The Prospects For Physical Immortality

by Frank R. Zindler

A lecture delivered at the 24th National Convention of American Atheists, Washington, DC, 13 June 1998. Earlier versions of the lecture appeared in the author’s column The Probing Mind, in this magazine in September, October, and November of 1985.

am not resigned to the shutting away of loving hearts in the hard ground.
So it is, and so it will be, for so it has been, time out of mind.
Into the darkness they go, the wise and the lovely. Crowned with lilies and with laurel they go; but I am not resigned.

Lovers and thinkers, into the earth with you.
Be one with the indiscriminate dust.
A fragment of what you felt, of what you knew,
A formula, a phrase remains, - but the best is lost...

Down, down, down into the darkness of the grave
Gently they go, the beautiful, the tender, the kind;
Quietly they go, the intelligent, the witty, the brave.
I know. But I do not approve. And I am not resigned.

From Dirge Without Music
by Edna St. Vincent Millay

The Ageless Query
Must we all die? This is a question which humankind in all ages have asked. In the Western world, the answer to this question has almost invariably been “yes.” What is, after all, more obvious than our mortality? To be sure, our mythologies are replete with characters such as Adam and Methuselah, who were imagined to have succeeded in eluding The Reaper for a number of centuries. But, significantly, even they at last cashed in their chips.

Our religions, for the most part, have given up hope for physical immortality altogether and have invented “spiritual” immortality as a rather anemic substitute for which to hope. Since eternity with neither bodies nor brains is hard to market, some religions have added the doctrine of bodily resurrection. But there is something profoundly immaterial about the bodies we will be issued when we’re mustered up beside the plastic petunias in Forest Lawn. Certainly our new bodies will not be equipped for fornication, and it is unthinkable that a resurrected Christian will recommence to urinate and defecate! Sneezing and sweating, too, seem unseemly pass-times for new-issue bodies. By the time one subtracts all the activities the resurrected “bodies” are not likely to perform, the bodies seem hardly to be bodies at all!

“All men are mortal,” said Socrates, and until the growth of modern biology Socrates seems to have had the last word on the subject. But today we may at least ask why this should be so. Why do people die?

“Because they are descended from animals,” the biologist replies. Which prompts the question, “But why do animals die?”

Part of the answer (apart from accidents and the fact that many animals are food for other animals) is that from a cost-benefit ratio point of view, maintaining animal bodies after the genes they carry have been passed on is wasteful. Just as a chicken is an egg’s way of making another egg, an animal body is a device used by genes to insure successful reproduction and transmission through time. From this perspective, bodies are simply packaging for genes - wrappings to be discarded once the genes have “done their thing.”

Sex Is for What?!!
Contrary to the opinion of the pope, the purpose of sex is not reproduction. Forms which reproduce sexually do so in order to provide new genetic combinations, to “reshuffle” the genes of the parent generation. Sexual recombination of genes allows evolution to occur much more rapidly than is the case in asexually reproducing organisms. Unfortunately, only sexually reproducing organisms die of “old age.” Death from old age is unknown in asexual forms such as bacteria or in forms such as amebas which reproduce sexually only upon certain occasions. These forms multiply by dividing, gradually losing their original identities as their material is passed on to daughter cells. Although such forms may die because of hostile environmental conditions, they never die of old age. They are truly immortal.

Whereupon the question naturally arises, Why do animals need to evolve? The ability to evolve is essential if species are to be able to adapt to rapidly changing environmental conditions. It would appear that in the evolution of life, the death of individuals has been necessary for the survival of life itself.

It is often the case that the longer the life-span of an organism, the slower is its rate of evolution. Thus, the giant redwoods, with life-spans that put even old Methuselah to shame, have changed only slightly since the time of the dinosaurs. In the same amount of time, however, our short-lived ancestors have been transformed from tiny, shrew-like creatures, cowering in the shadows of Mesozoic forests, into Prometheans who have stolen the fire of the sun.

We may be glad that our amphibian ancestors died, so that some of their offspring could evolve into reptiles. And we may approve of the fact that our reptilian ancestors died so that some of their descendants could become mammals and, eventually, human beings.

