A new study has shown that carrying one copy of a particular form of a lifespan-extending gene, called KLOTHO, is associated with enhanced cognitive abilities in humans regardless of age or sex. Furthermore, increasing klotho protein levels in mice resulted in better performance in learning and memory tasks. The findings of the study, which has been published in Cell Reports, may suggest a novel way to help individuals suffering with cognitive deficits, for example those with Alzheimer’s disease.
Global populations are aging, and as we age the risk of cognitive decline increases. It’s estimated that by 2040 over 80 million people across the world will suffer age-related memory problems. Furthermore, the number of people suffering with dementia is predicted to double every 20 years. Aging is a modifiable process; however, it’s currently unknown whether factors that prolong life can also offset age-related cognitive decline.
It has been demonstrated previously that a protein called klotho, which is an aging regulator, extends the lifespan of mice when overexpressed. Humans that possess one copy of a variant of the KLOTHO gene, called KL-VS, have higher levels of the klotho protein in their serum, generally live longer and also exhibit decreased rates of age-related heart disease. It was unknown, however, whether higher levels of this protein can prevent cognitive decline in aging individuals, which is where this study came in.
Researchers tested various cognitive skills of over 700 participants between the ages of 52 and 85, none of whom presented signs of dementia. Around 25% of the individuals possessed one copy of KL-VS, and although test performance decreased with age amongst all participants, those with one copy of KL-VS performed better overall on the cognitive tests than those with no copies, regardless of age or sex. As demonstrated previously, klotho protein levels were found to decrease with age in the participants, and those with one copy of KL-VS had higher levels of klotho in their serum than those with no copies.
To take this further, the scientists engineered mice to overexpress klotho and they found that these mice not only lived longer than control mice, but they also performed better in multiple learning and memory tasks, which was found to be independent of age. Furthermore, increased klotho levels also led to changes in two regions of the brain that contain networks critical to cognition; the hippocampus and the cortex.
Cells within the brain can communicate with each other by releasing molecules called neurotransmitters across the small gap that separates neurons called the synapse. One such transmitter is glutamate which binds to synaptic receptors such as the NMDA receptor. Learning and memory strengthens synaptic connections and involves coordinated activity of these glutamate receptors, and as we age their functions start to decline.
The team found that the engineered mice possessed more of a particular NMDA receptor subunit, called GluN2B, within synapses of the hippocampus and cortex when compared with control mice. This subunit is known to have key functions in learning and memory. Furthermore, when the researchers used a drug to block GluN2B subunit containing NMDA receptors, they eliminated the klotho-mediated learning and memory enhancement.
Taken together, these results suggest that alongside prolonging life, klotho also benefits cognitive and synaptic functions. “This could be a major step toward helping millions around the world who are suffering from Alzheimer’s disease and other dementias,” said Dena Dubal, lead author of the study and assistant professor of neurology at the University of California, San Francisco. “If we could boost the brain’s ability to function, we may be able to counter dementias.”
