The miracles of modern transplant surgery can still sometimes boggle the mind. That the beating heart of one person can be sewn into the living body of another to save their life can seem like a Frankensteinian feat. But today, this kind of surgery is a standard and established medical procedure rather than an experimental one: In 2025, in the United States alone, more than 4,500 hearts were transplanted, according to the American Heart Association.
The tragedy is that it’s not available to everyone. Many thousands of people snake through long organ donation lists waiting their turn, and many of them die before their number comes up. That’s partly because everyone wants to receive a young, healthy heart rather than an old and weary one—the younger the better. This could soon change, if recent findings about how organs age hold up.
Read more: “If Only Technology Had a Heart”
The desire for young organs has been partly driven by a speculative theory of rejuvenation: Research in mice known as heterochronic parabiosis, where an older and younger mouse’s circulatory systems are sewn together, suggested that the blood of a younger mouse could reverse age in an old one. Some hypothesized that something similar might happen with organ transplants.
But a team of scientists and surgeons from Harvard Medical School, together with a surgeon from Berlin, recently discovered that instead, an organ’s biological age can change to match that of its host after transplantation. When they sewed an old heart into a younger mouse or human, the organ seemed to turn back time, growing younger in its new dwelling, due to factors in the molecular environment.
The reverse was also true, however: When a younger heart was surgically transplanted into an older mouse or person, the young heart aged to match the body of its recipient. The organs “assimilate,” the scientists proposed, like a person who moves to a new place and learns the local language and customs so they can fit in.
In mid September, the team published their paper as a preprint, meaning it has not yet been peer reviewed, so the work still needs to be evaluated and validated—but the findings could have implications both for transplant surgery and the science of aging and rejuvenation. I spoke with coauthor Jesse Poganik, whose lab at Harvard Medical School studies the biology of aging, about the future of transplant surgery, cell senescence, and epigenetic clocks.
Was this finding something you expected when you started out?
Yes and no. Prior to this project, we were working with a system called heterochronic parabiosis, where you surgically join the circulatory systems of a young animal and an old animal to see how this affects tissue regeneration. It has been particularly popular in the aging field. We’ve shown, using epigenetic clocks, that in that model, the old mouse becomes biologically younger. We also know that the old mouse lives longer compared to controls after you detach the mice. And the young mouse becomes reversibly biologically older. Because of these experiments, in a sense, it was not surprising that we found when an old heart was put into a young organism, it became biologically younger or vice versa.
What was a little bit surprising was that in parabiosis, we see a very strong reciprocal effect. So old becomes young, young becomes old. Pretty much in every organ we've profiled, that’s true. Here, we didn’t see that. We were suspecting that we might see some reciprocal effect, some feedback onto the recipient organism—that a young heart might have made the older animal somewhat younger. But when we looked at the other organs of the recipient animals, we didn’t see any evidence of that. Young mice that received old hearts, based on the epigenetic clocks, did not become biologically older. Older mice who received younger hearts did not become biologically younger. But the graft itself, the transplanted heart, that’s where really strong effects were observed.
Were you able to look at systemic aging in the human patients who received transplants, as well?
Yes and no, again. On the one hand, we did look at baseline health indicators, and then also cardiovascular-specific ones. The difference is that, in the human case, it’s not only hugely more complicated. We used a syngeneic mouse model, meaning the two mice are inbred so that they have similar immune systems. They don’t need immunosuppression. They’re also not, for a lack of a kinder way of saying this, on the verge of death before they get the transplant.
For humans, of course, a heart transplant is a last resort. Because of the realities of waiting lists and so forth, many transplant recipients, particularly heart transplant recipients, are extremely sick by the time they get their new hearts. In other words, it’s not exactly one-to-one. The mouse model is also a heterotopic model, meaning there is actually a second heart that is implanted in the mouse. The first heart also remains. And that turns out to be an established model of heart-transplanted mice. It doesn’t recapitulate every single thing that goes on in a heart transplant in humans, but it turns out to be, from an experimental point of view, very helpful because the native heart that the mouse retains is a very useful control for us. When we looked at the feedback into the systemic environment, one of the things we looked at was the native heart, and we didn’t see any effects on the aging of the native heart.
To answer your original question about the humans, it’s a little hard to say because baseline health is generally improving anyway, simply because the people are so sick by the time they get the transplant. And the transplant usually turns out to be transformational in most cases for most recipients. The expectation is that the health improves in general.
Is there any sort of limit in terms of the viable difference in age between the donors and recipients of the transplants?
In the mouse model, there is a practical limitation as to what could be tested because the older mice simply don't have the resilience to survive any kind of major surgery. The old mice that we used in the study—old in air quotes—were 18 months old. That is not really an old mouse. But it’s the limit of what can be tolerated in terms of major surgery in lab mice. We did test a range of ages. We had the middle-aged mice, which were 12 months old, the older mice, which were 18 months, and then the young mice, which were three months old. We did see the effect at the different age permutations. Any older heart that went into any younger recipient became younger and vice versa.
