Human Aging Endothelial Cell Atlas Reveals Tissue-Specific Transcriptional Shifts in Vascular Aging

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Summary of  Nature Aging https://doi.org/10.1038/s43587-026-01247-3
Dr. Sarah Dobner et al.

Points

Researchers at CeMM harmonized single cell transcriptomic data from thirty four studies comprising over three hundred seventy five thousand endothelial cells across twelve human tissues throughout adulthood.
The resulting Human Aging Endothelial Cell Atlas revealed significant age associated transcriptional shifts including reduced angiogenic gene expression specifically localized within venous endothelial cell populations.
Comprehensive analysis demonstrated widespread alterations in extracellular matrix signatures and mechanotransduction pathways highlighted by increased nuclear accumulation of the YAP protein in older donors.
Investigators uncovered a prominent p21 linked transcriptional program across multiple tissue beds which correlated with cellular senescence observed in both laboratory and accelerated aging animal models.
Authors concluded that vascular aging exhibits high tissue specific heterogeneity providing a foundational high resolution reference to guide future therapeutic strategies for maintaining cardiovascular health.

Summary

This study evaluated age-associated transcriptomic shifts and cellular heterogeneity across the human vascular system using single-cell transcriptomics. Published in Nature Aging by researchers at CeMM Research Center for Molecular Medicine, led by principal investigator Laura de Rooij and first author Sarah Dobner, the investigation addressed the traditional oversight of endothelial cells (ECs) in aging research. Given that endothelial dysfunction increases susceptibility to cardiovascular disease and mortality, the research sought to construct a comprehensive atlas mapping molecular changes across adult human lifespan without confounding disease pathology.

The study harmonized data from 34 existing single-cell investigations, comprising over 375,000 endothelial cells derived from 290 samples across 12 healthy human tissues. Transcriptomic profiling revealed marked tissue-specific heterogeneity, including a pronounced downregulation of angiogenic gene expression in venous endothelial cells from older individuals. Furthermore, investigators observed widespread age-related alterations in extracellular matrix and mechanotransduction signatures, characterized by increased nuclear accumulation of the mechanosensitive protein YAP in older donor skin samples. The analysis also identified a robust p21-linked transcriptional program across multiple tissue beds, which correlated with cellular senescence when cross-referenced against in vitro cultures and murine accelerated aging models.

The authors conclude that the newly established Human Aging Endothelial Cell Atlas (HAECA) provides a high-resolution compendium of vascular aging across diverse human tissues. While some transcriptomic alterations reflect declining repair and regenerative capacity, others likely represent adaptive cellular stress responses. This open-access resource and interactive portal establish a vital framework for identifying therapeutic targets to preserve vascular health and mitigate age-related cardiovascular decline.

Link to the article: https://www.nature.com/articles/s43587-026-01247-3

References

Dobner, S., Kleissl, L., Tóth, F., Paxton, R. L., Yordanova, I., Brazdilova, K., Vanluyten, C., Aizenshtadt, A., Tóth, H., Burton, J., Kopf, A., Belyaeva, V., Ferencevic, K., Al-Nuaimi, D. A., Lichtenstein, M. A., Winter, G. E., Rendeiro, A. F., Bock, C., Kalucka, J., … de Rooij, L. P. M. H. (2026). Uncovering the transcriptional hallmarks of endothelial cell aging via integrated single-cell analysis. Nature Aging, 1–18. https://doi.org/10.1038/s43587-026-01247-3