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

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 and Stefan G. Tullius ()
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Jasper Iske: Brigham and Women’s Hospital, Harvard Medical School
Midas Seyda: Brigham and Women’s Hospital, Harvard Medical School
Timm Heinbokel: Brigham and Women’s Hospital, Harvard Medical School
Ryoichi Maenosono: Brigham and Women’s Hospital, Harvard Medical School
Koichiro Minami: Brigham and Women’s Hospital, Harvard Medical School
Yeqi Nian: Brigham and Women’s Hospital, Harvard Medical School
Markus Quante: Visceral and Transplant Surgery, University Hospital Tübingen
Christine S. Falk: Hannover Medical School
Haruhito Azuma: Osaka Medical College
Friederike Martin: Visceral and Transplant Surgery, Charité Berlin
João F. Passos: Robert and Arlene Kogod Center on Aging, Mayo Clinic
Claus U. Niemann: University of California San Francisco
Tamara Tchkonia: Robert and Arlene Kogod Center on Aging, Mayo Clinic
James L. Kirkland: Robert and Arlene Kogod Center on Aging, Mayo Clinic
Abdallah Elkhal: Brigham and Women’s Hospital, Harvard Medical School
Stefan G. Tullius: Brigham and Women’s Hospital, Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18039-x

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