Excessive apoptosis of naïve T cells resulting hyperactivation as a cause of mammalian aging

Wang, L.; Zhang, X.; Zhang, H.; Lu, K.; Li, M.; Li, X.; Ouyang, J.; Zhao, X.; Wu, X.; Liu, J.; Xing, M.; Liu, H.; Zhang, Y.; Tan, Y.; Li, F.; Deng, J.; Li, J.; Zhao, Y.; Wang, X.; Luo, Y.; Zhou, B.

doi:10.1101/2023.02.24.529806

bioRxiv · 10.1101/2023.02.24.529806

Excessive apoptosis of naïve T cells resulting hyperactivation as a cause of mammalian aging

Wang, L.·Zhang, X.·Zhang, H.·Lu, K.·Li, M.·Li, X.·Ouyang, J.·Zhao, X.·Wu, X.·Liu, J.·Xing, M.·Liu, H.·Zhang, Y.·Tan, Y.·Li, F.·Deng, J.·Li, J.·Zhao, Y.·Wang, X.·Luo, Y.·Zhou, B.

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Abstract

In mammals, the most remarkable T cell variations with aging are the shrinking of naive T cell pool and enlargement of memory T cell pool, which are partially caused by thymic involution. However, it remains an enigma whether these T-cell-related changes are consequences or causes of mammalian aging. In this study, we find that the T-cell specific Rip1 KO mice present similar age-related T cell changes and exhibit signs of accelerated aging, including inflammation, multiple age-related diseases and a shorter lifespan. Mechanistically, T cells lacking RIP1 displayed excessive apoptosis, leading to T cell compensatory proliferation, hyperactivation, increased inflammation, and ultimately premature death. Consistent with this, blocking apoptosis by co-deletion of Fadd in Rip1 deficient T cells significantly recovered the lymphopenia and imbalance between naive and memory T cell, substantially restored ageing-related phenotypes, and prolonged life span in T-cell specific Rip1 KO mice. These results suggest that changes in T cells play a causal role in mammalian aging. Therefore, replenishing or blocking apoptosis of naive T cells could offer new therapeutic approaches for aging and age-related diseases.

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Wang, L., Zhang, X., Zhang, H., Lu, K., Li, M., Li, X., Ouyang, J., Zhao, X., Wu, X., Liu, J., Xing, M., Liu, H., Zhang, Y., Tan, Y., Li, F., Deng, J., Li, J., Zhao, Y., Wang, X., Luo, Y., Zhou, B.. 2023-02-26. Excessive apoptosis of naïve T cells resulting hyperactivation as a cause of mammalian aging. https://doi.org/10.1101/2023.02.24.529806

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