Bolstering the Brain to Improve Cognition

Understanding how klotho enhances mental processes will teach us how the body transmits resilience to the brain.

What if you could take a hormone to refine your memory and spatial skills? Better yet, what if that hormone also could improve your motor function if you have Parkinson’s disease? 

Klotho, a hormone produced naturally in the kidneys and brain, has that potential, according to neurologist Dena Dubal, MD, PhD. She’s been studying the hormone for years because of its known life-extending and life-enhancing effects. Early on, she uncovered the link between klotho levels and better cognition. However, that was in people who carried a genetic variant that caused them to have continually high klotho levels throughout life. The burning question remained: Could klotho work as a drug to rapidly enhance cognitive function? 

The answer is yes, Dubal says. In a 2017 study, she gave a fragment of klotho protein to young, aging, and impaired mice. She saw improvements in the mice across a range of domains, including spatial learning and memory and working memory. The beneficial effects occurred within hours in young mice and far outlasted the time that klotho remained active in the body. In the older mice – equivalent to age 65 in humans – a single injection of klotho was enough to significantly improve their ability to navigate and learn new tasks. 

Dubal also gave klotho to mice engineered to produce a protein called alpha-synuclein, which is a hallmark of Parkinson’s disease and also contributes to Alzheimer’s. The klotho-treated mice showed improved motor function and learned better and more willingly than other impaired mice. 

The findings could not be more positive for patients – and for a researcher with such a passionate focus. But Dubal’s work is not done. Her next steps are to determine how and why klotho confers the benefits it does, given that it shows no evidence of crossing the blood-brain barrier, a layer of endothelial cells that protects the brain against infection. 

More recently, Dubal’s work has shown that women with Alzheimer’s live longer than men with the disease do because their second X chromosome provides an extra “dose” of a protective protein from a gene called KDM6A that only exists on that chromosome.  

“This protective mechanism on the X chromosome opens the possibility that we could increase resilience to Alzheimer’s and other neurodegenerative disorders by boosting KDM6A or other X factors in both men and women,” Dubal says.   

Dena Dubal is the David A. Coulter Professor of Aging and Neurodegenerative Disease.