Older donor hearts showed signs of rejuvenation in younger recipients

by · News-Medical

Transplanted hearts appeared to shift toward the biological age of their recipients, raising the possibility that some older donor hearts could gain a younger molecular profile in younger bodies.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Could younger recipients change the age of donor hearts?

However, a huge mismatch between the supply of donor organs and the demand for transplantation substantially limits access to this lifesaving procedure. To overcome this shortage, substantial efforts have been put forward in search of methods to expand the pool of transplantable organs.

Although there is no official upper age limit for heart donors, donors younger than 45 years are generally recommended, and relatively few transplant programs accept hearts from donors older than 50 years. As transplant programs seek to broaden the donor pool, hearts are increasingly transplanted between donors and recipients of different ages, a situation known as heterochronic transplantation.

In this context, recent evidence suggests that an older organism may experience cellular rejuvenation following exposure to the blood and systemic factors of a younger organism. Since heterochronic transplantation procedures involve exposure of an organ to an age-mismatched systemic environment, the exchange of aging features between donors and recipients may be possible.

Researchers led by teams at Brigham and Women’s Hospital and Harvard Medical School characterized the biological consequences of heterochronic heart transplantation performed both in animals and humans. They conducted multiomic profiling and analyzed advanced biomarkers of aging to explore how the biological age of a transplanted heart is modified inside the recipient’s body.

Transplanted hearts shift toward their recipients’ biological age

The researchers conducted a series of heterochronic transplantations using a mouse model of heterotopic cardiac transplant, wherein the recipient mouse retains its own heart and a second heart from the donor is connected to the carotid artery and jugular vein.

Four to six months after transplantation, they analyzed DNA methylation biomarkers of aging in experimental mice to assess how the systemic environment affects the transplanted heart and transplant-mediated changes in the mouse's native organs.

The findings revealed that the biological age of the transplanted heart is significantly affected by the recipient’s age. Specifically, DNA methylation clocks predicted that younger hearts transplanted into older recipients were biologically older than the donor’s age, while older hearts transplanted into younger recipients showed molecular signatures consistent with biological rejuvenation.

Further analysis of transplant-induced changes in DNA methylation levels at individual CpG sites showed anti-aging changes in older hearts transplanted into younger recipients and pro-aging changes in younger hearts transplanted into older recipients. Similar findings were observed in transcriptomic sequencing.

The functional enrichment analysis of the transcriptomic data indicated that the observed changes in biological age of transplanted hearts are associated with inflammatory, interferon, and mitochondrial processes. Mitochondrial translation, oxidative phosphorylation, and respiratory electron transport showed particularly strong changes in opposite directions depending on the age mismatch.

The researchers next tested whether the pattern extended to humans, analyzing archived heart biopsy samples from 11 transplant recipients whose donor-recipient age differences ranged from −24 to +50 years. The human data showed a similar pattern, with the estimated biological age of transplanted hearts associated with recipient age.

To explore the clinical relevance of biological age adaptation, the researchers analyzed detailed cardiac outcomes in hundreds of recipients one year after heart transplantation. The findings revealed that recipient age was associated with several functional outcomes, most consistently measures of exercise capacity. These findings provide clinical support for the molecular evidence of biological age assimilation observed in both animals and humans.

Biological rejuvenation could broaden the heart donor pool

The study reveals that the recipient’s systemic environment strongly influences the biological age of the transplanted heart. The study reports that the biological age of heterochronic heart implants is strongly affected by the recipient’s age; however, the reciprocal effect on the recipient’s systemic biological age is minimal.

Notably, the findings of the transcriptomic pathway analysis highlight mitochondrial and metabolic pathways as potential mechanisms underlying the observed biological age changes, although their causal role remains to be established.

The researchers caution that several questions remain. The mouse experiments used heterotopic transplants between genetically matched animals, which do not fully reproduce human heart transplantation or its immune responses. The human molecular analysis was also limited to biopsy samples from 11 patients, while the larger clinical analysis assessed outcomes only one year after transplantation. Longer-term studies will therefore be needed to determine whether the apparent rejuvenation persists and whether it translates into improved clinical outcomes.

Taken together, the study findings provide potential directions for future organ allocation protocols for transplantation, which may address the critical shortage of transplantable organs.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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