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Transplanted hearts assimilate the recipient's biological age

Jesse R. PoganikiD, Tomohisa MatsunagaiD, Alexander TyshkovskiyiD, Ake Tzu-Hui LuiD, Amin HaghaniiD, Hao Zhou, Friederike MartiniD, Steve HorvathiD, Michael M. GivertziD, Stefan G. TulliusiD, Vadim N. GladysheviD

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Abstract

Background. Despite the growing demand for transplantation, a shortage of donor organs persists, limiting access to this lifesaving procedure. To meet the increasing demand, organs are frequently transplanted across an age discrepancy between donor and recipients. Methods. We delineated biological age dynamics in heterochronic heart transplants performed in both mice and patients. We carried out multiomic profiling and applied advanced biomarkers of aging to understand the interactions between the transplanted organ and the host. Results. We show that the biological age of experimental heart transplants rapidly assimilates the age of recipients. Interestingly, this effect was limited to the grafted tissue without reciprocal effects on systemic biological age of the recipient. These effects were confirmed at the level of DNA methylation and gene expression. Extending our findings clinically using both omics and functional analyses, we show that the biological age of heterochronically transplanted hearts is strongly associated with the age of the recipient, rather than the donor, confirming the clinical relevance of our experimental findings. Conclusions. These data identify the systemic environment as a driving force on tissue biological age. The rejuvenation of older organs in young recipients suggests novel approaches to organ allocation that may expand the pool of transplantable organs.

In-depth summary

Claude Opus 5.5 · xhigh effort · 7 Nov 2026 · from the full text of version 1 (17 Sept 2026) · CC BY 4.0

DNA methylation clocks show heterochronic heart grafts shifting toward recipient age in syngeneic mice and 11 human recipients, while recipient mouse native heart, liver and blood show no consistent change.

Donor hearts are scarce and few programs accept donors older than 50, so hearts are increasingly transplanted across donor-recipient age gaps. Unlike heterochronic parabiosis, where the authors earlier saw biological age pass both ways between joined animals, transplantation puts one organ into a host of a different age, testing whether the systemic environment alone resets that organ's biological age.

Key results

  1. ShownIn mice, the DNA methylation (DNAm) age of heterochronic heart grafts shifts toward recipient age: young grafts in old hosts read older, and old grafts in young hosts read younger. The recipients' native hearts, livers and blood show no consistent change.

    Universal Clocks 2 and 3 and a mouse pan-tissue clock were applied to HorvathMammalMethylChip320 data 4 to 6 months after transplant. Graft age deviation (AgeDev) differed significantly by recipient age (ANOVA, unpaired t-tests; n = 4 or 5 per group). Isochronic grafts had generally higher AgeDev than native hearts. Native hearts showed only a slight AgeDev drop with young grafts in old hosts. · Heterochronic heart transplantation in mice…; Figure legends

  2. SuggestedIn 11 human heart recipients, biopsy DNAm age deviation (relative to donor age) tracks recipient age. It separates hearts moved from old donors into young recipients from hearts moved the other way.

    Archival endomyocardial biopsies on the HorvathMammalMethyl40 array (age disparity −24 to +50 years; old-to-young n = 5, young-to-old n = 6). AgeDev differed significantly between groups with the Horvath multi-tissue clock and Universal Clock 3 (unpaired t test); Universal Clock 2 agreed but was not significant. AgeDev correlated positively with recipient age (Pearson) for those two clocks. · Human Cardiac Transplants assimilate recipient…; Figure legends; Introduction

  3. ShownChanges at single CpG sites agree. In young grafts placed in old hosts, methylation changes correlate positively with normal aging changes; in old grafts placed in young hosts, the correlation is reversed.

    Against isochronic controls, young heterochronic grafts had 475 differentially methylated CpGs (324 up, 151 down; adjusted p < 0.05, Δβ > 5%) and old heterochronic grafts had 51 up and 62 down. The aging reference was old vs young sham native hearts (909 up, 1,641 down). Genome-wide Pearson correlations with this reference were positive for young and negative for old heterochronic grafts. · DNAm patterns at the CpG and gene levels…; Figure legends

  4. ShownHeart transcriptomes agree with the methylation results. On aging and longevity signatures, young heterochronic grafts score pro-aging, old heterochronic grafts score anti-aging, and all grafts score somewhat pro-aging against native hearts. Mitochondrial pathways move in opposite directions in young and old grafts.

