Gene variant associated with better aging, cognitive function, study finds

People who carry a gene variation associated with longevity have better brain cognition and are more resilient to aging, new research has found, paving the way for future treatments for brain aging and disease.

Using whole-brain analysis of healthy older adults, researchers  at the University of California, San Francisco (UCSF) found that those who had the gene variation, a single copy of the KLOTHO allele, called KL-VS, had larger volumes in the right dorsolateral prefrontal cortex (rDLPFC) of their brains— and therefore slightly better cognitive function.

KL-VS codes for a protein, called klotho, that circulates in the body and is present throughout the animal kingdom. It’s long been known that klotho, which is produced in the kidneys and brain, regulates aging.

The rDLPFC  region, which interacts with many other brain regions, is most known for its role in executive function, higher-level cognitive skills used to control and coordinate cognitive abilities and behaviors, such as attention, working memory, and decision-making.

“This type of cognition is really important in sophisticated and very simple types of thinking,” first author Jennifer Yokoyama, an assistant professor of neurology at UCSF told

The rDLPFC is very vulnerable to aging and tends to get smaller, leading to lower cognition, Yokoyama added.

“What our data means in the bigger picture is that people who carry the genetic code, one in five people, that confers a decade of resilience against expected decline in executive function and size of that region,” senior author Dr. Dena Dubal, an assistant professor of neurology at UCSF, told

The team also found that two copies of KL-VS, about three percent of people, was associated with a shorter lifespan, increased cardiovascular risk, worsened cognitive function, and a smaller rDLPFC.

The findings are one of the first showing the positive effect of a genetic variant on brain aging, researchers said, adding to their previously published research that found that boosting the level of KL-VS in mice lead to longer lifespan and increased brain function. With this understanding, scientists are one step closer to predicting healthy brain aging and treatment for diseases affecting rDLPFC, such as Alzheimer’s and Parkinson’s.

“The question we are answering next is what does this mean for [brain] disease and how can this be translated into some kind of therapeutic to help people suffering?” Dubal said.

“As we move into the world of personalized medicine, it will be really important and useful to know how one’s genetics, lifestyle and environment affect their trajectory for healthy or unhealthy brain aging,” she added.

The UCSF team performed whole-brain analysis on 222 cognitively normal adults aged 53 to 85. Participants underwent neurological tests including games and puzzles that probed different aspects of executive function, such as processing speed, strategizing, and shifting attention.

To further verify their findings, researchers looked at data from an additional 200 healthy adults aged 52 to 94 from the Memory and Aging Project at Rush University Medical Center and found the same link between presence of KL-VS and a larger brain region and better cognitive function.

Dubal and Yokoyama noted that their findings add to the rapidly growing evidence of the importance of KL-VS in brain function and cognition—  and the possibility of treatments using KL-VS to improve brain structure and function. The researchers are working on an ongoing study to see if KL-VS may protect patients with Alzheimer’s, both in terms of disease onset and trajectory— and whether or not having a higher level of the klotho hormone may preserve or boost cognitive functions in the midst of disease.

“Understanding our genome will be very powerful in moving us to better health through personalized medicine,” Dubal said. “And this may be an important part of the picture for understanding brain health.”