Juewon Kim ¹, Yunju Jo ², Donghyun Cho ³, Dongryeol Ryu ⁴

¹Basic Research & Innovation Division, Amorepacific R&D Center, Yongin, Korea. 
²Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
³Basic Research & Innovation Division, Amorepacific R&D Center, Yongin, Korea.
⁴Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea. 

Corresponding authors: Correspondence to Juewon Kim or Dongryeol Ryu.

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.