Robust octogenarians' DNA may hold secrets to healthy aging
San Francisco • Exactly why James Markam is alive and well is a bit of a mystery. The octogenarian has lost four siblings to cancer, heart disease and emphysema, all before they reached 62. Yet the retired airline executive recalls only one bout of sickness, culminating with a chest cold, 50 years ago.
Scientists are taking a deep look at Markam's genetics to see if something is protecting him from illnesses that affect others his age, such as Alzheimer's, cancer, diabetes and heart disease. Markam, 83, is one of more than 1,300 individuals identified as having what Eric Topol, director of the Scripps Translational Science Institute, called "Teflon-coated" genes.
"We think it's in the genome in these individuals," said Topol, who is leading research of healthy older people called the Wellderly Study at the La Jolla, Calif.-based institute. "You don't see any environmental thing that would be explaining this."
The first set of participants' genes should be sequenced by the end of the year, said Cliff Reid, chief executive officer of Mountain View, Calif.-based Complete Genomics, which is doing the work for free.
Scientists and pharmaceutical companies are closely watching Scripps' research project and others like it, eager for clues to help them develop new treatments to ward off diseases that have long afflicted the elderly. For drug companies such as Merck and Eli Lilly, the hope is that the research will lead to the creation of new billion- dollar blockbuster therapies.
The human genome is a transcript of an individual's DNA code containing the instructions for making cells in the body. Scientists say the genome may provide keys to understanding health and disease.
The projects reflect researchers' evolving views of how genetic mutations cause disease. While scientists once thought common genetic variants were responsible for many common diseases, recent research has changed that view. Instead, combinations of the millions of rare variants are the more likely culprits behind wide-spread ailments, making them difficult to identify.
Creating a clean map of a healthy genome that can be quickly compared to DNA that makes a person vulnerable to illness, the thinking goes, will allow researchers to more readily search for the roots of disease.
"What it does is accelerate discoveries of the basics of human disease," Reid said. "The Wellderly data set promises to offer a superior set of harmless variations, that will enable researchers to more effectively separate the harmless variations from the disease-causing variations."
Such potentially groundbreaking studies are only now becoming possible because of the rapid decline in the cost of sequencing. Translating an entire human genome required more than a decade of research and billions of dollars by the government's Human Genome Project, which completed the first sequence in 2003. Now, the same work can be done in days for thousands of dollars, and the price continues to decline.
A majority of seniors have at least one chronic condition, and many have multiple illnesses, such as hypertension, heart disease, cancer and diabetes, according to the U.S. Administration on Aging. Alzheimer's affects about 45 percent of Americans 85 or older, the Alzheimer's Association says.
In healthy individuals, "you might be able to find a mechanism that is either turning something on or off in a genetic profile that may convey protection against disease," Winifred Rossi, deputy director of the National Institute on Aging's geriatrics and clinical gerontology division, said in an interview. "If you find a mechanism that does that, then you could potentially create an intervention that mimics that protection."
While it's too early to tell whether the Wellderly Project will result in successful treatments, other continuing genetic studies of elderly individuals has led to some drug developments. Her institute is also studying the genetics of healthy elderly people in several projects, including one that tries to identify families of long-agers.
Nir Barzilai, director of the Longevity Gene Project at Yeshiva University's Albert Einstein College of Medicine in New York, has found several mutations that seem to aid healthy living in the centenarian Ashkenazi Jewish population.
"We're finding just as many variants for diseases in the centenarians as the rest of the population," said Barzilai, who is also taking advantage of advances in genetic sequencing. "They have something else that is relatively rare, that overrides or allows all those disease genes to be there."
One mutation he found affects the way the body regulates insulin-like growth factor 1, a substance involved with metabolism. Another variant controls the amount of beneficial cholesterol in their bodies.
Drugmakers have been trying to capitalize on these findings with mixed results. Pfizer, the world's largest drugmaker, and Roche Holding, the biggest global maker of cancer drugs, abandoned development of medicines meant to raise good cholesterol based on the research because they weren't working. Merck, the second-biggest drugmaker, and Indianapolis-based Lilly are still forging ahead with their version of these therapies. High-density lipoprotein, or good cholesterol, is thought to protect against heart disease.
These efforts may be in vain, according to a study last month. The report, in the British medical journal The Lancet, found that people with a genetic condition that causes high HDL have the same heart-attack risk as the general population.
Still, Barzilai said more developments are on the way.
"This is what we're excited about - there is a way to find a gene and then strategize and develop a therapy," he said.
Many in the Wellderly study have a range of reasons they think they've been so healthy, said Sarah Topol, a registered nurse and clinical trials coordinator for the Scripps Translational Science Institute. Topol, the daughter of the study's director, has interviewed all of the more than 1,300 participants over the phone and met many in person to take their blood or saliva samples. Participants must be in their 80s, with the average age about 87.
She said they have a wide range of personal habits from those who smoke and drink, to those who abstain and run marathons. The one link she sees is a positive attitude.
"There's nothing in their lifestyle that could explain it," she said. "I think that the most common theme is that people are upbeat, have a good sense of humor and just see the positive in life."
Most resist visiting doctors and taking their advice, Sarah Topol said. Many take supplements and will change their diets instead of taking prescription medicines, such as a 103-year-old woman in Riverside, Calif., who swears by a mushroom compound and an extract from lion's mane.
"She was feisty. I sat down with her and she said, 'I think I can fight you. I can fight anybody,' " Topol said. "She wanted to teach me how to shoot a bow and arrow."
Markam, the 83-year-old San Diego resident, also takes supplements containing fish oil, red yeast and glucosamine. He doesn't think his genes are anything special but feels lucky to have survived World War II and, later, being run over by a truck. He spends most of his time now running errands and tending a small garden of roses and a lemon tree in his backyard, as well as cracking jokes about his long and healthy life.
"They're trying to figure out how I could live so long and be so ugly," he said.
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