Smart seniors might have this gene variant

A gene variant that scientists already knew to be associated with longer life also seems to make people smarter, and may help offset the effects of normal cognitive decline in old age, according to a team of San Francisco researchers.
The findings, published Thursday in the journal Cell Reports, are encouraging news for the roughly 1 in 5 people who have the genetic trait, which is a variant of the klotho gene.

Beyond that, scientists hope the findings will help them develop tools for retaining, or even boosting, intelligence in people who have suffered cognitive losses, either from disease or through the normal course of aging. ‘Cognitive enhancer’ “What we’ve discovered is a cognitive enhancer,” said Dr. Dena Dubal, an assistant professor of neurology at UCSF and lead author of the study, which was done with researchers from the Gladstone Institutes. “This may represent a new way to treat problems of cognition in the brain.” The name of the gene comes from Greek mythology – Klotho is one of the three sisters of fate, and she spins the thread of life. The gene is responsible for secretions of the hormone klotho, which is thought to have effects on a variety of biological systems and has been shown to disrupt some processes associated with aging. Having a single copy of the klotho gene variant, called KL-VS, appears to increase the amount of klotho that circulates in the blood. Studies from the late 1990s, when the gene variant was discovered, found that people with the variant tend to live about five years longer than others, and in animals, the effect is even more profound. Cognitive loss – not necessarily dementia, but simple forgetfulness or slower thinking, for example – is almost universal among older people. Scientists involved with the new research had anticipated that klotho might slow down that cognitive loss. But that wasn’t what they found. People with the variant still experienced cognitive loss as they got older, but klotho seems to have pumped up their intelligence over a lifetime, giving them a greater cognitive reserve to draw from later in life, making their losses less pronounced. “Klotho increases cognition but doesn’t replace aging-related decline,” said Dr. Lennart Mucke, director of neurological research at Gladstone. “You’re just coming down from a higher level.” In a study of more than 700 people ages 52 to 85, the scientists found that those with the gene variant performed better on a variety of cognitive tests than those without it. Mucke noted that better test performance doesn’t necessarily translate into better “life performance.” “We don’t know whether people who carry this variant would be better at taking SATs or would land better jobs,” he said. Perhaps more exciting, scientists said, was another finding from the same study: that older, cognitively impaired mice performed better on tests of their brain power after they were engineered to produce more of the klotho hormone. That suggests that there’s hope for repairing damage done to an aging brain that already is showing signs of normal cognitive decline, scientists said. With the klotho study and others like it, “we are discarding right and left our old notions of the older brain and its capabilities,” said Dr. Molly Wagster, chief of the behavioral and systems neuroscience branch of the National Institute on Aging, part of the National Institutes of Health. “We’re learning more about the mechanisms underlying maintenance of good cognitive function and how we can capitalize on that,” she said. “The more that we learn about the brain’s capabilities, the more we can target prevention and interventions.” Communication lines Dubal and Mucke believe that klotho improves cognition by helping strengthen the communication lines between brain cells. They were able to show, in mice, that high levels of klotho in brain tissue were associated with high levels of a protein, called GluN2B, that helps build synapses. Future studies could look at whether cognition can be improved in older adults by simply boosting their klotho levels, or whether it might be more useful to work around klotho and improve GluN2B production. Scientists also want to know whether klotho could be used not just against normal age-related cognitive loss, but damage done by diseases like Alzheimer’s. “This may be relevant to a wide variety of diseases,” Dubal said. “It may represent a new way to treat problems of cognition in the brain – not necessarily treating the disease toxins, but countering the effects by boosting brain power.” The San Francisco study is actually the second report from the Bay Area this week to show that scientists can improve cognition in older, impaired animals. On Sunday, a team of researchers from Stanford and UCSF released a study showing that when old mice were given blood from young mice, they performed better on cognitive tests. Mucke and other scientists wondered whether klotho might also play a role in the blood-transfusion findings. Perhaps, he said, the hormone is more abundant in the young blood. Stanford neuroscientist Tony Wyss-Coray, senior author of the blood study, said his team’s findings underscored what the klotho team demonstrated – that the damage done by age isn’t necessarily permanent. “What our article shows is that the old brain is not frozen in time,” Wyss-Coray said. “You can potentially reactivate this old brain, and make it function again – at least in mice, at this point.”