To Be Continued

However successfully we dodge the misfortunes of life, however cautious, heroic or lucky we may be, the mere passage of time kills us. And before doing so, it impairs us, which is worse. Our chief defense against the awareness of death is that it can be put forward in time--it will happen, but not yet. Set a time limit and the defenses crumble--which is why cancer, the best-known terminal disease, inspires such horror in modern man. It is the most recognizable counterpart of that unpleasant skeleton that taps king, merchant and reveler on the shoulder in medieval paintings of the dance of death. The rarity of untimely death, thanks to modern medicine, sharpens our awareness of our other enemy, aging.

Aging means that we can name a year in which we shall no longer be alive. And there is another date, perhaps 15 or 20 years sooner, when, if things stay as they are, we shall be alive, but not fully. Death is bad enough, but before death there is, as Yeats puts it:

the death of friends, or deathof every brilliant eyethat made a catch in the breath.

This death before death will begin, for most of us, around 65 and will continue until it kills us. It's not strictly a disease; one may hope to avoid diseases. But age we cannot avoid. It's the only disease we've all got, and, like cancer patients, we know roughly when we may expect to fail and die of it.

If, that is, things stay as they are; and that depends largely on decisions now being made. Adults alive today between the ages of 20 and 50 are the first humans to stand a fighting chance of seeing science begin to bring the process of aging under control. If this happens, as it easily could, within the next 10 to 15 years, they may share that benefit. A relatively small investment now could make the accomplishment nearly certain. What amazes workers in this field of medical biology is that so few of the beneficiaries--and, indeed, so few scientists--realize how close we are to this achievement.

In his article The Immortalist [Playboy, May 1969], Alan Harrington rightly interpreted the mood of our culture: The present generation cannot, in fact, be immortal, but it is not prepared to go on being mortal on the present time scale. If Harrington's view seems brash at first, it still represents a ground swell of feeling that is about to be implemented in science. We can now begin to offer hard predictions, both as to what is possible in the prolonging of life and as to when developments will take place.

Speed in attaining a scientific possibility and minimal disturbance of society by it depend on technological forecasts. In 1938, Hahn and Strassmann demonstrated uranium fission and showed, though they didn't know it, that atomic energy was a feasible project. The first atomic bomb was used in warfare only seven years later. In 1961, John F. Kennedy was advised that, in the present state of the art, an American could be put on the moon by 1970, given enough Government support. That this was technically possible had been known since before the first Sputnik. All that was needed was the decision to go ahead.

Students of the future call the moment at which a major possibility is seen to be practicable the Hahn-Strassmann point. Often it passes unnoticed, except by the men on the job. This has happened with the control of human aging, less dramatically than with nuclear fission but just as definitely, over the past decade. We know that human aging can almost certainly be slowed and we know how to set about trying. The necessary research, moreover, is cheap by AEC and NASA standards. The whole project would probably cost as much as one Saturn rocket or one big-dish antenna. The prestige for the achievement of a "first" would be, in political terms, not far short of a moon landing. One can infer from this that even if aging research is not promoted as a priority, it will happen, and if it is so promoted, it will happen fast. With the present research investment, it is likely to happen in America, with a fundamental backup from world science.

Science has two ways of making people live longer: It can stop their dying before their time or it can try to slow down the figurative clock that controls aging, so that old age and death take longer to arrive. So far, it has done the first, and brilliantly. Now, with some Governmental funding, but with strikingly little public awareness of what's afoot, it is about to tackle the second.

In any of the privileged countries, you can expect to become old. This in itself is new--one generation back, your chances of doing this would have been far less secure. Medicine and surgery, prosperity and welfare, have ensured that--war, accident, pollution, suicide and bad luck aside--most of us can hope to die of old age. We shall not, that is, die as young adults of appendicitis or tuberculosis, or as mature adults of pneumonia or childbirth infection. We are most likely, in fact, to die of heart and vessel disease or of cancer. When we do, unless we overeat, smoke cigarettes or inherit a bad hand of genetic cards, we shall also be old. In spite of modern technology and medicine, we shall get old at the same age Moses and Pharaoh did. The human life span has probably not changed throughout history. What has happened through science is that most of us now reach the end of it.

The meaning of old age hasn't changed, either. Though some are harder hit by it than others, and though there are Bertrand Russells and Artur Rubinsteins, who keep the zest for living into their 80s, aging is still loss. At 50 we become stouter and slower; at 60 we tire more easily. Then the skin wrinkles, the muscles weaken, and by 70 our strength is on the average what it was at 14 or so. The mind may or may not stay clear; but if it does, the body cannot match it. And all the time, the mortality from disease steadily climbs. Old age and death are the two great intolerables and, of these, the first is probably less bearable, because we have to live through it. We say that age has its compensations, but we don't speak of compensation unless we've been injured, and few of our notions of compensation survive an open-eyed visit to an old-folks' home.

