The Heart’s Surprising Adaptability

The heart is undoubtedly one of the most vital organs in our body. Nestled within the protective embrace of the sternum and ribs, it continuously beats to ensure blood circulation, delivering oxygen, nutrients, and other crucial elements to every part of the body.

You might think, then, that there’s a fixed connection between the heart and the body it belongs to. What affects one should, logically, affect the other as well. But a new preprint study uploaded to bioRxiv—still awaiting peer review—suggests that this correlation may have its limits. When a heart is transplanted into a new body, something remarkable occurs.

The transplanted heart starts to adopt the biological age of its new host. For instance, older hearts placed in younger recipients seem to rejuvenate biologically, while younger hearts in older bodies exhibit signs of accelerated aging. This intriguing finding emerges from research led by molecular biologist Jesse Poganik from Harvard Medical School. It indicates that the biological age of an organ is not strictly inherent but is significantly shaped by the body surrounding it.

Moreover, this research could have profound implications for transplant medicine, potentially expanding the donor organ pool by revising current age restrictions for donors.

Typically, we think of aging in terms of chronological years, but that’s just one piece of a much more complex picture. Biological aging—the accumulation of molecular changes over time—doesn’t necessarily line up with the calendar and can differ widely between individuals.

Scientists have developed various methods to gauge biological age, with one common approach being epigenetic clocks, which identify specific patterns of chemical modifications (methyl groups) on DNA. Poganik and his team were curious if these clocks would shift when an organ is transplanted into a body significantly older or younger than its original environment.

To explore this, they started their experiments with mice. Using a known technique to perform heart transplants, they allowed the recipient to keep its original heart while a donor heart was connected to the blood vessels in the neck.

This method enabled the recipients to survive while researchers observed the impact of the transplant—specifically, how the host body influences the transplanted heart’s biology and vice versa.

The team conducted transplants between mice of varying ages, including young hearts into older mice and vice versa, while also performing same-age transplants as control. After four to six months, they examined DNA methylation in the hearts, livers, and blood of the mice.

What they found was fascinating. Both cohorts—young mice with older hearts and older mice with younger hearts—exhibited traits indicating that the transplanted organ was beginning to adopt the biological age of its new environment.

In older hearts transplanting into younger mice, signs of rejuvenation were apparent. Conversely, younger hearts planted in older mice portrayed signs of aging. Interestingly, this influence seemed to flow predominantly one way; the biological age of the original hearts, livers, and blood of the recipient mice largely remained unaffected by the age of the transplanted heart.

This suggests that in a new biological context, the heart tends to conform to the age of its new surroundings.

However, despite the insights gained through mouse studies, mice are not humans. For various ethical reasons, scientists can’t conduct the same type of transplants in humans. Still, human transplant records offer valuable data, with detailed medical histories and tissue samples available for retrospective studies.

Poganik and his team analyzed archived heart tissues from 11 transplant recipients, whose ages varied significantly compared to their donors—some were 24 years younger and others 50 years older. The analysis revealed findings similar to those observed in mice: the biological age of the transplanted hearts appeared more aligned with the recipients’ ages than the donors’.

Thus, an older heart in a younger recipient showed signs of rejuvenation, while a younger heart in an older individual seemed biologically older than its chronological age would indicate. Even though the sample size was relatively small, the resemblance to the mouse research provided encouraging evidence.

The researchers then sought additional confirming data beyond molecular markers typically acquired through challenging biopsy samples. They scrutinized follow-up records from hundreds of heart recipients collected one year post-transplant, which spotlighted various facets of heart function and physical performance.

In this larger dataset, the same trends were observed. As the recipient’s age increased, various features of the transplanted hearts’ structure and functionality were linked more closely to the recipients’ ages rather than the ages of the donors. A notable decline in exercise performance also aligned consistently with older recipients, irrespective of the donor’s age.

The implications of these findings could be significant for how hearts are selected for transplantation. While there is no formal upper age limit for heart donors, younger hearts are generally preferred. Recommendations typically favor donors under 45, and many transplant programs rarely accept hearts from individuals over 50.

If older hearts can shed some biological aging markers when transplanted into younger bodies, we may need to reconsider how we appraise an organ’s suitability based solely on chronological age. This could eventually facilitate the use of older donor hearts for younger recipients, addressing a critical shortage of available organs.

That said, many questions remain unanswered. For instance, the study doesn’t clarify whether the apparent rejuvenation translates into better long-term outcomes. We still don’t know how swiftly the changes occur in humans, how long they last, or if this phenomenon applies to other transplanted organs. Further research is necessary in these areas.

There’s also the mystery surrounding how the recipient’s body affects the newly transplanted heart. In their findings, the researchers noted changes related to mitochondrial and metabolic activities in the transplanted mouse hearts, hinting these pathways might play a role in the aging exchange between organ and body.

This study is an essential leap towards understanding these intriguing dynamics, and while it opens up new avenues for exploration, there’s still much more to uncover. Yet, the researchers remain hopeful that their findings could lead to improved outcomes for patients in need of transplants.

“Our carefully controlled mouse study paired with our extensively quality-controlled human DNA methylation data present compelling evidence supporting the age assimilation of tissues placed into heterochronic systemic environments,” they state.

The research is available on the preprint server bioRxiv.