Abstract
Dietary restriction (DR) is a highly effective and reproducible intervention that prolongs longevity in many organisms. The molecular mechanism of action of DR is tightly connected with the immune system; however, the detailed mechanisms and effective downstream factors of immunity that mediate the beneficial effects of DR on aging remain unknown. Here, to investigate the immune signaling that mediates DR effects, we used Caenorhabditis elegans, which has been widely used in research, to understand the underlying molecular mechanisms of aging and immunity. We found that the F-box gene, fbxc-58, a regulator of the innate immune response, is a novel mediator of DR effects on extending the health span of C. elegans. fbxc-58 is upregulated by DR and is necessary for DR-induced lifespan extension and physical health improvement in C. elegans. Furthermore, through DR, fbxc-58 prevents disintegration of the mitochondrial network in body wall muscle during aging. We found that fbxc-58 is a downstream target of the ZIP-2 and PHA-4 transcription factors, the well-known DR mediator, and fbxc-58 extends longevity in DR through an S6 kinase-dependent pathway. We propose that the novel DR effector, fbxc-58, could provide a new mechanistic understanding of the effects of DR on healthy aging and elucidate the signaling mechanisms that link immunity and DR effects with aging.