The truth is that having assured that most of us reach 70, conventional medicine has just about reached the point of diminishing returns. Cure of the two present leading causes of death--cancer and heart and vessel disease--would add about seven years to the total life epectancy, but mainly by helping those unlucky enough to contract these diseases young. At 65, the gain would be under two years; we should simply die a few months later of something else, for aging involves a steady increase in the number and variety of our infirmities. We could improve the quality of life to some extent--for example, by treating our old people decently--but this wouldn't be much of an improvement. The men in old-folks' homes were once vigorous, the women beautiful, or at least young. The only reason we don't follow Yeats and Dylan Thomas' advice and recognize the enormity of what is going to happen to us is that so far, it has looked inevitable.

If aging on the present time scale is really inevitable, we had probably better accept it with dignity. But all the scientific evidence is that it is not. Over the past 20 years, and almost unnoticed even by the general scientific community, an international campaign has been mounted to find out exactly what aging is and whether--and, if so, how--its rate can be slowed. At present, we still don't know exactly what it is, though we have several plausible theories. We do know that the rate of aging can be altered in rats and mice by relatively simple manipulations. In the next five to ten years, there will be experiments on man, to see whether the same techniques can be used clinically. If they can, then from rat and mouse experiments, we could reasonably expect a 20--40-percent increase in the period of adult vigor--the time, that is, before manifest aging changes set in. Insofar as any scientific prediction is safe, we can now say that the length of time before we do this and the number of adults alive today who will be able to benefit from it depend quite simply on the amount of money and energy we put into the project.

Aging is, in biological terms, the increasing inability of the body to maintain itself and perform the operations it once did. Most current theories assume that this results from a loss of information at the cell level. Mammals have basically two kinds of cells--those that are constantly renewed (skin cells, blood cells) and those that live as long as their owner and never divide (brain cells, muscle cells). Both types carry the basic instructions for their orderly behavior in the (continued on page 209) To be Continued (continued from page 114) form of blueprint molecules of deoxyribonucleic acid (DNA).

DNA is the key to most of modern biology. It consists of a long spiral molecule, rather like a computer tape. The chromosomes of each cell contain a number of these molecules, on which are stored, in coded form, all the information needed to turn that cell into a complicated organism--and to determine whether the organism will be a man, a rabbit or a peach tree. This molecule is Jim Watson and Francis Crick's "double helix," which won them a share of the Nobel Prize in 1962; we are just beginning to be able to read the language of its code, which is composed of a series of three-"letter" combinations.

DNA is like a master blueprint for the body and its maintenance. What happens is that from an identical blueprint file in every body cell, copies are taken, and these copies, in turn, are used to specify chemical machine tools, called enzymes. Since a baby differs from a man, and a muscle cell from a blood cell, the body clearly has an elaborate program for transcribing parts of this stored information at one time and ignoring, or switching off, others. If we had a full set of plans for a Saturn rocket, we would need to make one set of jigs and tools for the workshop that builds the engines and another for the guidance-system shop. If some of the blueprints were locked up as soon as the patterns were made, the life of that workshop would be limited to the life span of its now-irreplaceable tools.

Unlike engineering, in which parts are checked and rechecked, biological toolmaking is never 100 percent accurate. In old nematode worms, Israel's Dr. David Gershon has found that all the necessary chemical tools of certain kinds are there, but about half are not working properly. It seems highly probable that at some point in the chain, errors enter the manufacturing process. They may be in the original DNA blueprints, which become smudged or switched off in some or all of the cells with wear and the passing of time. They may be in the copying process or, more probably, in the machine tools, the enzymes. The mischief may be of many kinds. One kind is the injection of "noise," in the communication sense. Random scratches on a negative, wormholes in punch cards, nicks in a phonograph record are noise of this sort; they confuse the original message. Or it may be that since muscle cells and blood cells must clearly use different parts of their original, total blueprint file, some of the blueprints they possess may become unavailable to them and some parts of the system may not be renewable if damaged. The damage could affect nondividing cells so that they ceased to function properly, or it could affect dividing cells so that new cells formed by an old man differ from those of a baby, becoming impaired or foreign.

