In our rapidly aging world, the longevity protein klotho provides much-needed hope for treating neurodegenerative conditions such as Alzheimer's and Parkinson's disease.
The research was carried out by scientists at the University of California, San Francisco, and it was led by Dr. Dena Dubal, an associate professor of neurology at the university. Their findings were published in the journal Cell Reports.
This study builds on previous research that found that high levels of the klotho protein correlated with improved cognition. These previous studies looked at mice that had been genetically modified to have high levels of the protein, as well as with humans who naturally had such elevated levels.
What the new research adds is an investigation into the potential therapeutic use of this protein. More specifically, the new study examines whether or not the protein can be used as a drug to quickly improve cognition in mice that have either low levels of the protein, normal levels, or cognitive impairment.
About the relevance of the research, Dr. Dubal says, "With our new aging demographic, cognitive dysfunction and lack of mobility are now emerging as our biggest biomedical challenges, and there are no truly effective medical therapies for these debilitating problems."
However, her findings point to the protein hormone klotho as key for devising such therapies.
What is klotho?
Klotho is a protein that occurs naturally in the body - produced in the kidneys and the brain - which then goes on to circulate as a hormone.
As the researchers explain in their study, klotho is known to be involved in regulating several other key bodily processes and hormones, such as insulin and the growth of fibroblasts, which are a type of connective tissue cell that produces collagen, among other things.
Overexpression of the protein has been shown to be life-extending in humans and a variety of organisms, while low levels have been shown to shorten the lifespan.
With age, we lose this life-extending protein. Studies referenced by the authors of the current research have shown that klotho levels decrease with age, with increased levels of chronic stress, and in the presence of a neurodegenerative illness such as Alzheimer's disease or Parkinson's.
Previous studies have also shown that natural genetic overexpression of the protein boosts cognition and neural resilience, regardless of age. It is also known that the way it does this is at least partially by improving the connections between the neurons' synapses through the NMDA receptor, which is for glutamate.
But what was not known was whether or not klotho could be used therapeutically to achieve the same effects, and if so, how quickly it can do this. For this reason, Dr. Dubal and team set out to test its therapeutic potential.
How a klotho fragment boosts cognition
The team injected both young and aging mice (which were 18 months old - roughly the equivalent of 65 human years) with an alpha-klotho protein fragment (αKL-F), which is similar to the secreted hormone.
The researchers also created a mouse model wherein the rodents were genetically engineered to have excessive levels of alpha-synuclein - that is, a protein largely responsible for Alzheimer's and Parkinson's disease. They administered injections of αKL-F to these rodents as well.
Dr. Dubal and team went on to test the cognitive performance of these mice by subjecting them to a range of tests. These included the Morris water maze and the Y-maze, which assess spatial learning and spatial memory.
The tests revealed that young mice that had been treated with αKL-F for 4 days in a row drastically improved their cognition, and the cognitive benefits lasted for more than 2 weeks.
As for the aging mice, these showed cognitive improvements only 2 days after receiving just a single shot of the treatment.
Finally, receiving αKL-F treatment for a few days in a row helped to alleviate motor and cognitive impairment in mice with neurodegenerative illness.
The study also found that for the duration of the time that αKL-F boosted cognition, the neural signaling through the NMDA receptor was also enhanced, which, in turn, strengthened neural connections in the hippocampus, which is a brain area key for learning and memory.
Speaking to Medical News Today about the results of the new study, Dr. Dubal said, "When the impaired mice were treated with the hormone, they soon experienced the ability to move, learn, and remember better - all in spite of the high levels of toxic proteins in their brains."
"The klotho treatment increased the ability of their brains to withstand and even reverse effects of pathogenic proteins already present; it boosted their brain resilience."
Klotho may treat neurodegeneration
"The burning question in the field was, 'Does klotho have therapeutic potential?'" says Dr. Dubal, speaking about the significance and impact of their findings. "We now know that, yes, it does."
"Our findings suggest that treatment with a klotho fragment enhances brain function across the lifespan and could represent a new therapeutic strategy to boost brain resilience against neurodegenerative diseases like Alzheimer's and Parkinson's disease."
Dr. Dena Dubal
The way in which klotho improves cognition remains unclear, however. Dr. Dubal told MNT, "Surprisingly, we did not find evidence that [αKL-F] crossed into the brain. [...] This means that the klotho fragment probably sends a signal from the body to the brain - to increase brain function and boost its ability to counter toxicity."
In trying to elucidate the mechanism, she draws parallels with physical exercise. "It reminds us of the positive effects of body exercise on optimizing brain health. It also reminds us of the beneficial effects of young blood on rejuvenating the brains of old mice."
"In both scenarios, a systemic signal or signals enhance brain functions. Could klotho orchestrate or converge upon beneficial body-to-brain signals?"
In their future research, Dr. Dubal and her team plan to answer this question by investigating how exactly αKL-F sends signals to the brain to improve cognition.