ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1
Authors: Monet Bland
Ianessa Morantte
Richard Venz
Dunja Petrovic
T Keith Blackwell
Cole Haynes
Raffaella Emsley
Cyril Statzer
Collin Y Ewald
Pengpeng Liu
Jin Meng
Krina Patel
Alban Longchamp
Stacey Robida-Stubbs
Milos R Filipovic
William B Mair
Journal: Nature Communications (2022)
Discipline: Multidisciplinary
Keywords: mTORC1; protein synthesis; ATF-4; longevity; CTH-2
Affiliations: Eidgenössische Technische Hochschule Zürich, Department of Health Sciences and Technology, Institute of Translational Medicine, Schwerzenbach, Switzerland., Department of Genetics, Harvard Medical School, Boston, MA, USA., Joslin Diabetes Center, Research Division, Boston, MA, USA., Harvard Stem Cell Institute, Cambridge, MA, USA., Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany., Department of Vascular Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland., Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA., Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA, USA., Department of Genetics, Harvard Medical School, Boston, MA, USA. ., Joslin Diabetes Center, Research Division, Boston, MA, USA. ., Harvard Stem Cell Institute, Cambridge, MA, USA. ., Eidgenössische Technische Hochschule Zürich, Department of Health Sciences and Technology, Institute of Translational Medicine, Schwerzenbach, Switzerland. .

Abstract:  Inhibition of the master growth regulator mTORC1 (mechanistic target of rapamycin complex 1) slows ageing across phyla, in part by reducing protein synthesis. Various stresses globally suppress protein synthesis through the integrated stress response (ISR), resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that inhibition of translation or mTORC1 increases ATF-4 expression, and that ATF-4 mediates longevity under these conditions independently of ISR signalling. ATF-4 promotes longevity by activating canonical anti-ageing mechanisms, but also by elevating expression of the transsulfuration enzyme CTH-2 to increase hydrogen sulfide (H2S) production. This H2S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H2S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H2S levels, or enhancing mechanisms that H2S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition. 

Retracted: No

PubPeer comments:
 In this study, lice were collected from monkeys and human subjects living in the Amazon or in France, including homeless persons in Marseille. I have a question about the IRB approval for this study, since homeless persons might be considered to be a  vulnerable population (i.e., vulnerable to coercion), similar to veterans or prisoners in the US, although IRB rules might differ per country. Surprisingly, the IRB approval number listed in this paper (2010-A01406-33) is used for at least 17 studies, including this one. Although all of them involve homeless persons recruited from Marseille shelters, the studies themselves vary in terms of study protocols and treatment sample collection. The studies vary from collecting lice, treating subjects with drug-impregnated underwear, filling out questionnaires, medical exams, to nasal and pharyngeal sampling, skin swabbing, blood draw, rectal samples, sputum collection, and chest X rays. Moreover, the studies were performed from 2011 to 2020, spanning almost 10 years. Would the authors be willing to share the original 2010 ethical approval application here? Did they get approval for all these different studies spanning 10 years, in one single application? There is also confusion about which institution or ethical board approved the study. Some papers state that the study was approved by  our institutional review board , suggesting that this was a number referring to IRB approval by the Aix-Marseille Universitu00e9 and or Institut Hospitalo-Universitaire Mu00e9diterranu00e9e Infection, both listed as author affiliations. But in other papers, the IRB approval number appears to be an ANSM RCB authorization ID, as per  Informed consent was obtained from these subjects, and the study was approved by the u2018u2018Comitu00e9 de Protection des Personnes Sud Mediterranu00e9eu2019u2019 on January, 12, 2011 (ID RCB: 2010-A01406-33) , e.g. as mentioned in PLoS ONE 8(2): e58088. Either way, it would be of interest to take away any concern whether studies on this vulnerable populations were all performed within the original IRB approval scope. Here is the list of 17 papers that all appear to share the same ethical approval number: * Rezak Drali et al. - Journal of Clinical Microbiology (2012) p. 2229u20132233 - DOI: 10.1128 JCM.00808-12 * Rezak Drali et al. - PLoS ONE 8(2): e58088 (2013) - DOI: 10.1371 journal.pone.0058088 * Samir Benkouiten et al. - JAMA Dermatol. 2014;150(3):273-279 (2014) - DOI: 10.1001 jamadermatol.2013.6398 * Rezak Drali et al - Infection, Genetics and Evolution 39 (2016) 225u2013231 - DOI: 10.1016 j.meegid.2016.02.008 * Tran Duc Anh Ly et al. - Emerging Infectious Diseases (2017) - DOI: 10.3201 eid2311.170516 * Tran Duc Anh Ly et al. - Clinical Microbiology and Infection 25 (2019) 249.e1e249.e6 - DOI: 10.1016 j.cmi.2018.04.032 * Tran Duc Anh Ly et al. - Front. Cell. Infect. Microbiol. 9:86 (2019) - DOI: 10.3389 fcimb.2019.00086 * Tran Duc Anh Ly et al. - Journal of Epidemiology and Global Health (2019) - DOI: 10.2991 jegh.k.190510.001 * Tran Duc Anh Ly et al. - Infection and Drug Resistance 2019:12 1139u20131151 - DOI: 10.2147 IDR.S202048 * Nadia Amanzougaghene et al. - Parasites Vectors (2020) 13:177 - DOI: 10.1186 s13071-020-04036-y * Tran Duc Anh Ly et al. - European Journal of Clinical Microbiology Infectious Diseases (2020) - DOI: 10.1007 s10096-020-03889-6 * Tran Duc Anh Ly et al. - Travel Medicine and Infectious Disease 36 (2020) 101768 - DOI: 10.1016 j.tmaid.2020.101768 * Tran Duc Anh Ly et al. - Vector-Borne and Zoonotic Diseases (2020) - DOI: 10.1089 vbz.2019.2603 * Tran Duc Anh Ly et al. - Acta Microbiologica et Immunologica Hungarica (2021) - DOI: 10.1556 030.2021.01346 * Tran Duc Anh Ly et al. - Journal of Epidemiology and Global Health (2021) - DOI: 10.2991 jegh.k.201009.001 * Tran Duc Anh Ly et al. - Journal of Infection Volume 82, Issue 1, January 2021, Pages 60-66 - DOI: 10.1016 j.jinf.2020.11.026 * Tran Duc Anh Ly et al. - European Journal of Clinical Microbiology Infectious Diseases (2021) - DOI: 10.1007 s10096-020-04127-9 ,