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The End of Dying
By: William Lai
Asian Week, July 28, 2000
There is no mistaking the onset of aging. Fine wrinkles begin to appear on the face. Hair starts to turn gray. The unaided eye encounters problems focusing on nearby objects and eventually loses the ability to distinguish fine details. Men, especially, find it increasingly difficult to hear higher sound frequencies. The heart grows larger while the maximum breathing capacity of the lungs declines. The bladder progressively holds smaller amounts of liquid. Body fat migrates to hips and thighs in women and to the gut in men. As time passes, chronic illnesses like osteoporosis, arthritis and Alzheimer's disease strike with little warning.
Traditionally, scientists believed that aging was a biological process in which cells simply stopped dividing. Gerontologists, who specialize in aging, now know the explanation is not that simple. One theory links aging to cumulative cell-division errors. Another attributes it to the shrinkage of
telomeres, the structures at the tip of chromosomes. A third hypothesis suggests a connection with the build-up of so-called junk DNA, genetic material that does not have any obvious use. Other researchers zero in on environmental factors such as high-calorie diets. A common thread runs through all these studies: the belief that in unlocking the secrets of aging, doctors can devise ways of retarding and even reversing the process.
Genetics. Some light was shed on the mystery in 1996 when Chang-En Yu, Junko
Oshima, Ying-Hui Fu and other researchers identified the first human gene that affects aging. The breakthrough came from studies of people with the rare condition known as Werner's Syndrome. As they enter adolescence, sufferers develop wrinkled skin, lose their hair and become susceptible to diseases associated with the elderly such as cataracts, heart disease, diabetes and cancer. The researchers traced the abnormalities to mutations in the WRN gene, which controls the production of an enzyme belonging to a group known to play a crucial role in manipulating genetic material. The hope is that reengineering the defective WRN gene (it has been successfully cloned) could help cure Werner's Syndrome — and perhaps extend natural
lifespans.
A California team led by Richard Lerner, president of the Scripps Research Institute, has embarked on another approach. The researchers theorize that the mechanism of human aging and its associated diseases can be traced to a gradual increase in cell-division errors in tissues throughout the body. "This functional change begins slowly in middle age and increases gradually with advancing age," wrote Lerner in a recent issue of the journal Science. The theory is that those errors gradually alter the way key genes operate, which in turn causes the loss of tissue functions that result in aging. Imagine your cells as tiny gene factories where quality control of the manufacturing process naturally declines with the passage of time.
Lerner and his colleagues studied genes in actively dividing cells from young, middle-aged and old patients, and those with
progeria, another rare genetic disorder characterized by accelerated aging. The researchers found that 61 out of more than 6,000 genes examined showed consistent changes in expression — that is, there were slight differences in their characteristics depending on the age of the donor and whether the patient had
progeria. Some of the 61 genes are linked to chronic diseases such as age-related breast cancer and arthritis, and defects in organs like the kidney, heart and ovaries. Lerner cautions that the research is not conclusive. Further studies are needed before the process of aging can be completely understood.
Other researchers focus on telomeres, which are found on the tips of chromosomes (see picture above). Every time a chromosome replicates itself, its telomeres shorten in length. The older an organism is, the shorter are its
telomeres. Thomas Wan of the department of pathology at Hong Kong's Queen Mary Hospital is studying the telomere length-shortening process in patients with bone-marrow transplants. "This research is expected to unravel some of the questions about the role of
telomeres, telomerases and telomere dynamics in aging," he says. "Evidence that telomere dynamics may be involved in the control of the proliferative lifespan of human cells is compelling." If these shortened telomeres can be repaired, other researchers speculate, it might help delay aging.
Cloning. Research results released earlier this year suggest such repair work could possibly even reverse the whole process. Robert Lanza of Advanced Cell Technology, a bioengineering company based in Massachusetts, reported that six cloned calves had telomeres that were longer than expected. The week-old animals had telomeres that looked like those of newborn calves, although they were cloned from non-dividing adult cells. At two months, Lanza found the cloned calves developing normally — except for their
telomeres, which remained longer than normal. This was the reverse of Dolly the Sheep, the world's first cloned animal, whose telomeres are shorter than normal, suggesting that the animal will age unusually quickly.
