Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity

• Published in: Cell metabolism Vol. 29; no. 5; pp. 1192 - 1205.e8
• Main Authors: Wu, Ziyun, Isik, Meltem, Moroz, Natalie, Steinbaugh, Michael J., Zhang, Peng, Blackwell, T. Keith
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.05.2019
• Subjects: aging; ATF-7; C. elegans; dietary restriction; food intake; immunometabolism; innate immunity; insulin/IGF-1 signaling; longevity; p38 signaling; C. elegans; innate immunity; immunometabolism; ATF-7; insulin/IGF-1 signaling; longevity; p38 signaling; aging; dietary restriction; food intake
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2019.02.013

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. [Display omitted] •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 Wu et al. report that longevity from dietary restriction and reduced insulin/IGF-1 signaling involves modulation of a conserved p38–ATF-7 innate immunity pathway. This immunometabolic pathway is activated by nutrients independently of mTORC1. DAF-16/FOXO inhibits p38–ATF-7 immunity by reducing food consumption, thereby linking growth, appetite, immunity, and lifespan regulation.