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Tytuł:
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An aged immune system drives senescence and ageing of solid organs.
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Autorzy:
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Yousefzadeh MJ; Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Flores RR; Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Zhu Y; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
Schmiechen ZC; Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.
Brooks RW; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.
Trussoni CE; Division of Gastroenterology, Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN, USA.
Cui Y; Department of Chemistry, University of California Riverside, Riverside, CA, USA.
Angelini L; Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Lee KA; Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
McGowan SJ; Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Burrack AL; Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.
Wang D; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Dong Q; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Lu A; Department of Orthopedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
Sano T; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.
O'Kelly RD; Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
McGuckian CA; Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Kato JI; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.
Bank MP; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.
Wade EA; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.
Pillai SPS; Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Klug J; Department of Comparative Medicine, University of Washington, Seattle, WA, USA.
Ladiges WC; Department of Comparative Medicine, University of Washington, Seattle, WA, USA.
Burd CE; Departments of Molecular Genetics and Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
Lewis SE; Department of Physiology & Pharmacology, West Virginia University, Morgantown, WV, USA.
LaRusso NF; Division of Gastroenterology, Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN, USA.
Vo NV; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Wang Y; Department of Chemistry, University of California Riverside, Riverside, CA, USA.
Kelley EE; Department of Physiology & Pharmacology, West Virginia University, Morgantown, WV, USA.
Huard J; Department of Orthopedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
Stromnes IM; Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.
Robbins PD; Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA. .; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA. .
Niedernhofer LJ; Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA. .; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA. .
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Źródło:
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Nature [Nature] 2021 Jun; Vol. 594 (7861), pp. 100-105. Date of Electronic Publication: 2021 May 12.
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Typ publikacji:
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Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
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MeSH Terms:
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Aging/*immunology
Aging/*physiology
Immune System/*immunology
Immune System/*physiology
Immunosenescence/*immunology
Immunosenescence/*physiology
Organ Specificity/*immunology
Organ Specificity/*physiology
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
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References:
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EBioMedicine. 2017 Jul;21:21-28. (PMID: 28416161)
Nat Commun. 2012 Jan 03;3:608. (PMID: 22215083)
Free Radic Biol Med. 2015 Nov;88(Pt B):314-336. (PMID: 26066302)
Front Med (Lausanne). 2017 Jun 15;4:73. (PMID: 28664159)
Methods Mol Biol. 2019;1896:203-230. (PMID: 30474850)
Aging Cell. 2018 Apr;17(2):. (PMID: 29290100)
J Biol Chem. 2012 Jun 22;287(26):21846-55. (PMID: 22547097)
Sci Transl Med. 2018 Jul 11;10(449):. (PMID: 29997249)
J Clin Invest. 2004 Nov;114(9):1299-307. (PMID: 15520862)
Redox Biol. 2018 Jul;17:259-273. (PMID: 29747066)
BMJ Open. 2015 Feb 03;5(2):e006413. (PMID: 25649210)
Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15807-12. (PMID: 19805226)
Aging Cell. 2012 Aug;11(4):714-6. (PMID: 22530741)
J Am Soc Nephrol. 2011 Jan;22(1):165-75. (PMID: 21071523)
Pathobiol Aging Age Relat Dis. 2011;1:. (PMID: 22953032)
Nat Rev Cancer. 2015 Jul;15(7):397-408. (PMID: 26105537)
Annu Rev Pathol. 2010;5:99-118. (PMID: 20078217)
Aging Cell. 2009 Aug;8(4):439-48. (PMID: 19485966)
PLoS One. 2015 Apr 17;10(4):e0124661. (PMID: 25884630)
Aging Cell. 2016 Jun;15(3):400-6. (PMID: 26910559)
Cell. 2014 Nov 6;159(4):709-13. (PMID: 25417146)
Mol Cell Biol. 2008 Aug;28(16):5082-92. (PMID: 18541667)
Mech Ageing Dev. 2013 Jan-Feb;134(1-2):35-42. (PMID: 23262094)
Curr Protoc Cytom. 2017 Jan 5;79:9.51.1-9.51.25. (PMID: 28055114)
Exp Gerontol. 2018 Apr;104:9-16. (PMID: 29355703)
Nature. 2006 Dec 21;444(7122):1038-43. (PMID: 17183314)
Nat Immunol. 2013 May;14(5):428-36. (PMID: 23598398)
Nature. 2014 May 22;509(7501):439-46. (PMID: 24848057)
Aging Cell. 2015 Aug;14(4):644-58. (PMID: 25754370)
Nat Med. 2018 Aug;24(8):1246-1256. (PMID: 29988130)
Hepatology. 2012 Feb;55(2):609-21. (PMID: 21953681)
Hepatology. 2014 Jun;59(6):2263-75. (PMID: 24390753)
Biochim Biophys Acta. 1986 Sep 4;883(2):173-7. (PMID: 3091074)
Cell. 2013 Jan 17;152(1-2):340-51. (PMID: 23332765)
Pathobiol Aging Age Relat Dis. 2016 Mar 23;6:31478. (PMID: 27015829)
Stem Cells. 2013 Mar;31(3):511-25. (PMID: 23097336)
Eur J Immunol. 2016 Oct;46(10):2286-2301. (PMID: 27595500)
Cold Spring Harb Perspect Med. 2016 Jan 08;6(2):a025940. (PMID: 26747832)
Sci Transl Med. 2014 Dec 24;6(268):268ra179. (PMID: 25540326)
Nat Rev Immunol. 2018 Mar;18(3):153-167. (PMID: 28990585)
Nature. 2016 Feb 11;530(7589):184-9. (PMID: 26840489)
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Grant Information:
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R01 AG059711 United States AG NIA NIH HHS; R01 CA249393 United States CA NCI NIH HHS; T32 AG029796 United States AG NIA NIH HHS; P01 AG062413 United States AG NIA NIH HHS; R56 AG058543 United States AG NIA NIH HHS; U19 AG056278 United States AG NIA NIH HHS; R01 AG063543 United States AG NIA NIH HHS; P30 DK084567 United States DK NIDDK NIH HHS; P01 AG043376 United States AG NIA NIH HHS; R01 AG044376 United States AG NIA NIH HHS; R01 AG067193 United States AG NIA NIH HHS; R01 CA255039 United States CA NCI NIH HHS; R56 AG059676 United States AG NIA NIH HHS
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Substance Nomenclature:
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0 (DNA-Binding Proteins)
EC 3.1.- (Endonucleases)
EC 3.1.- (Ercc1 protein, mouse)
W36ZG6FT64 (Sirolimus)
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Entry Date(s):
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Date Created: 20210513 Date Completed: 20210726 Latest Revision: 20240404
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Update Code:
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20240404
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PubMed Central ID:
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PMC8684299
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DOI:
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10.1038/s41586-021-03547-7
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PMID:
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33981041
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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.
