Title: Is ageing a disease?

Key words: libido, chromosomes, membranes, genes, lifespan, eternal youth, collagenase, immune cells, DNA, telomeres, genetic defect, gerontologists, enzymes, helicase,

Date: April 2001

Category: Life Changes

Type: Article

 

Is Ageing a Disease?

We can live healthy lives well into our hundreds, some researchers claim. But is ageing really a disease that can be cured? David Concar investigates

IN The Creeping Man by Arthur Conan Doyle, an ageing professor attempts to rejuvenate his flagging libido with an injection of ground-up monkey testicles. The remedy works but, unhappily, the professor turns into an ape.

Research into ageing has often been the target of jibes about quacks peddling bizarre elixirs based on the sexual parts of animals. But these days the joke is wearing thin. Medicine's ability to keep people alive in their old age is far outstripping its ability to restore the vigour of their younger years. And that grim reality is driving a new assault - minus the monkey glands-on the underlying causes of ageing.

Brittle bones, grey hair, saggy skin, forgetfulness, loss of immunity, cancer, strokes, these are the all too obvious hallmarks of ageing. But inside cells, the landscape of old age looks very different. Chromosomes clock up random mutations, and their ends fray. Molecular debris piles up. Membranes get worn and ragged. And potentially most harmful of all, strange things happen to the activities of specific genes: useful ones shut down for good while less desirable ones mysteriously spring into life. These are the kinds of changes that some gerontologists are trying to halt or reverse, convinced that ageing need not be the inevitable consequence of a long life.

The high watermark of this new optimism can be seen in the glossy brochures of Geron Corp., the world's first biotechnology company devoted to developing drugs and therapies to treat ageing. The company's name and logo-an hourglass inside a double helix of DNA-wouldn't look out of place in a fictional tale of scientists searching for a gene for eternal youth. But Geron's labs on the outskirts of San Francisco are real enough. As are the aspirations of its scientists. "We hope to increase the lifespans of cells [using] compounds that reverse the abnormal expression of genes that occurs in ageing," Calvin Harley, Geron's scientific director, proudly told New Scientist last year. As skin cells age, for example, their genes churn out more and more collagenase, an enzyme that breaks down proteins needed to keep wrinkles at bay. Other switches in gene activity afflict immune cells, making them "deaf" to messenger molecules and infectious agents in old age. In Harley's view, these changes are as unacceptable as anything that happens in a disease-a vision that many octogenarians share. Texan millionaire Miller Quarles is even offering a prize of $100 000 for the person who discovers a "cure for the disease of old age".

At 81, however, Quarles might be better off blowing his cash elsewhere. Despite their optimism, most experts on ageing say, when pushed, that there is a world of difference between understanding what goes on in an ageing cell, and doing anything about it.

Radical differences

And perhaps of even greater concern to Quarles is that they also disagree-sometimes passionately-about the most likely route to success. Some biologists believe that the clocking up of random damage to DNA, proteins and cells is really all there is to ageing. This school sets great store by developing novel ways of limiting the damage wreaked by oxygen free radicals and other potentially hazardous by-products of fuel combustion in cells. Others, however, argue that there is a further reason why we decay in old age-our tissues lose the ability to produce new cells, and accumulate too many old ones. This school includes researchers who think the overarching answer to slower ageing lies in preventing the shortening of telomeres, non-coding pieces of DNA that sit at the ends of chromosomes.

One thing is crystal clear: new insights into ageing are being thrown up at an unprecedented rate. Take research into Werner's syndrome. People affected by this rare disease are cruelly wizened and grey by the time they reach their late-20s. They can expect to die from prematurely clogged arteries and heart disease in their late 40s or 50s. And all because they carry two copies of a defective gene. For years, gerontologists could only speculate about how the genetic defect behind Werner's syndrome accelerates ageing. Then, in a ground-breaking study in Science on 12 April this year, researchers led by Gerard Schellenberg, a molecular geneticist at the University of Washington in Seattle, showed that the Werner's gene codes for a type of enzyme known as a helicase.

Helicases split apart, or unwind, the two strands of the DNA double helix. Their job is vital: DNA has to be unwound before genes can become active and before dividing cells can pass on healthy copies of their chromosomes to new cells. Either or both of these vital functions may be compromised in Werner's patients. But the leading theory on why they age so fast is that helicases enable repair enzymes to weed out random mutations and breakages that constantly threaten the integrity of genes and chromosomes.

