Clotho, one of the three Fates in Ancient Greek mythology, was accorded the responsibility of spinning the threads of human lives. She was tasked with controlling not only the birth of each individual, but also the timing of each individual’s death. Named after this Greek spinner of life, the klotho protein, which was discovered in 1997, has been associated with longevity. Recently, a variant of the KLOTHO gene that codes for the klotho protein was linked to better cognitive abilities in humans.
A study conducted by researchers at the University of California, San Francisco (UCSF), published on Jan. 27 in the Annals of Clinical and Translational Neurology, highlights the structural brain differences and cognitive functioning in those who have one, two or no copies of the KLOTHO allele.
The researchers scanned the brains of 422 cognitively normal test subjects aged 53 and older to see if there were any correlations between the number of copies of the KLOTHO allele and the size of any brain area. They discovered that those who carried a single copy of the KL-VS variant of the KLOTHO gene possessed a larger right dorsolateral prefrontal cortex (rDLPFC), which is a region of the brain linked to decision making and planning. While the rDLPFC was noted to have shrunk with age regardless of the number of KLOTHO copies possessed by the participants, study subjects with one copy of the allele had notably larger rDLPFC volumes than those with two or no copies of the allele.
It’s been theorized that the larger rDLPFC volume may have enabled KL-VS heterozygous participants, those with one copy of the allele, to perform more efficiently on cognitive tests that assessed their working memory and processing speed. Both of these abilities depend on the decision making and planning areas of the brain. On the other hand, KL-VS homozygous test subjects, those with two copies of the KLOTHO allele, showed decreased rDLPFC volume and lower cognitive function. These results support the findings from other studies that implicate the negative impact of KL-VS homozygosity on lifespan, cognition and cardiovascular disease risk.
It is uncertain as to why KL-VS homozygosity results in such effects, though a possible explanation may be the production of mutant or abnormally low levels of the klotho protein. The genetic influence of the KL-VS genotype on the size of the brain volume and cognitive function also raises questions like whether KL-VS heterozygous individuals demonstrate an additional resistance against neurodegenerative, neurological or psychiatric illnesses.
The results of this study also provide additional support to previous findings by researchers at UCSF who, in collaboration with scientists from the Gladstone Institutes, discovered that middle-aged and older KL-VS heterozygote individuals demonstrated superior abilities on cognitive tests. Their three-year investigation required the analysis of the cognitive function of more than 700 people between the ages of 52 and 85. In addition, their work involved the modeling of the effects of the KL-VS variant on mice. The link between the KL-VS variant and cognition was substantiated by the discernment that the heterozygote variant seemed to enhance synaptic plasticity, the connections between neurons, by increasing cell receptor activity.
The previous investigation was the first to associate the KL-VS variant with enhanced cognition, and the findings of this current study suggest the importance of working to understand the mechanisms that allow KL-VS heterozygous individuals to maintain a larger rDLPFC volume and better brain function.
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