 related climbing ability to measure healthspan. DR extended lifespan and delayed decline in 34 climbing ability on average, but there was no evidence of correlation between these traits across 35 individual strains. Through GWAS, we then identified and validated jughead and Ferredoxin as 36 determinants of diet-dependent lifespan, and Daedalus for diet-dependent physical activity. 37Modulating these genes produced independent effects on lifespan and climbing ability, further 38suggesting that these age-related traits are likely to be regulated through distinct genetic 39 mechanisms. 40 peer-reviewed)

From discoveries in ageing research to therapeutics for healthy ageing

“…For example, analyses of dietary restriction in multiple recombinant inbred mice strains found both an increase and a decrease in lifespan, which was dependent on the strain 131 . Similar results have been obtained using more than 150 strains of flies 132 . The molecular basis for these differences in response to what had been assumed to be a universally beneficial intervention has not been established.…”

“…Although there are many examples of a connection between long lifespan and increased healthspan, more-recent studies in mice 142,143 , flies 132 and worms [144][145][146] have questioned the assumption that lifespan extension is always accompanied by an increase in healthspan. Future studies will need to address the effects of interventions on both of these aspects before attempting to translate these interventions into the treatment of human patients.…”

The hidden costs of dietary restriction: Implications for its evolutionary and mechanistic origins

“…Genotypes will differ in their longevity reaction norm to diet, rendering it impossible to know a priori whether a certain dietary composition constitutes the exact optimal longevity-directed diet (9,39). Genetic variation in the response to DR, reported in rodents (40) and flies (41), might therefore not necessarily, or wholly, constitute variation in the physiological mechanisms that connect DR to ageing. We propose that our dietary phenotypes may also be contingent upon the direction and degree in which these diets deviate from the optimum, which may be one explanation for the dissimilarity of results observed in similar experiments.…”

The importance of diversity and outreach in geroscience research: Insights from the Annual Biomedical Research Conference for Minority Students

“…(2) Healthspan extending interventions identified by geroscientists could help mitigate these existing health disparities. Multiple lines of evidence show that lifespan extending interventions preferentially benefit shorter-lived subpopulations in model systems (Rikke et al 2010;Schleit et al 2013;Wilson et al 2018).…”