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An aged immune system drives senescence and ageing of solid organs

Author

Listed:
  • Matthew J. Yousefzadeh

    (University of Minnesota
    University of Minnesota)

  • Rafael R. Flores

    (University of Minnesota
    University of Minnesota)

  • Yi Zhu

    (Robert and Arlene Kogod Center on Aging, Mayo Clinic)

  • Zoe C. Schmiechen

    (University of Minnesota Medical School)

  • Robert W. Brooks

    (The Scripps Research Institute)

  • Christy E. Trussoni

    (Center for Cell Signaling in Gastroenterology, Mayo Clinic)

  • Yuxiang Cui

    (University of California Riverside)

  • Luise Angelini

    (University of Minnesota
    University of Minnesota)

  • Kyoo-A Lee

    (University of Minnesota
    University of Minnesota)

  • Sara J. McGowan

    (University of Minnesota
    University of Minnesota)

  • Adam L. Burrack

    (University of Minnesota Medical School)

  • Dong Wang

    (University of Pittsburgh)

  • Qing Dong

    (University of Pittsburgh)

  • Aiping Lu

    (University of Texas Health Science Center at Houston)

  • Tokio Sano

    (The Scripps Research Institute)

  • Ryan D. O’Kelly

    (University of Minnesota
    University of Minnesota)

  • Collin A. McGuckian

    (University of Minnesota
    University of Minnesota)

  • Jonathan I. Kato

    (The Scripps Research Institute)

  • Michael P. Bank

    (The Scripps Research Institute)

  • Erin A. Wade

    (The Scripps Research Institute)

  • Smitha P. S. Pillai

    (Fred Hutchinson Cancer Research Center)

  • Jenna Klug

    (University of Washington)

  • Warren C. Ladiges

    (University of Washington)

  • Christin E. Burd

    (The Ohio State University)

  • Sara E. Lewis

    (West Virginia University)

  • Nicholas F. LaRusso

    (Center for Cell Signaling in Gastroenterology, Mayo Clinic)

  • Nam V. Vo

    (University of Pittsburgh)

  • Yinsheng Wang

    (University of California Riverside)

  • Eric E. Kelley

    (West Virginia University)

  • Johnny Huard

    (University of Texas Health Science Center at Houston)

  • Ingunn M. Stromnes

    (University of Minnesota Medical School)

  • Paul D. Robbins

    (University of Minnesota
    University of Minnesota)

  • Laura J. Niedernhofer

    (University of Minnesota
    University of Minnesota)

Abstract

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 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.

Suggested Citation

  • Matthew J. Yousefzadeh & Rafael R. Flores & Yi Zhu & Zoe C. Schmiechen & Robert W. Brooks & Christy E. Trussoni & Yuxiang Cui & Luise Angelini & Kyoo-A Lee & Sara J. McGowan & Adam L. Burrack & Dong W, 2021. "An aged immune system drives senescence and ageing of solid organs," Nature, Nature, vol. 594(7861), pages 100-105, June.
    • Handle: RePEc:nat:nature:v:594:y:2021:i:7861:d:10.1038_s41586-021-03547-7
    DOI: 10.1038/s41586-021-03547-7
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    Citations

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    Cited by:

    1. Moujtaba Y. Kasmani & Paytsar Topchyan & Ashley K. Brown & Ryan J. Brown & Xiaopeng Wu & Yao Chen & Achia Khatun & Donia Alson & Yue Wu & Robert Burns & Chien-Wei Lin & Matthew R. Kudek & Jie Sun & We, 2023. "A spatial sequencing atlas of age-induced changes in the lung during influenza infection," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Betz, Ulrich A.K. & Arora, Loukik & Assal, Reem A. & Azevedo, Hatylas & Baldwin, Jeremy & Becker, Michael S. & Bostock, Stefan & Cheng, Vinton & Egle, Tobias & Ferrari, Nicola & Schneider-Futschik, El, 2023. "Game changers in science and technology - now and beyond," Technological Forecasting and Social Change, Elsevier, vol. 193(C).
    3. Stefano Suzzi & Tommaso Croese & Adi Ravid & Or Gold & Abbe R. Clark & Sedi Medina & Daniel Kitsberg & Miriam Adam & Katherine A. Vernon & Eva Kohnert & Inbar Shapira & Sergey Malitsky & Maxim Itkin &, 2023. "N-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer’s disease mouse model," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Kaushik Bhattacharya & Samarpan Maiti & Szabolcs Zahoran & Lorenz Weidenauer & Dina Hany & Diana Wider & Lilia Bernasconi & Manfredo Quadroni & Martine Collart & Didier Picard, 2022. "Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Xu Feng & Liwen Wang & Ruoyu Zhou & Rui Zhou & Linyun Chen & Hui Peng & Yan Huang & Qi Guo & Xianghang Luo & Haiyan Zhou, 2023. "Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Xiaoduo Tang & Jingyan Ren & Xin Wei & Tao Wang & Haiqiu Li & Yihan Sun & Yang Liu & Mingli Chi & Shoujun Zhu & Laijin Lu & Junhu Zhang & Bai Yang, 2023. "Exploiting synergistic effect of CO/NO gases for soft tissue transplantation using a hydrogel patch," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Yonggang Fan & Weixin Zhang & Xiusheng Huang & Mingzhe Fan & Chenhao Shi & Lantian Zhao & Guofu Pi & Huafeng Zhang & Shuangfei Ni, 2024. "Senescent-like macrophages mediate angiogenesis for endplate sclerosis via IL-10 secretion in male mice," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    8. Xu Zhang & Vesselina M. Pearsall & Chase M. Carver & Elizabeth J. Atkinson & Benjamin D. S. Clarkson & Ethan M. Grund & Michelle Baez-Faria & Kevin D. Pavelko & Jennifer M. Kachergus & Thomas A. White, 2022. "Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    9. Nini Zhang & Xinpei Wang & Mengya Feng & Min Li & Jing Wang & Hongyan Yang & Siyu He & Ziqi Xia & Lei Shang & Xun Jiang & Mao Sun & Yuanming Wu & Chaoxue Ren & Xing Zhang & Jia Li & Feng Gao, 2024. "Early-life exercise induces immunometabolic epigenetic modification enhancing anti-inflammatory immunity in middle-aged male mice," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    10. Cox, Lynne S., 2022. "Therapeutic approaches to treat and prevent age-related diseases through understanding the underlying biological drivers of ageing," The Journal of the Economics of Ageing, Elsevier, vol. 23(C).

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