Journal Article

An aged immune system drives senescence and ageing of solid organs

Huard, Johnny, Wang, Dong, Dong, Qing, Burd, Christin E., Stromnes, Ingunn M., Robbins, Paul D., Sano, Tokio, McGuckian, Collin A., Kato, Jonathan I., Bank, Michael P., Niedernhofer, Laura J., Lu, Aiping, Wade, Erin A., Zhu, Yi, Schmiechen, Zoe C., Pillai, Smitha P. S., Kelley, Eric E., Brooks, Robert W., Ladiges, Warren C., Yousefzadeh, Matthew J., Cui, Yuxiang, Trussoni, Christy E., Lee, Kyoo-A, McGowan, Sara J., LaRusso, Nicholas F., Burrack, Adam L., Klug, Jenna, Angelini, Luise, Vo, Nam V., O’Kelly, Ryan D., Wang, Yinsheng, Flores, Rafael R., Lewis, Sara E.

2021

Overview

Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly 1 , 2 . To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1 , which encodes a crucial DNA repair protein 3 , 4 , in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence 5 – 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 mice 8 – 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 in trans , 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 function 11 , 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. An aged, senescent immune system has a causal role in driving systemic ageing, and the targeting of senescent immune cells with senolytic drugs has the potential to suppress morbidities associated with old age.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/136/7 / 631/208/135 / Age / Aging / Aging - drug effects / Aging - immunology / Aging - pathology / Aging - physiology / Animals / Blood / Bone marrow / Cell cycle / Damage / Deoxyribonucleic acid / DNA / DNA damage / DNA Damage - immunology / DNA Damage - physiology / DNA repair / DNA Repair - immunology / DNA Repair - physiology / DNA-Binding Proteins - genetics / Endonucleases - genetics / ERCC1 protein / Female / Flow cytometry / Healthy Aging - immunology / Healthy Aging - physiology / Homeostasis - immunology / Homeostasis - physiology / Humanities and Social Sciences / Immune response / Immune system / Immune System - drug effects / Immune System - immunology / Immune System - physiology / Immunosenescence / Immunosenescence - drug effects / Immunosenescence - immunology / Immunosenescence - physiology / Leukopenia / Lymphocytes / Male / Mice / Morbidity / Mortality / multidisciplinary / Organ Specificity - drug effects / Organ Specificity - immunology / Organ Specificity - physiology / Organs / Rapamycin / Rejuvenation / Rodents / Science / Science (multidisciplinary) / Senescence / Sirolimus - pharmacology / Spleen / Spleen - cytology / Spleen - transplantation / Splenocytes / Therapeutic targets / Transplantation