As the world's population ages rapidly, cognitive deficits have become a major challenge requiring pharmacological intervention. In a paper published July 3 in Nature Aging, Stacy Castner and colleagues have now shown that administration of an endogenously produced peptide hormone that is significantly reduced with age can improve spatial memory in monkeys. In doing so, they demonstrated for the first time that normalizing a naturally occurring longevity factor promotes cognitive function and possibly compensates for neurodegenerative changes.
Klotho is named after the Greek goddess Clotho, the goddess of fate who spins the thread of life. The Klotho gene encodes a transmembrane protein that binds to receptors for fibroblast growth factors (FGFs), but is also found in secreted (hormonal) form. Previous work in mice had shown that Klotho injection can extend lifespan and increase synaptic plasticity. Interestingly, individuals with elevated levels of Klotho or genetic Klotho variations have been shown to have a lower risk of dementia in old age.
The current study tested the effects of Klotho on the cognitive abilities of non-human primates (rhesus monkeys with an average age of 22 years) before and after a single injection of Klotho. In a behavioral experiment, the monkeys had to remember the location of a treat hidden in one of several jars by the experimenter. Dena Dubal, co-author of the study and a physician at the University of California at San Francisco, compares this test to the ability to remember where you parked your car in a parking garage - a task that becomes increasingly difficult as you get older.
The monkeys performed significantly better on these tests after receiving Klotho. Before the injection, they identified the correct locations about 45% of the time; after the single injection, they did so 60% of the time. This improvement persisted for at least two weeks and was seen at relatively low doses of Klotho (10 μg/kg). It is still unclear exactly how Klotho exerts its effect on cognition and why it lasts longer. Indeed, Klotho itself cannot cross the barrier from the blood to the brain. Therefore, there must be intermediates involved that remain to be discovered.
Reference:
Castner SA, Gupta S, Wang D, ..., Williams GV, Dubal DB (2023) Longevity factor klotho enhances cognition in aged nonhuman primates. Nature Aging 3:931
Image credit: Cemile Bingol