Forever Young

The new scientific search for immortality

Ronald Bailey from the August/September 2002 issue

(Page 2 of 6)

How do cells know when to stop? Through telomeres, caps composed of repetitive DNA sequences at the ends of chromosomes. These function somewhat like the aglets on the ends of shoelaces that keep them from unraveling. Through a peculiarity in DNA replication, each time a cell divides, its daughter cells lose a tiny bit of their telomeres. Once the telomeres are gone, the cell stops dividing and becomes senescent.

Two types of cells do not suffer this problem. One is the germ cells that are the progenitors of sperm and eggs. Their telomeres are restored by an enzyme called telomerase, making them essentially immortal. The other group is cancer cells. They can divide without limit, which is what makes them so deadly.

Significant aging is a relatively new phenomenon. Over evolutionary history, once creatures began to falter in any way, they were eaten or dropped dead of disease -- eaten by bacteria, as it were -- so they never had a chance to get old. "As soon as an animal in the wild starts to slow down even a little bit, it's eliminated from the population very quickly," says Simon Melov, a researcher at the Buck Institute, a nonprofit organization devoted to aging research. "Aging is not a natural state for us either," he adds. "The evidence we have indicates that 10,000 to 20,000 years ago, most people didn't live much past 30." Today, the only creatures that actually experience aging are human beings and the animals they protect, such as pets and livestock.

The Roots of Aging

But what is aging, anyway? We all know it when we see it, but it's very hard to tease aging itself from the various diseases that accompany it. Michael Straight, a former editor of The New Republic, was asked when he was 80 what it felt like to be an old man. Straight replied, "I feel like a young man who's got something very bad wrong with him." In the language of gerontology, there are no good biomarkers for aging.

Even today, many things besides aging kill people -- primarily, diseases and accidents. Then again, as we age we become increasingly vulnerable to the shocks and diseases that can kill us. In modern societies, disease plays a relatively small role in killing off younger people: If all the causes of death in the United States before age 50 were eliminated, average life expectancy would increase by only three and a half years. Meanwhile, Jay Olshansky has estimated that if all deaths from heart disease, cancer, and stroke were eliminated entirely the average life expectancy in the United States would increase to between 90 and 95. In the 19th century the insurance actuary Benjamin Gompertz pointed out that as people age, their chance of dying doubles every eight years or so. Thus, a 35-year-old is twice as likely to die at age 43 and four times as likely to die at age 51.

Is there an upper limit on human lifespans? Researchers reported in the April 29 Science that life expectancy has been increasing at about two and a half years per decade for the last 160 years. Demographers like Olshansky, they note, have been consistently wrong in predicting an upper limit to human life expectancy. In 1928, for example, the demographer Louis Dublin predicted that average life expectancy in the United States would never exceed 64.75 years. Today it is 76.7.

At this rate of improvement, the authors of the Science report conclude, "record [average] life expectancy will reach about 100 in six decades." Still, as far as we know, the maximum human life span is the 122 years achieved by the cigarette-smoking French woman Jeanne Calment, who died in 1997.

Aging is accompanied by lots of simultaneous changes -- graying hair, thinning bones, weakening muscles, failing immune systems. So far, researchers have not figured out whether those changes are aging itself or just symptoms of some more general process of decay.

Scientists are now in wide agreement that aging can largely be traced to the damage done to our cells by free radicals. A free radical is an atom or molecule that has at least one unpaired electron, causing it to be very chemically reactive. Lots of free radicals are created in cells as they produce energy. Free radicals disrupt a cell's DNA and protein synthesis and repair mechanisms. The Berkeley biologist Bruce Ames has calculated that oxygen radicals damage the DNA inside each cell some 10,000 times per day.

Each time a cell replicates, it copies all of the billions of DNA base pairs that comprise its genome. Cells are very crowded and chemically energetic places, so miscopying sometimes occurs. Fortunately, evolution has devised molecular machines that can rapidly read and then correct most of the copying mistakes, keeping the cells to a fantastically accurate rate of one error per billion nucleotide replications. However, each time the repair mechanisms miss a mistake, it becomes encoded in the DNA -- and the next time duplication occurs, the miscopied DNA is treated as correct. As a result, errors accumulate over time. Miscopied genes lead to the production of distorted proteins, which are inefficient when they work at all. The accumulated molecular damage causes a 0.5 percent decline per year in overall physical capacity after age 30.

Increasingly, researchers are focusing their attention on the damage free radicals cause in the tiny energy-producing organelles called mitochondria. Like any other power plant, mitochondria produce not just energy but also wastes and pollution, including copious free radicals. As good as mitochondria are at mopping these up, some of them nevertheless get loose and damage the tiny DNA genomes at the heart of the mitochondria. Free radicals create a cellular death spiral by mutating mitochondrial DNA, which in turn degrades their energy production and increases the production of free radicals, refueling the cycle.

Other research points to another process linking free radicals to aging. Apparently, we are literally cooking ourselves to death. In cooking, sugars and proteins stick together to form tasty brown crusts like those on French toast. Our own metabolisms are a form of low-temperature cooking that causes sticky sugars such as glucose to cross-link with proteins to create advanced glycation end products (AGEs). AGEs are biological junk that accumulates in cells, interfering with their functions over time. For example, AGEs reduce the elasticity and flexibility of the collagen in our ligaments. They are also linked to diabetes and to cardiovascular disease.

In a related process, our cells' recycling centers, called lysosomes, become clogged with cross-linked proteins and other cellular rubbish. This cellular gunk is called lipofuscin. Lipofuscin-filled lysosomes slowly crowd and hinder other cellular functions.

Another process involving free radicals is inflammation. Inflammation occurs when our immune system cells drench invaders such as bacteria and viruses with free radicals to rip them apart. The problem is that sometimes the inflammatory attacks don't ratchet down when the threat is gone, and our immune cells keep pumping out free radicals. Chronic inflammation has been linked to many diseases associated with aging, including arthritis, atherosclerosis, diabetes, Alzheimer's, and cancer.