Source: Guardian
Date: 30 June 2001

A lease on life

It is almost within our grasp. There are now medications that make worms live longer. Mice are responding, too. So it won't be long before humans might be able to live to 120 or more. In this special report, James Meek talks to the scientists who can make it happen and asks: do we really want to live for ever, or even into the next century?

James Meek

There must have been old people in Australia in the 1960s, but Simon Melov doesn't remember seeing any until his English grandparents came to visit, when he was five or six years old. One day, his grandmother was washing her hands in the sink. He watched. He remembers studying her hand, and all of a sudden looking up at her lined face and realising how different she appeared from him and his parents. His mind lurched. He thought, "What is that?"

Few people remember the moment in their childhood when they discovered ageing. For Melov, it became an obsession. He devoured science fiction, enraptured by books such as Robert Heinlein's 1973 novel Time Enough For Love, about a man born in the 20th century who lives to be 2,000 years old. In his early teens, Melov was already plotting out a career in a field that barely existed: the science of how and why we age, and whether ageing can be slowed or stopped.

At 38, reality has merged with Melov's dreams. He is a biochemist experimenting with previously untried drugs which, he believes, are capable of lengthening human lifespan. Hidden behind a set of anti-contaminant barriers at the Buck Institute near San Francisco, mice are being dosed with them. They have already been shown to work in worms. Within a year, they are likely to be given to human volunteers.

The human patients will be taking the drugs, known as synthetic catalytic scavengers, or SCS compounds, as a treatment for strokes and radiation burns. But they will be watched for signs that the destructive processes which wear down the trillions of cells in their bodies over the years are being chemically restrained. If that happens, it means that a yearning as old as civilisation - artificially to extend human lifespan - is within reach.

"It's going to require some time, and it's also going to require a lot of critical analysis and replication," said Melov. "But we're not talking about decades here. Science moves fast now." In the 1980s, that kind of talk would have put Melov out on the lunatic fringe, in with the army of fraudsters and fantasists who for millennia have cashed in on our reluctance to surrender youthful vigour to the inexorable hand of time.

Largely obscured from the public in the white noise of scientific claim and counter-claim, the past decade has seen a revolution. A current of research flowing through the heavyweight journals is eroding conventional wisdom that maximum human lifespan is fixed at about 120 years. We may not be machines, the argument runs, but our bodies are: wonderful, flexible, self-maintaining machines. Once we isolate the cellular mechanisms that allow us to age, there is no obvious reason why we shouldn't reset them, repair them, or help them to repair themselves.

"Over the past 2,000 years, we haven't come very far, and there's been a lot of snake oil, a lot of claims made without any real impact on human lifespan," said Melov. "Hygiene has changed tremendously, infant mortality has changed tremendously, but intervention in the basic ageing process hasn't really been realistic until the last 10 years. I think the next 10 years is going to be very, very interesting."

The Buck Institute for Age Research rises over oak trees on a hillside high above Highway 101, the six-laner that crosses the Golden Gate Bridge from San Francisco into Marin County. It opened last year. It aims to be the world's leading centre for scientific investigation into what makes us grow old, but it is already more than that. It is a shouted statement of intent from the US baby-boomers, as the first of them head into their 50s, that they don't intend to go quietly to their retirement homes and their graves after three score years and 10. The Buck isn't some low-slung clutter of brick and fibreglass. The trustees of a billion-dollar trust fund, left by the philanthropist Beryl Buck, commissioned the architect IM Pei, who designed the Louvre pyramid, to build it. He has given them a $50m temple of science that would satisfy the imagination of HG Wells or Cubby Broccoli. Built of razor-edged blocks of yellow limestone, it is filled inside with light, air and glistening expanses of floor across which tiny figures walk with a tock-tock of heels. The aspiration is clear. The best scientists will be drawn, and will deliver answers to some of the deepest mysteries of life and death.

The Buck has competition. At Cynthia Kenyon's lab at the University of California, San Francisco, they have found that modifying a single gene in a worm can double its lifespan. As with Melov's drugs, it's a big jump from worms to people, but Kenyon is certain that the transition is possible.

The wider scientific community is used to extraordinary claims for anti-ageing therapies. But the fact that startling results are now being achieved in labs run by respected scientists, scrupulously checked and peer-reviewed, is splitting the field of ageing research into two warring camps. In one are those who believe, like Melov and Kenyon, that extending maximum human lifespan is practical and desirable. In the other are those who believe quality of life, rather than length, is what matters.

Leonard Hayflick, a veteran of the ageing field, wants to see science building on the medical triumphs of the last century, which saw average lifespan soar, in the case of Britain to 75 for men and 80 for women. Trying to break the 120-year barrier is a waste of time, he argues. Much better to focus not on lifespan but on healthspan, lengthening our active lives.

