Biology

Clearance of Senescent Cells as a Way to Expand the Donor Organ Supply


Researchers here provide a proof of principle to suggest that the presence of senescent cells in older organs contributes meaningfully to transplant rejection, via mechanisms that spur greater immune activity. This is of course only one of the ways in which senescent cell accumulation with age contributes to degenerative aging, the dysfunction of cells and tissues throughout the body. It may be possible to apply senolytic treatments that clear senescent cells to donor organs prior to transplantation (preferably), or to the patient immediately following transplantation (with the risk that it will suppress regeneration for a short time, as senescent cells are involved in the wound healing process), in order to allow greater viability of those organs and fewer complications in the transplantation process. It is worth noting that a sizable fraction of organ donors are older people, old enough to have a meaningful increase in the senescent cell burden.

The world population is aging rapidly. Organ transplantation is the treatment of choice for patients with irreversible end-stage organ failure. The supply of organs, however, is limited, resulting in prolonged waiting times with many patients dying or becoming too ill to be eligible for transplantation. Currently, the most obvious strategy with potential for closing the gap between demand and supply would be to enable the use of organs from older deceased donors that currently are frequently discarded.

Aging is associated with increased senescent cell burden that is linked to chronic, low grade, sterile inflammation. Increased levels of cytokines, including IL-6, IFN-γ, and TNF-α, contribute to the pro-inflammatory secretome of senescent cells, termed the senescence-associated secretory phenotype or SASP. Damage-associated molecular patterns (DAMPs), which include mitochondrial DNA (mt-DNA), also increase with aging. Relationships among senescent cell accumulation, mt-DNA, the SASP, outcomes of transplantation in clinically relevant disease models, and the potential to mitigate injury and augmented immunogenicity of older organs by targeting senescent cells have so far not been tested. However, recent studies propose that circulating mitochondria and mt-DNA might mediate early allograft dysfunction.

Ischemia and reperfusion injury (IRI) is characterized by initial tissue hypoxia with metabolic changes and subsequent further damage with the reintroduction of oxygen and elevated shear forces during reperfusion. Local tissue injury is followed by a systemic sterile inflammatory response, mediated by DAMPs including mt-DNA.

Here we show that cell-free mitochondrial DNA (cf-mt-DNA) released by senescent cells accumulates with aging and augments immunogenicity. IRI 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 inflammaging and present senolytics as a potential approach to improve transplant outcomes and availability.

Link: https://doi.org/10.1038/s41467-020-18039-x

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