More than 30 years after it was identified as a key ‘longevity gene,’ the protein klotho has been used to boost the cognitive function of aging rhesus macaques, paving the way for human trials.
Following on from recent mice models, an international team of scientists found that the working memory and task-completion abilities of 18 rhesus macaques (Macaca mulatta), aged an average of 22 years (the human-equivalent of around 65), was boosted when injected with the klotho protein.
The researchers include scientists from the University of California, San Francisco, Weill Institute for Neurosciences, who have focused studies on klotho and regenerative cognitive function for more than half a decade.
In the study, the monkeys had to repeatedly navigate easy and difficult mazes to find a treat, in order to see how well they remembered the most direct path. The animals repeated the tasks four hours later. after being dosed with klotho, raising the protein levels to that of juveniles. While they only showed a 6% average improvement for the easy mazes, they fared about 20% better on the harder task. The memory boost was shown to last at least two weeks.
Interestingly, the dosage was relatively much lower than in mice trials.
The transmembrane protein family klotho, which as three subfamilies, including the most often referenced alpha-klotho, was only identified in 1997 and its function is still not completely understood. However, it does play a key role in aging, regulating many of the pathways such as phosphate levels and insulin signaling.
The protein, named after the Greek goddess Clotho who spun the thread of human life, is naturally produced in the kidneys and depletes with age. Its deficiency is a factor in arterial stiffening, hypertension and vascular degeneration, among many other age-related health conditions.
Previously, studies have shown how klotho expression has boosted cognitive function in mice models, from how intermittent fasting influenced its levels to how plasma transfusions from younger to older animals resulted in muscle regeneration.
One of the current study’s co-authors, Dena Dubal compares the cognitive tests to real-world experiences like needing to remember where you left your car in a parking lot, or recalling a string of numbers, two skills that decline as you age.
Dubal, now a physician-researcher at the University of California San Francisco’s Weill Institute for Neurosciences, has been studying the life-extending potential of klotho for years.
“For humans, the end game really is: how can we increase our ‘healthspan?’” Dubal said in 2018. “And that may go hand in hand with an increase in lifespan, because the things that help us to live longer are also the things that help us to live better.”
While there’s still much unknown about the mechanisms involved in klotho’s restorative abilities, Dubal said this current research provides “a very strong reason to jump into human clinical trials now.”
The research was published in the journal Nature Aging.