L-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans

Abstract

The pathways that impact longevity in the wake of dietary restriction (DR) remain still ill-defined. Most studies have focused on nutrient limitation and perturbations of energy metabolism. We showed that the L-threonine was elevated in Caenorhabditis elegans under DR, and that L-threonine supplementation increased its healthspan. Using metabolic and transcriptomic profiling in worms that were fed with RNAi to induce loss of key candidate mediators. L-threonine supplementation and loss-of-threonine dehydrogenaseincreased the healthspan by attenuating ferroptosis in a ferritin-dependent manner. Transcriptomic analysis showed that FTN-1 encoding ferritin was elevated, implying FTN-1 is an essential mediator of longevity promotion. Organismal ferritin levels were positively correlated with chronological aging and L-threonine supplementation protected against age-associated ferroptosis through the DAF-16 and HSF-1 pathways. Our investigation uncovered the role of a distinct and universal metabolite, L-threonine, in DR-mediated improvement in organismal healthspan, suggesting it could be an effective intervention for preventing senescence progression and age-induced ferroptosis.