Abstract
Dietary restriction extends lifespan in evolutionarily diverse animals. A role for the sensory nervous system in dietary restriction has been established in Drosophila and Caenorhabditis elegans, but little is known about how neuroendocrine signals influence the effects of dietary restriction on longevity. Here, we show that DAF-7/TGFβ, which is secreted from the C. elegans amphid, promotes lifespan extension in response to dietary restriction in C. elegans. DAF-7 produced by the ASI pair of sensory neurons acts on DAF-1/TGFβ receptors expressed on interneurons to inhibit the co-SMAD DAF-3. We find that increased activity of DAF-3 in the presence of diminished or deleted DAF-7 activity abrogates lifespan extension conferred by dietary restriction. We also observe that DAF-7 expression is dynamic during the lifespan of C. elegans, with a marked decrease in DAF-7 levels as animals age during adulthood. We show that this age-dependent diminished expression contributes to the reduced sensitivity of aging animals to the effects of dietary restriction. DAF-7 signaling is a pivotal regulator of metabolism and food-dependent behavior, and our studies establish a molecular link between the neuroendocrine physiology of C. elegans and the process by which dietary restriction can extend lifespan.
Highlights
Adult reduction in caloric intake and restriction of feeding periods have been shown to substantially increase lifespan across evolutionarily diverse organisms [1,2]
We further find that age-related changes in expression of this neuroendocrine signal contribute to the declining efficacy of nutritional interventions as PLOS Genetics | DOI:10.1371/journal.pgen
We investigated the role of the DAF-7/TGFβ pathway in lifespan extension in response to dietary restriction using the bacterial deprivation (BD) method, where animals are moved to solid media completely lacking a bacterial food source during adulthood [3,4]
Summary
Adult reduction in caloric intake and restriction of feeding periods have been shown to substantially increase lifespan across evolutionarily diverse organisms [1,2]. Such treatments have been referred to as dietary restriction (DR). Other studies have suggested that external cues are critical in eliciting a DR response that extends lifespan in C. elegans [9] In both C. elegans and Drosophila, the efficacy of DR treatment can be abrogated by the addition of food odors, and longevity in Drosophila can be extended by reduction of olfactory function [10,11]. A pair of gustatory neurons in C. elegans, the ASI neuron pair, have been shown to be required for lifespan extension in response to dietary restriction [6]
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