Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity

• DOI: 10.1016/j.cmet.2019.02.013
• Publication Date: 2019-03-21T14:43:42Z
• Authors: Ziyun Wu; Meltem Isik; Natalie Moroz; Michael J. Steinb...; Peng Zhang; T. Keith Blackwell
• Keywords: 2. Zero hunger; Aging; Longevity; Forkhead Transcription Factors; Mechanistic Target of Rapamycin Complex 1; p38 Mitogen-Activated Protein Kinases; Activating Transcription Factors; Immunity, Innate; Eating; Animals; Insulin; Insulin-Like Growth Factor I; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Caloric Restriction; Signal Transduction

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.