The klotho protein is a hormone that is produced by the kidneys and the brain.
Cognitive function refers to higher functions like reasoning, attention, memory and language that result in acquisition of knowledge. High levels of klotho have been associated with better cognition and physical performance in aging, while the reverse has been found with people with low klotho levels.
‘A fragment of the klotho protein, when administered to mice, improved cognition in young as well as old mice, as well as motor function in those with high α-synuclein levels.’
Previous studies conducted in genetically modified mice that produced high klotho levels showed that cognition was better in these mice. However, it was not known if cognition could be improved if the protein was injected, just like a medication.
Scientists injected a fragment of the klotho protein (αKL-F) into three groups of mice - young, aging and those with excess α--synuclein protein.
In humans, the--synuclein protein level is usually high in those with age-related neurodegenerative diseases like Parkinson's
and Alzheimer's disease
Based on various tests conducted on the mice, the scientists found that:
- The protein fragment improved cognition in young mice. The benefits occurred within hours, and lasted much longer (2 weeks) than the time that klotho was expected to remain active in the body
- Klotho also improved cognition in aging mice. The effect lasted 2 days longer than the time that the klotho fragment was predicted to be eliminated from the body
- In mice that produced excess α-synuclein, klotho improved motor function, in addition to cognitive function. Thus, its benefits may not only be limited to cognitive function but also extend to motor function. However, klotho did not affect the level of the α-synuclein. The scientists also indicate based on their experiments that the motor function improved without causing anxiety or hyperactivity.
Patients with neurodegenerative conditions like Alzheimer's disease and Parkinson's disease show reduced brain function and have limited treatment options. Therefore, any medication that could improve brain function
would be useful in these patients. The beneficial effect of klotho in improving motor function in mice with excess α-synuclein suggests that it may be useful in patients with neurological conditions like Parkinson's and Alzheimer's disease.
The way in which the klotho produced its effects is not known. For a drug to have an effect on the brain, it has to pass from the blood through a barrier called the blood-brain barrier to reach the brain. Klotho does not cross the blood-brain barrier. Its beneficial effects appear to be at the level of the synapse, the junction between nerves.
It could possibly cause changes in the synapses that contributed to its long lasting effect.
Klotho appears to increase the activation of the GluN2B subunit of the NMDA receptor in the synapse, without increasing the number of the GluN2B subunits.
The NMDA receptor takes part in the transmission of signals across synapses through a chemical called glutamate, and plays an important role in learning and memory. Blocking of these subunits did not allow their activation by klotho, which in a way proves this mechanism of action.
The particular fragment of klotho used in the experiment appears to be the part of the hormone that is responsible for its cognitive effects. Thus, by removing the additional segments, the cognitive benefits of klotho can be retained, while other possible effects of klotho can be separated out.
Further research on this intriguing hormone will hopefully result in the development of a medication for neurological diseases and improve the lives of several afflicted patients.
- Leon J, Moreno AJ, Garay BI, Chalkley RJ, Burlingame AL, Wang D, Dubal DB, Peripheral Elevation of a Klotho Fragment Enhances Brain Function and Resilience in Young, Aging, and α-Synuclein Transgenic Mice. Cell Reports (2017); 20 (6): 1360-1371