In the humans, the cohort that we profiled with the molecular clocks was relatively small—just 11 patients—and that was because we were accessing historical pathology samples. We were limited in terms of the numbers that we could ask the pathology people to pull from the archives. We chose those 11 patients in the cohort because they had pretty extreme mismatches between the age of the donor and the age of the recipient. The older hearts in younger individuals range from something like seven years to 24 years difference. The younger hearts in the older patients were more consistently around the 20-year difference. At Brigham and Women’s Hospital where we drew this cohort from, that actually turns out to be the most common situation. Most donors are chosen because they’re young.
To loop back to your original question, is there a limit? I would say it seems that the principle of biological age assimilation, the heart taking on the biological age of the recipient, seems like it happens at all practical age differences that we tested. And because Brigham is a major academic medical center where more of these extreme cases take place, it probably allowed us to have more of an insight actually into what happens in real life.
You and your coauthors report that some earlier studies had shown in mice that transplanting an older heart into a younger mouse can cause the surrounding cells to age, and here you found that was not true. How do you reconcile those findings?
This was a study done by our coauthor, Stefan Tullius, the chief of transplant surgery at the Brigham and Young Women’s Hospital. His lab also has a very strong research program where they have a lot of these mouse models of transplantation. His lab and the second author on the paper, Tomohisa Matsunaga, did all of the mouse surgery, which is highly technical. They had a previous study where they transplanted old hearts into young animals, and what they found was that the transplant increased the burden of senescent cells in other organs.
How do we reconcile that?
There’s a knee-jerk association that people have between senescent cells and aging. Part of the problem is that senescence as a term is in some cases synonymous to the term aging, but senescence and senescent cells really are just one facet of aging. Our team and some others believe that epigenetic clocks, which is the primary readout that we used in this paper, are a more integrative measure of aging.
There’s an open question in the field: What does the overall burden of senescent cells in any given tissue actually tell us about the overall state of biological age? In reality, there have not been that many studies that have looked at the direct relationship between senescent cell burden and biological ages read out by a molecular clock. I should also say that there’s a huge body of work predating even the epigenetic clock field, spearheaded by pioneers like Judy Campisi. She showed that while senescent cells are associated with aging and generally increase with aging, they also turn out to be extremely essential for a huge number of important things—for instance, keeping cancer at bay. They’re also hugely important in development.
All of that is to say, senescent cells are one facet of aging. They may contribute to the effects that we see, but overall, it doesn’t seem to shift the biological age as assayed by these clocks in a significant way that can be detected.
You note that what causes the donor organ to take on the age of its recipient is the molecular environment, and in the older recipients, accumulated molecular damage. What kind of molecular damage specifically are you talking about?
Basically, all of it. There are a number of competing theories in the aging field about what is the main driver or causative factor of aging. Some people believe it is a programmed process, the same way that development is programmed. I come more from the point of view that aging represents an accumulation of molecular damage.
There are the straightforward things that most people associate with molecular damage: things like DNA cross links, mutations, misfolded proteins, things like that. But there are also all of the side products that arise from the imperfection of biology as a system. Enzymatic reactions are extremely efficient, but they are not 100 percent perfect, so they can lead to damaging metabolites or damaging proteins, things like that. That is why it is probably the case that when we think about targeting aging, when we think about reversal of biological age, if that’s possible, there are certain aspects of aging that are probably reversible and certain that are simply not.
One very specific form of damage is cysteine oxidation. At lower levels of oxidation, it doesn’t represent damage at all. It’s just molecular signaling, and it’s reversible. But at a certain stage, it becomes biologically irreversible. The cell simply does not know how to deal with a cysteine that is that oxidized except to completely turn over the protein. I hypothesize that the same is true if you extend that across all the different kinds of molecular damage that accumulate during aging. Some kinds are reversible, and others are not.
Do the findings have any other implications for biomedical treatments of aging?
On the one hand, if this biological age assimilation principle holds and applies in general across different organs, it means we have identified a broadly applicable principle in transplant medicine. The other thing that may be important is the fact that we didn’t see feedback on the system, only on the graft organ. That really raises a question about the potential value of highly targeted aging treatments. If I had a magic wand that could rejuvenate the heart in an older individual, the question that I think our data raises is, does that matter? Three months later, six months later, one year later, the organ could just reassimilate the biological age of the recipient. There are some great new tools that are being innovated in the field, letting us look at the age of organs and cell types. Could some therapeutics be powerful enough to outpace the effect of biological age assimilation?
There’s a history of these reports that people who get transplanted organs develop the preferences of the deceased person, food preferences, or other quirks of personality. Does your research tell us anything about that phenomenon?
I don’t know. Maybe, maybe not. That really is the straightforward answer. Clearly there is an exchange between the donor and the recipient. At the very basic conceptual level, that’s what these data show us, because that must be what mediates the effect that we see in terms of the biological age. Whether that extends to other things, I really don’t know, but it’s an interesting question. The other interesting thing is the mismatch between recipient and donor sex. It’s not something that we really looked into at any great level of detail here, but it was just one curious thing that came out of looking at the data: They aren’t always matched, which you think would be more of a problem than it turns out to be, apparently. 
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