Luckily, we don't have to find out which of these mechanisms is instrumental in aging. We can alter its rate without knowing. In fact, we are most likely to pinpoint the kind of information loss that's occurring by seeing what tends to counteract it. Basically, we have one big choice: If we're dealing with a phonograph record that is scratched with use until it's unplayable, we need to slow down the rate at which scratches accumulate--for example, by cleaning the stylus and excluding grit and dust. II we're dealing with a record that can be played once only and not restarted, we might conceivably find ways of running it more slowly--but not so much so as to distort the music. Either of these procedures would prolong the performance.

In rats and mice, we already know of several maneuvers that will prolong life. The oldest and simplest of these is food restriction. The life span of mice can be doubled, both by gross calorie restriction, which keeps them juvenile, and by feeding them only two days out of three. Besides postponing aging, this regime virtually eliminates tumors in some strains of mice. The lack of excess calories may slow down copying generally or cut the rate of noise injection or conserve irreplaceable machine-tool molecules. It may retard some built-in program in the body. It may even work simply as a challenge that makes the natural control machinery work better. Starved mice have big adrenal glands, and there are some adrenal hormones that can by themselves double longevity in long-lived mouse strains, probably by controlling copying processes or by preventing the rejection of divergent cells. Whether the technique of food restriction would work in man, and particularly whether it would work when started in adult life, we can find out only by trial.

Another group of approaches is based on an area of research that made great strides in the Sixties: immunology. Biologists are trying to understand and control the body's defenses against foreign cells so as to ensure the success of transplant surgery. They are unraveling the machinery that prevents grafts from taking and, in so doing, are finding more and more instances in which the body appears to react against or reject its own tissues. These conditions become commoner with age, and it seems almost certain that self-rejection plays a part, perhaps a leading part, in age changes. Either our cells alter and become criminals or our bodily policemen alter and start attacking law-abiding citizens. Drugs and hormones of the kind given to cover transplant operations are already being tried with some success as anti-aging agents in mice; and in some strains of old mice, removal of the spleen--an important organ in the rejection process--makes them survive to great ages.

Yet another approach is based directly on the error-in-copying idea. Large manmade molecules, and molecules in organic materials such as margarine or leather, perish with time through attack by chemical agents known as free radicals. A free radical has been likened to a convention delegate away from his wife; it's a highly reactive chemical agent that will combine with anything suitable that's around. Chemists protect such things as chicken feed, cornflakes and automobile tires by adding to them substances known as antioxidants, which mop up these unwanted agents and slow down the perishing process. The body contains both free radicals and long-lived molecules--among them, the fibers that keep our skin elastic and the blueprint molecules of DNA. If any such perishing reactions occur with aging, it ought to be possible to slow all of them down by administering some of the nonpoisonous antioxidants now added to groceries, but in far bigger doses, without waiting to find out exactly where the damaging processes are located.

A position paper on the practical side of age slowing in animals in 1971 would run roughly like this: (1) We now have perhaps half a dozen ways of slowing down aging or lengthening life or both in rats and mice. (2) The exact way these methods fit together, the nature of the aging clock and whether there is one clock or more are unanswered questions, but we should be close to an answer within five years. (3) It's not certain that any of the known age-slowing methods would work in man. (4) Whether they would and whether they would work in adult life, can be found only by trying them. (5) If they don't, then it's likely that similar and equally simple methods will. (6) Human experiments will be started within the next three to five years, probably at more than one center.

The reason these techniques haven't already been tried in man has nothing to do with ethics; it's simply that, because the investigators age as well as their subjects, 70-to-80-year experiments are, for practical and psychological reasons, no go. As long as we could measure aging only by following lifelong mortality figures, as insurance actuaries do, experiments on anti-aging agents were confined to rats and mice, which live but a few years. But we can now move into human studies, because greater knowledge of age changes and the advent of automated clinical laboratories and computers make it possible to measure the rate of aging in the short run.

The new strategy is to choose a battery of measurements--chemical, psychological and clinical--that change with age and follow them over a period of, say, five years, starting at a given age, such as 50. The measures are picked to be so varied that any factor that slows the rate of change in all of them would be likely to act by slowing down aging in general. This approach reduces the problem of how to retard aging in man to the size of an ordinary medical experiment, using some 500 volunteers over three to five years, like the assessment of low-cholesterol diets in heart disease.

Battery tests for aging are one of the few beneficent spin-offs from the bomb. They were developed at the Brookhaven nuclear-research laboratories to measure the rate of aging in Hiroshima survivors. (Reassuringly, the survivors didn't age faster.) Equipment like that which would be needed to carry out such tests on normal people already exists in many U. S. centers, such as the Kaiser-Permanente Medical Centers in San Francisco, Oakland and Walnut Creek, California. We could start human experiments next week, measuring such things as hair graying, skin elasticity, change in body chemicals, hearing and mental agility as indexes of the speed at which aging is progressing.