"I challenge anyone to describe a scenario in which the power by a human to arrest or stop the ageing process will benefit either individuals or society in general, despite the glib belief that it's desirable," said Hayflick. "I'm an optimist. Anyone who believes in manipulating the human ageing process is a terrible pessimist. I don't want to be alive when that's possible. I don't want to give another Adolf Hitler, a Saddam Hussein, another 50 years of life. Every time someone like that dies a natural death, people should thank their God, whoever that might be, for the phenomenon of ageing." One April day in 1934, at the age of 69, William Butler Yeats entered the Harley Street clinic of an Australian sexologist, Norman Haire. Sunk into gloom, convinced that his inspiration and his sexual potency were decaying together, the poet had heard about an operation that promised to rejuvenate old men.

Although the procedure was called a Steinach operation (after its inventor, Eugen Steinach, a Viennese doctor), it was, in effect, a vasectomy. It took 15 minutes. From a scientific point of view, it shouldn't have worked. But Yeats, who had dreaded the effect of age on his virility since he was young, wanted so hard to believe in it that he was, mentally at least, given new energy. Six months later, he embarked on a close new friendship with a beautiful 27-year-old actress, Margot Ruddock. His late poetry - he lived and wrote until 1939 - burned with fresh fire, and some defensiveness. The Dublin papers started calling Yeats "the gland old man".

The poet wrote The Spur, a four-line verse: "You think it horrible that lust and rage/Should dance attention upon my old age;/They were not such a plague when I was young;/What else have I to spur me into song?"

The Steinach operation didn't always renew its beneficiaries. Sigmund Freud had it done in 1926. He said it did nothing for him. Another Steinach patient, Albert Wilson, was so enthusiastic about the benefits of the operation that he booked the Albert Hall to deliver a lecture entitled How I Was Made Twenty Years Younger. On the eve of the lecture, he died.

The yearning to live longer and the yearning to be beautiful and sexually potent for longer are very close, but distinct. They're both about ageing. But a therapy for one is not necessarily a therapy for the other. Even the most optimistic of the ageing researchers I spoke to did not foresee their research leading to a century of smooth skin and virility. They see ageing slowed, not frozen. Yet that's what millions of Britons and Americans want, and believe they can have. The take-up figures show huge faith in two genuine anti-ageing therapies that don't actually lengthen life, and may shorten it: Viagra, and cosmetic surgery.

"I don't want to be 42. I want to be 22 again," said John Pickering, clinical services manager of Transform, the Manchester-based cosmetic surgery chain that operates in 15 towns, mainly in the Midlands and the north of England. "People are looking for a quick fix.

I agreed with Jack Dee on Big Brother when one of the other contestants was telling him that a vegetarian diet puts 10 years on your life, and he said, yes, it puts 10 years on at the end, when you're shitting and pissing yourself, and you don't want to live like that.

"There's a lot of disposable income up here, unemployment's low, people aren't paying fortunes for their housing. It's buoyant. There are a lot more things to do outside work than ever before, and you've got to have the face for it, you've got to look good. Longevity pills? Well, it depends on the life you're going to lead, and how fit you're going to be when you get to that stage. I don't think people think long-term. They think 'I'm reasonably fit now, I've got money in the bank, I see the difference cosmetic surgery makes, I want it now'. We see it with fat removal. Some of the treatments we do you won't see the results for up to six months. We've had people coming back after three days complaining that there's no difference."

The first facelift was carried out by a Berlin surgeon, Eugen Hollander, in 1901. The way he told the story, the initiative and the design was the patient's, not his - a Polish baroness had worked out that if skin in front of her ear was removed, the skin around her mouth would be tightened, and she would look younger, so she made a sketch of her plan, presented it to Hollander, and told him to get on with it. Each year in the US, hundreds of thousands of facelifts and smaller "lunch-hour" procedures such as fat, collagen and Botox injections are carried out. Britain's smaller cosmetic surgery market is projected to be worth more than 250m by 2004, and although much of that covers fat reduction and breast enlargement, a significant proportion will be "anti-ageing" work.

We march into the third millennium convinced that we can become better, writes Sander Gilman in his cultural history of aesthetic surgery, Making The Body Beautiful. "We can change our bodies and our lives. We will fit ourselves into society by restructuring our bodies to make our souls happy... For the acquisition (not merely the pursuit) of happiness - or at least the absence of sadness - is the great promise of our post-Prozac world. Aesthetic surgery is one of the means by which we believe we can accomplish this goal."

Surgery and the little blue pill are not the answer to ageing. What they do show is how much people are willing to pay, and what they are willing to submit themselves to, in order to gain more for their bodies than nature provided. There comes a point where the importance of beauty treatment and impotence therapy are overridden by the simple desire for a few more years of life. Who wants to live for ever? Only a fool. Who wants to die today? A few desperate people. But nobody wants to die next month.

