Rejuvenating Old Organs

Rejuvenating Old Organs To Increase Donor Pool For Transplantation

Organs from older, deceased donors are frequently discarded or not utilized despite the limited supply of organs available for patients on waitlists for transplantation. The reason why many patients do not survive the time it takes for an organ to become available is due to the gap between demand and supply of organs, which causes very long wait-times. The potential to close this gap can be got from available older organs. But patients may be put at greater risk of adverse outcomes and transplant rejection as older organs can also often provoke a stronger immune response.

By leveraging a new class of drugs known as senolytics, which target and eliminate old cells, investigators from Brigham and Women’s Hospital are leading efforts to breathe new life into older organs. The team presents evidence that senolytic drugs may help rejuvenate older organs,  using clinical and experimental studies, which could lead to a wider pool of organs eligible for donation and to better outcomes. The journal Nature Communications published this study’s results.

At the Brigham, the Division of Transplant Surgery’s Chief, Stefan G. Tullius, MD, Ph.D., the corresponding author said, “The current demand for

organ transplantation can be reduced with the help of older organs available as they have the potential to contribute to mitigating the demand. A substantial step forward for helping patients can be taken if we can utilize older organs in a safe way with outcomes that are comparable.”

Senescent cells accumulate as organs age and these cells escape the body’s usual means of destroying older, unneeded cells, and they no longer divide. Cell-free mitochondrial DNA, the mt-DNA is released by the senescent cells. This rise in mt-DNA, which also accumulates in older organs, is tied to organ rejection, suggests recent studies.

Evidence that the accumulation of mt-DNA provokes an immune response leading to organ failure and rejection was presented by Tullius and colleagues in their Nature Communications paper where they identified senescent cells as the key source of mt-DNA. Senolytic drugs force senescent cells back into the cell cycle, thus, the researchers examined whether outcomes can be improved using senolytic drugs. Using a combination of the senolytic drugs dasatinib and quercetin, the researchers treated organ donors in a mouse model. It was seen that the drugs decreased inflammation, reduced mt-DNA levels, and reduced the number of senescent cells. Senolytics treated old organs’ survival was akin to the organs originating from young donors.

To evaluate whether organs can be treated effectively with senolytic drugs after they are harvested and whether senolytic drugs may have the same effects on human organs from older donors and the same degree of success in clearing senescent cells, further mechanistic studies are needed, since the authors carried out their therapeutic experiments in a mouse model. The authors have determined that augmented levels of mt-DNA circulate in older organ donors as they have already started with the first steps in humans.

Tullius said, “By using a perfusion device to flow senolytic drugs over organs and measure whether or not there are improvements in levels of senescent cells, we are well prepared to take the next step toward clinical application as we have not yet tested the effects clinically. To optimize the use of organs from older donors, our data provide a rationale for considering clinical trials treating organs, donors, and/or recipients with senolytic drugs.”

Rejuvenating Old Organs To Increase Donor Pool For Transplantation