Small Molecule from Natural Phytochemical Mimics Dietary Restriction by Modulating FoxO3a and Metabolic Reprogramming

Kim, Juewon; Lee, Shin‐Hae; Cho, Miook; Lee, Jee Young; Choi, Dongkyu; Lee, Hye Yeon; Cho, Siyoung; Min, Kyung‐Jin; Suh, Yousin

doi:10.1002/adbi.201900248

Cited by 6 publications

(5 citation statements)

References 40 publications

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“…Collectively, the DR-related metabolite threonine increased the healthspan by the induction of antioxidative protection. It was furthermore interesting to note that previous studies on anti-aging compounds and metabolites, which reported DR-mimic activity, including syringaresinol 27 , metformin 28 , and α-ketoglutarate 29 , also increased the threonine content in C. elegans (Fig. 1j ).…”

Section: Resultsmentioning

confidence: 75%

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

Kim

Cho

et al. 2022

Nat Commun

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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.

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Section: Resultsmentioning

confidence: 75%

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

Kim

Cho

et al. 2022

Nat Commun

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“…Collectively, the DR-related metabolite threonine increased the healthspan by the induction of antioxidative protection. It was furthermore interesting to note that previous studies on anti-aging compounds and metabolites, which reported DR-mimic activity, including syringaresinol 26 , metformin 27 , and α-ketoglutarate 28 , also increased the threonine content in C. elegans (Fig. 1j).…”

Section: Identification Of Longevity-related Metabolites and Their Effects On C Elegans Healthspanmentioning

confidence: 75%

L-threonine mediated DAF-16/HSF-1 activation inhibits ferroptosis and increases healthspan

Kim

Cho

et al. 2022

Preprint

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The pathways that impact longevity in the wake of dietary restriction (DR) pathway remain still ill-defined. Most studies have focused on nutrient limitation and perturbations of energy metabolism to explain the beneficial effects of DR. We showed that the essential amino acid L-threonine was elevated in Caenorhabditis elegans under DR, and that L-threonine supplementation increased its healthspan. To elucidate the underlying mechanism, we conducted metabolic and transcriptomic profiling using LC-MS/MS and RNA-seq analyses in worms that were fed with RNAi to induce loss of function of key candidate mediators and evaluated healthspan. L-threonine supplementation and loss-of-threonine dehydrogenase, which govern L-threonine metabolism, increased the healthspan of C. elegans by attenuating ferroptosis in a ferritin-dependent manner. Transcriptomic analysis of C. elegans supplemented with L-threonine showed that FTN-1 encoding ferritin was elevated, implying FTN-1 is an essential mediator of longevity promotion through L-threonine. Organismal ferritin levels were positively correlated with chronological aging and L-threonine supplementation further increased ferritin levels, which 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.

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“…For example, in vitro results showed that syringaresinol exerted antioxidant activities, hence could affect the pathogenesis of fatigue (84). Besides, syringaresinol can activate SIRT1, which increases the antioxidant capacity through activation of nuclear factor (erythroid-derived 2)-like 2 (85). In general, compounds with similar chemical structures tend to have similar biological properties.…”

Section: Discussionmentioning

confidence: 99%

Feasibility study on the use of “Qi-tonifying medicine compound” as an anti-fatigue functional food ingredient based on network pharmacology and molecular docking

Cao

et al. 2023

Front. Nutr.

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IntroductionFatigue has attracted broad attention in recent years due to its high morbidity rates. The use of functional foods to relieve fatigue-associated symptoms is becoming increasingly popular and has achieved relatively good results. In this study, network pharmacology and molecular docking strategies were used to establish the material basis and mechanisms of Chinese herbal compounds in fatigue treatment. According to traditional medicine theories and relevant guidance documents published by the Chinese Ministry of Health, four herbal medicines, including Eucommia ulmoides Oliver bark, Eucommia ulmoides Oliver male flower, Panax notoginseng, and Syzygium aromaticum (EEPS), were selected to constitute the anti-fatigue herbal compound that may be suitable as functional food ingredients.MethodsThe major active ingredients in EEPS were identified via comprehensive literature search and Traditional Chinese Medicine Systems Pharmacology database search. Corresponding targets for these ingredients were predicted using SwissTargetPrediction. The network was constructed using Cytoscape 3.9.1 to obtain key ingredients. Prediction of absorption, distribution, metabolism, excretion and toxicity properties was performed using the ADMETIab 2.0 database. The anti-fatigue targets were retrieved from GeneCards v5.13, OMIM, TTD and DisGeNET 7.0 databases. Then, the potential targets of EEPS in fatigue treatment were screened through a Venn diagram. A protein–protein interaction (PPI) network of these overlapping targets was constructed, and the hub targets in the network selected through topological screening. Gene Ontology and KEGG pathway enrichment analyses were performed using the DAVID database and the bioinformatics online platform. Finally, AutoDock tools were used to verify the binding capacity between the key active ingredients and the core targets.Results and DiscussionThis study identified the active ingredients and potential molecular mechanisms of EEPS in fatigue treatment, which will provide a foundation for future research on applications of herbal medicines in the functional food industry.

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Small Molecule from Natural Phytochemical Mimics Dietary Restriction by Modulating FoxO3a and Metabolic Reprogramming

Cited by 6 publications

References 40 publications

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

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

L-threonine mediated DAF-16/HSF-1 activation inhibits ferroptosis and increases healthspan

Feasibility study on the use of “Qi-tonifying medicine compound” as an anti-fatigue functional food ingredient based on network pharmacology and molecular docking

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