Donated livers can be made biologically younger

Once an organ is removed from a donor’s body, the clock starts ticking. Surgeons usually flush the organ with a preservative solution, bag it, and put it on ice—where it immediately starts to degrade. The team has a matter of hours to get it into a recipient’s body. There’s another option—one that has been growing in popularity in recent years, especially for donated organs that aren’t in the healthiest state. Some hospitals opt to put them on machines that pump them with nutrients and remove waste products, usually for around six to 12 hours. It’s a bit like being back in a body. This allows doctors to assess the organs, and some recent studies suggest that time spent on these perfusion machines helps them do better once they’re transplanted. Now, scientists have found that perfused organs seem to get younger, at least at a molecular level. The research, shared with MIT Technology Review, provides molecular clues as to why organs from younger donors are known to have a higher success rate. It might also help explain why perfused organs are less likely to fail once they make it into a recipient.  The researchers behind the study hope to find new ways to test the health of donated organs and potentially develop additional tools to repair organs that might otherwise be discarded. “If [we] can improve the utilization of organs beyond what the current systems can do, then that’s a win in my book,” says Jesse Poganik, who studies aging at Brigham and Women’s Hospital in Boston and coauthored the study. Clocking organs Poganik—along with colleagues including Heidi Yeh and Alban Longchamp, transplant surgeons at Mass General Brigham—used “aging clocks” to assess donated livers. These are scientific tools designed to measure biological age—a result that is meant to convey more about the health status of an organ (or person) than chronological age. In an initial experiment, the team used a clock to look at the patterns of chemical marks on DNA in 37 samples taken from 19 donated livers. Such epigenetic patterns are known to change as we age. But when the team compared samples from livers kept on ice and those that were perfused, the team found a “striking” pattern in the latter. “Machine-perfused livers, in spite of being older or having other disadvantageous characteristics, had a biological age that was lower than [non-perfused] livers that were chronologically younger,” says Yeh, who led the work. To investigate further, Yeh and her colleagues analyzed another 208 samples from 103 donated livers. This time, they used different aging clocks—ones that essentially measure how genes are working. They studied samples biopsied from the livers after they had been stored for up to around six hours either in cold storage or on machine perfusion. In most cases, they also assessed a second sample taken around an hour after the livers had been transplanted into a recipient. Once the organ’s blood supply is reestablished in the body, “you have a few other things to do,” says Longchamp. “Then you just do a quick biopsy before you close.” According to the clocks, which were developed to measure age and risk of death, the machine-perfused livers were biologically younger, the team found. “Pumping them at 34 degrees with oxygen and nutrients actually reversed the biological age,” says Longchamp. The results have been been shared with colleagues at an industry conference, he says.  “If you adjust out chronological age … to have a fair head-to-head comparison, the difference between the two is on the order of 30%,” says Poganik. “It’s logical to say that perfusion drives this effect.” The biological ages of all the livers tended to increase as soon as they were put into a recipient’s body, probably as a result of stresses on the organs. But still, the effect endured—the perfused organs remained biologically younger.  Nathanael Raschzok, a transplant surgeon at Charité Universitätsmedizin Berlin in Germany who was not involved in the research, says the work is impressive. But it’s not yet clear what these changes might mean for the recipients of these organs, he says. The organs in the study were donated by people in their 30s, 40s, and 50s. Raschzok wants to know the effect of perfusion on the liver of an 80-year-old. “Every so often, we use organs from 70-, 80-, 85-year-old donors,” he says. A better understanding of why the organs appear to be getting biologically younger might lead to therapies that achieve the same effect with a drug that could potentially be used to treat a donated organ for a fraction of the price, he adds. That’s important because perfusion is expensive—Raschzok says it costs around €10,000 in Germany (a quarter of the budget for a transplant), while the cost in the US comes to around $80,000 to $100,000 per organ, says Yeh. Molecular repair Yeh and her colleagues weren’t able to study most of the livers before perfusion. That’s because donated organs are generally not considered to be under the purview of the hospital until they’ve been placed on perfusion machines, she says. (Organ procurement procedures vary, but for the team as Mass General Brigham, donated organs are put on perfusion devices at the donor’s hospital. “There’s this sort of nebulous period where it’s not clear who the organ belongs to,” says Yeh.) Still, by looking at the genes and molecular pathways that seem to be altered in perfused organs, she and her colleagues can garner some clues. At a molecular level, the team saw changes in cell pathways linked to inflammation and the structure of tissues, for example. They also saw more activity in a pathway that allows cells to remove and recycle damaged cell parts, says Yeh. Poganik hopes to develop some kind of test that would determine which organs, on the basis of their biological age, are suitable for transplantation. He and his colleagues are also experimenting with potential drug treatments that might push the biological age of an organ even lower. In the meantime, any liver that is not from a “perfect, young, brain-dead donor” could probably benefit from perfusion, says Yeh. The devices are already transforming transplant surgery. Just a few years ago, she says, she and her colleagues would avoid using livers from people who’d suffered a circulatory death (when the heart stops beating and there’s a damaging lack of blood flow to organs) and were over 40. Today, they use livers from such donors over the age of 70. “Perfusion has completely changed the landscape of transplantation in the last three years,” she says.