Old hearts become biologically younger when transplanted into younger people: ScienceAlert

The heart is undoubtedly one of the most important organs in the body.

It sits in your chest, carefully shielded by the sternum and ribs, constantly pulsing to maintain blood flow, carrying oxygen, nutrients, and other essential substances to each end of your body.

It might be reasonable to think that there is an indelible connection between the heart and the body in which it resides: processes that affect one inevitably affect the other.

But a new preprint, uploaded to bioRxiv and yet to be peer-reviewed, suggests that this may only be true to a point. Take the heart out of the body and put it in a new one, and something incredible happens.

The transplanted heart begins to take on the biological age of its new owner.

Older hearts transplanted into younger recipients appear to become biologically younger, while younger hearts placed in older bodies show signs of accelerated aging.

That’s the fascinating finding of a study led by molecular biologist Jesse Poganik of Harvard Medical School, suggesting that the biological age of an organ is not entirely intrinsic to the organ itself, but is strongly influenced by the body around it.

And it could, they say, ultimately save lives – by relaxing current constraints on donor age limits, thereby expanding the pool of organs available to people in need of transplants.

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Although we tend to think of age in terms of the number of years an organism has lived, chronological age is only part of the complex process of aging.

Much of it has to do with biological aging: the accumulated molecular and physiological changes that accompany aging do not necessarily proceed on schedule and can vary from person to person.

Scientists have developed several methods to estimate this biological age. Among the most widely used are epigenetic clocks, which look for characteristic patterns of chemical tags called methyl groups attached to DNA.

Poganik and his colleagues wondered whether these clocks would change when an organ was suddenly transplanted into a body significantly older or younger than the one it was born into.

The answer to this question started with mice.

Researchers performed heart transplants in mice using an established technique in which the recipient retains their original heart, while the donor heart is connected to blood vessels in the neck.

This approach allows animals to stay alive while researchers study the effects of the transplant – in this case, the two-way relationship between the body’s possible effect on the transplanted heart and the transplanted heart’s effect on the body.

The team performed transplants between mice of different ages, including young hearts in old mice and old hearts in young mice, as well as transplants of the same age for comparison.

Four to six months later, they looked at DNA methylation in the transplanted hearts, the mice’s original hearts, their livers and their blood.

This is where things got interesting. In younger mice given older hearts than in older mice given younger hearts, the transplanted organ began to assimilate the biological age of its new body.

Older hearts from younger mice showed signs of rejuvenation, while younger hearts from older mice showed signs of accelerated aging.

Interestingly, the effect appears to be largely one-sided. The biological age of recipients’ original hearts, livers, and blood was mostly unaffected by whether the transplanted heart came from an older or younger donor.

It seems that, transplanted into a new ecosystem, the heart adopts the biological age of its new home.

But for all their similarities for research purposes, mice are absolutely not humans.

For many very good reasons, scientists can’t cut humans open and insert a second heart to see what happens — but humans are frequent recipients of transplants, and these procedures generate detailed medical records and tissue samples that can be studied retrospectively.

Poganik and colleagues obtained archived heart tissue taken from 11 transplant recipients, from biopsies taken during follow-up care after their transplants.

The ages of these patients differed significantly from their donors, ranging from recipients 24 years younger than their donor to 50 years older.

And when the researchers analyzed DNA methylation in these samples, they found much the same as in mice.

The biological age of transplanted hearts was more closely associated with the age of recipients than with that of donors.

This meant that an older heart transplanted into a younger person showed signs of biological rejuvenation, while a younger heart transplanted into an older person appeared biologically older than its chronological age would suggest.

Although the sample was very small – just 11 patients – the similarity to what the researchers had observed in their mouse experiments was promising.

So the researchers looked to see if they could find evidence of this beyond molecular markers only accessible through hard-to-obtain biopsy samples.

This was available in other data from transplant follow-up care – detailed recordings of heart function and physical performance of hundreds of heart recipients, collected a year after transplantation.

Here too, the trend has continued.

When the researchers analyzed the records, they found that several aspects of the structure and function of the transplanted hearts were associated with the age of the recipients rather than the donors.

But the most obvious effects appeared in physical performance: functional capacity and maximum oxygen consumption decreased with the age of the recipient, regardless of the age of the given heart.

According to the researchers, these findings could have important implications for how donor hearts are selected for transplantation.

Although there is no official age limit for heart donors, younger hearts are generally preferred. The researchers note that donors younger than 45 are recommended and few transplant programs routinely accept hearts from donors older than 50.

But while an older heart may lose some of the biological characteristics of its age after transplantation into a younger body, chronological age alone may not tell the whole story of the organ’s potential.

Researchers suggest this could eventually allow hearts from older donors to be considered for younger recipients, opening the way to a desperately limited pool of available organs.

However, there is still a lot we don’t know. In particular, the study does not show whether the apparent rejuvenation of older hearts translates into better long-term outcomes.

We also don’t know how quickly the transformation occurs in humans, how long it lasts, or whether other transplanted organs undergo a similar change; additional studies in this direction are necessary.

It is also unclear how exactly the recipient’s body exerts this influence on a transplanted heart. But the researchers found a possible clue in the genetic activity of transplanted mouse hearts.

Changes associated with mitochondrial and metabolic processes were particularly significant, suggesting that these pathways may play a role in the exchange of aging characteristics between an organ and its new body.

The study is an important step that sheds light on something intriguing, but there are still many steps to take.

Still, the researchers are optimistic that their work could pave the way for better options for transplant patients.

“Our carefully controlled mouse study, coupled with our largely quality-controlled human mDNA data, presents compelling evidence supporting age-mediated assimilation of tissues placed in heterochronic systemic environments,” they write.

The research is available on the bioRxiv preprint server.