T cells with dysfunctional mitochondria induce multimorbidity and premature senescence
Authors: Manuel Desco
Lorena Cussó
Arancha R Gortazar
Francesc Baixauli
María Mittelbrunn
Bruno Hernaez
Enrique Gabandé-Rodríguez
Arantzazu Alfranca
Elisa Carrasco
Juan Francisco Aranda
Antonio Alcamí
Gabriela Desdín-Micó
Maria N Navarro
Eva Maria Blanco
Borja Ibañez
Jorge Oller
Gonzalo Soto-Heredero
Pablo Fernández-Marcos
Journal: Science (2020)
Discipline: Multidisciplinary
Keywords: immunometabolism; age-associated diseases; T cells; dysfunctional mitochondria; mitochondrial transcription factor A (TFAM)
Affiliations: Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain., Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain., Hospital Universitario de la Princesa, Madrid, Spain., Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Madrid, Spain., Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain., Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain., Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain., IIS-Fundación Jiménez Díaz, Madrid, Spain., Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain., Bone Physiopathology Laboratory, Applied Molecular Medicine Institute (IMMA), Universidad San Pablo-CEU, Madrid, Spain., Metabolic Syndrome Group - BIOPROMET, Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM+CSIC, Madrid, Spain., Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany., Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. .

Abstract:  The effect of immunometabolism on age-associated diseases remains uncertain. In this work, we show that T cells with dysfunctional mitochondria owing to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, these cells instigate multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death. T cell metabolic failure induces the accumulation of circulating cytokines, which resembles the chronic inflammation that is characteristic of aging ("inflammaging"). This cytokine storm itself acts as a systemic inducer of senescence. Blocking tumor necrosis factor-α signaling or preventing senescence with nicotinamide adenine dinucleotide precursors partially rescues premature aging in mice with Tfam-deficient T cells. Thus, T cells can regulate organismal fitness and life span, which highlights the importance of tight immunometabolic control in both aging and the onset of age-associated diseases. 

Retracted: No

PubPeer comments:
 The findings arise from the observation that Tfam deletion in the CD4 (and CD8) compartment leads to a shorter lifespan when compared to littermates. However, these conclusions do not fully seem to be taking into account that Treg-specific Tfam deletion leads to lethal autoimmunity by ~6 weeks of age, presumably mediated by an uncontrolled T effector cell response. In the present study, both Tregs and T effector cells lack Tfam. Logically, if the KO mice used herein (which lack Tfam in both Tregs and Teffs) are surviving longer than 6 weeks, the deletion of Tfam in Teffs seems to be protective anti-inflammatory rather than deleterious. ,