Klotho gene therapy holds promise for suppressing aging-associated cognitive decline

Investigators have developed a gene therapy with the potential to reduce aging-associated cognitive decline. The study would have implications for neurodegenerative diseases like Alzheimer's disease and multiple sclerosis.

Several decades ago, scientists showed that mutations in the Klotho gene led to accelerated aging and reduced life expectancy in mice. Mice lacking Klotho developed neuronal degeneration and memory problems. Recent studies revealed that upregulation of Klotho preserved cognitive functions in mice. Besides, some studies indicated that people who had genetic variants that upregulate Klotho secretion tended to have better cognitive functions. The evidence supports a key role of Klotho in aging.

Investigators from the Universitat Autònoma Barcelona (UAB) looked at the role of Klotho in cognitive processes. Published in an advance online publication by Molecular Psychiatry, the study showed that one injection of Klotho gene therapy into the central nervous system could significantly enhance learning and memory in mice. The results suggest that Klotho gene therapy might be used to prevent or treat cognitive impairment caused by aging.

In the study, the investigators used an adeno-associated viral vector to deliver the klotho gene to increase Klotho levels in the brains of mice at middle age (12 months). Adeno-associated virus (AAV) infects humans and animals, but it's non-pathogenic, meaning that it doesn't cause disease. AAV is often used as a gene delivery vector due to several desirable features of this virus. For example, AAV can efficiently infect both dividing and non-dividing cells and can insert genetic material into a cell's genome with near 100% certainty.

Adult male mice were divided into two groups: the treated group that was injected with an AAV vector encoding the secreted Klotho isoform, and the control group that was injected with an AAV vector carrying a non-coding DNA sequence. To investigate the long-term effect of Klotho overexpression in the brain, the researchers compared the physical conditions and cognitive performance of the two group of mice. The results showed that overexpression of Klotho in the central neuronal system did not significantly affect body weight or sensorimotor skills but ameliorated age-related motor decline and improved cognitive performance in old mice.

In conclusion, the study adds to the growing body of evidence that Klotho plays a critical role in cognitive function. Moreover, one injection of Klotho gene therapy into the central neuronal system appears to be sufficient to induce long-term protective effects.

Most of the studies on Klotho's functions have been made in transgenic mice that overexpress or lack the protein. The new study, however, alters the levels of Klotho in adult mice. Besides, previous research has been mainly focused on the transmembrane and the processed forms of Klotho, while the new study investigates the secreted Klotho isoform. The researchers assume that their study may be the first to demonstrate that the secreted Klotho protein alone is sufficient to improve cognitive function in vivo.
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