SCIENCE: HOW TO LIVE LONGER

Forget melatonin and royal jelly. Gene therapy is leading the way to the fountain of youth, says Michael Hanlon

The search for the elixir of youth has traditionally been the speciality of the quacks, the conmen and the sweet-talkers, who are more interested in lucre than in biology. But, as the century rolls to a close, all that is about to change. Every month, it seems, an announcement is made of another fantastic discovery of a gene for this or the imminent identification of a gene for that. There is the smell of a breakthrough in the air, just as there was in the 19th century, when the penny dropped about germs, sanitation and vaccination. Could we be on the verge of the greatest medical advance ever seen, even greater than the defeat of smallpox or cholera - the defeat of time itself?

Before we can halt or reverse the ageing process, we need to understand why it occurs. To most people, this is a stupidly easy question. We age, surely, because our bodies are machines. They wear out, just like cars or washing machines. Nothing can last forever. Besides, if we didn't age and die, the world would be a pretty crowded place. It is inevitable, evolution has determined that we age, for the good of the species.

This idea is as pervasive as it is wrong. The "ageing is good for us" hypothesis, with its almost puritan, religious overtones, perhaps explains the historical curiosity of why more biologists have not worked on a cure for human mortality. After all, their lives, quite literally, depend on it. In fact, we do age because of evolution, operating through the mechanism of natural selection. The evo- lutionary theory of ageing, first proposed in the 1930s, has been accepted by just about every biologist working in the field and is very simple. It states that our bodies have been honed over the millenniums to survive for just long enough to have children and bring them up. Any genes that would help us to survive long after this would not be inherited, as we would probably have been killed by wild animals, disease or starvation before they took effect.

But in the modern Western world, we have exterminated the dangerous animals and vaccinated ourselves against disease, we have antibiotics and plentiful food, and we regularly live longer than we are "supposed" to. In other words, we age, because we grow old. The diseases and degenerations of ageing - cancers, loss of skin and muscle tone, Alzheimer's, bone and cartilage deterioration - are the result of random mutations that have not been sieved out by natural selection. The life that begins at 40 is a life on borrowed time, charting a path through a minefield of hazardous mutations and biochemical imperfections, a minefield left undisturbed by the clearing hand of natural selection.

We know quite a lot about what happens to our bodies as they get old, and why. Certain genes have a major impact on the development of cardiovascular disease, the biggest single killer. Oxidants, including "free radicals" - destructive molecules produced by our bodies as a byproduct of our normal metabolic processes - seem to be involved in many of the degenerative changes of ageing, such as arthritis, cataracts and the development of cancer. Our ability to deal with oxidants declines with age, and there is probably a genetic basis for this. Our glucose metabolism also goes awry as we get older. One of the results of this is collagen deterioration. Collagen, a protein, forms the foundation of skin, arteries, tendons and ligaments, parts of the body particularly vulnerable to the ageing process. And although much money is currently being made from the sales of dietary anti-oxidants and various other potions that would seem, on the face of it, to offer real hope in the battle for eternal youth, scientists are sceptical.

Steven Austad, a zoologist at the University of Idaho is one of the world's foremost experts on gerontology, or the science of ageing. In his recent book, Why We Age, he lays into the makers of eter- nal-youth potions. Royal jelly, melatonin, massive doses of vitamin C and dietary anti-oxidants, together with thousands of herb extracts, algae, monkey glands and body parts from various endangered species have all, he says, brought plenty of extra cash to the unscrupulous but precious little extra life. There is not a single existing drug, or treatment, or recommended lifestyle or therapy which has been proved to slow the natural ageing process. Some, such as melatonin and many of the unidentified Chinese potions, may even be harmful.

However, this situation will almost certainly change, and sooner rather than later. Scientists are probing the genetic codes of some very simple animals and finding genes that have exciting implications. Professor Austad thinks that some insignificant and slimy invertebrates may be shedding light on our deteriorating glucose metabolism. "We have been looking at the genes of nematode worms. Some of the genes that we have found seem to be analogous to those which may cause ageing in humans, for example a gene similar to the insulin receptor. This seems to be related to the animal's sugar metabolism, and we know that a lot of what goes wrong during ageing is to do with our sugar metabolism. There is also some research being done right now on fruit flies, which has found that those which produce a lot of anti-oxidants live longer. I have heard they have been successful in trying to insert these genes into mice, and that will be big news if it is confirmed." When asked what the likelihood was of anyone alive today still being around in 200 years, Austad says: "I think that is highly unlikely. But people born in 10 years or so, quite possibly. I think by 2020 we will have the capacity, by gene therapy, to start to alter the ageing process to some extent."

Gene therapy represents our best hope in the battle against senescence. Despite what you may have read in the press, not a single person anywhere in the world has been successfully treated by this technique. But scientists are close, very close, to making it work. "Gene therapy has not been successful in humans yet, but it will be before long and offers great promise now that we are uncovering what the basic ageing processes are," Austad says.

