A Klotho Gene Therapy Produces Long-Lasting Cognitive Enhancement in Mice
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.
Just varying the levels of the Klotho gene is not enough to give the results you need for better cognition or longevity. There are perhaps 50 SNP's in the Klotho gene, and you need the right alleles that benefit cognition or longevity. That is why CRISPR technology seems so promising, as it may allow geneticists to edit your genome to give you the right alleles if you did not inherit to good ones.
@Biotechy
Which ones are the right alleles and is it known why exactly these alleles produce the benefit, but not other ones?
The SNP rs9536314 GT is the most beneficial for cognition and longevity. I am homozygous for the T allele, which has less dementia and CVD. The alleles modify the code for the proteins that express the beneficial factors for cognition or longevity. I have checked my raw DNA data for the Klotho gene, and found that I am homozygous for the beneficial allele of at least 7 SNP's. It takes a little literature search to find out what alleles are beneficial for each SNP (homework).
I don't think the same would happen in humans. Upgrading klothos will downregulate insulin and vitamin D, which in humans may lead to more glucosepane and DNA damage. We've gotta stop depending on mice so much. They might be abundant, cheaper and more easily modified in the short run, but they're a waste of time and money in the long run.
Here is a little more detail on my Klotho gene comments above. The Klotho SNP rs9535314 G allele has several diseases associated with it if you are homozygous for it. I usually start with SNYpedia when looking for which allele is favorable for cognition, longevity etc. That is why I do not mind being homozygous for the T allele, and some researchers question the full validity of the heterozygous condition giving the best longevity and cognition for the gene. For the other SNP's, the best source I found was the 2011 paper by Sebastiani Whole Genome Sequences of a male and Female Supercentenarian, Ages greater than 114. For the Klotho gene, they list 7 SNP's and list the rs Number and longevity allele. That is where I got most of my info in my earlier comment. Incidently, I am actually homozygous for 8 SNP's, as I did not count that one earlier, because most researchers have found the heterozygous condition to be better for cognition and longevity than the T allele that I am homozygous for, and that some researchers think may actually be the better allelic condition.
Or a person could do regular vigorous aerobic exercise to stimulate klotho and get the other myriad benefits of the exercise along with it.
After reviewing the figures, the effect sizes of cognitive benefit are not particularly impressive. Gene therapy straight into the brain should yield much greater benefits to be warranted. If these effects were achieved with a non-toxic compound, then they would be more noteworthy.
Klotho's close ties to insulin/IGF-1 signaling suggest to me that it isn't a novel area of research because the observed benefits may be derivative of reduced insulin and possible modulation of vitamin D signaling.