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

Nat Commun. 2020 Aug 27;11(1):4289. doi: 10.1038/s41467-020-18039-x.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aging / physiology
  • Animals
  • Cell Differentiation
  • Cell-Free Nucleic Acids
  • Cellular Senescence / drug effects
  • Cellular Senescence / physiology
  • Cytokines / metabolism
  • DNA, Mitochondrial / adverse effects*
  • DNA, Mitochondrial / metabolism
  • Dasatinib / pharmacology*
  • Dendritic Cells / immunology
  • Dendritic Cells / physiology
  • Heart Transplantation / adverse effects
  • Heart Transplantation / methods
  • Humans
  • Inflammation / etiology
  • Inflammation / prevention & control*
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Middle Aged
  • Organ Transplantation / adverse effects
  • Organ Transplantation / methods*
  • Quercetin / pharmacology*
  • Reperfusion Injury / genetics
  • Reperfusion Injury / immunology
  • Tissue Donors

Substances

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