Asked last year what was good about growing old, Lauren Bacall, now 77, was blunt. She said: "Not much. No, you know what they say, 'Getting older ain't for sissies!' Considering the alternative it is great, but in actual fact it is a nightmare because you see yourself disintegrate."

The "alternative" is death. From the point of view of most teenagers, anyone who reaches 50 has, conceptually, already boarded the bus to the valley of death. In our 30s, it is astonishingly easy to believe that being dead might be preferable to being a wrinkly 85-year-old. But by the time we reach our 70s, we don't want death to rob us of the next decade, or the next.

One day I called up Norman Rawlings, a retired foundryman living in Shipley. Rawlings is 75. He had just come back from a nursing home in Guiseley visiting his 108-year-old mother, Florence; she recently turned 109, one of the oldest women in Britain. Florence heads a huge family: six living children - a seventh child, a son, died during the second world war - 16 grandchildren, 23 great-grandchildren and six great-great-grandchildren.

Norman said that his mother was in two minds about living so long. "She says God's forgotten her and passed her by," he said. "She always says she'd rather be gone. But she stays. She obviously fights against it. She don't ail much."

He knows that the longevity of his mother and his brothers and sisters - their ages range from 88 to 68 - means his own chances of living on are good. The idea of decades stretching ahead are daunting. He has a beautiful garden, but he gets bored with it: he misses the foundry, and would go back to work if he could.

"I'm not sure myself about living to be 100. I think things ought to take their course," he said. "Having said that, I think the mid-80s is a nice age. If you're capable and can still have a pint or two."

Human beings are older than they used to be. Swedish scientists showed recently that in their own country, maximum age at death had increased by about eight years since the 1860s, from 100 to 108. That was a fiddly calculation. But you don't have to be an expert in demographics to see how life expectancy has gone up. In his book Time Of Our Lives, the British biogerontologist Tom Kirkwood points out that the shock at Princess Diana's death had much to do with our growing unfamiliarity with death as something affecting the under-65s. Diana was 36 when she died; today, only 2.3% of Britons will die before their 35th birthday. In the 1880s, without modern antibiotics, vaccines and surgical techniques, accidents and infectious diseases killed 43% of Britons before they reached Diana's age. Further up the chart, the figures are even more telling. For every million people born, 61% now survive to the age of 75. At the end of the 19th century, it was only 16%. By 2020, a billion people worldwide will be over 60. In Britain, the fastest growing age group is centenarians; there are around 9,000 now, and their numbers are doubling every decade.

As we age, we experience bizarre changes. Jaws shrink and gums recede; teeth fall out. Bones become thinner and prone to break. Joints become damaged and inflamed. Memory and mental processes are impaired. Blood vessels wear away and their walls stiffen, as do lungs. Eyesight and hearing begin to dull. Skin sags and wrinkles.

Why does it have to be this way? Why has nature given us this lifespan, and not a longer or a shorter one? The Pacific coast of North America, where many of the world's most outspoken researchers on life-extension work, abounds in natural Methuselahs. Why should it be, after all, that the bristlecone pines of the Sierra Nevada in southern California can live for 4,000 years, or the redwoods of the foggy north are still stretching their 350ft green crowns to the light when they are a 1,000 years old, while other plants are lucky to last decades? Why should we fade and die at the threshold of our second century when one species of mammals, bowhead whales off Alaska - as new research suggests - live to be 220?

The simple answer doesn't do much for our human sense of dignity. From the point of view of evolution, our bodies are nothing more than disposable devices, to be discarded after reproduction. Think of evolution approaching human beings as a designer faced with a set of problems. The aim is to design a creature that can survive to sexual maturity and reproduce itself. The creature will need to match its energy expenditure to the food available, will face a certain set of environmental hazards (cold, disease, sabre-toothed tigers) and will need to be able to correct cumulative mistakes that crop up in its cells as they divide and manufacture proteins.

The design for humans that evolution came up with hundreds of thousands of years ago is the one we're stuck with today. It's a superb piece of work, dazzling in its intricacy and ingenuity, but it has limitations that only our sheltered society has been able to appreciate. The self-repair mechanism works well up until the point we reach sexual maturity, in the late teens and 20s. After that, it begins to fail. Repair is costly in terms of energy; once a person has reared children, why go on repairing the parent?