Lanza believes the type of cell used for cloning may explain the difference. His team utilized fiber-producing cells, called fibroblasts, rather than mammary cells, which was the case with the sheep. Assuming that the rate of cell-aging applies to the entire body, say the researchers, humans cloned using fibroblasts could live up to 200 years. Of course, this is pure conjecture. The success rate of cloning experiments is still very low. It took 1,900 attempts before the researchers produced the six cloned calves. All suffered the usual problems of cloned animals such as high-blood pressure, breathing difficulties and over-large size. More important, the ethics of human cloning remains a thorny issue.
If not an entirely cloned human, how about one with cloned organs? The length of the telomeres in the cloned cows suggests that cloned tissues may last 50% longer than normal. The technique may someday be used to "grow" new tissues for elderly patients, with the goal of prolonging their life indefinitely. But that may entail frequent transplants. Recent reports indicate that the
telomere-lengthening phenomenon in the six cloned cows is found only in cells that are younger than six months. Still, even if cloned organs do not confer immortality, they could save lives. Theoretically, the new tissues will not be rejected by the body, which is one major cause of failure in current organ-transplant operations.
"Junk" DNA. Leonard Guarante of the Massachusetts Institute of Technology is working on another promising research. He and his colleagues conclude that "junk" DNA in yeast cells causes aging. Yeast has its own version of the Werner's Syndrome gene. Yeast "sufferers" were found to have accumulated extra circles of ribosomal DNA. When the researchers blocked or slowed the production of the extra genetic material, yeast lifespans were extended. "These findings provide a novel link between metabolic rate and aging in yeast, and perhaps, higher organisms," says
Guarante. Such as humans. About 90% of the human genome is not known to do anything. If the yeast research is applicable to people, this junk DNA might help explain why we age.
Diet. Yet another area of inquiry revolves around diet. Over many years, studies of several animal species have consistently shown that a 25% to 30% reduction in the consumption of calories retarded aging. A team led by Tomas Prolla and Richard Weindruch investigated the genetic basis of these results. One group of mice was placed on a standard diet. A second group had meals with 76% of the calories fed the first. The researchers then profiled the action of 6,347 genes in each mouse. Some 2% of the genes were found to have changed significantly as the first group aged. These same genes, however, remained intact in mice on the reduced diet. The findings suggest that a low-calorie diet slows metabolism and dampens stress responses, which could help drug-makers mimic its age-retarding effects.
Age-Related Maladies. Other researchers are tackling the specific illnesses of the elderly. Parkinson's disease is an incurable affliction, but its symptoms — tremors, rigid limbs and slowness of movements — can now be controlled. In a first for Asia, doctors at Hong Kong's Prince of Wales Hospital treated five patients last year using a procedure known as deep-brain stimulation, which was pioneered in France and the U.S. 10 years ago. An electrode is inserted into the brain to stimulate either the thalamic nuclei or the subthalamic nuclei. Patients turn on or off a watch-sized pulse generator implanted under their skin (see illustration). Alzheimer's disease, which attacks memory functions, remains incurable too. But drugs are being developed to slow its progress. New studies unveiled at the World Alzheimer Congress 2000 this month raise hopes that Alzheimer's can be prevented.
It may sound incredible, but some scientists are confidently predicting that, within this century, they can push the maximum human lifespan beyond 120 years, most of it free from Parkinson's disease and other old-age maladies. And after that? If science can indeed decipher the language of aging, it may ultimately offer humanity the promise of immortality. The prospect alarms ethicists. "This could lead to a future in which people might be driven to a form of 'generational cleansing,'" warns John Harris, a member of the British government's Human Genetics Commission. He envisages intense competition for jobs, space, food and other resources. Then again, immortals will have all the time in the world to devise solutions to these and other related problems.
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