Donated livers can be made biologically younger
Donated livers can be made biologically younger
捐赠的肝脏可以实现“生物学年轻化”
EXECUTIVE SUMMARY 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. 执行摘要 一旦器官从捐赠者体内取出，倒计时就开始了。外科医生通常会用防腐液冲洗器官，将其装袋并置于冰上——此时器官便会立即开始退化。医疗团队只有几个小时的时间将其植入接受者的体内。
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. 还有另一种选择——近年来这种方法越来越受欢迎，特别是针对那些健康状况不佳的捐赠器官。一些医院选择将器官放置在灌注机上，通过机器为其输送营养物质并清除代谢废物，通常持续 6 到 12 小时。这有点像让器官“重回”人体。这种方法使医生能够评估器官状况，近期的一些研究表明，在这些灌注机上停留的时间有助于器官在移植后表现得更好。
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. 现在，科学家们发现，经过灌注的器官似乎变年轻了，至少在分子水平上是这样。这项与《麻省理工科技评论》分享的研究，为“为何年轻捐赠者的器官成功率更高”提供了分子层面的线索。这也可能有助于解释为什么经过灌注的器官在植入接受者体内后，发生衰竭的可能性更低。
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. 该研究团队希望找到评估捐赠器官健康状况的新方法，并可能开发出额外的工具来修复那些原本会被丢弃的器官。波士顿布莱根妇女医院研究衰老问题的学者、该研究的合著者 Jesse Poganik 表示：“如果我们能超越现有系统的能力，进一步提高器官的利用率，那在我看来就是一种胜利。”
Clocking organs 器官“计时”
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. Poganik 与麻省总医院布莱根分院的移植外科医生 Heidi Yeh 和 Alban Longchamp 等同事一起，利用“衰老时钟”来评估捐赠的肝脏。这些科学工具旨在测量生物学年龄——其结果比实际年龄更能反映器官（或人）的健康状况。
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. 在初步实验中，团队使用“时钟”观察了取自 19 个捐赠肝脏的 37 个样本中 DNA 化学标记的模式。众所周知，这种表观遗传模式会随着年龄的增长而改变。但当团队比较了冰存肝脏和灌注肝脏的样本时，他们在后者中发现了一种“惊人”的模式。领导这项工作的 Yeh 说：“机器灌注的肝脏，尽管本身年龄较大或存在其他不利特征，但其生物学年龄却低于那些实际年龄更小的（未灌注）肝脏。”
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. 为了进一步研究，Yeh 和她的同事分析了来自 103 个捐赠肝脏的另外 208 个样本。这一次，他们使用了不同的衰老时钟——本质上是测量基因运作方式的工具。他们研究了肝脏在冷藏或机器灌注下保存约 6 小时后的活检样本。在大多数情况下，他们还评估了肝脏移植到接受者体内约一小时后采集的第二个样本。
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. Longchamp 说，一旦器官在体内重新建立血液供应，“你还有其他几件事要做，然后在缝合前做一个快速活检。”研究团队发现，根据旨在测量年龄和死亡风险的“时钟”显示，机器灌注的肝脏在生物学上更年轻。Longchamp 说：“在 34 摄氏度下用氧气和营养物质进行泵送，实际上逆转了它们的生物学年龄。”
The results have 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.” 他说，研究结果已在行业会议上与同行分享。Poganik 表示：“如果你剔除实际年龄的影响……进行公平的直接比较，两者之间的差异约为 30%。说灌注驱动了这种效应是合乎逻辑的。”
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. 所有肝脏的生物学年龄在植入接受者体内后往往会立即增加，这可能是器官承受压力的结果。但这种效应依然存在——经过灌注的器官在生物学上仍然更年轻。
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. 未参与此项研究的德国柏林夏里特医学院移植外科医生 Nathanael Raschzok 表示，这项工作令人印象深刻。但他指出，这些变化对器官接受者意味着什么尚不清楚。研究中的器官来自 30 多岁、40 多岁和 50 多岁的捐赠者。Raschzok 想知道灌注对 80 岁老人肝脏的影响。“我们经常使用 70 岁、80 岁、85 岁捐赠者的器官，”他说。
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. 他补充说，更好地理解为什么器官看起来在生物学上变年轻了，可能会带来新的疗法，即通过药物实现同样的效果，而成本仅为灌注的一小部分。这一点很重要，因为灌注非常昂贵——Raschzok 说在德国大约需要 1 万欧元（占移植预算的四分之一），而 Yeh 表示在美国每个器官的成本约为 8 万到 10 万美元。
Molecular repair 分子修复
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 at 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.) Yeh 和她的同事无法在灌注前研究大多数肝脏。她说，这是因为捐赠器官在被放置到灌注机上之前，通常不被视为处于医院的管辖范围内。（器官获取程序各不相同，但对于麻省总医院布莱根分院的团队来说，捐赠器官是在捐赠者所在的医院被放置到灌注设备上的。“有一个模糊的时期，不清楚器官到底属于谁，”Yeh 说。）
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. 尽管如此，通过观察灌注器官中似乎发生改变的基因和分子通路，她和同事们还是获得了一些线索。在分子水平上，团队观察到了与炎症和组织结构相关的细胞通路发生了变化。Yeh 说，他们还观察到一种允许细胞清除和回收受损细胞部分的通路活性更高。
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. Poganik 希望开发出一种测试方法，根据生物学年龄来确定哪些器官适合移植。他和他的同事们也在试验潜在的药物治疗方法，这些方法可能会将器官的生物学年龄进一步降低。