But confound it! We have arrived! We are here! We are beginning to take control of our own evolution, and we don’t need to continue the wasteful process of evolution by natural selection! Admitting the desirability of a little improvement here, and a few changes there, we like ourselves, and we would like to savor the sauce of life for at least a couple of millennia - even if not, perhaps, for ever.

Admitting the biological necessity for death in the past, is death still necessary? Is death still desirable? (Only biologists and manic-depressives ask such questions!) Is death still inevitable, now that we have become a form of life conscious of itself - aware of its origins and using the insights of science to chart its future course?

It Ain’t Necessarily So
I believe the answers to all these questions is an emphatic “No!” We no longer need to die. Mortality is not an a priori necessity. Biology should enable us to become essentially immortal. As we approach the year 2,000, we have already made astonishing break-throughs in the understanding of aging. We face a new millennium in which - as I shall try to show - aging will become first preventable and then reversible.

Before attempting to justify this claim, I would note that for as long as our ancestors have been recognizable members of the species Homo sapiens, they have feared death. Only the noblest of our kind have failed to cower and quail when touched by the shadow that precedes the Great Dark. While still they lived in caves, our ancestors feared to travel in the Valley of the Shadow. And men and women created gods and goddesses in their own images - soothing fictions to help them face the fact of their mortality.

Like their human inventors, religions have come and gone, have lived and died. Though not one of them has ever taken so much as one successful step toward the actual conquest of death (indeed, almost all religions have been a major obstacle in the path of those who might have done so), most religions have fed upon fear. Priests have waxed fat in direct proportion as they have developed the ability to fool people into believing that they do in fact hold magic powers over death.

For millennia our superstitions have sold us an ersatz immortality and prevented us from seeking out the real one. It is only in the last century - which has seen the growth of science into a force great enough to expose this inventive fiction for the first time - that our kind has been able, systematically, to investigate the differences between life and death. And only in the last few decades have we found the courage to seek a cure for dying.

In trying to justify my hope that essential immortality should be achievable very soon, I must declare the subject of “accidental” death to be beyond the scope of my discussion. A person run over by a steam-roller in the year 2,020 will be just as dead as the one run over in 1998. I shall, therefore, limit my discussion to the kind of death conceived to be the terminus of old age.

“Senectus ipse morbus est” (“Old age is itself a sickness”) said the Roman poet Terence, who flourished in the second century BCE. “Old age is itself a sickness,” echo the majority of modern biologists. No longer believing that sickness comes either from god or the devil, biologists now view aging and death as just another disease in need of cure - just like smallpox, cholera, or cancer.

Self-Destruct Genes
While the sickness model of aging and death may prove unable to explain everything, it is a good place to begin. In order to cure any disease, it is usually necessary to identify the causative agent and discern the nature of the damage which must be repaired. To fight effectively, one must first know the enemy. To cure aging, we must first seek out its causes.

Fortunately, we do not have to look very far in order to get lots of ideas about the causes of aging. There are some things which practically leap up to capture our attention.

Consider salmon, for instance.

Salmon are hatched in freshwater streams, develop, and then descend to the sea to grow to sexual maturity. As much as five years after their birth, the nubile fish reascend the rivers which gave them life to consummate their nuptials. At this time a most remarkable transformation occurs. The formerly sleek, silvery-blue fish become a dull, reddish brown. The males in particular become ugly and misshapen. As the fish spawn, they grow suddenly old. Most die within a few days after the fertilization of the eggs. Rare indeed is the salmon that survives to spawn again. It is as though the fish had happened into a never-sought-for Fountain of Senility.

Similar to the case of the salmon, though even more dramatic, is the case of the mayflies. These insects are classified in an order named Ephemerida, in recognition of their ephemeral existence. All but one or two days of their entire lives are spent as aquatic larvae. At last they emerge from the water, try out their new-found wings, perpetuate their race - and perish. Within hours, their temporary terrestrial tenure is at an end.

And then there are carrots.

