Cell Metabolism
Volume 29, Issue 5, 7 May 2019, Pages 1192-1205.e8
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Article
Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity

https://doi.org/10.1016/j.cmet.2019.02.013Get rights and content
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Highlights

  • Dietary restriction longevity requires modulation of nutrient-regulated immunity

  • Nutrients activate the p38–ATF-7 immunometabolic pathway independently of mTORC1

  • Insulin/IGF-1 signaling affects immunity and aging in part by curtailing food intake

  • DAF-16/FOXO lowers food consumption, linking feeding and immunity to growth signals

Summary

Chronic inflammation predisposes to aging-associated disease, but it is unknown whether immunity regulation might be important for extending healthy lifespan. Here we show that in C. elegans, dietary restriction (DR) extends lifespan by modulating a conserved innate immunity pathway that is regulated by p38 signaling and the transcription factor ATF-7. Longevity from DR depends upon p38–ATF-7 immunity being intact but downregulated to a basal level. p38–ATF-7 immunity accelerates aging when hyperactive, influences lifespan independently of pathogen exposure, and is activated by nutrients independently of mTORC1, a major DR mediator. Longevity from reduced insulin/IGF-1 signaling (rIIS) also involves p38–ATF-7 downregulation, with signals from DAF-16/FOXO reducing food intake. We conclude that p38–ATF-7 is an immunometabolic pathway that senses bacterial and nutrient signals, that immunity modulation is critical for DR, and that DAF-16/FOXO couples appetite to growth regulation. These conserved mechanisms may influence aging in more complex organisms.

Keywords

innate immunity
C. elegans
aging
longevity
ATF-7
p38 signaling
dietary restriction
insulin/IGF-1 signaling
food intake
immunometabolism

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