A Fasting-Responsive Signaling Pathway that Extends Life Span in C. elegans

SummaryIntermittent fasting is one of the most effective dietary restriction regimens that extend life span in C. elegans and mammals. Fasting-stimulus responses are key to the longevity response; however, the mechanisms that sense and transduce the fasting stimulus remain largely unknown. Through a comprehensive transcriptome analysis in C. elegans, we find that along with the FOXO transcription factor DAF-16, AP-1 (JUN-1/FOS-1) plays a central role in fasting-induced transcriptional changes. KGB-1, one of the C. elegans JNKs, acts as an activator of AP-1 and is activated in response to fasting. KGB-1 and AP-1 are involved in intermittent fasting-induced longevity. Fasting-induced upregulation of the components of the SCF E3 ubiquitin ligase complex via AP-1 and DAF-16 enhances protein ubiquitination and reduces protein carbonylation. Our results thus identify a fasting-responsive KGB-1/AP-1 signaling pathway, which, together with DAF-16, causes transcriptional changes that mediate longevity, partly through regulating proteostasis.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► JNK/AP-1 signaling and DAF-16 play a central role in fasting-stimulus responses ► AP-1 and DAF-16 mediate induction of fasting genes that play key roles in life-span extension ► The SCF E3 ubiquitin ligase complex is a target of fasting-responsive signaling ► Fasting enhances protein ubiquitination, causing a reduction in protein carbonylation