Carrots, as everyone knows, are biennial plants. That is, they live exactly two years, flower, go to seed, and die. They die not at the end of one year, nor at the end of three. Almost always, they self-destruct at the end of two years. A similar, but more impressive phenomenon, is seen in the so-called “seventeen-year locust” - actually a cicada - which lives for sixteen years as a larva, emerges as an adult in its seventeenth year, mates, and seeks out a recycling service for its carbon atoms.

Is there any relationship between salmon, mayflies, cicadas, and carrots? I think so. The precision with which their aging and death occur makes one suspect that there is some sort of genetic predestination at work. It is as though evolution has equipped these species with self-destruct genes whose function is to get older generations out of the way in order to avoid competition with their descendants.

Coin a Word
Back in the early 1980s, when I first started writing on this subject, no technical word for such self-destruct genes existed, and so I coined one. I termed them opsephoneal genes (from the Greek, opse, meaning “late” and phoneus, meaning “murderer”). Alas, the term has not caught on, even though (as we shall see) such genes have at least something to do with aging in all animal species.

Are opsephoneal genes at work in human aging?

When forty winters shall besiege thy brow,
And dig deep trenches in thy beauty’s field,
Thy youth’s proud livery, so gaz’d on now,
Will be a tatter’d weed, of small worth held:
Then being ask’d where all thy beauty lies,
Where all the treasure of thy lusty days,
To say within thine own deep-sunken eyes
Were an all-eating shame and thriftless praise...

-- William Shakespeare, Second Sonnet

While humans are neither annual nor biennial, they are - if I may be permitted the barbarism -proverbially three-score-and-tennial. While improved care and nutrition have steadily increased man’s life expectancy, they have not significantly increased his life span. That is still nearly fixed at about seventy years, although some recent authors feel the human life-span really to be about 110 years. (The world record is held by a French lady who died recently at the age of 122.) This reinforces the suspicion that opsephoneal genes are at work.

The suspicion is further strengthened by the bizarre disease known as Werner’s progeria - premature old age. By the age of eight, a child may be biologically eighty. It seems as though something has happened to activate prematurely a normally dormant opsephoneal gene. (The same effect might be achieved, of course, by the sudden turning off of a gene needed for some vital function, or by a mutation in such a gene.) It seems not irrational to suppose, therefore, that if something can turn on such a gene prematurely, we should be able to find a way to turn off - or at least delay such a gene as well.

Many people, when discussing the genetic aspect of aging with me, express the hope that aging will not prove to be genetically predestined. They shrink from the notion as if it were a sort of biological Calvinism. “What hope can we have if our very genes are against us?” they ask.

Actually, if suicide genes were the whole story, we would be in great luck. For we already know a great deal about what turns genes on and off. Hormones, for instance, are busy at this moment turning on and off various of the reader’s genes as he reads these words. Other genes are turned on or off as a result of the buildup of various, simple chemicals in the cell. Still other genes may be inhibited by large protein molecules located at strategic positions in the nucleus of the cell.

Turn It Off
Most exciting of all, genetic engineers have learned to read and write in genetic code. It is now a daily occurrence for human genes (made of DNA) to be combined with particular synthetic or natural sequences of DNA which will guarantee expression (turning on) of the gene in a new host cell, say, a bacterium. That which genetic engineers turn on, can be turned off as well. In any event, if aging and death were due to the action of suicide genes alone, the cure for old age would be conceptually no more complicated than finding the legendary Fountain of Youth. All we would need to do would be to find a drug or some other form of “magic bullet” which was specific for the gene in question and was able either to repress it or permanently disarm it.

As we shall see shortly, a genetic basis for aging has indeed been discovered. But before considering it further, I think there are other factors in aging which merit our immediate attention. There are factors which, even if they should prove not to be the central cause of aging, nevertheless are worth dealing with first - for the simple reason that they would, if dealt with effectively, allow us to buy extra time during which we might grapple with any remaining problems. If we are to be the first immortal generation, we must somehow “buy time.” We must try first to retard the aging process and stop it. Then we may seek to undo the ravages already wrought by time.

Stalling The Reaper
Although I am convinced we have a genetic predisposition to succumb to the injuries accumulating over time, there are other factors with which we must deal first, even if they should prove not to be the central cause of aging. These are problems which, if dealt with effectively, would allow us to buy extra time during which we could grapple with The Reaper himself.

