Confronting the ravages of old age

JOHN BARBER July 7 1986

Confronting the ravages of old age

JOHN BARBER July 7 1986

Confronting the ravages of old age


Achieving productive, healthy old age is one of man’s cherished dreams. But even the impressive medical advances of the past century have failed to provide the ultimate scientific objective, and a cure for aging remains elusive. Still, it is a goal sought by increasing numbers of researchers in North America. And last week four members of a research group at New York’s Rockefeller University disclosed promising results from experiments with a chemical that may prevent some of the worst ravages of old age. Their report on tests involving laboratory rats is part of a broad-based effort to discover the most basic mechanisms of aging, a search that many scientists say will intensify as Canadian and U.S. populations become progressively older. Said University of Toronto gerontologist James Kirkland: “Manipulating the human life-span is still in the realm of science fiction—but just barely. It is coming close to being a reality.”

The experiments conducted by the Rockefeller researchers—published in last week’s issue of Science magazine—gave some indication of progress toward that goal. The five-month tests focused on diabetes, a disease that accelerates such conditions as hardening of the arteries and loss of flexibility, which are also associated with old age. From findings in earlier research, the scientists theorized that glucose in the bloodstream was responsible for producing those illnesses. The group found that excessive glucose does affect the aging process by stimulating cross-linking—bonding between proteins in blood vessel walls and a variety of other molecules, including identical proteins and blood cholesterol.

The Rockefeller researchers added that the reaction then results in narrow, more rigid vessels and may also hasten the formation of plaque

or protein lumps in the bloodstream.

Arteriosclerosis is one of the most common crippling diseases of old age. But the Rockefeller scientists found that they could protect diabetic rats from contracting symptoms of the disease by injecting them with amino-

guanidine, a synthetic chemical compound they developed. They said that the chemical appears to work by bonding with glucose-modified proteins, pre-empting harmful cross-linking. The group’s leader, Michael Brownlee, added that they intend to test the drug’s effectiveness in a series of trials involving healthy human volunteers within a year. He is optimistic that aminoguanidine may prevent age-related arterial diseases that cause stiffness of joints.

The effect of aminoguanidine is the latest addition to a growing body of knowledge showing how aging occurs at its most basic level. But research results are still inconclusive, and there is no agreement among scientists on the causes of aging. Some of them say that aging results from a gradual buildup of damage to the body over many years. Others say that aging is genetically preordained—a built-in ticking clock—and they have mounted an intensive study of the genes and enzymes thought to have a role in ad-

vancing the aging process. Each group of theories has produced intriguing leads and some dramatic experimental results, but the breakthrough that could lead to new treatments for the diseases of old age remains elusive. Said Denham Harman, a leading age

researcher at the University of Nebraska: “The thing that is badly

needed today is a major effort to find the biological cause of aging.”

Harman is a leading proponent of a widely accepted theory about aging. He claims that the body ages as a result of lifelong bombardment by highly active particles of oxygen molecules, known as free radicals. Those particles occur naturally in the course of breathing, and they are known to damage genetic material in cells. In fact, free radicals produced in the body by radioactive fallout are directly responsible for radiation sickness, the symptoms of which can resemble premature old age. Said Harman: “We use these free radicals all the time for normal processes. At the same time, they inflict an awful lot of damage, and slowly over time that causes aging.”

Harman and other scientists have attempted to test that theory by feeding laboratory animals small amounts of so-called antioxidant compounds, known to neutralize free radicals. In

some cases, such compounds as Vitamin E appeared to extend the animals’ lives slightly—but the time gained was not sufficient to confirm the theory. Still, recent studies have shown that eating antioxidants does little to raise the overall level of the compounds within the body. According to Richard Cutler, a molecular biologist with the Gerontology Research Center in Baltimore, Md., recent experiments which he has conducted suggest that all animals maintain a constant level of antioxidants in the same way that some

maintain body temperature. He added that when animals consume extra antioxidants, their bodies simply stop producing the compounds.

To follow up on those findings, Cutler’s five-member team is now designing a dramatic experiment to prove or disprove the free-radical theory. The team will make use of genetic engineering to, as Cutler put it, “construct” a new species of mouse capable of producing double the normal amount of a potent antioxidant known as superoxide dismutase (SODE). With a clone of the gene responsible for producing the compound, the researchers will attempt over the next year to breed a litter of mice with two SODE-producing genes.

Ordinarily, mice never live longer than about

three years. But if the free-radical theory is correct, the genetically engineered mice will probably live significantly longer than that.

Scientists who subscribe to genetic theories of aging have long discounted the free-radical theory. And Calvin Harley, a biochemist at McMaster University in Hamilton, Ont., says that there is “one very good reason” for that. He noted that all mammals have an almost identical biochemical structure. And if free radicals are the sole cause of aging, each species should

have approximately the same lifespan. Instead, maximum life-spans among mammals vary from a few years for mice to the approximately 115 years enjoyed by a few exceptional human beings. According to Harley, those observations strongly indicate that age is genetically determined.

And despite recent evidence that the longerliving species produce greater amounts of antioxidants, there are other compelling reasons that support a genetic theory of aging. For one thing, experiments show that cells taken from young animals divide a greater number of times than cells taken from older individuals of the same species. In addition, cells from longerS lived species will divide 2 more often than cells s from short-lived species.

That evidence has stimulated a search for genes that may have an effect on the aging process. Over the past three years Thomas Johnson, a researcher at the University of California at Irvine, has demonstrated that changing a single gene in a species of worm increased its life-span by 60 per cent. Still, scientists do not expect to achieve similar results so easily among higher organisms. Said Harley: “To look for a single gene that gives rise to aging in a cell or an organism is futile. There are many genes involved.” In fact, George Martin of the University of Washington in Seattle, a leading expert on the genetic theory of aging, recently calculated that up to seven per cent of all human genes could play a role in aging.

If there are a variety of causes, it would help to explain why some people are more susceptible to different agerelated diseases than others. But one aspect of Martin’s research that offers a tantalizing suggestion of a simpler cause involves a rare disease known as Werner’s syndrome. That disease occurs in children of parents who each have a defect in a single gene. Those unfortunate children develop normally until they reach adolescence, when they prematurely develop many signs of old age, including greying hair, cataracts, arteriosclerosis and osteoporosis. Most die in their mid-forties. According to Martin, the fact that a duplication of one bad gene produces Werner’s syndrome indicates that a single defective enzyme causes a range of age-related problems. Still, it is more likely that many different genes cause aging. Declared Martin: “It is not very likely that we will ever be able to develop one magic bullet that will extend the life-span enormously.”

Indeed, most scientists are concentrating on finding methods of controlling age-related diseases. Harley says that within the next 20 years doctors may have the means to postpone those diseases and lengthen the average life-span. The University of Toronto’s Kirkland stressed that the principal objective was not “to make people live 500 years and feel like they’re 500 years old.” Instead, he added, “the real aim of most of the people who are working in this area is to extend the period of the life-span that is useful and functional.” Clearly, medical science is a long way from discovering the secret of immortality. But if the current research into the biology of aging fulfils even a fraction of its promise, it will remove an ancient fear by conquering many of the diseases that ruin the final years of human life.

—JOHN BARBER in Toronto

Retired couple; Brownlee (below): impressive advances but no cure for aging