This study performed heterochronic heart transplants in mice and found that the graft’s epigenetic age shifts toward that of the recipient rather than remaining at the donor’s. The same direction was observed in biopsies from 11 human heart transplant recipients.
Alternative hypothesis: The epigenetic age of the graft is influenced by cell composition. Methylation clocks applied to bulk tissue are highly sensitive to the cellular makeup of the sample, and a transplanted heart is infiltrated by recipient-derived immune cells, which carry the recipient’s epigenetic age. The clinical measures may also reflect the recipient’s overall age rather than the graft. VO₂max, for example, depends on skeletal muscle and pulmonary function as well as cardiac output, so older recipients would be expected to perform worse regardless of the donor heart they received.
Ideally, the molecular work would be repeated using a sex-mismatched or CD45.1/CD45.2 transplant to quantify what proportion of the graft is recipient-derived — or, at minimum, cell-type deconvolution of the existing transcriptomic data. Clinically, serial echocardiography over several years would distinguish an effect that increases with time, as rejuvenation predicts, from one that remains constant, as a fixed recipient-side effect would.
In figure 3, it looks like the transcriptomics signature showed an "aging-like" signature in the homochronic transplanted hearts as well as the heterochronic transplanted hearts indicating surgery specific effects, is that your read of it?
Yes, Figure 3 does show an aging-like gene expression pattern in age-matched transplants, not just age-mismatched ones. Compared with native hearts, transplanted hearts show increased inflammatory signaling and reduced expression of mitochondrial pathways (Figure 3B–D).
This suggests that transplantation itself has an effect, although we can't tell whether it's due to surgical stress, altered graft physiology, or changes in cell composition.
However, there does appear to be an additional effect of recipient age. When compared with age-matched transplants, young hearts placed in old recipients show more aging-like changes, while old hearts placed in young recipients show changes in the opposite direction.
So I think both effects may be present. The remaining question is how much of the apparent aging or rejuvenation reflects changes within the heart cells themselves versus changes in the types of cells present in the graft.
Very interesting study addressing whether host environment modulates graft biological age. However, the central conclusion that transplanted hearts assimilate recipient biological age appears vulnerable to a major confounding factor: recipient immune infiltration and cellular composition. Prior single-cell/single-nucleus profiling in human cardiac allografts (e.g., Li et al., Circulation 2024; PMC11105989) demonstrates that donor tissue-resident macrophages are rapidly replaced by recipient-derived monocyte/macrophage populations post-transplant. Because bulk DNAm and transcriptomic clocks are sensitive to cell-type proportions, an influx of recipient leukocytes could artificially drive graft clock readouts toward recipient age without true intrinsic parenchymal remodeling. Has the team run reference-based deconvolution to test whether this assimilation persists within pure parenchymal compartments (e.g., cardiomyocytes or cardiac fibroblasts)? Additionally, providing per-sample DNAm matrices and gene-level RNA counts would allow the community to benchmark these compositional effects directly.