Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5–7 in the immune system only. We show that Vav-iCre+/−;Ercc1−/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8–10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/−;Ercc1−/fl or aged wild-type mice into young mice induced senescence intrans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/−;Ercc1−/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
Bibliographical noteFunding Information:
Acknowledgements This work was supported by the National Institutes of Health (NIH) grants P01 AG043376 (P.D.R., L.J.N., E.E.K., J.H.), RO1 AG063543 (L.J.N.), R56 AG059676 (L.J.N.), U19 AG056278 (P.D.R., L.J.N., W.C.L.), P01 AG062413 (P.D.R., L.J.N.), R56 AG058543 (W.C.L.), R01 AG044376 (N.V.V.) and the Glenn Foundation (L.J.N., C.E.B.). M.J.Y. is supported by The Irene Diamond Fund/American Federation on Aging Research Postdoctoral Transition Award. Mass cytometry and panel design were performed by S. Farwana and K. D. Pavelko at the Mayo Clinic Immune Monitoring Core. We thank J. Zhao, C. Bukata, K. Melos and M. Calubag for their assistance in measuring senescence. All mouse illustrations were made with BioRender.
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PubMed: MeSH publication types
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- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't