Researchers have explained in Nature Aging how klotho, a factor associated with longevity, improves the cognitive abilities of rhesus macaques.
Moving on from mice
This paper begins with a discussion of klotho and how it relates to aging. In mice, klotho has been found to improve cognitive function [1], even though systemic administration does not cross the blood-brain barrier [2]. Additionally, humans with genetically high levels of klotho have less risk of dementia with age [1].
However, administering klotho as a treatment in humans has never been tested. This research takes a step closer towards that goal, moving on from mice to rhesus macaques, whose cognitive functions and genetics are considerably closer to those of people.
Rhesus and human klotho are very similar
The klotho protein that exists in these animals has a 4% difference from the human version. The researchers began their experiments by first confirming that rhesus klotho works in mice. As expected, administering the protein increased its levels in serum and improved mouse cognition at an appropriate dose, increasing both synaptic plasticity, which reflects learning ability, and the ability to navigate a maze.
With those results in hand, the researchers turned to the animals it was derived from. The macaques in this experiment were, on average, nearly 22 years old, which is roughly equivalent to 65-year-old people. The researchers used a spatial delayed response test, which is meant to assess memory and involves the hippocampus and the prefrontal cortex, two regions that are strongly affected by aging [3].
Administering rhesus klotho to these monkeys improved their performance in both normal difficult memory tasks. Normally, rhesus monkeys get about half of the difficult answers correct and 70% of the normal answers correct. The treated monkeys scored approximately 10% higher than the control group on the hard tasks and 5% better on the normal tasks; both of these results were well over statistical significance. These benefits were first tested four hours after administration, and they continued at the same intensity for at least two weeks afterwards.
The positive effects of klotho in rhesus macaques were found only at 10 micrograms per kilogram. A double dose had far less of an effect, which did not reach statistical significance above the control group, and a triple dose might have worsened performance.
It seems to be time for human trials
The researchers conclude their discussion by suggesting that klotho administration may improve cognition in older human beings. Human clinical trials are required to first find an appropriate dosing regimen and determine side effects. If it is found to be safe and works in people at the same speed that it works in animal models, klotho may quickly become a go-to standard for people suffering from cognitive decline.
Literature
[1] Dubal, D. B., Yokoyama, J. S., Zhu, L., Broestl, L., Worden, K., Wang, D., … & Mucke, L. (2014). Life extension factor klotho enhances cognition. Cell reports, 7(4), 1065-1076.
[2] Leon, J., Moreno, A. J., Garay, B. I., Chalkley, R. J., Burlingame, A. L., Wang, D., & Dubal, D. B. (2017). Peripheral elevation of a klotho fragment enhances brain function and resilience in young, aging, and a-synuclein transgenic mice. Cell reports, 20(6), 1360-1371.
[3] Herndon, J. G., Moss, M. B., Rosene, D. L., & Killiany, R. J. (1997). Patterns of cognitive decline in aged rhesus monkeys. Behavioural brain research, 87(1), 25-34.
