biostudies-literatureDesdin-Mico GJuan de la CiervaEuropean Research CouncilAtracción de Talento Investigador GrantFondo de Investigación Sanitaria del Instituto de Salud Carlos III1371-1376https://www.ebi.ac.uk/biostudies/studies/S-EPMC7616968biostudies-literatureUnknown368(6497)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 premaScience (New York, N.Y.)T cells with dysfunctional mitochondria induce multimorbidity and premature senescence.PMC7616968ERC-2016-StG 715322-EndoMitTalk8197752017-T2/BMD-5766CP 19/014, PI16/188, PI19/00855715322Ibanez BAlcami AGortazar ARAranda JFAlfranca ANavarro MNHernaez BBaixauli FDesco MDesdin-Mico GMittelbrunn MSoto-Heredero GGabande-Rodriguez ECusso LCarrasco EFernandez-Marcos PBlanco EMOller JfalseT cells with dysfunctional mitochondria induce multimorbidity and premature senescence.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 prema2020-01-01T00:00:00Z2020 Jun2025-04-26T01:34:35.577Z2025-04-06T10:14:43.325ZS-EPMC76169683243965910.1126/science.aax0860