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. 2025 Feb 4;37(2):542-556.e14.
doi: 10.1016/j.cmet.2024.12.008. Epub 2025 Jan 21.

Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation

Dunja Petrovic  1 , Luke Slade  1 , Yiorgos Paikopoulos  1 , Davide D'Andrea  1 , Nevena Savic  2 , Ana Stancic  2 , Jan Lj Miljkovic  3 , Thibaut Vignane  1 , Maria Kyriaki Drekolia  4 , Dusan Mladenovic  5 , Nikola Sutulovic  6 , Alice Refeyton  7 , Milica Kolakovic  8 , Vladimir M Jovanovic  9 , Jasmina Zivanovic  2 , Marko Miler  2 , Valentina Vellecco  10 , Vincenzo Brancaleone  11 , Mariarosaria Bucci  10 , Alva M Casey  3 , ChakShun Yu  3 , Siva Swapna Kasarla  1 , Karl William Smith  1 , Ayten Kalfe-Yildiz  1 , Martin Stenzel  1 , Antonio Miranda-Vizuete  12 , Roland Hergenröder  1 , Prasad Phapale  1 , Olivera Stanojlovic  6 , Ivana Ivanovic-Burmazovic  8 , Marija Vlaski-Lafarge  7 , Sofia-Iris Bibli  4 , Michael P Murphy  13 , Vesna Otasevic  2 , Milos R Filipovic  14
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Free article

Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation

Dunja Petrovic et al. Cell Metab. .
Free article

Erratum in

  • Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation.
    Petrovic D, Slade L, Paikopoulos Y, D'Andrea D, Savic N, Stancic A, Miljkovic JL, Vignane T, Drekolia MK, Mladenovic D, Sutulovic N, Refeyton A, Kolakovic M, Jovanovic VM, Zivanovic J, Miler M, Vellecco V, Brancaleone V, Bucci M, Casey AM, Yu C, Kasarla SS, Smith KW, Kalfe-Yildiz A, Stenzel M, Miranda-Vizuete A, Hergenröder R, Phapale P, Stanojlovic O, Ivanovic-Burmazovic I, Vlaski-Lafarge M, Bibli SI, Murphy MP, Otasevic V, Filipovic MR. Petrovic D, et al. Cell Metab. 2025 Mar 4;37(3):789. doi: 10.1016/j.cmet.2025.01.023. Epub 2025 Feb 1. Cell Metab. 2025. PMID: 39894020 No abstract available.

Abstract

Ergothioneine (ET), a dietary thione/thiol, is receiving growing attention for its possible benefits in healthy aging and metabolic resilience. Our study investigates ET's effects on healthspan in aged animals, revealing lifespan extension and enhanced mobility in Caenorhabditis elegans, accompanied by improved stress resistance and reduced age-associated biomarkers. In aged rats, ET administration enhances exercise endurance, muscle mass, and vascularization, concomitant with higher NAD+ levels in muscle. Mechanistically, ET acts as an alternative substrate for cystathionine gamma-lyase (CSE), stimulating H2S production, which increases protein persulfidation of more than 300 protein targets. Among these, protein-persulfidation-driven activation of cytosolic glycerol-3-phosphate dehydrogenase (cGPDH) primarily contributes to the ET-induced NAD+ increase. ET's effects are abolished in models lacking CSE or cGPDH, highlighting the essential role of H2S signaling and protein persulfidation. These findings elucidate ET's multifaceted actions and provide insights into its therapeutic potential for combating age-related muscle decline and metabolic perturbations.

Keywords: NAD; ergothioneine; healthspan; hydrogen sulfide; persulfidation.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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