Longevity Gene Keeps Brain Agile

A genetic variation that helps people live longer may also help keep their minds intact as they age. A study of a group of elderly people of Ashkenazi Jewish descent found that those with the genetic variation, which changes the way the body processes cholesterol, perform better on tests of mental ability.

Nir Barzilai, study author and head of the Longevity Genes Project at Albert Einstein College of Medicine, in New York, previously showed that the same genetic variation was more common among Ashkenazi Jews who live to be 95 or older. After uncovering this and other genes associated with longevity, the researchers examined whether the genes could explain why some people have sharper minds when they age. Barzilai says that studying cognitive ability in aging is important since most people want to reach old age but “they want to get there with their brain, and not just the body.”

The researchers found that in a group of 158 people age 95 and older, those with the variant were twice as likely to pass tests of mental agility as those with a different version of the gene: 61 percent of those with the protective variant had good cognitive function, compared with 30 percent of controls. The researchers also confirmed these findings using a younger group of Ashkenazi Jews in the Einstein Aging Study, also based at Albert Einstein College of Medicine. Among 124 people ages 75 to 85, those with the gene variant were five times more likely to be protected from dementia and perform well in memory tests. Ashkenazi Jews–Jews of Eastern-European descent–are a tight-knit group with a relatively uniform genetic makeup, making it easier for researchers to identify important differences among them.

The genetic variation causes people to produce less of a protein called cholesterol ester transfer protein (CETP). Barzilai says that CETP has two functions: it helps move cholesterol from the arteries to the liver, and it helps control the size of cholesterol particles circulating in the blood. People with the protective gene variant have higher levels of “good” HDL cholesterol and also produce bigger cholesterol particles, which scientists believe may not stick to blood-vessel walls as easily as small particles do.

It’s not yet clear how CETP affects the brain. But Benjamin Wolozin, a scientist at Boston University Medical Center who studies the role of cholesterol in Alzheimer’s disease, says, “It’s easy to imagine that changes in CETP could affect cognitive function.” Cholesterol is an important component of brain cells, Wolozin says, and cholesterol levels in the blood also affect the health of blood vessels that supply the brain with oxygen.

Drugs that mimic the effect of this genetic variation by lowering levels of CETP are already being tested as potential therapies for preventing heart disease. CETP inhibitors have been highly anticipated by cardiologists because they can raise the level of HDL cholesterol; current cholesterol drugs only lower the level of “bad” LDL cholesterol. However, Pfizer recently halted trials of its CETP inhibitor torcetrapib after the drug raised death rates in patients, which has prompted concerns that similar drugs will also fail.

Although the safety of CETP inhibitors is in question, Barzilai believes that companies developing the drugs should be looking at how they affect the brain as well as the heart. He believes that lowering CETP may not only help preserve healthy brain function but might also help prevent mental decline from Alzheimer’s disease.

The study, published this week in Neurology, is part of an ongoing effort to learn why some people who live long lives do so in better health than others do. “Most people study the genetics of disease, not the genetics of successful aging,” says Richard Lipton, study coauthor and head of the Einstein Aging Study. Researchers believe that examining the genes of long-lived people can offer scientists a guide for creating drugs that mimic the effects of their age-defying genes. Lipton says that the gene variation may help protect people from diseases of the brain, but that “there may also be a separate health-promotion effect distinct from the disease-prevention effect.”

Thomas Perls, a physician who leads the New England Centenarian Study at Boston University Medical Center, says that this latest finding “points to the utility of studying these extremely old individuals.” Researchers can take advantage of a phenomenon called “demographic selection” by focusing on people who survive when their peers have died out. “The older you get, the healthier you’ve been,” Perls explains.

But Perls says that although the current finding is promising, this gene variation, like other genetic variations that have been linked to longevity, has relatively modest effects. “As with all the other genes that groups including ours have discovered, it’s not a blockbuster. It’s not like we have found ‘the gene’ ” that controls aging. Perls says that longevity is probably highly complex, and living an exceptionally long life a long life may require a rare combination of different factors.