Extra genes, extra years?

Right now, Schellenberg and David Galas, chief scientist with Darwin Molecular, the biotechnology company that helped to trace the Werner's gene, are looking for the counterpart of the gene in mice so that they can make transgenic animals carrying mutant helicase genes. Such animals may well be prone to the kinds of cancers and heart diseases that afflict Werner's patients. If they are, Darwin Molecular will swiftly market the animals as "research tools" for studying the diseases of old age.

Gerontologists, however, are keen to learn the answer to another question altogether. If a lack of helicase accelerates ageing, will lab animals that are engineered to carry extra copies of the helicase gene live longer? If the answer turns out to be yes, that will suggest that boosting helicases could also extend lifespan in humans. But most researchers are sceptical. Galas points out that boosting helicase in bacteria kills them. And Tom Kirkwood, professor of biological gerontology at the University of Manchester, counsels against viewing helicase as the be-all and end-all of human ageing. "The gene may be just one component of a rather larger complex network of genes that keep our bodies in good shape," he says. Underscoring that view, some tissues, notably brain cells, are unscathed by the Werner's gene and age as normal.

Besides, when it comes to preventing ageing due to damaged DNA and proteins, strengthening the repair systems is just one approach. Another is to curb the rate at which the damage happens in the first place. For example, only last month, Jeff Poulin, Marguerite Kay and their colleagues at the University of Arizona in Tucson reported that the brain and immune cells of mice fed high doses of vitamin E clock up damage to proteins more slowly than mice on normal diets. This confirms a long line of studies suggesting that antioxidant vitamins neutralise reactive free radicals, and-in theory at least-slow cellular ageing. The question researchers must now answer is whether swallowing antioxidants can also slow the ageing of whole organisms.

Meanwhile, health zealots are taking to heart a different approach to combating the hazardous by-products of food combustion in cells. For decades, biologists have known that rats and mice reared on draconian diet live 30 to 40 per cent longer than normal. Now, a research team led by George Roth at the National Institute on Aging in Maryland is looking to see if the same thing happens to our primate cousins. For the past nine years, they have been monitoring the progress of some 200 captive squirrel and rhesus monkeys kept on a variety of diets.

Lean burn

This year, Roth and his colleagues reported that slashing monkeys' food intake by 30 per cent for several months leads to a roughly 1 C drop in their body temperature-a sign, says Roth, that restricting calories triggers a fundamental change in the way cells use energy, at least in the short term.

Captive rhesus monkeys normally live for 30 to 40 years, so it will be a long time before Roth and his colleagues know if minimalist diets increase primate longevity. But so far the monkeys' metabolic response to the drastic slash in calories mimics that seen in mice and rats. If it continues, Roth says, the monkeys could end up living ten or more years longer than normal.

Roth says he is swamped with requests for information from humans who would like to ape his lean and hungry monkeys. Indeed, some Methuselah wannabes are already eating less in the name of longevity. Roy Walford, a biologist at the University of California at Los Angeles, for example, consumes a meagre 1800 calories a day (most people eat 3000) in the hope of attaining the magic age of 120 years old. But persuading most humans to do likewise may not be so easy.

That's why Roth is keen to uncover the molecular mechanisms underlying the life-extending effects of caloric restriction. Finding these, he says, would open the way to designing drugs that trick cells into thinking they are being deprived of energy when in fact they get a normal supply. That way, suggests Roth, we could all have our cake, eat it, and live a long time.

The bad news is that the research is at a very early stage. One theory is that ageing in cells is caused by sugar molecules gumming up the body's works by forming complexes with proteins and other vital molecules. Cutting calories-and hence the rate at which sugars are released inside cells-may slow this down. But depriving cells of energy may not just make the wheels of metabolism turn more slowly, argues Roth. It may also boost the activities of specific genes and enzymes that help to protect DNA and proteins from damage by free radicals and other poisons. Still, it could be years before biologists know enough to develop drugs that could trigger similar molecular changes. Meanwhile, say critics, we don't yet know what the full biological and psychological implications of caloric restriction would be. Energy deprived rats, mice and monkeys cannot tell you how they feel, although cold and hungry is probably a good guess.

