An aged immune system drives senescence and ageing of solid organs

被引：589

作者：

Yousefzadeh, Matthew J. ^{[1
,2
]}

Flores, Rafael R. ^{[1
,2
]}

Zhu, Yi ^{[3
]}

Schmiechen, Zoe C. ^{[4
]}

Brooks, Robert W. ^{[5
]}

Trussoni, Christy E. ^{[6
]}

Cui, Yuxiang ^{[7
]}

Angelini, Luise ^{[1
,2
]}

Lee, Kyoo-A ^{[1
,2
]}

McGowan, Sara J. ^{[1
,2
]}

Burrack, Adam L. ^{[4
]}

Wang, Dong ^{[8
]}

Dong, Qing ^{[8
]}

Lu, Aiping ^{[9
]}

Sano, Tokio ^{[5
]}

O'Kelly, Ryan D. ^{[1
,2
]}

McGuckian, Collin A. ^{[1
,2
]}

Kato, Jonathan I. ^{[5
]}

Bank, Michael P. ^{[5
]}

Wade, Erin A. ^{[5
]}

Pillai, Smitha P. S. ^{[10
]}

Klug, Jenna ^{[11
]}

Ladiges, Warren C. ^{[11
]}

Burd, Christin E. ^{[12
,13
]}

Lewis, Sara E. ^{[14
]}

LaRusso, Nicholas F. ^{[6
]}

Vo, Nam V. ^{[8
]}

Wang, Yinsheng ^{[7
]}

Kelley, Eric E. ^{[14
]}

Huard, Johnny ^{[9
]}

Stromnes, Ingunn M. ^{[4
]}

Robbins, Paul D. ^{[1
,2
]}

Niedernhofer, Laura J. ^{[1
,2
]}

机构：

[1] Univ Minnesota, Inst Biol Aging & Metab, Minneapolis, MN 55455 USA

[2] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA

[3] Mayo Clin, Robert & Arlene Kogod Ctr Aging, Rochester, MN USA

[4] Univ Minnesota, Sch Med, Ctr Immunol, Minneapolis, MN 55455 USA

[5] Scripps Res Inst, Dept Mol Med, Jupiter, FL USA

[6] Mayo Clin, Div Gastroenterol, Ctr Cell Signaling Gastroenterol, Rochester, MN USA

[7] Univ Calif Riverside, Dept Chem, Riverside, CA 92521 USA

[8] Univ Pittsburgh, Dept Orthopaed Surg, Pittsburgh, PA USA

[9] Univ Texas Hlth Sci Ctr Houston, Dept Orthoped Surg, McGovern Med Sch, Houston, TX 77030 USA

[10] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA

[11] Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA

[12] Ohio State Univ, Dept Mol Genet, Columbus, OH 43210 USA

[13] Ohio State Univ, Dept Canc Biol & Genet, Columbus, OH 43210 USA

[14] West Virginia Univ, Dept Physiol & Pharmacol, Morgantown, WV 26506 USA

来源：

NATURE | 2021年 / 594卷 / 7861期

基金：

美国国家卫生研究院;

关键词：

T-CELLS; IN-VIVO; BIOMARKER; EXPRESSION; PHENOTYPE;

D O I：

10.1038/s41586-021-03547-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 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 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.

引用

页码：100 / +

页数：26

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