Research in mice shows how aging brain blood vessels may affect brain health

• Aging is associated with blood flow changes in the brain.
• These changes may be linked to an increased risk of neurodegenerative conditions .
• A new mouse study maps how these changes vary throughout different brain regions.
• The authors hope that their results will improve our understanding of how and why neurodegenerative conditions begin.

Using a mouse model, a group of scientists recently explored vascular changes in the aging brain. For the first time, they investigated how these changes play out across the entire brain.

The study, which appears in Nature Communications , finds that the deepest sections of the brain are most significantly affected.

They also note that regions of the brain involved in Alzheimer’s are particularly susceptible to age-related changes in vascular function, which may help explain why cell death occurs in these areas.

How do aging blood vessels affect brain health?

Dementia, Parkinson’s, and other neurodegenerative conditions are still very challenging to treat, and they have no cure. Many questions about their origin remain unclear.

One factor that binds them together is that they are all caused by the death of neurons, or brain cells. For this reason, much of the existing research focuses on how and why this cell death plays out.

However, the brain’s vascular system may be a primary reason for this neuronal death.

As the authors of the new study point out, diseases that impact blood vessels, like stroke, atherosclerosis, and type 2 diabetes, all increase the risk of vascular dementia.

Impaired blood transport in the brain can mean that cells do not get the energy they need, and metabolic waste may not be carried away. This, too, can cause brain cell death.

“It is becoming increasingly recognized that disruption to the brain’s vasculature may precede the neuronal damage associated with neurodegenerative disease and other types of dementia,” the authors write.

Because the largest risk factor for neurodegenerative conditions is age, understanding how blood vessels change as we grow old may provide vital clues into how these conditions begin.

What happens as blood vessels in the brain age?

Previous research in this vein mostly focuses on the larger vessels of the brain in specific brain regions. In contrast, the latest study also investigates micro-vessels and examines the whole brain.

Thanks to recent advances in technology, scientists can now view the entire vascular network of a mouse brain in 3D. The scientists found a number of distinct changes in the brain’s vascular system during aging.

For instance, there was a significant reduction in vascular length density. This is a measure of the length of blood vessels compared with the area they are in.

So, a reduction in vascular length density means there are likely to be sections of tissue that are not well served by blood vessels. Similarly, there was less branching of blood vessels, which would have the same effect.

Why do brain blood vessels become more meandering with age?

The scientists also noted changes in arterioles, which are small blood vessels that branch off larger arteries. Some arterioles supply blood to the outer layer of the brain, these are called surface arterioles.

From these surface arterioles, so-called penetrating arterioles branch off to head into the deepest layers of the brain. These, the scientists found, were increasingly tortuous and meandering with age. They explain that this impairs blood flow “by increasing flow resistance.”

Medical News Today spoke with ​​José Morales, MD , a vascular neurologist and neurointerventional surgeon at Pacific Neuroscience Institute in Santa Monica, CA. We asked Morales, who was not involved in the study, why blood vessels may become more torturous over time.

He told us:

“I speculate the decreased branching may contribute to this phenomenon by increasing resistance within the flow circuit, but shear stress on the artery over time would also be a contributing factor.”

We also contacted Mustali Dohadwala, MD , the sole practitioner of Heartsafe LLC in North Andover, MA. He told us that “compromise in the integrity of the endothelial lining” may also be a cause, which could be due to inflammation among other reasons.

It may also be because the blood vessels have a reduced ability to constrict and relax, explained Dohadwala, who was not involved in the study.

Because penetrating arterioles were more affected than surface arterioles, this means that deeper parts of the brain may be more likely to experience reduced oxygen and nutrient supply.

The scientists noted other changes, too: The radius of these blood vessels — how wide they are — grew significantly, particularly in micro-vessels. They also became more “leaky.”

The changes above were most pronounced deeper within the brain, particularly the deepest cortical layer, known as layer 6 . This layer is important for regulating sleep. The authors suggest that this might help explain why sleep often becomes dysregulated with age.

Another factor for cell death in Alzheimer’s?

Because the scientists studied the whole brains of the animals, they could zero in on regions where changes were more pronounced.

One such region is the basal forebrain , which sends neuronal projections widely throughout the brain. In this brain area, vascular density was particularly reduced. There was also a marked reduction in cells called pericytes .

Pericytes are multipurpose support cells present in intervals along the length of blood vessels. Among other roles, they promote the formation of new blood vessels, help maintain the blood-brain barrier, and control blood flow.

Some neurons in this region are particularly sensitive, and in Alzheimer’s disease, their degeneration is responsible for memory loss.

The authors suggest that vascular changes in the basal forebrain may help explain the cell death associated with Alzheimer’s disease.

Another brain area that is significantly impacted by aging is the entorhinal cortex. In this region, they measured significantly reduced vascular length and, again, fewer pericytes.

The entorhinal cortex also plays a part in Alzheimer’s disease.

Changes in oxygen delivery may also play a role in the aging brain

Finally, the researchers investigated oxygen delivery to the brain. They found that red blood cells’ oxygen-carrying capacity reduced with age.

At the same time, because of the reduced length and branching of blood vessels, brain tissue was more likely to receive inadequate levels of oxygen.

To compound the issue further, because aging brain cells are “hyperexcitable,” they are more energy-hungry than brain cells in younger animals.

To summarize, red blood cells carry oxygen less well, there are fewer blood vessels, and older brain cells need more oxygen. These changes all work together to make the brain much more susceptible to hypoxia — a lack of oxygen.

Also, in younger brains, hypoxia normally triggers the formation of new blood vessels. In the aging brain, this response is impaired.

Overall, the authors conclude that the negative vascular effects of aging are most pronounced in the deepest layers of the brain. And that these changes may trigger compensatory responses, such as increasing the number of pericytes in the layers of the brain nearer the surface.

This, in turn, may cause blood flow to be redistributed toward the surface layers. Because oxygen delivery is less efficient in older age, these changes make deep cortical layers particularly vulnerable to cell death.

Do these findings in mice apply to humans?

As this study uses mice, we must be careful about extrapolating to humans. “Aging in mice may not accurately reflect aging in humans, given our different lifespans and divergent physiology,” Morales told MNT .

However, he also explained that “While there will certainly be divergence between species, many of our cells share very similar genetic programming and physiological functioning.”

“We have evidence to support this,” he continued, “and can infer that many of the same molecular mechanisms that signal age-related changes are conserved evolutionarily.”

This research brings us one small step closer to understanding how neurodegenerative conditions may begin. Because treatments are currently far from perfect, understanding the changes that drive these diseases may be the key to reversing them before symptoms arrive.

In the future, Morales hopes they will conduct similar studies in humans: “There are a number of novel, very high-resolution imaging modalities, such as hierarchal phase-contrast tomography and novel cell labeling 7T MRI techniques that could be potentially used in human longitudinal studies to corroborate key elements of these animal model findings.”