In theory, evolution could have come up with a different design, a human who reached sexual maturity decades later, or who went on having children for longer. But then the sabre-tooth factor kicks in. In mankind's hunter-gatherer days, the chances were that something would kill you before you reached your mid-30s. It might have been famine, or murder, or a predator, or a nasty bacterium. There would have been no evolutionary point in having a man or woman who was in their physical prime at 70, if they had only a million-to-one chance of surviving violence and illness for that long. We're a bit like cars. Maybe you could design and build a car that would last 1,000 years. But why would you, if the cars cost a billion pounds each, and were 99% likely to be destroyed in an accident in half that time?

All wild animals, including wild humans, have this in common: they seldom live long enough to find out what getting old is like. "When humans reach the age of 18 or 19 or 20, they reach their maximum physical capacity, but most of it is redundant," said Hayflick. "Once you reach that point, nature doesn't give a damn what happens to you. The proof is that, for more than 99.9 % of the time we have been on this planet, life expectancy at birth has been under 20 years, and we have survived. It's only been in the blink of an eye, in evolutionary terms, that we have had people living with life expectancies of 60, 70, 80. That's a new experience for humans. It's never happened before."

The wide acceptance of the evolutionary theory of ageing has not daunted those who believe we can artificially lengthen life. On the contrary, it has emboldened researchers to hunt for the cellular repair mechanisms that seem to work so well when we are young but that begin to break down as we pass through our 30s. They are daring to hope mankind could pick up where evolution left off.

There will never be a clinical trial of a lifespan-extending drug, as such, in human beings. Drugs company shareholders aren't going to wait around, grow old and die themselves while researchers follow volunteers through a 100-year experiment. To take the first steps, scientists need an animal that is outstandingly fecund, cheap to keep, and has a very short natural life span. The nematode worm, c. elegans, is only one millimetre long, and breeds like there's no tomorrow, which after 22 days there isn't - that's how long it usually lives. On the face of it, it is a primitive form of life, far removed from human beings. We have 100 trillion cells in our bodies. The worm has exactly 959. We have 100 billion brain cells. The worm has 302. But if you compare the number of genes, we don't look so superior. The worm has 19,000. Latest estimates suggest we have about 30,000. It's that genetic complexity which convinced researchers, long before nematodes were used in ageing research, that they could be an experimental model for higher animals such as human beings.

It was Gordon Lithgow, a microbiologist at Manchester University, who used nematodes to test whether the SCS drugs really did have an effect on lifespan. His worm ranch is a deceptively casual affair. When he showed me around, he rummaged in a box with much clattering and shuffling, pulled out a plastic dish and slotted it into a microscope. To the naked eye, the worms were barely visible, but through the eyepiece I could see sleek silvery beasts at play in a lake of culture fluid - old ones, mature ones, baby ones, wriggling away in ignorance of their honour as prospective Methuselahs.

Worms were the bait that got Lithgow hooked on ageing. Originally from the west of Scotland, he was working for Ciba Geigy in Switzerland in 1991, wondering if he would find anything interesting to do with his degree, when he opened up a copy of the journal Science and read a paper by Colorado University's Tom Johnson. The contents stunned him.

"I read the opening paragraphs and realised that this was the description of a single gene which, when modified, extended the lifespan of a worm by 70 or 80%," he said. "It was just unbelievable. My pulse started racing. I thought this is incredible, this is it - if this is right, then understanding how ageing happens will be solved in the way we've solved other problems.

"Before that, the first paragraph of everything I'd read about ageing said something like 'ageing is a complex multi-factorial process, controlled by environmental factors and many thousands of genes'. And then along comes a guy like Tom Johnson and says, 'Well, maybe that's right, but I've manipulated this one gene, which in molecular terms means I've slightly shifted this cloud of electrons from here to here, and that influences the entire lifespan of the organism.' "

Johnson called the gene "age-1". The effect of altering it was to turn it into a powerful mechanism against one of the body's known internal enemies - free radicals - rogue oxygen-based molecules that go blundering through our cells, damaging DNA and proteins.

About one-and-a-half billion years ago, an ancestor of worms and humans entered into a Faustian pact. Our common forefather was a single-celled organism, advanced enough for primeval soup society, but sluggish and ill-fitted for greater things. One fateful day, a microbe entered the cell and forged a symbiotic relationship. The microbe eventually became something called a mitochondrion, excelling at the manufacture of a substance called ATP, which provides energy for life-sustaining chemical reactions. That ancient marriage of cell and mitochondrion is still with us. Almost every one of our cells contains a descendant of that ur-microbe, churning out ATP like a miniature power station. Unfortunately, like most power stations, mitochondria produce waste, in the form of free radicals. Without mitochondria, those single cells would never have had the competitive advantage to evolve into human beings. It is far from proven, but the price we and our relatives - worms, mice, mushrooms - pay for having come this far may be mortality. "Without the mitochondrion, life as we live it is not possible," said Lithgow. "It's a bit like having a nuclear reactor in your back garden. You've got all this cheap energy, but you've also got all these incredibly toxic byproducts."

