Transplanted Hearts May Take On Their Recipient’s Biological Age

The heart is unquestionably among the body’s most vital organs.

Located in the chest and protected by the sternum and ribs, it beats continuously to keep blood circulating, delivering oxygen, nutrients and other crucial substances throughout the body.

It is therefore natural to assume that the heart and the body containing it are inseparably connected: anything that affects one must affect the other.

However, a new preprint posted on bioRxiv, which has not yet undergone peer review, indicates that this connection may have limits. Remove a heart from one body and transplant it into another, and a remarkable change may occur.

The transplanted heart appears to adopt the biological age of its new recipient.

Older hearts placed in younger recipients seem to become biologically younger, whereas young hearts transplanted into older bodies display evidence of faster ageing.

That is the striking conclusion of research led by Harvard Medical School molecular biologist Jesse Poganik. It suggests an organ’s biological age is not determined entirely within the organ, but is heavily shaped by the body surrounding it.

The researchers say the finding could eventually save lives by easing existing restrictions around donor age and increasing the supply of organs for people awaiting transplants.

Biological age and epigenetic clocks

We commonly measure age by the number of years an organism has existed, but chronological age represents only one aspect of the complex ageing process.

Biological ageing accounts for the accumulated molecular and physiological changes linked with getting older. It does not necessarily progress in step with the calendar, and its rate can differ substantially between individuals.

Researchers have created several methods for estimating biological age. One of the most widely used approaches is the epigenetic clock, which identifies distinctive patterns in chemical markers known as methyl groups that are attached to DNA.

Poganik and his team wanted to know whether these clocks shift when an organ is abruptly moved into a body that is considerably younger or older than the one in which it developed.

They began by investigating the question in mice.

Heart transplants in mice reveal age assimilation

Using an established mouse transplantation method, the scientists transplanted hearts while leaving each recipient’s original heart in place. A donor heart was instead connected to blood vessels in the neck.

This technique keeps the animals alive while allowing scientists to examine the transplant’s effects. In this instance, they could assess the two-way relationship between the body’s potential influence on the transplanted heart and the donor heart’s potential effect on the body.

The researchers carried out transplants between mice of different ages, including old hearts into young mice and young hearts into old mice. They also performed same-age transplants as a comparison.

After four to six months, they assessed DNA methylation in the transplanted hearts, the mice’s original hearts, their livers and their blood.

The results became particularly compelling at this point. Whether young mice received old hearts or old mice received young hearts, the transplanted organ started to match the biological age of the body it had entered.

Old hearts in young mice displayed indications of rejuvenation, whereas young hearts in old mice showed evidence of accelerated ageing.

Notably, the effect seemed to run largely in one direction. The biological ages of recipients’ own hearts, livers and blood were mostly unchanged by whether the donor heart had come from an older or younger mouse.

In other words, a heart transplanted into a new ecosystem appeared to take on the biological age of its new home.

Evidence from human heart transplant recipients

Despite their usefulness in research, mice are not humans.

For several sound reasons, researchers cannot place a second heart into a person simply to observe the outcome. Yet people regularly receive transplants for medical reasons, producing extensive clinical records and tissue samples that can be reviewed retrospectively.

Poganik and his colleagues obtained stored heart tissue from 11 transplant recipients. The samples came from biopsies collected during post-transplant follow-up care.

The patients’ ages varied markedly in comparison with those of their donors: recipients ranged from 24 years younger than their donor to 50 years older.

When the team examined DNA methylation in these tissues, they observed much the same pattern found in mice.

The biological ages of transplanted hearts were more strongly linked to recipients’ ages than to the ages of their donors.

Thus, an old heart transplanted into a younger person showed signs of biological rejuvenation, while a young heart given to an older person seemed biologically older than its chronological age would indicate.

The sample was extremely small, involving only 11 patients, but its consistency with the mouse results was encouraging.

The scientists then sought evidence beyond molecular markers, which can only be measured using biopsy samples that are difficult to obtain.

Such evidence was available through other follow-up data: detailed records of cardiac function and physical performance from hundreds of heart transplant recipients, gathered one year after their operations.

The same pattern appeared there as well.

On analysing these records, the researchers found that several measures of the transplanted hearts’ structure and function were associated with recipient age rather than donor age.

The most pronounced effects involved exercise performance. Both functional capacity and maximum oxygen consumption fell as recipient age increased, irrespective of the donated heart’s age.

The researchers say these findings could carry significant consequences for selecting donor hearts for transplantation.

There is no formal maximum age for heart donors, but younger hearts are typically favoured. The team notes that donors under 45 are recommended, while few transplant programmes routinely accept hearts from donors over 50.

Yet if an older heart can shed some biological markers of age after being transplanted into a younger body, chronological age alone may not provide the full picture of that organ’s potential.

The researchers propose that older donor hearts could ultimately be considered for younger recipients, expanding a critically limited organ supply.

Much remains uncertain. Most importantly, the study does not establish whether the apparent rejuvenation of old hearts results in improved long-term outcomes.

It is also not yet known how rapidly this transformation occurs in humans, how long it persists, or whether other transplanted organs experience a comparable change. Further research is needed to address these questions.

Precisely how a recipient’s body imposes this influence on a transplanted heart also remains unknown. However, the team identified a possible hint in gene activity within transplanted mouse hearts.

Changes connected with mitochondrial and metabolic processes stood out in particular, suggesting that these pathways may contribute to the transfer of ageing characteristics between an organ and its new body.

The study is a meaningful step towards understanding a compelling phenomenon, although many further steps are required.

Even so, the researchers are hopeful that their findings could lead to improved choices for transplant patients.

"Our carefully controlled mouse study paired with our extensively quality-controlled human DNAm data present compelling evidence supporting age assimilation of tissues placed into heterochronic systemic environments," they write.

The research is available on the preprint server bioRxiv.

This article was fact-checked by Fiona MacDonald and edited by Fiona MacDonald. Although we take pride in our process, we are only human. If you notice an error, please let us know.