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, Stefan G. Tullius

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Article number4289
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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