In the search to reverse age-related cognitive decline, the Klotho hormone has captivated researchers with its potential to unlock the secrets of cognitive aging and neurodegenerative disorders. Our bodies naturally produce Klotho in the kidneys in two forms: a protein that inserts itself into cell membranes and a secreted hormone that circulates the bloodstream. Higher levels of the hormone form ha d been found to correlate with increased cognition and reduced risk for age-related diseases such as Alzheimer’s disease.
As we age, Klotho hormone levels naturally decline. Emerging animal studies, however, have found that injecting Klotho directly into the bloodstream may preserve memory and even reverse age-related cognitive decline. Although Klotho does not seem to cross the blood-brain barrier, introducing low doses of this hormone into mice was shown to boost working memory and increase neural plasticity. Now, a recent study published in Nature found that enhancing Klotho levels can improve higher-order cognitive function in rhesus macaque monkeys, suggesting that humans may experience similar benefits.
The team from Yale began their experiments by synthesizing a hormone form of Klotho that is naturally secreted by monkeys. To confirm its biological potency, Castner et. al first injected the synthesized hormone into young mice. With only a low 10 µp/kg dose of Klotho, the mice had six times more of this hormone circulating their blood compared to the control mice. Four hours after Klotho was given, the mice exhibited considerable activity in the hippocampus, the primary location for learning and memory. After completing a simple maze task, Castner et. al observed that the Klotho-enhanced mice had more new synaptic connections compared to the control mice that did the same task. Increased connections between neurons is known to correspond with enhanced learning and long-term memory.
Once it was confirmed that the synthesized hormone improved cognition in young mice, Castner et. al administered the same 10 µp/kg dose of Klotho to a group of adult monkeys. The ages of these monkeys corresponded with the human equivalence of 45 to 85 years of age, allowing investigators to determine whether Klotho can reverse age-related cognitive decline.
The experiments were completed over the course of three months. In the first month, the monkeys learned to complete spatial delayed response tasks that measured normal and high memory load. The normal memory load task was simple. Each monkey was presented with four wells, one of which contained a cue for a food reward. After a few moments, a screen dropped down to obscure their view of the wells. Once the wall came up, the monkey was able to retrieve the food reward by reaching into the well that had contained the cue. To test high memory load, the investigators increased the number of wells, as well as the time between the cue and testing phase. Their performance from these tasks was used to measure their baseline cognitive function.
Following this first set of experiments, all the monkeys underwent a scam injection to habituate them to the stress of the procedure. In the days following the sham injection, they underwent another round of normal and high memory load tasks. Investigators did not observe a difference in performance compared to the initial baseline scores, confirming that the procedure itself had no impact on cognition.
Finally, a group of monkeys were injected with the synthesized Klotho hormone. As the team expected, they performed significantly better on both the normal and high memory load tasks. The monkeys continued to outperform the control group for more than two weeks after Klotho was given. The cognitive benefits of Klotho are not only immediate (within four hours of the injection) but also seem to be long lasting, suggesting that this hormone may enhance long-term memory.
Given how significant the cognitive benefits were with only a low dose of 10 µp/kg, Castner et. al speculated whether higher doses of Klotho could further enhance learning and memory. To their surprise, performance did not increase when the dosage was doubled or even tripled. It is possible that exposure to more Klotho beyond what is naturally produced throughout one’s lifespan can actually impair cognition by interfering with signaling systems.
Overall, these findings suggest that Klotho supplementation may help preserve, and perhaps, reverse age-related cognitive decline. The role of this hormone in the body, however, remains an ongoing area of research. As it circulates through the bloodstream, Klotho has been shown to reduce oxidative stress and inflammation, two critical hallmarks of aging. Unlocking the various roles that Klotho plays in the body may hold the secret to living longer.