Improving Health Span by Slowing Age-Related Cognitive Decline

Two University of Oklahoma (OU) scientists have been awarded more than $2 million in grants from the Hevolution Foundation to further their studies on age-related cognitive impairment, with an emphasis on improving “health span” (the number of years a person remains healthy).

Because the process of aging increases the risk for memory problems and dementia, researchers must understand why as a first step toward delaying cognitive issues until later in life. The Hevolution Foundation invests in science that aims to uncover the root causes of aging.

“As we have longer life spans, it’s really important to identify ways to simultaneously promote increased health spans. It’s challenging when you have loved ones who have severe illness or cognitive impairment, yet they are not dying; they are physically able to keep living. We want to help people stay healthier longer,” said Hevolution grant recipient Shannon Conley, PhD, an assistant professor of cell biology in the OU College of Medicine, who is leading the work with Anna Csiszar, PhD, a professor of neurosurgery in the OU College of Medicine.

Blood vessel function

In their project, they are trying to better understand how two types of cells in blood vessels work together for brain health but become dysfunctional as a person ages. Endothelial cells, which line the blood vessels, and smooth muscle cells, which are on the outside of the vessels, collaborate to help the brain respond to everyday stimuli, like sound or taste.

During aging, they can undergo cellular senescence, a kind of limbo when the cells aren’t dead, but neither are they functioning normally and proliferating. As a result, the cells can no longer perform their usual tasks, which then causes the blood vessels to have trouble contracting and relaxing normally. That vascular dysfunction sets the stage for cognitive impairment and eventually dementia. The researchers want to understand how cellular senescence leads to blood vessel dysfunction.

“We believe the link is something called de-differentiation: The endothelial cells and smooth muscle cells essentially lose their identity during senescence and become generic cells that don’t function well,” Conley said. “Understanding these mechanisms that lead to age-related defects in blood vessel function is really important for making progress toward a treatment or cure for dementia. You wouldn’t necessarily think that the blood vessels are the place to look, but there is so much evidence that blood vessel dysfunction is one of the earliest changes in the brains of people who develop dementia.

“When we think about dementia, we think about damage to the neurons in your brain. But if the blood vessels in the brain are not functioning well, then the neurons don’t have enough energy or oxygen and eventually will degenerate. In addition, the blood vessels are important for clearing waste materials, so if the blood vessels aren’t working properly, then you have an accumulation of abnormal material that will contribute to neuronal dysfunction.”

Metabolic factors and aging

The second grant recipient, Sreemathi Logan, PhD, an assistant professor of biochemistry and physiology at the OU College of Medicine, wants to understand the metabolic factors, including obesity, that influence cognition during aging. A central question of her research is why some people’s brains seem to be resilient, while others are susceptible to cognitive problems and diseases like Alzheimer’s.

For her studies, she separates aging mice into two groups: those with “intact” cognition and those with impaired cognition.

“Because we separate mice into different subgroups of varying cognitive function, we can better try to understand what specific cells are doing in the brain that contribute to healthy brain aging vs. impaired cognition,” she said. “My previous research has shown that mice mirror the differential cognitive abilities that humans exhibit and thus are a good model to investigate the incidence and progression of dementia with age.”

The group of cognitively impaired, older mice experience dysfunction of their mitochondria, which are responsible for providing energy to the brain. Loss of mitochondrial function can lead to persistent inflammation that is driven by cellular senescence, a hallmark of aging. Even though senescent cells have stopped dividing, they remain active, spewing out harmful substances that cause inflammation, further impairing cognition.

With this grant, Logan is studying the brain-adipose axis: how excess fat in the body, especially around the belly, affects cognition during aging. In particular, she is testing whether a ketogenic diet (high fat and reduced carbohydrates) can target cellular senescence. Existing research suggests that reducing carbohydrates, even in a high-fat diet, helps the body use fat more efficiently. Theoretically, that would lower the inflammatory factors of senescence and reduce the negative effects of fat on the brain.

Logan’s grant also allows her to investigate whether senolytics (drugs that target senescent cells) can positively affect cognition by regulating fat metabolism, the process of breaking down fat in the diet so it can be used for energy.

“Cognitive health is an important part of health span,” Logan said. “By understanding the biological underpinnings of why some mice perform better than others, we hope to eventually translate our findings to humans with varying cognitive abilities and design individualized treatments to improve cognitive function in older adults.”