    Old vs young sham hearts: >100 differentially expressed genes. Native hearts of heterochronic recipients: few to none. Heterochronic vs isochronic grafts: many. Mitochondrial translation, oxidative phosphorylation and respiratory electron transport fell in young and rose in old heterochronic grafts. Inflammatory pathways rose in all grafts. · Transcriptomic analysis shows a composite of…; Functional enrichment analysis reveals factors…; Figure legends

  5. SuggestedOne year after transplant, older recipient age (adjusted for donor age and sex) is associated with lower exercise capacity and with some electrocardiographic and echocardiographic measures. The authors read this as functional support for age assimilation.

    Standardized coefficients per standard deviation of recipient age: functional capacity (p = 9.3×10-4, n = 162) and VO2 max (p = 4.8×10-4, n = 151) were lower and stayed significant after BMI adjustment. Ventricular rate (n = 317) and posterior wall thickness (n = 275) were significant. Corrected QT, septal thickness and VE/VCO2 slope were not, and ejection fraction only trended. · Functional cardiac outcomes in human recipients…; Figure legends

Methods, data and reproducibility

Syngeneic heterotopic heart transplants among young (3 months), middle-aged (1 year) and old (1.5 to 1.67 years) C57Bl/6 mice were profiled 4 to 6 months later by DNA methylation (DNAm) array, DNAm clocks and heart transcriptomes. Archival human endomyocardial biopsies were scored with DNAm clocks, and one-year cardiac function was modelled on recipient age, adjusted for donor age and sex.

  • Syngeneic heterotopic heart transplants (heterochronic, isochronic) and shams in young, middle-aged and old mice; graft and native hearts, liver and blood on HorvathMammalMethylChip320 · mouse (C57Bl/6) · n = n = 4 or 5 per group
  • Transcriptome sequencing of graft and native mouse hearts · mouse · n = n = 4 to 6 per group
  • Heart transplants at Brigham and Women's Hospital, 2002 to 2022 (donor and recipient ages) · human
  • Archival endomyocardial biopsies from heterochronic heart transplant recipients, HorvathMammalMethyl40 array · human · n = 11 patients (O to Y n = 5; Y to O n = 6)
  • One-year post-transplant electrocardiographic, echocardiographic and cardiopulmonary stress test parameters from recipients at the authors' center · human · n = n = 151 to 317 per parameter
Methods & tools
HorvathMammalMethylChip320 array, HorvathMammalMethyl40 array, Universal Clock 2 (pan-mammalian DNAm clock), Universal Clock 3 (pan-mammalian DNAm clock), Mouse pan-tissue DNAm clock, Horvath multi-tissue DNAm clock, Transcriptomic signatures of aging and longevity, Hallmark gene sets, Principal component analysis
Reproducibility gaps
The text has no code repository, data accession or data availability statement. Group-level results are in supplementary Tables S1 to S5, which are not part of the provided text.
Limitations (6)
  • The mouse model is heterotopic (the native heart stays in place) and syngeneic. It therefore differs from orthotopic clinical transplantation and has no alloimmune response. · stated by the authors
  • Human DNAm data came from historical fixed, paraffin-embedded biopsies, which the authors note are not ideal for methylation profiling. · stated by the authors
  • Functional outcomes cover only one year after transplant, so long-term effects such as chronic allograft vasculopathy or mortality are not addressed. · stated by the authors
  • It remains untested how long the rejuvenation lasts, whether it improves hard clinical outcomes, and whether it applies to other organs. · stated by the authors
  • Samples are small: n = 4 to 6 mice per group and 11 human biopsies split 5 vs 6. There is no independent human replication cohort. · noted in this summary
  • The text reports coefficients for recipient age only. Exercise measures such as VO2 max also depend on non-cardiac factors in the recipient, so they are only indirect evidence that the graft itself changed biological age. · noted in this summary

Read this if you study how the systemic environment drives tissue aging, apply DNA methylation clocks to grafted tissue, or weigh donor age criteria in heart allocation.

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