Klotho is a longevity-associated gene in mice and humans, but in recent years researchers have seemed more interested in delving into its effects on cognitive function. Now a team has demonstrated that one of the various forms of klotho protein can be increased via gene therapy in order to produce long-lasting cognitive enhancement following a single treatment. This is somewhat more interesting than earlier work involving genetic manipulation of klotho levels, and similar to another study that used a different protein derived from the klotho gene. It remains to be seen as to whether this sort of approach will hold up for human subjects, though some of the evidence for human cognitive function to associate with klotho levels is intriguing.
αKlotho is a gene regulator of aging, increasing life expectancy when overexpressed and accelerating the development of aging phenotypes when inhibited. Research has shown that elevating Klotho levels have beneficial effects on synaptic and cognitive functions through a mechanism involving the NMDA receptor (NMDAR). Moreover, studies in three independent human cohorts showed that human carriers of the klotho KL-VS allele, which increases secretion of Klotho in vitro, obtained better results in various cognitive tests.
To date, all studies have focused on the transmembrane and the processed forms of Klotho (named m-KL and p-KL). In pioneering work, it was recently demonstrated that alternative splicing of Klotho (s-KL) produces a stable truncated isoform. This work also shows a strong correlation between high expression levels of the two klotho transcripts in brain and healthy status while aging. Significantly, the secreted s-KL isoform is almost exclusively found in brain, while m-KL is mostly expressed in kidney and to a lesser extent in brain. This suggests s-KL may have an important role in the brain.
More detailed study revealed that the s-KL protein could be detected in different murine brain regions involved in learning and memory processes, such as prefrontal cortex, motor cortex, and hippocampus. Conceivably both isoforms may have similar roles, but as they are transcribed differently, they may have distinct functions. Here we study the role of s-KL in cognitive processes. We hypothesise it is a neuroprotective protein involved in the onset and/or progression of cognitive deficits associated with aging. To explore its effects, we modified s-KL levels in the brains of adult wild-type C57Bl/6J mice using AAVrh10 gene therapy vectors.
This study demonstrates for we believe the first time in vivo that 6 months after a single injection of s-KL into the central nervous system, long-lasting and quantifiable enhancement of learning and memory capabilities are found. More importantly, cognitive improvement is also observable in 18-month-old mice treated once, at 12 months of age. These findings demonstrate the therapeutic potential of s-KL as a treatment for cognitive decline associated with aging.