Stealth DNA May Control Aging

Most scientists who study human longevity search for genes that determine who is most likely to make it to age 100. Researchers at the University of Miami are taking a different approach: They’re studying the genes that allow people to stay healthy into old age.

By focusing on Amish people who have lived to 80, the researchers hope to pinpoint the genes that promote “successful aging”—the ability to live without disease, depression, frailty, or loss of independence for longer than average. “We’re looking not just to predict how old you’ll get, but how well you’ll age,” says William K. Scott, professor of human genetics at the university’s school of medicine.

Scott and his colleagues think they may have found one such key to successful aging. On Friday they will present a paper showing that 15 percent of healthy Amish octogenarians have “haplogroup X,” a genetic pattern within the mitochondria, which are the regions of cells that generate energy and help guard against deterioration. Haplogroup X is generally found in only 2 percent of Europeans, from whom the Amish descended. In the University of Miami study, only 3 percent of the control group—Amish people who had made it to 80 but suffered from significant disease or disability—had the genetic variant. The paper will be featured during a session at the American Society of Human Genetics’ annual meeting in Washington, D.C.

Researchers who study aging have long suspected that mitochondria play a role in aging. Mitochondria are responsible for processing metabolized food particles into adenosine triphosphate, which fuels vital cellular processes. They’re also involved in cell growth and differentiation. But the ability of mitochondria to function properly seems to decline with age.

Understanding the reason for that decline—and the genes that might control it—has been challenging. Mitochondria have their own DNA, which is passed down from the mother only. This unique chromosome has variations, called haplogroups. Nine such haplogroups have been well characterized in people of European descent, Scott says. But only haplogroup X was found to be prevalent among healthy aged people in the University of Miami study.

Isolated communities have become popular laboratories for studying longevity. In addition to Scott’s team, which is working with Amish families in Indiana and Ohio, a group at the University of Maryland is researching aging in the Amish of Pennsylvania. And Michael H. Crawford, director of the University of Kansas’s laboratory of biological anthropology, has spent years studying Mennonites in the Midwest. “The advantage of working with a homogeneous population is, you’re reducing the variances that can be associated with the environment,” Crawford says. Mennonites and Amish “don’t drink, don’t smoke. Most do some sort of physical activity. They don’t sit around working on a computer all day.”

But there can be pitfalls to this approach. Crawford says it’s hard to parse whether environment and lifestyle play as much of a role in successful aging as genetics, especially when the control group comes from the same community as the experimental group. What’s more, he says, tight-knit communities may not have enough genetic diversity to allow scientists to find variations such as haplogroups.

In fact, other scientists who study very-long-lived people have failed to find a mitochondrial connection. Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine, is studying Ashkenazi Jews who are 95 and older. He published two papers on haplogroups that showed no association with aging. “The mitochondria hypothesis in aging is very important; it’s just the evidence hasn’t been good,” Barzilai says. He adds that he did find a peptide in mitochondria that seems to be associated with aging—a discovery that illustrates how complicated the genetic picture is. “Maybe it’s not as simple as haplogroups,” he says.

The overall role of genetics in successful aging remains controversial. Linda Fried, dean of Columbia University’s Mailman School of Public Health, points to a study of Swedish twins in the 1990s undertaken by the MacArthur Foundation, which popularized the term “successful aging.” “Only 30 percent of variability in physical function and 50 percent of variability in cognitive function were heritable,” she says. Genetics, therefore, “can’t explain everything.”

Scott agrees that his team’s finding is just a starting point. He hopes to replicate the experiment in non-Amish people of European descent, to determine whether the results can be generalized to other populations. He also plans to study the DNA of people who have haplogroup X, so he can better describe how the variant alters mitochondrial function.

Further studies, Scott adds, should take into account environment and lifestyle, as well. Amish men and women have healthy diets, strong religious beliefs, and livelihoods that revolve around farming, with little help from modern machinery. “They’re more physically active than most,” Scott says. “We need to try to get clues about how these factors influence mitochondria.”