A more radical approach to the problem of ageing is to slow the whole biological timetable from the cradle to the grave. At McGill University in Montreal, Siegfried Hekimi and his colleagues have created mutant nematode worms which prove this can be done in simple organisms. Movement, defecation, ageing, you name it, these worms do it all more slowly or less frequently. Whatever the identity of the genes affected, Hekimi suspects that the worms age more slowly because their cells burn less food and hence produce fewer free radicals.

So far, no one has suggested that similar genetic mutations should ever be introduced in to humans. For a start, such genes may not even exist in humans. What is more, not every biologist sees ageing in humans as a straightforward tussle between molecular repair and damage. Some think cell division, which doesn't hppen in adult worms, might be an important piece in the puzzle of ageing in our own species.

Unless they are doctored to make them immortal, cells in lab cultures run out of steam after a limited number of divisions. The cells "senesce". They don't die, but they do stop dividing, and they can no longer produce new DNA. In culture at least, cells from short-lived species tend to senesce after fewer divisions than cells from long-lived species, and skin cells from an 80-year-old person will run out of steam quicker than those from a fetus.

The key question is does the same state of exhaustion afflict cells in living tissues? If it does, argue some gerontologists, this could explain ageing in tissues with high rates of cell division, such as the skin and immune system. In the past, many biologists were doubtful. They argued that such tissues have a huge surplus capacity for replacing worn-out or damaged cells, and that crucial evidence that senescent cells build up in tissues like skin was missing. Now, Judith Campisi, a molecular biologist at the University of California at Berkeley, and other researchers are reviving the theory.

Last year, Campisi and her team discovered a molecular marker for senescent cells-an abnormal form of the enzyme galactosidase. Using this marker, the researchers found that thirty-somethings have almost no senescent cells in their skin, while folk in their 70s and 80s have "multiple clusters" of the cells in both the dermis and epidermis. The study helped to dispel Campisi's own doubts. "A couple of years ago I was not at all convinced that cell senescence had much to do with ageing," she says. "But I've changed my mind."

Unruly pensioners

And the rethink doesn't end there. When dividing cells run out of steam in the body, one might naively expect them to turn into kindly "pensioner" cells whose only crime is to occupy house room that might be better filled by more active cells.

This is no benign old age, however. Campisi's team has shown "that a number of proteins, genes and enzymatic processes are altered in these senescent cells". And altered, mind you, in ways that could make the cells harmful to healthy tissue. Senescent skin cells produce that wrinkle-inducing collagenase, for example, while the endothelial cells that line the arteries, the gut and other organs pump out interleukin 1, which can trigger tissue-damaging inflammation.

In theory, then, preventing cells from senescing might help to slow down ageing. But how to do it? Back at Geron, Harley and his colleagues are racing to find the gene that they believe will help to provide the answer, and seal the company's fortunes in the process.

The gene carries the code for an enzyme called telomerase that prevents the telomeres, the end of the chromosomes, shortening. All human cells carry this gene, yet few bother to switch it on and produce any telomerase. The cells of virulent tumours do, however. Over the past 18 months, telomerase's fame has spread, fuelled by evidence suggesting that it helps tumour cells achieve their dangerous immortality. This alone would make the gene for telomerase hot property. New tests for diagnosing and monitoring cancers, transgenic animals for testing anticancer drugs targeting telomerase, all would become possible once the gene was found. And the gene's value- commercial as well as scientific-will be higher still if Harley and his colleagues are right about something else. The researchers believe that what makes cancer cells deadly might also be used to keep healthy cells youthful. The reason for this ironic twist lies in the details of how telomerase works.

When cells divide repeatedly the telomeres gradually wear away. Eventually they are snipped to the quick, leaving chromosomes unable to replicate properly and putting DNA at risk of being damaged or lost. Cells with shrunken telomeres must stop dividing or risk turning cancerous. In short, claim Harley and his colleagues, the wearing away of telomeres is like a time bomb ticking away inside cells. And when it explodes, the damaged cells senesce to contain the damage.

In some cells, however, the telomerase enzyme can dampen the fuse, and put a stop to telomere shortening. Take sperm. No matter how many times these cells divide in the testes, their telomeres never shrink because telomerase is always active. And findings just published by Jerry Shay, a cancer biologist at the Southwestern Medical Center in Dallas, and his colleagues, show that the enzyme is also switched on in embryo cells, explaining how embryo cells can divide so furiously in the womb. Now, it turns out, it may be possible to artificially elongate telomeres to keep adult cells young too.

