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 cellfree mitochondrial DNA (cf-mt-DNA) released by senescent cells accumulates with aging and augments immunogenicity. Ischemia reperfusion injury induces a systemic increase of cfmt-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.

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

“…The TLR9 inhibition during polymicrobial sepsis may protect from sepsis-induced AKI and immunosuppression ( 200 ). Senolytics also protect from TLR9 activation-mediated inflamm-aging and age-specific inflammatory responses occurring due to mtDNA recognition and increase life span ( 201 – 203 ). Further studies are required in the direction.…”

The role of extracellular DNA in COVID-19: Clues from inflamm-aging

“…during inflamm-aging) and in COVID-19 patients. In this regard, two recent investigations identified extracellular mtDNA released by senescent cells as a key factor of inflamm-aging ( Iske et al, 2020 ), as well as the level of circulating mtDNA as a predictor of COVID-19 severity ( Scozzi et al, 2020 ) . We also focus on extracellular telomeric DNA (telDNA) as crucial source of extracellular anti-inflammatory DNA exhaustible with aging ( Storci et al, 2018 ; Bonafè et al, 2020b ).…”

“…Under this perspective, the age-dependent shortening of telomeres represents a mechanism of depletion of extracellular anti-inflammatory DNA reservoir in aged people. Following this reasoning, it is not surprising that telomere shortening and high levels of extracellular mtDNA have been linked to a large number of age-related disease with inflammatory pathogenesis ( Storci et al, 2018 ; Bonafè et al, 2020a ; Iske et al, 2020 ; Aguado et al, 2019 ; Bruno et al, 2020 ). Hence, extracellular DNA in aged people is more likely to stimulate inflammation, due to a concomitant increase of extracellular mtDNA and a decrease in extracellular telDNA.…”

Senescent cells and macrophages: key players for regeneration?

“…Moreover, the administration of the senolytic compounds ABT-737 or Dasatinib plus Quercetin (DQ) in vivo induces apoptosis in senescent cells and leads to clearance in mouse skin, lung and the haematopoietic system, and subsequently improves tissue repair [70][71][72][73]. Moreover, DQ administration promotes the survival of transplants from aged mice [74]. Taken together, these studies highlight the opposing roles of senescent cells in injury and repair, and the variation in their function as a result of timing, degree and type of injury.…”

“…Moreover, the administration of the senolytic compounds ABT-737 or Dasatinib plus Quercetin (DQ) in vivo induces apoptosis in senescent cells and leads to clearance in mouse skin, lung and the haematopoietic system, and subsequently improves tissue repair [ 70 – 73 ]. Moreover, DQ administration promotes the survival of transplants from aged mice [ 74 ].…”