Age control will hit American business and social-service planning within months as a contingency and within a few years as a fact. Until now, the fixed human life span of threescore and ten has been one of the few facts that planners have been able to depend upon. Forecasters in all fields seem unaware of how close we are to having this hitherto solid basis demolished. In spite of efforts to foresee technological changes, it's almost certain that age control will take everyone by surprise.

Similarly, the aging public seems unaware that a little informed lobbying now could get them longer life. There is a bill before Congress to set up a National Institute of Gerontology, which could be the biological counterpart of NASA. So if anyone asks, "What can I do today to slow down my own aging?" the answer is, not jogging, not taking antioxidants, not living on lettuce alone. It is, rather, backing this kind of initiative, so that we know in time what to do. There's no point in wasting our time on advertised nostrums and Continental professors who are rumored to rejuvenate Popes and the wives of millionaires. These can only rejuvenate someone else's bank balance. We had better put our money on hardnosed science, and as soon as possible.

Gerontologists today face problems similar to those the rocket men had in the Thirties; they are a little better funded but no more fully appreciated at top decision-making levels. Probably, only a few million dollars stand between these men and historic results. Without the money, they will get there but too late to benefit many of us.

The aim of what we're doing is clear enough. We're looking for some agent that can be applied as late in life as possible and that will slow down all symptoms of aging. Success will neither abolish old age nor prolong it--nor, in all probability--shorten it. It will simply make it occur later. For a ten-year gain, a man of 60 who has been treated will be as he would have been, untreated, at 50, with the same vigor and the same diseases. At 80, he will be the man he would have been at 70. If we can tamper with the taximeter to give us more miles for our dollar, the journey will be longer, but it will be substantially the same, in that we shall still age and die, but we won't have to spend so big a fraction of life in so comfortless an anteroom, nor enter it so soon. We aim to create for the 1970s and 1980s a new medicine, based on control of the rates at which things happen and grounded on the view that it's easier to alter a rate than rewrite a program. On this principle, it should be far easier to make cancer or heart disease occur ten years later than it would otherwise have done than to prevent or cure it altogether.

What we're not trying to do is equally clear. We're not trying to prolong old age by keeping people alive beyond their years of vigor; medicine is doing that now, which is why gerontology is so urgent a study. Nor are we envisaging longer life by prolonging childhood. This is probably feasible and might be easier, but it would be far from ideal. Nor are we contemplating the spinning out of a fixed amount of life by taking it in sections, punctuated by periods of hibernation. That, too, is probably feasible, but it's a different project, of interest chiefly to astronauts and to the historically inquisitive.

Prediction in science is difficult, but we can make a few reasonable guesses about what we can accomplish. Among these are the following: By the year 1990, we will know of an experimentally tested way of slowing down age changes in man that offers an increase of 20 percent in life span. We will know whether it works only when all the subjects have died; but judging by the tests we now have, we should not be far off in our predictions. The agents involved will be simple and cheap--dietary tricks or maintenance chemicals, not transplants, intensive-care units nor tailor-made serums that would be available only to the wealthy and to VIPs.

Direct application of the results will be possible world wide, at about the same rate as, and probably more cheaply than, antibiotics since 1940. All countries will elect to use them, or at least will be unable--as with the pill in Catholic Italy--to prevent their use. How widely people choose to use them will depend, no doubt, on what forts of agents are available. If longevity requires tiresome and lifelong diet restriction, the model of cigarettes and high-cholesterol foods suggests that most of the Western public doesn't value longevity highly enough to make itself uncomfortable. All that will happen in this case is that application will be delayed until we find a painless method of getting around our self-indulgence.

Who will benefit can be seen only by trial. At the moment, the odds seem fair that a man or a woman of 50 today can expect some benefit, provided we waste no time; while a man or a woman of 20 certainly can look forward to extra years of vigor. Bearing in mind the rate of growth in biology and the intensification of the research effort that would surely follow the first and minimal human demonstration, one bonus could lead to others. We are now contemplating a 20 percent gain--15 extra years before aging sets in. It could be more or less. Probably, we're wise to set our sights low. The point is that in the long run, it's the first step that counts. That step could be five percent, but it could as well be ten percent, and there is nothing but the analogy from mice to help us guess.

Will people want to live longer? Obviously, when it seems really possible, they will. At the moment, they are coy about saying so, partly for fear it may not happen and partly because they think of longer life as it is now--meaning longer infirmity. Ask a 40-year-old if he would like to stay as he is for another 15 years and the answer will be different.