The theory that free-radical damage is the central factor in ageing goes back to the 1950s. The wild swings in the lifespan of worms created by tinkering with genes involved in repairing that damage seemed powerful additional evidence. For decades, scientists (and non-scientists looking for a way to make easy money) have sought a drug that would counter the effects of free radicals in animals. Vitamins C and E are known antioxidants, but results in the lab have been disappointing. One of the body's own anti-free radical agents, a powerful enzyme known as SOD, has been synthesized, but it, too, does not seem to work well when delivered externally.

In 1997, while working in Atlanta, Melov was investigating new kinds of antioxidants when he came across Eukarion, a tiny firm on the outskirts of Boston that was working with a novel class of drugs called synthetic catalytic scavengers. There are two extraordinary things about SCS chemicals that appeal to ageing researchers. First, with every reaction each SCS molecule mops up one of the most pernicious free radicals - a superoxide ion - but makes another dangerous molecule, hydrogen peroxide, harmless. The other bonus is that they are catalytic. In other words, unlike vitamin C, they aren't one-shot deals: every time an SCS molecule does its work, another SCS molecule is created - the drug will go on working for as long as it remains in the body.

After some encouraging early results, Melov asked Lithgow if he could carry out a full trial of two of Eukarion's drugs in nematode worms. Lithgow agreed. The outcome, achieved in 1998 but only published last September in Science, was historic. The drugs increased the lifespan of the worms, on average, by 44%. Even more telling, a mutant worm that suffered acute free-radical damage and usually died early had a normal nematode lifespan restored by the chemical. It was the first time that a drug had been convincingly shown to extend the lifespan of any organism. When the news broke, Eukarion was besieged by people offering themselves as guinea pigs for the first human trials.

I asked Lithgow if he would take an SCS himself. He said he wouldn't. "There are dangers in taking any compounds," he said. "There are particular dangers in interfering with something you've defined as an ageing mechanism, because free radicals are also used in the body to do things that are useful. For every fact we've got at the moment, there are a thousand questions."

Eukarion is about to seek permission from the US Food and Drug administration to carry out clinical trials of SCS compounds in humans, to treat radiation burns caused by cancer therapy, and stroke-related brain damage. Susan Doctorow of Eukarion, who developed the SCS drugs with the company's founder, Bernard Malfroy, said: "We're not going to test our compounds for their effects on ageing. But if the effect of treating diseases of old age is to extend life, everyone's going to be happy."

In California, Melov also says he wouldn't take an SCS until its toxicity had been tested in human volunteers. But he is more gung-ho than Lithgow or Doctorow about the future of the drug as an anti-ageing therapy. "I think in the next few years we will see extension of lifespan in mammals through both genetic and pharmacological approaches, and at that point there will be a very substantial paradigm shift," he said. "We have mice which are undergoing this therapy as we sit here. It's under way."

No one is sure yet how a mammal dosed with SCS compounds would age if its lifespan was extended. In worms, the animal lives longer but grows at the same rate and remains fertile. It doesn't sink into a long, slow decline. This is the Tithonian nightmare, named after Tithonus, the mortal of Greek legend who was loved by Eos, goddess of the dawn. She begged Zeus to make him immortal, and he did. But she forgot to ask for her lover to remain youthful, and he lapsed into helpless senility. "I think from what we understand of the biology at this stage this is not going to happen," said Melov. "All of our model systems to date show that if you increase lifespan, by whatever strategy, you increase healthspan, too."

Melov showed me one of the SCS compounds, codenamed Euk-134. He shook a little out of a test tube on to a piece of paper. It was a pitch-black powder resembling iron filings. I rubbed some between my thumb and finger. It left a yellow, nicotine-like stain. While his head was turned, and in gross violation of his instructions, I put a little on the end of my tongue. It had a bitter taste. As I drove down the hill later, I tried to sense if I felt any younger. I didn't. I was still 38, my back still hurt from the rental-car seat, and it was still raining.

We think that time travel is impossible, but all of us are travellers through time. We travel into the future at the steady rate of one second every second, and travel into the past as far as our dreams and memories allow.

Centuries ago, the young regarded the old with awe. They had made an extraordinary journey through time and had seen things no one else around them had seen. Who else was there to inspire the twentysomethings with stories of their glorious ancestors, and to reassure them when the waters rose and the sheep sickened that there had been floods and plagues before, and they'd coped?

In 2001, the over-70s don't have the rarity value they used to. The country teems with time travellers who have survived the voyage from the 1930s and beyond. Buoyed along by prosperity and modern medicine, many have arrived with their health and mental powers only lightly affected by the journey, and are eager to travel on. The young don't crowd around the old for stories of the days before television, any more than tourists returning to Heathrow from an Orlando package tour are mobbed like Chistopher Columbus for tales of the unknown.

