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

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.

SUBMITTER: Iske J

PROVIDER: S-EPMC7453018 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Iske Jasper J Seyda Midas M Heinbokel Timm T Maenosono Ryoichi R Minami Koichiro K Nian Yeqi Y Quante Markus M Falk Christine S CS Azuma Haruhito H Martin Friederike F Passos João F JF Niemann Claus U CU Tchkonia Tamara T Kirkland James L JL Elkhal Abdallah A Tullius Stefan G SG

Nature communications 20200827 1

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 ...[more]

PMID: 32855397

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Project description:BackgroundNeurobehavioral functioning is widely recognized as being an important consideration in lung transplant candidates, but little is known about whether these factors are related to clinical outcomes. The present study examined the relationship of neurobehavioral functioning, including measures of executive function and memory, depression, and anxiety, to long-term survival among lung transplant recipients.MethodsThe sample was drawn from 201 patients who underwent transplantation at Duke University and Washington University who participated in a dual-site clinical trial investigating medical and psychosocial outcomes in transplant candidates with end-stage lung disease. All patients completed the Beck Depression Inventory-II (BDI-II) and Spielberger State-Trait Anxiety Inventory at baseline and again after 12 weeks, while a subset of 86 patients from Duke University also completed neurocognitive testing. Patients were followed for survival up to 12 years after completing baseline assessments.ResultsOne hundred eleven patients died over a mean follow-up of 10.8 years (SD=0.8). Baseline depression, anxiety, and neurocognitive function were examined as predictors of posttransplant survival, controlling for age, 6-min walk distance, FEV, and native disease; education and cardiovascular risk factors were also included in the model for neurocognition. Lower executive function (hazard ratio [HR]=1.09, P=.012) and memory performance (HR=1.11, P=.030) were independently associated with greater mortality following lung transplant. Although pretransplant depression and anxiety were not predictive of mortality, patients who scored>13 on the BDI-II at baseline and after 3 months pretransplant had greater mortality (HR=1.85 [95% CI, 1.04, 3.28], P=.036).ConclusionsNeurobehavioral functioning, including persistently elevated depressive symptoms and lower neurocognitive performance, was associated with reduced survival after lung transplantation.Trial registryClinicalTrials.gov; No.: NCT00113139; URL: www.clinicaltrials.gov.

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

Publications

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

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