Health Sciences Report Winter 2005

How to Live Exceptionally Long without Growing Old:
The Search for Genetic Clues

By Chantelle Turner
Photos By Tim Kelly

Envision the ends of shoelaces. Or a lighted fuse. Or the final centimeter of tape threaded through a cassette recorder. Each has been suggested as a visual aid to understanding telomeres.

Located at the end of chromosomes, telomeres are repetitions of a sequence of nucleotides, TTAGGG, that occur hundreds to thousands of times in tandem. Every time a cell makes a copy of itself, some of the telomeric DNA is lost, which gradually shortens the telomeres. And, as University of Utah researchers discovered, shorter telomeres are linked to earlier death in certain individuals.

For those who find questions of their own mortality lurking in the dark, telomeres may be best pictured as they appear through a microscope when stained: the fl uorescent tips shine like tiny yellow eyes.

"When I turned 30, I'd lie down at night and think: what's left? We're only going to get old and die," recalled U of U molecular biologist Richard M. Cawthon, M.D., Ph.D.

He was completing a residency in psychiatry at the time. The son of two physicians who'd recently retired, he'd always imagined helping people by preventing and treating disease. But he found himself continually worrying about his patients long after he'd left the clinic. "Then, one night, I thought: I'll work on aging!"

"If you cure only heart disease, you'll extend a person's life two or three years. If you cure heart disease and cancer, the two major causes of death, you'll still only extend their life a few more years," he explained, because the risk of developing another life-threatening disease increases exponentially with age.

"But if you could slow down aging, then you could extend life expectancy by decades," he said. "Aging is a huge cause of death, though most people don't think of it in those terms."

Cawthon joined the U School of Medicine faculty in 1991, and, since 1995, has devoted himself to studying the genetics of human aging. He and his colleagues made a major breakthrough several years ago. In the February 1, 2003, issue of the international medical journal, The Lancet, the U team reported that, in people over the age of 60, shortened telomeres in the blood are associated with increased risks of dying from heart disease or infectious diseases.

The discovery raised new questions for Cawthon, research associate professor at the University's Eccles Institute of Human Genetics. Are shorter telomeres markers of an underlying cause of disease, or of a fundamental process of aging? Would measuring the length of telomeres lead him to genes that regulate the rate of aging in people?

Cawthon was invited to collaborate with researchers at Utah State University (USU). They'd launched a pilot study in 1995 of the cognitive performance and decline of the Cache County Cohort (CCC), a group of 5,092 individuals consisting of nearly everyone aged 65 years or older living in Cache County, Utah. Principal investigator Ron Munger, Ph.D., director of the USU Center for Epidemiologic Studies, asked Cawthon to join a more general investigation of aging in the cohort.

For a geneticist, the CCC has distinct advantages. "These people have a shared environment. They're from the same geographic region, they're all Caucasian, and they're almost all non-smokers," said Cawthon. "Many diseases are caused by the interaction between genes and the environment. These people have had little variation in their environmental exposures, though there are some we still need to look at, such as diet."

A colleague from the University's Huntsman Cancer Institute, Richard A. Kerber, Ph.D., an epidemiologist and associate professor of oncological sciences, linked all members of the CCC to the Utah Population Database (UPDB), a genealogical database of more than 2 million people that includes information on births and causes of death for the past 100 years. The researchers could look at the ancestors and biological relatives of cohort members to determine whether there was a familial link to excess longevity. That would be consistent with genes playing a role in aging, said Cawthon.

The U researchers also are studying the age at which the women had children to determine whether late fertility is associated with longer lives. Studies in fruit fl ies had shown that the life span doubled for both males and females that had been grown for many generations from the last laid eggs. In the UPDB, they are testing whether the brothers and sisters of women who had their last child after age 46 have a greater chance of living past age 90.

"There may be a shared factor--it could be a gene--that affects both reproductive and whole organism aging, and therefore benefits both males and females," noted Cawthon.

Ken R. Smith, Ph.D., U professor of family and consumer studies, who collaborated with Cawthon and Kerber on the Lancet study, is delving further with a fi ve-year grant from the National Institute on Aging (NIA) in 2003. Dubbed the "US FLAG" "Utah Study of Fertility, Longevity, and Aging" the project focuses on families with at least two members in their 90s. The researchers are interviewing the elderly and their adult children, usually in their 60s and 70s, as well as their children's cousins. In each subject, they will measure many biomarkers related to disease, such as resting heart rate and white blood count, to determine whether the offspring have shifted towards healthy marker levels. Studies have shown that individuals with either lower resting heart rates or lower white blood counts tend to live longer.

The researchers also will compare the offsprings' levels to those of their cousins' adult children of the elderly person's deceased siblings. If genes do play an important role in longevity, then the cousins' biomarker levels should be shifting toward faster aging.

Next year, Cawthon will begin measuring the telomeres of the study participants. He's also developing assays to look at mitochondrial DNA damage, since this type of damage accumulates with age in some tissues and may increase the risk of age-related diseases. Oxidative stress is damage to DNA, proteins, and lipids that is caused by oxidants. Highly reactive substances containing oxygen, oxidants can result from infl ammation and infection, as well as from the consumption of alcohol and the smoking of cigarettes. Accelerated telomere shortening, at least in cells grown in culture, is a known consequence of oxidative stress.

"We're looking for genes controlling telomere length. If we're really lucky, we could find one in a year," noted Cawthon. "In US FLAG, we also might fi nd genes not related to telomeres. Families allow us to do linkage analyses [a technique to identify chromosomes that harbor genes involved in a disease], which can lead us to a gene we haven't even thought of."

Genes that slow the aging process already have been identifi ed in yeast, fruit fl ies, nematode worms, and mice. In humans, one version of the APOE gene increases an individual's risk of developing Alzheimer's disease, while a different version has been associated with a higher chance of living to 100.

Once genes that regulate human aging are identifi ed, then researchers can study the biochemistry the genes affect and, eventually, develop drugs that will slow the aging process. "If we didn't have the problem of aging, we could live an average of 1,000 years," estimates Cawthon. He had asked colleagues to calculate life expectancy rates if, after age 20, people's risk of dying remained the same as it was at age 20, rather than doubling every eight years.

But would anyone want to live to be 1,000?

"Most people think of aging as senescence, or growing old. No one wants to extend life and have functional problems. Cells and tissues deteriorate; diseases creep in," he acknowledged.

"The goal is to extend the healthy phase of adult life, not old age," said Cawthon, who served on a NIA panel that characterized people who live exceptionally long. Rather than life span, the NIA prefers using the term health span, which it defi nes as "survival without disease or disability."

"You'd have a series of lifetimes to do things you're interested in," said the U geneticist. "There could be a lot of social benefits to living longer. They're plenty of problems like poverty and war to work on, so I don't see anybody getting bored very soon."

What surprises Cawthon is that the genetics of human aging is still largely unknown: "By the time I reached 50, I thought surely we'd have figured out aging." To which he added, "There are just not enough people working on it!"

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