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

• DOI: 10.1038/s41467-020-18039-x
• Publication Date: 2020-08-27T10:04:31Z
• 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
• Keywords: Adult; Inflammation; Male; Aging; Science; Q; Dasatinib; Cell Differentiation; Dendritic Cells; Organ Transplantation; Middle Aged; DNA, Mitochondrial; Article; 3. Good health; Mice, Inbred C57BL; Mice, Inbred DBA; Reperfusion Injury; Animals; Cytokines; Heart Transplantation; Humans; Quercetin; Cell-Free Nucleic Acids; Cellular Senescence

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