This 20 percent prediction is based on research by those in the field. It jibes fairly well, however, with studies by the RAND Corporation and the drug firm of Smith Kline and French, scientific predictions of the future, based on a series of questions answered by numerous scientists and experts in other fields. RAND put the middle date for "significant extension" of human life at 2023, Smith Kline at 1993--though this does not allow for the treated subjects to age and be counted. From these studies, the 10 to 20 percent increase should not be far behind, for example, the chemical or immunologic control of cancer.

If this, rather than immortalism or hopeful predictions of 200-to-300-year life spans, is a realistic model, it still leaves us with some thinking to do. For a start, our society is as geared to a 70-year life span as our houses are to people between five and six feet tall. A life span with an upward limit around 70 to 80 has been the one certain factor on which insurance, promotion prospects, pensions and politics have been based. A 20 percent gain could be absorbed--but the first artificial breakthrough will knock the floor at one blow from under all these calculations and from under all past actuarial experience, because there is no knowing, for planning purposes, where it will stop. To some of the questions this will provoke from citizens who find science worrisome, if not dangerous, we can only reply with more questions.

Population is already one of our leading panics, and a justifiable one. Longer life, if it comes as one increment only, will mean greater numbers. This will be adjusted by time, but only if it's a once-and-for-all bonus, and then the bulge will fall when population problems are beginning to hit hard. On the other hand, the gain will be wholly in the productive and (unless we stick rigidly to already obsolete retirement practices) nondependent years. This, in fact, could be a gain. Today our preproductive dependency lasts about 20 years and our postproductive about 10, leaving a working life of only 40 years. In 1990, the number of Americans over 65 will be over 27,000,000 compared with about 20,000,000 now. More years of vigor will mean that many of these can still be "young." More years will also mean more sex, but not necessarily more children. At the moment, sexual activity declines with age, not for physiological reasons but through the cultural fiction that it ought to do so and because order people tend to play the age roles convention assigns. Longer life would give us the option, perhaps, of effectively living two different, consecutive lives--as we are starting to do today, but more effectively. Longer youth and adulthood would even out the discrepancy in the opportunity to do this that now exists between men and women, who are harder hit in taking up that option than are males. Women, it has been quipped, have a menopause, but men have no womenopause. Two separate lives, one fertile, the other companionate? It seems possible. Against the demographic objectors, it can be said that the population explosion will destroy us in any event, unless it is controlled, and abstaining from the application of gerontology will not prevent this. Like air pollution and the arms race, it must be dealt with now as a condition of survival.

Sheer turnover of human beings is another anxiety point. People are by nature rigid: The science and politics of today are already dictated by what their exponents learned 40 years ago, in a society that's changing so fast that the young are practically out of sight. Can we afford a 20 percent increase in life span, if that means a 40 percent increase in the tenure of professors, Senators and company presidents? Nobody knows. What is clear is that even a slight breach in the primeval human certainty that we will die between the ages of 70 and 90 will produce vast changes in our self-estimate. Show once that aging can be pushed back and, like the generation that has lived with the pill, we shall never be able to go back to the old attitudes. Admit that aging and death are not only intolerable but postponable and nothing, including our life style and our willingness to update ourselves, can ever be the same. In fact, if the rigidity attributed to the elderly is due to aging at the biological level, it will probably be postponed along with wrinkles and cancer. If it's a social convention, it will have to be unlearned. Since it needs unlearning urgently today, we hardly stand to lose.

I am as worried as anyone about the idiotic misuse of technology. But the potential misuse of aging research doesn't keep me awake at night. If it did, I wouldn't devote my time to it. Partial control of human aging is something that's going to happen. Unless we are slothful or overcome by disaster, it's probably going to happen within our lifetime, and some of us will be beneficiaries. Morally, it should be beneficial. Every gain in our ability to stave off death increases our respect for life--our own and others'.

This will not be luxury medicine; it will almost certainly not be abusable by restriction to wealthy, prominent or powerful people. In fact, rate-control concepts in public health will supersede, more economically, a great deal of the luxury medicine that, by its diminishing returns in quality of life, now raises embarrassing priority issues. The only big questions are how soon it will happen, how large the gain will be and whether it will catch us unprepared to iron out preventable personal and economic side effects. So far, I have seen only one pension policy that writes in a waiver in the event of a science-based change in normal life span: The insurance companies should be worrying about that, not about the litigatory possibilities of shenanigans based on cryogenic suspension through deep-freezing annuitants. The thing that really matters is that all of us should know what's going on and how it may shortly affect us. If we're willing to back the workers in the field with public awareness--and with money--we can hope to roll back our own old age, as well as our children's. The next five years will settle whether or not we do.