Brain function in aged monkeys improves with Klotho injection

With a single 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 cognitive function in old monkeys. The authors believe that these results mark a potential first step towards using klotho in a clinical setting to improve cognitive performance.

The article, “Longevity factor klotho improves cognition in aged nonhuman primateswas published in natural aging.

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

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

Researchers led by Stacy A. Castner wanted to see if aging rhesus macaques would benefit from the cognitive-enhancing effects of klotho 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 goal was to see if they could improve the cognitive performance of rhesus macaques by administering a dose of klotho that would increase serum levels to a level seen in humans throughout life and be comparable to therapeutically effective increases in the 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. The primary analysis focused on a 10 g/kg dose of klotho, as it resulted in 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 assess the cognitive abilities of senior rhesus macaques, specifically the performance of frontotemporal circuits and brain regions like the hippocampus and the prefrontal cortex. The SDR test assesses working and spatial memory under low (NML) and high (HML) memory loads.

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

Their secondary goal 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. Importantly, the higher doses tested did not impair cognition, as the 2-5% changes were not statistically increased or decreased. Nevertheless, it is still unclear 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 and more “physiological” levels of the hormone in the body.