Transplanted mouse and human hearts take on the biological age of their new recipients, according to a Harvard Medical School preprint posted on bioRxiv. The findings suggest that older donor organs might be safely rejuvenated in younger patients, potentially widening the restricted donor pool for lifesaving transplants.
Modern organ transplantation remains bound by strict biological margins and a severe shortage of available organs. Doctors typically recommend donors younger than 45 years old, although older ones who show no signs of significant coronary artery disease are also considered due to risks of worse outcomes. Yet the sheer volume of patients awaiting surgery continues to climb. In the United States alone, heart transplants reached 4,636 procedures in 2024, marking an 81.5 percent increase since 2013, according to recorded health data. Hundreds of individuals worldwide still die annually while waiting for a matching organ.
To investigate whether donor age limits could be safely stretched, a research team led by Harvard Medical School molecular biologist Jesse Poganik examined biological age dynamics in experimental and clinical transplants. Their work reveals that an organ’s cellular age is not entirely fixed when it moves into a new host body.
Mouse Transplants Demonstrate Rapid Age Assimilation
To test how systemic environments alter tissue health, Poganik and his collaborators performed heterochronic heart transplants across various age groups of laboratory mice. By attaching the graft to blood vessels in the neck while leaving each animal’s native heart intact, extra hearts from young mice (3 months old), middle-aged mice (1 year old), and old mice (1.5–1.67 years old) were transplanted into recipient mice by connecting the graft to blood vessels in the neck. Mice typically live for 2 to 2.5 years, placing these experimental age brackets roughly in line with human young adulthood, middle age, and old age.
Four to six months after surgery, the animals were euthanized to allow multiomic profiling and DNA methylation testing. As organisms age, chemical methyl groups (CH₃) consisting of one carbon and three hydrogen atoms attach to DNA molecules, serving as primary molecular clocks to estimate biological age.
“The young systemic environment can reverse certain aspects of biological age, but others may be irreversible,”
Jesse Poganik, Harvard Medical School
The analysis showed that younger hearts grafted into older animals developed accelerated aging, whereas older hearts grafted into younger recipients displayed biological rejuvenation. Intriguingly, the effect operated in one direction. The biological ages of the recipient animals’ original hearts, livers, and blood remained unaffected by the age of the transplanted tissue according to the epigenetic measurements.
Human Heart Biopsies Confirm Laboratory Findings
Seeking clinical relevance beyond animal models, the Harvard team turned to archived tissue samples. They analyzed heart biopsies from 11 human transplant recipients chosen because of substantial age gaps between the donor and the recipient, ranging from 8 to 24 years for older hearts placed in younger individuals, and 38 to 50 years for younger hearts placed in older patients as noted in the study cohort.
DNA methylation analysis of these human samples confirmed the laboratory findings.
“The remarkable thing is that we found exactly the same effects that we saw in the mice,”
Jesse Poganik, Harvard Medical School
To understand what these molecular shifts meant for actual physical performance, the researchers examined electronic medical records and follow-up care data for hundreds of human heart recipients one year after their operations. Physical measures tracked closely with the age of the recipient rather than the age of the organ donor according to the clinical database review. Specifically, functional capacity and peak oxygen consumption were lower in older recipients regardless of whether the inserted heart came from a young donor as recorded in hospital follow-ups.
Mechanisms and Limitations Under Scrutiny
While the findings offer an intriguing glimpse into tissue plasticity, researchers emphasize that the work remains preliminary. The study was posted as a preprint on bioRxiv and has not yet undergone independent peer review.
Commenting on the project, Michael Sagner—a clinical adviser in longevity and preventive medicine at King’s College London who did not participate in the research—pointed out certain constraints inherent to the study’s design. The surgical procedure itself introduced pro-aging side effects, including heightened inflammation as researchers tracked graft-recipient crosstalk.
Notable alterations in the behavior of genes linked to mitochondrial and metabolic functions were documented by the team in murine subjects. Poganik suggests that some functional decline tied to aging likely remains irreversible.