351. An aged immune system drives senescence and ageing of solid organs.
- Author
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Yousefzadeh MJ, Flores RR, Zhu Y, Schmiechen ZC, Brooks RW, Trussoni CE, Cui Y, Angelini L, Lee KA, McGowan SJ, Burrack AL, Wang D, Dong Q, Lu A, Sano T, O'Kelly RD, McGuckian CA, Kato JI, Bank MP, Wade EA, Pillai SPS, Klug J, Ladiges WC, Burd CE, Lewis SE, LaRusso NF, Vo NV, Wang Y, Kelley EE, Huard J, Stromnes IM, Robbins PD, and Niedernhofer LJ
- Subjects
- Aging drug effects, Aging pathology, Animals, DNA Damage immunology, DNA Damage physiology, DNA Repair immunology, DNA Repair physiology, DNA-Binding Proteins genetics, Endonucleases genetics, Female, Healthy Aging immunology, Healthy Aging physiology, Homeostasis immunology, Homeostasis physiology, Immune System drug effects, Immunosenescence drug effects, Male, Mice, Organ Specificity drug effects, Rejuvenation, Sirolimus pharmacology, Spleen cytology, Spleen transplantation, Aging immunology, Aging physiology, Immune System immunology, Immune System physiology, Immunosenescence immunology, Immunosenescence physiology, Organ Specificity immunology, Organ Specificity physiology
- Abstract
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 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 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 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.- Published
- 2021
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