For those just setting out, the prospect is of a longer voyage still. Today, British parents can expect a healthy newborn baby to live about 75 years if it's a boy, 80 if it's a girl. That's life expectancy: the average. Without any new medical discoveries, a remarkable number will see in the 22nd century. On present trends, tens of thousands of the 700,000 British babies born this year will live to be 100 or more.

If scientists such as Melov and Kenyon are right, even these limits will be breached. If science manages to cure the diseases of old age, all that will be left to cure is ageing itself, and that, they believe, is possible. What if it was? What if average life expectancy in Britain increased to 120? The longest-lived would see their 190th birthday. At 35, you might have lived only a fifth of your life.

If scientists did come up with anti-ageing drugs, there would be powerful arguments against administering them while children were growing up, but they would be steadily less useful as natural ageing set in. Although dosing the healthy with prophylactics against getting old would generate titanic ethical debates, medication could be made available from, say, age 20. This could make a 35-year-old the equivalent of a 28-year-old; at 50, you'd seem around 36; at 100, as spry as a present day 63-year-old.

An enhanced-lifespan world would have strange consequences. At the moment, accidents - mainly traffic accidents - come a distant third after heart disease and cancer as a cause of death in the developed world. If life expectancy went up to 120, the likelihood of a healthy person's life being cut short in an accident would rise sharply. In the imaginations of the lifespan-extension camp, the future is filled with nonagenarian bungee-jumpers and white-water rafters, but if, at 60, you had your whole life in front of you, just crossing the road might seem risky enough. Divorce rates are so high now that two out of five couples who embark on marriage will see it end in separation before one of them dies. It puts a heavy demand on love to ask it to keep men and women together for 50 years. What of 100 years of marriage, or 150? What if one partner took anti-ageing medication and another didn't? What if friends, as well as lovers, siblings, children, aged at different rates?

Culturally, the generations are already Balkanised. It is hard with the lifespan we have now for someone born in 1920 to find a common language with an 80s baby. If lifespan was stretched further, the strain of keeping the multigenerational peace would make the creation of a harmonious multiethnic Britain look simple. Those who grew up loving Glenn Miller and Bing Crosby may find it hard to deal with Aphex Twin, but supposing there were millions of Britons alive today who grew up not knowing recorded music of any kind? Not just without computers, but without electricity? Not just veterans of the second world war, but jingling their medals from the siege of Mafeking?

Working life would undergo a revolution. There would be no question of keeping the retirement age at 65. There is a harsh truth here. State, private and occupational pensions are paid out on the expectation that the average pensioner will die not long after they stop working. Already, because of the five-year difference in life expectancy between men and women, women who buy annuities out of private pension plans on retirement get a lower monthly payout than men, even if they step down at the same time.

To keep the actuaries happy in a long-life world, decades would need to be added to the retirement age. There is a brave hope that the long-lived masses to come would hop eagerly from career to career, stopping off to acquire new specialisms along the way. But would they? British judges, for instance, don't seem eager to retire, or switch careers, as it is. How much more chilling if we had a judiciary that had first donned horsehair a century ago, when women didn't have the vote, when John Buchan wrote bestselling novels with white heroes who taught black men their place, when society was clearly divided into masters and servants. In almost 50 years on the throne, the Queen shows no sign of having learned anything, least of all when to quit and take up some other activity.

The pioneering time travellers who have already made it to their 11th, 12th or even 13th decades have shown that it is possible to stake out a new life, far away from where in time they were born. The oldest person for whom reliable records exist, the Frenchwoman Jeanne Calment, who died in 1997 aged 122, appeared to enjoy herself to the end. She even managed to outlive the lawyer who took over her flat in exchange for a lifetime pension: his family, locked into the contract, lost heavily on the deal.

In Sardinia, where there is an extraordinary, and so far unexplained, cluster of male centenarians and supercentenarians (110-plus), the Brundu brothers, Pietro, 103, and Antonio, 101, have managed to keep loneliness, retirement homes and dependence on their children at bay by moving in together.

Gayirkhan Iriskhanov, from Dagestan in the Russian-owned part of the Caucasus - an area famed for its long-lived inhabitants - claims to be 134, although he is probably only 112. He is the patriarch of a family of 95 children, grandchildren and great-grandchildren, but he cooks for himself and, despite offers, prefers bachelorhood after outliving three wives.

It's hard to know where to draw the line between ageing and the diseases of old age. An 80-year-old man may be in perfect health, yet if a 20-year-old had the constitution of the same 80-year-old, he'd be hospitalised. Fewer than 1% of death certificates in Britain give old age as a cause of death. Yet everyone, as they get older, experiences a hardening of veins and arteries, a central cause of cardiovascular disease, which is the commonest cause of death in the developed world.

