Abstract
Dietary restriction (DR) is a dietary regimen that extends lifespan in many organisms. One mechanism contributing to the conserved effect of DR on longevity is the cellular recycling process autophagy, which is induced in response to nutrient scarcity and increases sequestration of cytosolic material into double-membrane autophagosomes for degradation in the lysosome. Although autophagy plays a direct role in DR-mediated lifespan extension in the nematode Caenorhabditis elegans, the contribution of autophagy in individual tissues remains unclear. In this study, we show a critical role for autophagy in the intestine, a major metabolic tissue, to ensure lifespan extension of dietary-restricted eat-2 mutants. The intestine of eat-2 mutants has an enlarged lysosomal compartment and flux assays indicate increased turnover of autophagosomes, consistent with an induction of autophagy in this tissue. This increase in intestinal autophagy may underlie the improved intestinal integrity we observe in eat-2 mutants, since whole-body and intestinal-specific inhibition of autophagy in eat-2 mutants greatly impairs the intestinal barrier function. Interestingly, intestinal-specific inhibition of autophagy in eat-2 mutants leads to a decrease in motility with age, alluding to a potential cell non-autonomous role for autophagy in the intestine. Collectively, these results highlight important functions for autophagy in the intestine of dietary-restricted C. elegans.
Highlights
Dietary restriction (DR), defined as limited food intake without malnutrition, is the most robust and conserved intervention currently known to delay aging
Intestinal Autophagy during Dietary Restriction Improves Health genes involved in autophagy are required for lifespan extension through DR; it is not clear whether autophagy in individual tissues plays critical roles in DR-mediated longevity
Our major findings include: (i) Inhibition of autophagy in the intestine prevents the long lifespan observed in eat-2 mutants; (ii) the intestine of eat-2 mutants contains an expanded lysosomal compartment and flux assays indicate increased autophagosome turnover, consistent with elevated autophagy in this tissue; (iii) intestinal autophagy is required for the improved intestinal integrity observed in eat-2 mutants; (iv) autophagy inhibition impairs motility in older animals; and (v) inhibition of autophagy in the intestine accelerates the motility decline in eat-2 mutants
Summary
Dietary restriction (DR), defined as limited food intake without malnutrition, is the most robust and conserved intervention currently known to delay aging. Since many physiological effects of DR are evolutionarily conserved, genetically tractable model organisms such as the nematode C. elegans can be exploited as tools to identify the molecular events underlying DRmediated lifespan extension [1]. Cytoplasmic components are first encapsulated within a double-membrane structure called an autophagosome. This structure subsequently fuses with an acidic lysosome to form an autolysosome, in which the sequestered cargo is degraded by hydrolases [2]. Of particular note is ATG8, a family of lipid-binding proteins, which play essential roles in autophagosome formation, cargo recruitment, and autophagosome–lysosome fusion [2]. ATG8 proteins get post-translationally modified and inserted into both the inner and outer autophagosomal membranes and GFP-tagged ATG8 proteins are commonly used as markers to assess steady-state levels of autophagosomes in many species [2], including C. elegans, which contain two ATG8 homologs, LGG-1 and LGG-2 [3]
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