T cells with dysfunctional mitochondria induce multimorbidity and premature senescence

Desdín-Micó, Gabriela; Soto-Heredero, Gonzalo; Aranda, Juan; Oller, Jorge; Carrasco, Elisa; Gabandé‐Rodríguez, Enrique; Blanco, Eva; Alfranca, Arántzazu; Cussó, Lorena; Desco, Manuel; Ibáñez, Borja; Gortázar, Arancha R.; Fernández-Marcos, Pablo J.; Navarro, M.; Hernáez, Bruno; Alcamı́, Antonio; Baixauli, Francesc; Mittelbrunn, Marı́a

doi:10.1126/science.aax0860

Cited by 360 publications

(297 citation statements)

References 31 publications

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“…T cell mitochondrial dysfunction also accelerates senescence. It was recently demonstrated that Tfam fl/fl Cd4 Cre mice (where mitochondrial transcription factor A (TFAM) is depleted in CD4 + and CD8 + lymphocytes) prematurely died due to multiple age-related changes [ 29 ]. Taken together, the full extent of the molecular pathways involved T c senescence are not completely elucidated.…”

Section: Mechanisms Of T Cell Senescence Inductionmentioning

confidence: 99%

Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

Liu

Stachura

et al. 2020

Cancers

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The inability of tumor-infiltrating T lymphocytes to eradicate tumor cells within the tumor microenvironment (TME) is a major obstacle to successful immunotherapeutic treatments. Understanding the immunosuppressive mechanisms within the TME is paramount to overcoming these obstacles. T cell senescence is a critical dysfunctional state present in the TME that differs from T cell exhaustion currently targeted by many immunotherapies. This review focuses on the physiological, molecular, metabolic and cellular processes that drive CD8+ T cell senescence. Evidence showing that senescent T cells hinder immunotherapies is discussed, as are therapeutic options to reverse T cell senescence.

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Section: Mechanisms Of T Cell Senescence Inductionmentioning

confidence: 99%

Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

Liu

Stachura

et al. 2020

Cancers

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“…45 Compounds that alter the mitochondrial behavior in cells from old donors, or any of the other signatures we modeled in our system, may improve the response to infection in older adults. 46 Altogether, there are many significant differences between young and old viral immune responses as measured by dozens of features in our multi-phenotype aging profile. Normalized averages for features measuring the intensity distribution of mitochondria membrane potential in T cells from old and young donors exposed to rVSV-ΔG-mCherry at a 10× MOI.…”

Section: Dysfunction In the Viral Immune Response In Aging Adultsmentioning

confidence: 98%

A Multi-Phenotype System to Discover Therapies for Age-Related Dysregulation of the Immune Response to Viral Infections

White

Komalo

Nicolaisen

et al. 2020

Preprint

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Age-related immune dysregulation contributes to increased susceptibility to infection and disease in older adults. We combined high-throughput laboratory automation with machine learning to build a multi-phenotype aging profile that models the dysfunctional immune response to viral infection in older adults. From a single well, our multi-phenotype aging profile can capture changes in cell composition, physical cell-to-cell interaction, organelle structure, cytokines, and other hidden complexities contributing to age-related dysfunction. This system allows for rapid identification of new potential compounds to rejuvenate older adults’ immune response. We used our technology to screen thousands of compounds for their ability to make old immune cells respond to viral infection like young immune cells. We observed beneficial effects of multiple compounds, of which two of the most promising were disulfiram and triptonide. Our findings indicate that disulfiram could be considered as a treatment for severe coronavirus disease 2019 and other inflammatory infections.

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“…In particular, they show an age-related decline in mitochondrial function – which could be related to dysfunctional mitophagy [ 36 ]. In fact, mice engineered to have dysfunctional T- cell mitochondria display accelerated senescence and “inflammaging”, highlighting the point that T-cells can determine organismal fitness and lifespan [ 37 ]. This does support data indicating the importance of a healthy T-cell response in defending against the virus [ 38 , 39 ].…”

Section: Mitochondrial Function In Inflammaging and Immunosenescencementioning

confidence: 99%

“…For instance, evidence does indicate a clear role for mitochondria in ageing-related disease and mortality, but not necessarily chronological age [ 156 ]. However, data does suggest that inducing mitochondrial dysfunction alone in T-cells can induce premature senescence, driving “inflammaging” and a tendency towards a cytokine storm [ 37 ]. One well known concept in ageing is the idea of declining organ reserve, which at the molecular level, is related to a loss of excess metabolic capacity – in particular, bioenergetics and mtDNA, as well excess telomere capacity [ 157 ].…”

Section: The Immune System Hormesis and Mitochondriamentioning

confidence: 99%

SARS-CoV-2 and mitochondrial health: implications of lifestyle and ageing

Nunn

Guy²,

Brysch

et al. 2020

Immun Ageing

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Infection with SARs-COV-2 displays increasing fatality with age and underlying co-morbidity, in particular, with markers of the metabolic syndrome and diabetes, which seems to be associated with a “cytokine storm” and an altered immune response. This suggests that a key contributory factor could be immunosenescence that is both age-related and lifestyle-induced. As the immune system itself is heavily reliant on mitochondrial function, then maintaining a healthy mitochondrial system may play a key role in resisting the virus, both directly, and indirectly by ensuring a good vaccine response. Furthermore, as viruses in general, and quite possibly this new virus, have also evolved to modulate immunometabolism and thus mitochondrial function to ensure their replication, this could further stress cellular bioenergetics. Unlike most sedentary modern humans, one of the natural hosts for the virus, the bat, has to “exercise” regularly to find food, which continually provides a powerful adaptive stimulus to maintain functional muscle and mitochondria. In effect the bat is exposed to regular hormetic stimuli, which could provide clues on how to resist this virus. In this paper we review the data that might support the idea that mitochondrial health, induced by a healthy lifestyle, could be a key factor in resisting the virus, and for those people who are perhaps not in optimal health, treatments that could support mitochondrial function might be pivotal to their long-term recovery.

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T cells with dysfunctional mitochondria induce multimorbidity and premature senescence

Cited by 360 publications

References 31 publications

Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

A Multi-Phenotype System to Discover Therapies for Age-Related Dysregulation of the Immune Response to Viral Infections

SARS-CoV-2 and mitochondrial health: implications of lifestyle and ageing

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