Of the billions spent annually on medical research, a tiny fraction goes towards ageing research. The big funders, such as the Medical Research Council in the UK or the National Institute on Ageing in the US, will not fund human lifespan experiments. If you want to get public money for that, you have to present it as a study of a particular disease, such as Alzheimer's. This is not surprising. Cure Alzheimer's and other forms of late-onset dementia, cure diseases of bones and joints, such as osteoarthritis and rheumatism, and the decades of decline endured by so many people in their 70s, 80s and 90s would be transformed.

"We want to compress the many years spent in decrepitude to a minimum," said Leonard Hayflick. "It's the only acceptable scenario: to live to some arbitrary old age where your physical and mental capacities remain completely intact, and then to drop dead at the stroke of midnight. Of all scenarios I can think of, that's the only one that makes sense, and it's not perfect by any means, because I don't think anyone would accept dropping dead at full capacity."

Opponents of investment in serious anti-ageing research can muster a powerful array of arguments. Even if lifespan-extension drugs could be made to work, they would be powerless against environmental factors. Carcinogens would still be all around us. Sunshine would still make us wrinkly - most skin ageing is now thought to be caused by light.

The complexity of the human machine means that there are few medicines without side-effects. "There are just too many ageing processes that are simultaneous," said Caleb Finch, of the University of Southern California, author of the most authoritative guide to comparative ageing in different species. "There's a classic problem clinicians are facing: women who have serious loss of bone as they grow older. If you supply them with oestrogen, you'll slow that loss. You reduce the risk of a hip fracture. But by giving them oestrogen, you also increase the risk of cancer."

There are moral objections, too, of course. It seems incredible that a single health measure, taken overnight, can raise a normal newborn child's life expectancy by 40 years. That health measure exists. It is a plane flight. Forty years is the difference in life expectancy between a baby born in Britain and a baby born in Sierra Leone. "The biggest thing to extend lifespan is clean drinking water, and the fact that everyone in the world doesn't have access to that is a much bigger moral issue than any lifespan extension through some drug will ever be," conceded Lithgow. "The rich and the developed will have access to technology that the poor and the underdeveloped won't have. It's abhorrent, of course, the idea that a certain amount of money will be able to buy you an extra 50 years of life. But, unfortunately, that's what we have at the moment. The moral issues we have to think about when it comes to lifespan extension are actually not very different from the moral issues that we should be dealing with at the moment."

Some in the lifespan-extension camp see cynical calculations at work - among them Michael Rose of the University of California at Irvine, who has doubled the life of fruit flies by forcing them to go on reproducing for longer. "They don't want social security to be fucked up. It's that simple," he said. "Governments do not want a Manhattan Project on ageing because all these OECD countries are in hock big time with their pension plans, and the last thing they need is some scientist coming along and blowing up their budgets. It's Armageddon."

Rose, who is certain that his fly work shows human metabolisms could be manipulated to extend life, has given up trying to get money for ageing research from the public sector. But his graduate students still sit around a bench like assembly-line workers, methodically analysing thousands of fruit flies. "After fruit flies get to a certain point, ageing stops, and you have a different phase of life in which organisms cease to age. In some cases, life seems to get better," said Rose. "This is the phase I call immortality."

There is statistical evidence, he points out, that when humans become very old - in their 90s - they stop ageing, although by that time enough damage has been done to prevent them living for ever. "Can we make organisms that hit immortality really fast and go on living? Instead of making a fruit fly that lives twice as long, one that lives 30 times as long? That's what we are working on. Please don't imply that I'm thinking of doing this in humans in 10 years' time, but two or three centuries from now we may well be able to make humans live for thousands of years. The basic biology says we can do this.

"I personally don't have a blood lust where anti-ageing is concerned, but to me it's like this really interesting, challenging technological objective. There's that sort of race-to-the-moon aspect to it. Of course, if I really had a desire to be a benefactor to humanity I'd work on infant diarrhoea."

There are two opposing visions of super-long life, a dream and a nightmare. The ideal is sketched by Virginia Woolf in her novel Orlando - of a hero/heroine born in the 16th century who ages so slowly that, 400 years later, he/she is only in his/he 30s; time enough to sow wild oats, see the world, make and lose fortunes, change sex to become a mother and wife, acquire wisdom, sense the passing of the ages and, at last, become a writer. All without a wrinkle. Orlando stays beautiful to the last.

In Gulliver's Travels, Jonathan Swift sees the dark side. The Struldbruggs are born immortal but, instead of staying young, they age as quickly as ordinary people. They have to come to terms with an infinity of decrepitude.

