Science: Terrible! T-cell mitochondrial dysfunction causes premature aging and a variety of diseases.

Learn about the latest advances in neuroscience ● click the blue letter to focus on us ● the decline of immune capacity in the elderly increases the risk and severity of infectious diseases.studies have shown that T lymphocyte is one of the immune cell populations most affected by aging, which is manifested in the impairment of effector function and T cell memory formation, so the immune response ability is reduced.in aging mice, the number and activation of initial T cells were decreased, and there were aging related mitochondrial dysfunction in T cells (1).the research on aging related immune system mainly focuses on B lymphocytes, T cells, natural killer cells, etc.on May 21, 2020, the Spanish scientific research team published an article in the journal Science, which revealed the important role of T cells in the aging process, and emphasized the importance of immune metabolism.TFAM is a nuclear gene encoding mitochondrial transcription factor A (TFAM), which can stabilize mitochondrial DNA (mtDNA) and initiate mtDNA replication.the researchers found that 2-month-old tfam-cd4 knockout mice (TFAM knockout of CD4 and CD8 T cells) showed mitochondrial dysfunction in wild-type mice at 22 months old. The number of CD4 and CD8 T cells decreased, the mitochondrial DNA content of T cells decreased sharply, and the key components of mitochondrial respiratory chain could not be expressed normally.these results suggest that tfam-cd4 knockout mice exhibit metabolic, phenotypic and functional characteristics of aging T cells.in order to further confirm whether the immune function of 2-month-old tfam-cd4 knockout mice is low, researchers infected 2-month-old tfam-cd4-knockout mice, 2-month-old wild-type mice and 22-month-old wild-type mice were infected with highly pathogenic mouse poxvirus, which could lead to diseases similar to human smallpox- All CD4 knockout mice and 22 month old wild type mice died 10 days after infection, while 2-month-old wild-type mice survived.this indicated that the immune function of mice was decreased after the mitochondrial function of T cells was destroyed.although the 2-month-old tfam-cd4 knockout mice showed the characteristics of aging of T cells, the phenomenon of premature aging was actually after 7 months old, while the wild-type mice entered the aging period about 15 months.tfam-cd4 knockout mice showed obvious thinning of subcutaneous fat, decreased exercise ability and shortened the average life span to 12 months.in terms of metabolism, glucose uptake and skeletal muscle tension decreased.severe cardiac disorders, vascular lesions, reduced left ventricular thickness, reduced left ventricular diameter and volume, and aortic dilatation.77% TFAM - CD4 knockout mice developed aortic regurgitation.in addition, transcriptomics showed that the expression levels of aging related genes in liver and heart tissue were significantly increased.T cells in the peripheral system can enter the brain and cause dyskinesia. these results indicate that tfam-cd4 knockout mice have a variety of diseases, multiple tissues aging, and easy to die. how does the premature aging phenotype of TFAM - CD4 knockout mice cause? Previous cell experiments in vitro have shown that cancer cells and Th1 type cytokines can induce aging (2). Th1 cytokines are mainly secreted by Th1 helper T cells, such as IL-2 (interleukin-2), IFN - γ (interferon gamma), TNF - β (tumor necrosis factor - β), etc. researchers found that there were a large number of inflammatory factors in the peripheral of tfam-cd4 knockout mice, which showed the characteristics of aging inflammation. tfam-cd4 knockout mice blocked TNF - β signal for 7 weeks, and nicotinamide ribose (NR) for 10 weeks also alleviated most cardiovascular functions and partially blocked aging symptoms. in general, we found that metabolic changes in the immune system can accelerate the aging process, leading to multiple diseases and premature death. the disorder of mitochondrial metabolism in T cells leads to peripheral cytokine storm, which eventually leads to aging of multiple tissues and organs. References: 1. N. Ron Harel, G. notarangelo, J. M. ghergurovich, J. A. Paulo, P. T. sage, D. Santos, F. K. satterstrom, defective resuscitation and one-carbon metabolism contribute to improved Na ï ve T cell activation in aged mic. Proc. Natl. Acad. SCI. U.S.A. 115, 13347–13352 (2018). doi:10.1073/pnas.1804149115 Medline2. T-helper-1- cell cytokines drive cancer into senescence. Nature 494, 361–365 (2013)3.T cells with dysfunctional mitochondria induce multimorbidity and premature senescence，Desdín-Micó et al., Science 10.1126/ science.aax0860 (2020)