May 19, 2014

Longevity Gene Linked to Better Brain Skills

Senior couple studying together.

People with a variant form of a lifespan-related gene tend not only to live longer but to have better cognitive skills than those who lack the variant, a new study reports. Experiments done in mice might help explain why. The findings could lead to new approaches for improving thinking skills at various life stages.

The gene KLOTHO is named for a Greek mythological goddess of fate. Previous studies found that increased levels of the klotho protein can extend lifespan, whereas disruption of klotho can speed up aging. It’s been unclear, however, whether klotho might also have an effect on cognitive function, which typically declines with age.

To examine the potential link between klotho and cognition, Dr. Dena Dubal of the University of California, San Francisco, and her colleagues focused on a KLOTHO variant called KL-VS. Earlier studies had found that people with one copy of this variant tend to live longer and have a reduced risk for stroke. In contrast, having 2 copies of the KL-VS variant (a rare occurrence) had opposite effects on lifespan and stroke risk.

The researchers analyzed the relationship between KL-VS and cognition in more than 700 people, ages 52 to 85, who had no signs of dementia and were all participating in clinical studies. The research was supported in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA). The study appeared online in Cell Reports on May 7, 2014.

The participants were given a variety of cognitive tests, including measures of learning, memory, and attention. The 26% of participants who carried just one copy of the KL-VS variant performed better on the tests than those who had no copies, at all ages. Because people with the KL-VS variant also had elevated blood levels of klotho, the researchers concluded that the variant might enhance cognition by boosting klotho activity or levels.

The researchers next examined how the klotho protein affects learning and memory in mice. Mice genetically engineered to overproduce klotho lived longer and had higher levels of klotho in the brain’s hippocampus, an area that controls some types of learning and memory. The klotho-enhanced mice performed better on several learning and memory tests, regardless of age. In one test, the mice remembered the location of a hidden target in a maze better, which allowed them to find it twice as fast as control mice.

Brain tissue analysis of the klotho-enhanced mice showed that their synapses had more of a receptor subunit called GluN2B than control mice. The presence of GluN2B at synapses has previously been associated with changes in synaptic strength and learning and memory. When klotho mice were treated with a drug that blocked GluN2B-containing receptors, their ability to perform on learning and memory tests was reduced. The results suggest that increasing the presence of GluN2B-containing receptors may be one way that klotho could enhance cognitive skills.

“This could be a major step toward helping millions around the world who are suffering from Alzheimer’s disease and other dementias,” says Dubal. “If we could boost the brain’s ability to function, we may be able to counter dementias.” The researchers caution, however, that additional research is needed to better understand the effects of klotho.

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References: Life Extension Factor Klotho Enhances Cognition. Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, Sturm VE, Kim D, Klein E, Yu GQ, Ho K, Eilertson KE, Yu L, Kuro-O M, De Jager PL, Coppola G, Small GW, Bennett DA, Kramer JH, Abraham CR, Miller BL, Mucke L. Cell Rep. 2014 May 7. pii: S2211-1247(14)00287-3. doi: 10.1016/j.celrep.2014.03.076. [Epub ahead of print]. PMID: 24813892.

Funding: NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA); S.D. Bechtel Jr. Foundation, Coulter-Weeks Foundation, MetLife Foundation, and American Federation for Aging Research.