"When they come to four-score Years, which is reckoned the Extremity of living in this Country, they had not only all the Follies and Infirmities of other old Men, but many more which arose from the dreadful Prospect of never dying," wrote Swift. "They were not only Opinionative, Peevish, Covetous, Morose, Vain, Talkative, but uncapable of Friendship, and dead to all natural Affection, which never descended below their Grand-children. Envy and Impotent Desires are their prevailing Passions."

Roy Walford is neither an Orlando nor a Struldbrugg. At 76, he has been thinking about how we grow old for more than 60 years, since he wrote a high-school essay about it in San Diego in 1941. Most of the lifespan-extension optimists I met in California said they took no special steps to stay young. Walford is different. He has done more than any other respected academic in the ageing research field to live the theories he puts forward.

Walford argues that the only therapy proven to extend natural lifespan in mammals is calorie restriction. Most of his peers would agree. Bluntly, it means eating less. Not just keeping your body at its natural "set point", where you would be considered quite healthy and not overweight, but taking it below that, by 10 or 20%. It fits in well with the free-radical theory of ageing. Evolution may have given us mechanisms that can subtly slow our metabolisms in time of food shortages, giving us time out from breeding and, to some extent, ageing. Less energy in, less energy out, less ATP - fewer free radicals. It's just that fasting is so much more bleak a prospect than a lick of bitter black powder before bedtime.

Walford did much of the pioneering work on the effects of calorie restriction in rodents. By forcing rats and mice to fast, he was able to double their lifespan. He's subjected himself to the same experiment for much of the past two decades. Although his popular book is called the 120-Year Diet, he thinks a calorie-restricted human could reach 140.

Typically, for breakfast, he'll eat a milk shake with bananas and a muffin. Lunch is a big vegetable salad; dinner, steamed vegetables and fish. The only thing ruled out is calories without nutrients, or anything with a lot of sugar in. A little alcohol is allowed but smoking is forbidden. His own set point is about 150 pounds - "That's what I wrestled at in college" - and he's got it down to about 132.

Besides his lab work he has set up a guerrilla theatre troupe to oppose the Vietnam war, hunted rare fish in the Matto Grosso, taken the body temperatures of Indian fakirs, walked across Africa from Dar Es Salaam to Kinshasa and lived for years in a hermetically sealed artificial "biosphere". Opposite his chair is a blown-up black-and-white photograph of one of his fellow biospheronauts. She is young, fey and naked.

Walford has passed the average lifespan for American males by four years, his blue eyes are still bright, and he is alert. But his face is deeply lined and his voice is thin and hoarse. He seems frail. He's old. More than that: without any disrespect for a wise and charming man, he doesn't look good for his age. At 72, Hayflick, who says he follows no particular anti-ageing regimen, could easily pass for someone in his early 60s. Walford is 76, but you wouldn't be surprised to hear he was in his mid-80s. He pointed out that environmental and genetic variability meant that extended human life will still vary greatly in length, whatever you do.

I asked him whether, perhaps, a varied life was a substitute for an extended one. Wouldn't it be sad if scientists offered the world a way to lengthen our lives simply so we could eat junk food and sit on the sofa playing Nintendo for another 50 years?

"I'm not going to be satisfied with only going to be 80 or 85 just because a lot of other people don't know what to do with their lives," he replied.

When the French writer Michel Houellebecq's cult novel, Atomised, appeared in English last year, whether because they were mesmerised by the sex or because they thought it silly, few of the critics paid much attention to the science of it - the goal of one of the heroes, a molecular biologist, to redesign humanity at the atomic level to create an immortal successor race. Houellebecq was romantic to suggest a single man could do it. But he was prophetic in a sense. In an uncoordinated, unspoken, piecemeal way, redesign of humanity is what the researchers and human geneticists who work on ageing are inching towards. Big jumps in human lifespan are going to come only from tinkering at the level of molecules, and that is going to work only when our knowledge of the way hundreds of thousands of different molecules interact in our cells is far deeper than it is now.

That doesn't mean drugs to make us live a little longer couldn't be with us as soon as Melov thinks. The 20th century gave us several extra decades of life expectancy; the 21st could give us another one, and increase maximum lifespan, too.

I think we'll take those extra years, if they're offered. I think we'll take them in the full knowledge that we still don't know how to use the extra years we have already. We'll take them grudgingly, as a poor substitute for eternal youth, but we'll take them all the same, because, whatever our bluff and bravado, the art of leaving life at just the right time is so much harder than staying until called.

At the University of California, I got talking to a graduate student from Portugal, Nuno Oliveira. The work with worms intrigued him. Taking it to humans was something else. "I don't really understand the deep reason why people want to live longer. Is it fear of death? Because you'll die, anyway. Is it fear of physical and mental decay? Well, you'll get that all the same, even if you die later."
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