An ambitious plan to sequence 100 genes in 1,000 healthy old people could shed light on genetic variations that insulate some people from the ailments of aging, including heart disease, cancer, and diabetes, allowing them to live a healthy life into their eighties and beyond. Rather than focusing on genetic variations that increase risk for disease, scientists plan to focus on genes that have previously been linked to health and longevity.
In recent years, advances in genetic screening technologies have allowed scientists to start searching the genome for clues to healthy aging and a lengthy life span. That work has revealed that the genomes of healthy old people are not blemish free. "These people have genetic susceptibility markers for many serious diseases, including cardiovascular disease, stroke, and diabetes, but they don't get any of these diseases," says Eric Topol, a cardiologist and head of the Genomic Medicine Program at the Scripps Translational Science Institute, in La Jolla, CA, who is leading the project. "What is the explanation? What might account for their insulation from these diseases?"
To answer that question, researchers are collecting blood samples from 1,000 people age 80 or older who have never suffered any serious illnesses and do not take medication. They plan to sequence 100 genes, known from animal research and other studies to influence health and aging. "We are especially interested in major housekeeping, master-control genes like [those involved in] DNA repair or insulin growth factor-1," a protein hormone involved in cell growth, says Topol. Enzymes involved in DNA repair are of interest in longevity research because cells often accumulate mistakes in their DNA sequence with age, and defects in some mouse and human DNArepairgenes trigger what looks like premature aging. The receptor for insulin growth factor-1 (IGF1) has been shown to affect aging in mice, nematodes, and flies.
Most previous studies have sequenced only a small number of genes or used gene microarrays, which can quickly detect common genetic variations throughout the genome. But recent research suggests that a number of rarer variations in different genes play a role in health and disease. Sequencing allows researchers to determine if healthy older people are more likely to carry variations that either make protective factors function more efficiently or hinder the activity of harmful factors.
Topol and his collaborators will compare the gene sequences from the healthy volunteers with DNA samples collected from people who died from age-related diseases before they reached their eighties. The scientists have already found that the healthy people had only a slightly lower probability of carrying disease-linked variations. That supports the idea that protective genes are playing a major role in people's successful aging.
Scientists hope that identifying the molecular basis for this protective effect will enable them to mimic it with drugs. "We believe longevity genes are protecting against several age-related diseases rather than just one," says Nir Barzilai, head of the Longevity Genes Project at Albert Einstein College of Medicine, in New York, who is not involved in the Scripps study. "From a pharmaceutical perspective, it would be more cost effective to target these pathways, and it would really imitate exceptional longevity rather than just treating the diseases themselves."
Barzilai has already identified a couple of candidates for longevity genes. In an ongoing study of people of Ashkenazi Jewish descent age 95 or older, Barzilai and his colleagues showed that the elderly group was more likely to carry a gene variant that changes the way that people process cholesterol. More recently, the scientists sequenced the genes for IGF1 and its receptor and found mutations unique to female centenarians.
While Barzilai is taking a different approach to the gene hunt--using microarrays--he says that each group looks forward to learning what the other finds. Having two large studies of the genetics of healthy aging will allow each to confirm its findings in a second population--a crucial test of the validity of large-scale genomic studies.