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Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation.

Authors: Jasper Iske|||Midas Seyda|||Timm Heinbokel|||Ryoichi Maenosono|||Koichiro Minami|||Yeqi Nian|||Markus Quante|||Christine S Falk|||Haruhito Azuma|||Friederike Martin|||João F Passos|||Claus U Niemann|||Tamara Tchkonia|||James L Kirkland|||Abdallah Elkhal|||Stefan G Tullius

Journal: Nature communications

Publication Type: Journal Article

Date: 2020

DOI: PMC7453018

ID: 32855397

Affiliations:

Affiliations

    Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|||Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.|||Institute of Transplant Immunology, Hannover Medical School, Hannover, Lower Saxony, Germany.|||Department of Urology, Osaka Medical College, Osaka, Japan.|||Department of General, Visceral and Transplant Surgery, Charité Berlin, Berlin, Germany.|||Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.|||Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA.|||Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.|||Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. stullius@bwh.harvard.edu.

Abstract

Older organs represent an untapped potential to close the gap between demand and supply in organ transplantation but are associated with age-specific responses to injury and increased immunogenicity, thereby aggravating transplant outcomes. Here we show that cell-free mitochondrial DNA (cf-mt-DNA) released by senescent cells accumulates with aging and augments immunogenicity. Ischemia reperfusion injury induces a systemic increase of cf-mt-DNA that promotes dendritic cell-mediated, age-specific inflammatory responses. Comparable events are observed clinically, with the levels of cf-mt-DNA elevated in older deceased organ donors, and with the isolated cf-mt-DNA capable of activating human dendritic cells. In experimental models, treatment of old donor animals with senolytics clear senescent cells and diminish cf-mt-DNA release, thereby dampening age-specific immune responses and prolonging the survival of old cardiac allografts comparable to young donor organs. Collectively, we identify accumulating cf-mt-DNA as a key factor in inflamm-aging and present senolytics as a potential approach to improve transplant outcomes and availability.


Chemical List

    Cell-Free Nucleic Acids|||Cytokines|||DNA, Mitochondrial|||Quercetin|||Dasatinib

Reference List

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