TY - JOUR
T1 - An aged immune system drives senescence and ageing of solid organs
AU - Yousefzadeh, Matthew J.
AU - Flores, Rafael R.
AU - Zhu, Yi
AU - Schmiechen, Zoe C.
AU - Brooks, Robert W.
AU - Trussoni, Christy E.
AU - Cui, Yuxiang
AU - Angelini, Luise
AU - Lee, Kyoo A.
AU - McGowan, Sara J.
AU - Burrack, Adam L.
AU - Wang, Dong
AU - Dong, Qing
AU - Lu, Aiping
AU - Sano, Tokio
AU - O’Kelly, Ryan D.
AU - McGuckian, Collin A.
AU - Kato, Jonathan I.
AU - Bank, Michael P.
AU - Wade, Erin A.
AU - Pillai, Smitha P.S.
AU - Klug, Jenna
AU - Ladiges, Warren C.
AU - Burd, Christin E.
AU - Lewis, Sara E.
AU - LaRusso, Nicholas F.
AU - Vo, Nam V.
AU - Wang, Yinsheng
AU - Kelley, Eric E.
AU - Huard, Johnny
AU - Stromnes, Ingunn M.
AU - Robbins, Paul D.
AU - Niedernhofer, Laura J.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/6/3
Y1 - 2021/6/3
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-021-03547-7
DO - 10.1038/s41586-021-03547-7
M3 - Article
C2 - 33981041
AN - SCOPUS:85105793854
SN - 0028-0836
VL - 594
SP - 100
EP - 105
JO - Nature
JF - Nature
IS - 7861
ER -