Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation.
Jasper IskeMidas SeydaTimm HeinbokelRyoichi MaenosonoKoichiro MinamiYeqi NianMarkus QuanteChristine S FalkHaruhito AzumaFriederike MartinJoão F PassosClaus U NiemannTamara TchkoniaJames L KirklandAbdallah ElkhalStefan G TulliusPublished in: Nature communications (2020)
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.
Keyphrases
- cell free
- circulating tumor
- dendritic cells
- cystic fibrosis
- single molecule
- mitochondrial dna
- immune response
- induced apoptosis
- ischemia reperfusion injury
- oxidative stress
- circulating tumor cells
- nucleic acid
- endothelial cells
- copy number
- physical activity
- cell cycle arrest
- middle aged
- heart failure
- signaling pathway
- stem cells
- regulatory t cells
- risk assessment
- kidney transplantation
- cell proliferation
- metabolic syndrome
- endoplasmic reticulum stress
- bone marrow
- pi k akt
- atrial fibrillation
- adipose tissue
- stress induced
- weight loss