In an attempt to understand causes of aging and organismal death C. elegans, we have established new tools for longitudinal studies in aging worm cohorts. We have characterized age-related pathologies and developed a high-throughput method for simultaneously performing survival assays on over a hundred age/genotype combinations. Applying these methodologies to the study of age-related changes in Age mutants, we have uncovered two new phenomena, both requiring autophagy. Using time-lapse recordings of blue death fluorescence (Coburn et al. PLoS Biology, 2013) to automate mortality scoring in worm populations, we performed semi-automated stress assays in multiwell plates, following daily changes in heat resistance in various Age mutants and conditions. Unexpectedly, we observed an age increase in resistance to acute heat (42°C) in N2 hermaphrodites, peaking between days 6 and 8 of adulthood, and decreasing thereafter. Mutation of daf-2 (insulin/IGF-1 receptor) markedly extended the period of maximum resistance, while mutation of daf-16 (FoxO transcription factor) shortened it. Overall, both amplitude and timing of the peak correlated positively with mutant longevity and this phenomenon required DAF-16, HSF-1 and an intact autophagy pathway. In a parallel line of investigation, we simultaneously assessed age-related pathologies in a range of Age mutants (see presentation by Ezcurra et al.). Two salient pathologies, extracellular yolk accumulation and intestinal atrophy, were correlated across genotypes and individuals, suggesting a causal link. In wild type N2, both phenomena occurred only in hermaphrodites, but they could be induced in males by feminization using mab-3 mutations. Autophagy mutants showed striking reductions in both extracellular yolk accumulation and intestinal atrophy. Accordingly, protein and lipid yolk components were also reduced. Intestinal-specific RNA interference of autophagy genes was sufficient to recapitulate these effects. Taken together, these results identify a likely mechanism of intestinal atrophy, a major pathology of aging in C. elegans: autophagy-dependent conversion of intestinal biomass into yolk. It implicates autophagy as a modulator of energy flux in C. elegans adulthood, generating energy and metabolites to satisfy the high energetic demand of yolk synthesis and afford optimal stress handling during the reproductive period. This work further suggests that early ageing in C. elegans is characterized by robust activity rather than metabolic decline.
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