With just one administration of a specific protein called klotho, researchers from the Yale School of Medicine and the University of California, San Francisco (UCSF) observed improvements in the cognitive function of old monkeys. The authors speculate that these results mark a potential first step toward using klotho in clinical settings to improve cognitive performance.

The article, “Longevity factor klotho enhances cognition in aged nonhuman primates,” was published in Nature Aging.

The longevity factor klotho naturally decreases with age. Klotho improves cognitive performance in mice through transgenic overexpression and acute peripheral administration, and systemic elevation of Klotho in mice improves synaptic plasticity, cognition, and neural resilience to aging and neurodegenerative diseases like Alzheimer’s and Parkinson’s.

Studies show that people with higher levels of klotho, whether from a genetic KLOTHO variation or other causes, have improved cognitive abilities, reduced neuropathological measures, and a lower risk of developing dementia associated with aging and Alzheimer’s disease. However, it is unclear whether treatment with Klotho could improve cognition in elderly non-human primates (NHPs).

Researchers led by Stacy A. Castner wanted to see if aging rhesus macaques would benefit from klotho’s cognitive enhancement effects like mice do. Rhesus macaques, like humans, experience cognitive decline as they age, but unlike humans, this decline is caused by synaptic changes rather than significant neuronal loss.

Their primary objective was to see if they could improve cognitive performance in rhesus macaques by administering a dose of klotho that would raise serum levels to a level seen in humans throughout their lifespan and be comparable to therapeutically effective increases in mice.

To do this, they administered a single subcutaneous dose of vehicle or rhesus klotho to aged rhesus macaques (mean age = 21.78 years; putative human age = 65 years) and then tested the animals’ cognitive abilities. Primary analysis focused on a dose of 10 g/kg klotho because it yielded increases in klotho comparable to those found naturally in humans and mice.

The Yale and UCSF team used the spatial delayed response (SDR) task to evaluate the cognitive abilities of senior rhesus macaques, specifically the performance of fronto-temporal circuits and regions of the brain like the hippocampus and prefrontal cortex. The SDR test evaluates working and spatial memory under both low (NML) and high (HML) memory loads.

Rhesus macaques treated with a single injection of 10 g/kg klotho showed improved HML performance just four hours later, mirroring the rapid improvement in mouse cognition. At two weeks, the benefits of klotho-mediated cognition enhancement in HML were still noticeable. The average NML performance was also improved by this dose of klotho, and the improvement was maintained across multiple tests in the first two weeks after treatment ended. There was no sex difference in the klotho-mediated improvement.

Their secondary objective was to investigate whether or not the beneficial effects of klotho on cognition are dose-dependent by administering it to rhesus macaques at higher doses. A higher dose of klotho did not improve monkey brain function, even at 30 micrograms per kilogram. It is important to note that the higher doses tested did not impair cognition, as the 2–5% changes were not statistically increased or decreased. Nonetheless, it is still unknown whether doses even higher than those tested could impair cognition.

Collectively, these findings suggest that NHPs, which share a complex genetic, anatomical, and functional brain with humans, also benefit from klotho-mediated cognitive enhancement. These findings also imply that a therapeutic window of cognitive enhancement in humans may require lower, more ‘physiological’ levels of the hormone in the body.

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