Scientists map how human blood vessels age cell by cell across the body

With every heartbeat, blood surges through a vast network of vessels that delivers oxygen, nutrients and other essential substances to even the most remote corners of the human body. These vessels are far more than passive tubes. Their inner walls are lined with a thin layer of specialized cells called endothelial cells, which regulate blood flow, control what passes into surrounding tissues and help coordinate responses to injury. They even contribute to the specific functions of the organs they serve, forming a protective barrier in the brain or supporting filtration in the kidneys. Yet as people grow older, this finely tuned system can become dysfunctional, increasing susceptibility to cardiovascular disease and its associated mortality.

Although endothelial cells are essential for vascular and organ function, they are often overlooked in studies of aging. What happens inside endothelial cells as people age, and why their function may deteriorate over time, has remained poorly understood. That question is what motivated an international research team led by Laura de Rooij, a principal investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Rather than studying blood vessels as whole structures, the team examined the activity of genes in individual endothelial cells. This approach, known as single-cell analysis, makes it possible to see which genes are active in each cell and how that activity changes with age. By bringing together data from previously published single-cell studies, the researchers saw an opportunity to uncover patterns of vascular aging that might otherwise have remained hidden.

The resulting study, published in Nature Aging and led by first author Sarah Dobner, a PhD student in de Rooij's group, produced the Human Aging Endothelial Cell Atlas, a resource for examining how vascular cells change with age. The researchers aggregated data from 34 existing studies, covering more than 375,000 cells from 290 samples across 12 human tissues. By focusing on tissues classified as healthy or non-diseased, they aimed to identify molecular changes associated with aging itself rather than changes primarily linked to diagnosed disease. The atlas is a resource that allows scientists to examine how different populations of vascular cells change across the human body, and an accompanying interactive portal described in the study is intended to help researchers investigate these molecular changes and identify promising directions for future experiments.

One of the most striking observations concerned the cells lining veins. These cells can give rise to sprouts that develop into new blood vessels, an important part of vascular renewal. In older individuals, the atlas showed reduced activity of several genes involved in vessel formation. The researchers suggest this could help explain why blood vessels may become less capable of renewing themselves with age, although the study did not directly measure repair capacity. Across multiple tissues, the team also observed increased activity of genes associated with inflammation and with cellular senescence, a state in which cells stop dividing and can influence their surroundings. As Dobner explained, endothelial aging does not look the same across the vascular system, and only by bringing together data from different tissues could the team identify patterns that might have been missed by studying individual organs or endothelial cell types in isolation.

A second discovery concerned how endothelial cells respond to their physical environment. These cells constantly sense the forces of flowing blood and the material surrounding them, translating mechanical signals into biological responses. The atlas revealed age-related changes in genes involved in this mechanosensing process. Experiments in human skin tissue provided further supporting evidence: a protein called YAP, which helps cells respond to mechanical forces, was found more frequently inside the nuclei of endothelial cells from older donors. The researchers themselves frame this as an open question: does increased YAP activity help endothelial cells cope with age-related changes, or does it contribute to the deterioration of blood vessel function?

The team also identified a group of genes associated with p21, a protein that can slow or stop cell division. Comparisons with laboratory-grown endothelial cells and with mouse models of accelerated aging supported a connection between this gene signature and cellular senescence. However, the researchers caution that these genes also participate in stress responses and vessel growth, so they cannot reliably distinguish permanently senescent cells from cells that are simply responding to other age-associated challenges. Understanding these differences, the authors argue, will be essential before scientists can determine which cellular processes should be targeted in future efforts to maintain vascular health.

The findings come with important limitations that the researchers state openly. The study compared people of different ages rather than following the same individuals over time, which means it captures associations between age and gene activity rather than tracking changes within a single person’s vessels. In addition, incomplete information about donors’ lifestyles and medical histories limits the conclusions that can be drawn. These constraints do not undermine the atlas’s value as a hypothesis-generating resource, but they do mean that its signatures of aging will need to be tested through further experimental work.

Despite these limitations, the atlas makes clear that vascular aging is neither uniform nor simple. Some of the observed changes may contribute to declining function, while others could represent the body’s attempts to protect itself. Distinguishing between the two, the researchers argue, will be essential for discovering how blood vessels might one day be kept healthy for longer. De Rooij emphasized that the atlas gives researchers a way to explore vascular aging across the human body rather than treating all blood vessels as if they age in the same way, providing a resource to investigate which changes accompany endothelial aging, which may contribute to declining vascular function, and which could reflect how endothelial cells adapt to their changing environment.

By cataloguing how gene activity in endothelial cells shifts across 12 tissues and across the human lifespan, the atlas offers a systematic starting point for asking which of those shifts are drivers of disease and which are consequences or compensatory responses. The interactive portal accompanying the study is designed to make that exploration accessible, allowing scientists to query the data and identify promising directions for future experiments before committing to new laboratory work.

The study, titled “Uncovering the transcriptional hallmarks of endothelial cell aging via integrated single-cell analysis,” was published in Nature Aging on 23 October. It was supported by a range of funders including the Austrian Science Fund, the Austrian Academy of Sciences, the Research Council of Norway, the Lundbeck Foundation, the Novo Nordisk Foundation and the Carlsberg Foundation, among others. For now, the atlas stands as a map rather than a set of answers: a detailed record of how the inner lining of the human vascular system changes with age, and a tool for the experiments that will determine what those changes mean for health in later life.

Subject of Research: Single-cell analysis of endothelial cell aging across human tissues

Article Title: How our blood vessels age from within

Article References: How our blood vessels age from within. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: endothelial cells, vascular aging, single-cell analysis, gene expression, cellular senescence, inflammation, YAP protein, blood vessels, Nature Aging, Human Aging Endothelial Cell Atlas, mechanosensing, cardiovascular disease