So far, it has only been partially clarified why our memory declines with age and whether this can possibly be stopped. A study with aging rhesus monkeys now shows that a special protein can apparently improve their mental performance. Even a single dose of this “Klotho” protein improved the monkeys’ memory for around two weeks, as the scientists report. This confirms similar results from tests in mice and suggests that this endogenous but declining protein plays a role in primate memory. According to the research team, the Klotho protein could thus offer approaches to therapy against mental deterioration and memory loss in humans as well.
It’s a typical sign of aging: over the years, the performance and plasticity of our brain decreases. Even without neurodegenerative diseases such as Alzheimer’s or Parkinson’s, this leads to a gradual deterioration in mental performance and memory problems. It is true that this reduction can be counteracted by brain training, a healthy lifestyle and an active social life. However, he cannot be prevented entirely. The complexity of both the aging processes and our thinking organ makes it difficult for scientists to find effective and concrete starting points for effective pharmacological countermeasures or therapies.
Clotho protein affects metabolism and brain
However, in recent years, studies have found evidence that a specific endogenous protein may play an important role in brain aging and fitness. This Klotho protein circulates in the blood as a hormone and influences, among other things, the insulin balance, the signaling chains for certain growth factors and various receptor functions. Typically, levels of this protein are high in newborns and children and then steadily decrease throughout life. Although this hormone cannot cross the blood-brain barrier, it also appears to affect the brain and mental performance: “Studies show that people with elevated Klotho levels for genetic or other reasons have better mental performance as they age, delayed neuropathological symptoms and have a lower risk of senile dementia and Alzheimer’s disease,” report Stacy Castner of Yale University in New Haven and her colleagues. Additionally, when older mice are given additional Klotho, they show improved synaptic plasticity, better mental performance, and greater resilience to dementia.
In order to find out whether this effect of Klotho can also be transferred to primates, Castner and her team have now investigated this in rhesus monkeys. “Rhesus monkeys are 93 percent phylogenetically identical to humans, have similar genetic diversity and demonstrate higher cognitive functions,” explains the team. “Like humans, rhesus monkeys experience mental degradation and synaptic changes in various brain regions, including the hippocampus and the prefrontal cortex, with aging.” , Castern and her colleagues have now tested for the first time. To do this, they gave 18 rhesus monkeys, which were around 21 years old on average – this corresponds to a human age of around 65 years – a single dose of ten micrograms of protein per kilogram of body weight injected under the skin. Before and at regular intervals afterwards, they had the rhesus monkeys complete memory tests. The monkeys had to remember in which of up to nine identical looking containers a piece of food had been placed. These tests were conducted at different levels of difficulty.
Lasting effect after a single dose
It turned out that the administration of the Klotho protein had an effect just four hours after the injection: The monkeys performed significantly better in the memory tests than before the treatment. In contrast, this was not the case in control animals that had only received a saline solution. The positive effect on the memory performance of the rhesus monkeys also lasted for at least two weeks. This was particularly evident in the tasks that made more demands on the brains of the aging animals. “Taken together, our data provide evidence that giving Klotho can improve mental performance in aging rhesus monkeys,” Castern and her colleagues write. This effect lasts well beyond the half-life of the protein in the blood. This could indicate that this protein causes longer-lasting changes in brain metabolism and other functions important for cognitive performance. However, additional tests with a higher dose of Klotho of 20 and 30 micrograms per kilogram of body weight showed that this effect cannot be increased at will: the higher doses brought no improvements compared to the lower ones.
According to Castern and her team, these results suggest that humans could also benefit from treatment with the Klotho protein. Restoring the normal childhood levels of this hormone in the blood seems to hold particular promise. “A systemic low-dose Klotho treatment could prove to be therapeutically effective in aging people,” say the researchers. Before this can happen, however, further questions must first be clarified, they emphasize. So far it has not been clarified which “messengers” the Klotho protein uses to influence brain functions, because it does not penetrate into the brain itself. In addition, it was to be investigated whether even lower concentrations of this protein might also have an effect and how long the effect lasts at most.
Source: Stacy Castner (Yale School of Medicine, New Haven) et al., Nature Aging, doi: 10.1038/s43587-023-00441-x