The idea is quite simple. In theory. By deciphering the human genetic code (which groups of scientists are doing now all over the world in the Human Genome Project), we should be able to locate and identify the killer genes, the landmines lurking in our DNA, that cause our bodies to let us down when we get old. Some good ones to start with would be those which predispose us towards Alzheimer's disease, those (probably thousands of them) associated with some of the common cancers, and, in particular, the genes which control our immune systems, which are particularly prone to ageing. It is failure of the immune system that leads to the deaths of millions of elderly people from relatively trivial ailments like pneumonia, influenza and post-operative infections. Once we have identified these genes, we may be able to alter them, or switch them off. Few diseases and degenerations of ageing will be controlled by a single gene. There will be hundreds, or thousands, and the disease may be affected by the interaction of these genes with other genes, and in nearly every case the genetic information interacts to a degree with the person's environment. So it's a big task.

But Steven Austad, like most scientists, thinks it is not an impossible one. If we can identify a gene, and modify it in the lab, the next problem is how to get the "good" genetic information into the body. How can we design a drug that is able to insert sections of modified DNA into our cell nuclei, a fiddly process, fraught with difficulties, not least of which is that anything trying to invade our cells, even if it has our best interests at heart, will be pounced on immediately by our ever-vigilant immune systems?

Happily, something already exists that is very good at finding its way into our cell nuclei and modifying its DNA: viruses. A virus is nothing more than a strand of DNA encased in a protein coat. Viruses, like all organisms, exist to make copies of themselves, and the way they do this is cunning. Instead of eating their hosts or stealing its food, like many parasites, viruses "borrow" their victim's cells to make new viruses. Unfortunately, in the process, the host's cells will die or be crippled - a fate that may be suffered by the victim as a whole if enough cells are affected.

The body can defend itself, usually successfully. The resulting battle generates a lot of heat and noise which we feel as inflammation and tenderness. Some viruses, though, are extra cunning. They attack the very cells designed to repel viral attack: our immune cells. One virus in particular, the Human Immunodeficiency Virus (HIV) has proved to be a spectacularly good machine for getting round our immune system and destroying it from within. Now, thanks to years of heavily-funded and concentrated research, we know what makes up the genetic code of HIV and how it works. Ironically, it may be the case that in a few decades we could be using HIV viruses modified in the laboratory not to kill us, but to cure us of a host of ageing diseases, particularly those relating to immunity problems. "It is certainly possible that we will use the HIV virus. It obviously has good ways of getting into our immune cells, and one day we could use this ability to our advantage," Austad says. "The immune system is a very important part of the ageing system, and HIV is all about the immune system."

So what of the future? Not the science fiction future of the 23rd century, but the near future that most of us will live through. Steven Austad believes that quite soon, say in 30 or 40 years, we will be able to take a cocktail of drugs and genetic therapies throughout our lives that will take over where evolution left off and enable us to live longer and healthier lives. "I do think that increase in absolute longevity and increase in average longevity will go together. That means that more people will live to greater ages, and in better health. By, say 2100, you are going to see people who are 140, 150 years old. I'm confident of that."

All this will cost. In the United States, the insurance companies, which have a vested interest in keeping their customers alive, well and paying, will be all too happy, one supposes, to pay for tests and treatments. In Britain, the burden of providing anti-ageing therapies which work will fall on the NHS, assuming it still exists. Many people, millions certainly, will be happy to pay whatever it costs for a few extra decades. In the Third World, though, solving the older problems of providing adequate food and clean drinking water are likely to be the priority for many years yet.

There may be costs, too, other than financial. Increasing lifespan may reasonably be assumed to lead to a degree of overcrowding. But this assumption ignores two facts. First, any society that is likely to have the means to provide expensive anti-ageing drugs to its populace is also likely to be a society where contraception is freely available and women have fewer children. In some countries, such as Germany, the population has started to decline. Second, even if every single ageing disease and degeneration were to be conquered, people would still only have a limited lifespan. The modern world, though largely free of man-eating lions, is still far from devoid of risk. Several infectious diseases will be giving us trouble for some time yet. People will carry on smoking, falling down the stairs, electrocuting themselves and dying in their cars in their millions. One suspects that violent crime (a significant mortality factor in some countries) is also here to stay. And of course, there is war. Amazingly, it has been calcu-lated that if all other risks, including the risks of old age, were to be removed, the average European or north American could still only expect to live 210 years or so before being killed on the road.

The psychology of living to 150 in good health is quite another thing, although Austad is optimistic. "There have been such changes in our lives in the last century, but we seem to have adapted well to all the extraordinary things in the 20th century, like mass air travel. I have every faith in our ability to cope with these developments," he says. But there may be real drawbacks. "One of the ways you may be able to keep people alive for 150 years is by keeping them pre-pubescent until they are in their forties, using hormone treatments. I'm not sure people would go for that. Maybe there is going to have to be some sort of trade-off, say between losing the ability to have lots of children in return for a longer life."

'Why We Age' by Steven N Austad, is published by John Wiley and Sons, price pounds 19.99

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