Diet restriction-induced healthy aging is mediated through the immune signaling component ZIP-2 in Caenorhabditis...

Dietary restriction (DR) robustly delays the aging process in all animals tested so far. DR slows aging by negatively regulating the target of rapamycin (TOR) and S6 kinase (S6K) signaling pathway and thus inhibiting translation. Translation inhibition in C. elegans is known to activate the innate immune signal ZIP-2. Here, we show that ZIP-2 is activated in response to DR and in feeding-defective eat-2 mutants. Importantly, ZIP-2 contributes to the improvements in longevity and healthy aging, including mitochondrial integrity and physical ability, mediated by DR in C. elegans. We further show that ZIP-2 is activated upon inhibition of TOR/S6K signaling. However, DR-mediated activation of ZIP-2 does not require the TOR/S6K effector PHA-4/FOXA. Furthermore, zip-2 was not activated or required for longevity in daf-2 mutants, which mimic a low nutrition status. Thus, DR appears to activate ZIP-2 independently of PHA-4/FOXA and DAF-2. The link between DR, aging, and immune activation provides practical insight into the DR-induced benefits on health span and longevity.