Transplantation waitlists grow longer. And potential donor organs grow older and older and less transplantable. And patients who need organ transplants grow more and more desperate. But something else may grow—hope. According to a new study, transplantable organs don’t have to be young, they just have to be youthful.
Looking to older organs would seem an unlikely way to close the gap between donor organ supply and demand. After all, organs from older, deceased donors are frequently deemed unsuitable for transplantation. These organs often show age-specific responses to injury and increased immunogenicity. Consequently, these organs usually put patients at greater risk of adverse outcomes and transplant rejection.
But older organs can be revitalized by senolytic drugs, report investigators from Brigham and Women’s Hospital (BWH). Senolytic drugs can target and eliminate the senescent cells that accumulate in older organs. These cells withdraw from the cell cycle and cease to perform useful functions. They won’t even die. Instead, they linger while secreting inflammatory factors.
The BWH investigators, led by Stefan G. Tullius, MD, PhD, chief, division of transplant surgery and professor of surgery, Harvard Medical School, have found that the burdens that accompany cellular senescence include rising levels of cell-free mitochondrial DNA (mt-DNA). This finding is relevant to organ transplantation because evidence has been accumulating that mt-DNA is immunogenic.
In a recent study, Tullius and colleagues not only make the case that mt-DNA provokes an immune response that leads to organ failure and rejection, they also present evidence that senolytic drugs force senescent cells, the source of mt-DNA, back into the cell cycle, allowing the body to clear them.
Details appeared recently in Nature Communications, in an article titled, “Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation.”
“Ischemia reperfusion injury induces a systemic increase of cf-mt-DNA that promotes dendritic cell-mediated, age-specific inflammatory responses,” the article’s authors wrote. “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.”
In a mouse model, the investigators treated organ donors with a combination of the senolytic drugs dasatinib and quercetin. The drugs reduced the number of senescent cells, reduced mt-DNA levels, and decreased inflammation. Most relevantly, the survival of old organs treated with senolytics was comparable to that of organs originating from young donors.
“Older organs are available and have the potential to contribute to mitigating the current demand for organ transplantation,” said Tullius. “If we can utilize older organs in a safe way with outcomes that are comparable, we will take a substantial step forward for helping patients.”
Since the authors carried out their therapeutic experiments in a mouse model, further mechanistic studies are needed to evaluate whether senolytic drugs may have the same effects on human organs from older donors and the same degree of success in clearing senescent cells, as well as whether organs can be treated effectively with senolytic drugs after they are harvested. The authors have already started with first steps in humans and determined that augmented levels of mt-DNA circulate in older organ donors.
“We have not yet tested the effects clinically,” Tullius noted, “but we are well prepared to take the next step toward clinical application by using a perfusion device to flow senolytic drugs over organs and measure whether or not there are improvements in levels of senescent cells.
“Our data provide a rationale for considering clinical trials treating donors, organs, and/or recipients with senolytic drugs to optimize the use of organs from older donors. The goal is to help to close the gap between organ availability and the needs of the many patients currently on transplant waiting lists.”