Three months ago, Shay and his Dallas colleague Woodring Wright, produced the first, tentative evidence that cells with artificially lengthened telomeres live longer in lab cultures. Looking for ways to shorten telomeres in cancer cells, the researchers inadvertently stumbled on a class of DNA-like molecules that make cancer cells grow even longer telomeres. Fusing these cells with normal cells produced non-cancerous "hybrid" cells with elongated telomeres-and lifespans about double those of normal hybrid cells.

In Wright's view, this is "strong evidence that telomere length is the clock that counts cell divisions" in ageing. But many biologists are reserving judgement until the telomerase gene has been found and researchers have done what everyone acknowledges to be the key experiment-genetically manipulating lab mice to see if longer telomeres mean longer lifespans for the whole organism.

Forever young

Not that the absence of that crucial experiment has stopped some telomere fans from getting wild-eyed. In Reversing Human Aging, a feverishly optimistic book published in the US earlier this year, American doctor and neuroscientist Michael Fossel speculates about a future world full of people living for hundreds of years thanks to what he calls "telomere therapy". Telomerase, says Fossel, is every pension fund manager's nightmare. Scientists, he says, are on the eve of discovering how to manipulate the enzyme to reset the telomere clocks that determine cell lifespan. And the result will be a generation of Methuselahs. "Before 2015," writes Fossel, "telomere therapy will be available to us all . . . the most remarkable change in all human history will have begun."

Gerontologists' reactions to Fossel's extravagant claims range from the amused to the outraged. Discovering drugs or gene therapies to switch on telomerase inside specific cells and tissues in the human body won't be easy, they say. Nor is it clear it would be safe to do so in cells that normally lack the enzyme. After all, cancer cells have high levels of the enzyme. Some even question whether the loss of telomeres in dividing cells really is that important to ageing, pointing to the awkward fact that mice have very long telomeres but very short lifespans.

But telomere enthusiasts continue to hit back. For example, Harley and his colleagues have uncovered evidence of abnormally fast telomere shortening in tissues where the demand for cell replacement is often high, such as the inside walls of middle-aged arteries that are subjected to onslaughts from cholesterol plaques and other stresses.

And Shay says that two teams will soon publish evidence showing that T cells from AIDS patients not only divide fewer times in culture than similar cells from healthy people of the same age, but that the cells have shorter telomeres as well. This suggests that HIV infection accelerates ageing of the immune system by keeping it perpetually on full throttle.

One way to slow down the immune system's ageing, suggests Shay, might be to remove T cells from patients at an early stage in the infection and regrow the telomeres with telomerase. Later on, when the patients get sick, these rejuvenated T cells could be given back to them. "You'd be running a risk," says Shay. "Turn telomerase on and you might get cancer, but on the other hand the cells would keep proliferating. You'd be on the fine edge of a sword."

Sting in the tail

But for some, the knife edge of telomerase therapy, whether it be applied to AIDS or to ageing, is just too sharp. Campisi and others believe it's no accident that dividing cells are preprogrammed to run out of steam. Cell senescence may be one of the body's many mechanisms for preventing tumour growth early in life. Scientists' attempts to reverse cell senscence to prevent ageing may therefore carry a nasty sting in the tail-an increased risk of youthful cancers. The challenge for scientists in future, says Campisi, is to find ways of "reversing the unsavoury effects of replicative senescence without causing runaway cellular proliferation".

In the meantime, the spectre of Conan Doyle's ape-professor lives on. For when it comes to extending lifespan, there invariably seems to be a biological cost waiting in the wings. Sometimes an unacceptable one. History shows, for example, that castratos and eunuchs lived longer than their sexually active brethren; but castration has yet to catch on as a method of prolonging male life. Even something as simple as eating less in the name of longevity carries a risk of reduced fertility and increased sensitivity to the cold, not to mention rake-like thinness.

Conan Doyle would have suffered no such problems. A great bear of a man who enjoyed a life of literary lunches, he died of a heart attack at the age of 71, secure in the knowledge that he had found a foolproof yet completely safe way to achieve immortality. Invent the world's most famous fictional sleuth.

From New Scientist magazine, vol 150 issue 2035, 22/06/1996, page 24

© Copyright New Scientist, RBI Ltd 2000