Two such factors for immediate attention are cellular oxidation and molecular cross-linking. As we shall see, these two factors are quite interrelated.

When life first originated, billions of years ago, the earth’s atmosphere was rather similar to the atmospheres of the outer planets. It lacked molecular oxygen. Though we tend to think of oxygen as essential for life, the first steps toward the formation of living systems would have been impossible had there been more than tiny amounts of oxygen in the atmosphere. For oxygen would have destroyed the simple organic molecules present on the early earth long before they could have joined together to form the complicated molecules needed in living systems. For all early forms of life - indeed, for some anaerobic bacteria yet today - oxygen was a poison, a substance destructive to the machinery of the cell.

Some while after life began, an evolutionary crisis developed. Although the first photosynthetic microorganisms were not oxygen-producers, eventually photosynthetic algae evolved which began to produce what was to be the first worldwide environmental pollutant: molecular oxygen. From that time on, algae and the plants descended from them have given off oxygen as a waste-product of photosynthesis, and nearly all forms of life on earth have had to develop physiological defenses against it or perish. Over billions of years of evolution, most living things have “turned adversity to advantage,” and are now actually dependent upon this erstwhile enemy for the production of energy.

But oxygen can still be an enemy in the cell. In a process analogous to rusting, it can still break down the compounds of which life is made. It may also cause the production of enormously reactive particles called free radicals.

Free radicals may often be to cells what bulls are to china shops: dangerous. They may attack any of the giant molecules of the cell, including the genes themselves (DNA molecules). They may chemically activate molecules in such a way as to cause two or more of them to link together, producing giant, insoluble molecular monsters. In short, oxidation may lead to the formation of free radicals; free radicals may activate proteins and other molecules and cause them to crosslink and join together. And that - as we shall see — may lead to trouble.

One of the most dramatic examples of the destructive power of oxidative free-radical processes in human aging is the damage done to structural proteins - molecules which give us our characteristic shapes, provide a stage on which the chemical marriages and divorces known as “life” can be solemnized, and serve as selective barriers between the participants in these rites and the often-hostile audience known as “the environment.”

One such protein is collagen. Perhaps the most abundant single protein in the body, collagen accounts for twenty-five to thirty percent of total body protein. It is abundant in skin, bones, tendons, and the walls of blood vessels, and it is frequently encountered as a sort of wrapping around the cells of many other organs of the body. It is a major component of connective tissue. It is often associated with another major structural molecule, elastin.

Collagen and elastin molecules are normally long and fibrous in shape. In young persons these molecules are able to move freely past and around each other. The skin, therefore, is elastic and resilient. When pinched, young skin will snap immediately back into shape.

As a person ages, however, his collagen and elastin molecules become progressively oriented parallel to each other, very much as though they were crystallizing. The older one becomes, the more these molecular fibers become welded together, side-by-side, as a result of oxidation-induced cross-linkage. Thus the skin of old people becomes inelastic, deformed, wrinkled, and leathery. As a matter of fact, tanning - the process whereby skin is turned into leather - is actually an artificial process which causes cross-linking of collagen! If we could find a way to prevent excessive cross-linking of just these two molecules (some cross-linking is necessary, unless one is a jellyfish!), we could eliminate almost entirely the cosmetic debilities of old age.

The “forty winters,” the “deep trenches,” and the “deep-sunken eyes” which Shakespeare bemoans all relate to the oxidative cross-linking of collagen and elastin, accelerated by the harsher environment of Elizabethan England. Ironically, it was not the forty winters which dug the trenches, but rather the forty summers with their free-radical-producing ultraviolet rays! Sun-tanning is not just a color-producing process: sun-tanning is tanning in the leather-making sense as well! Ultraviolet light, like oxygen, is our enemy. And so, as we shall see, is glucose.

Most readers will agree that preventing the appearance of old age would itself be a significant achievement. But I am confident that the true effect of the process would be more than “skin-deep”! As mentioned above, many cells are surrounded by a wrapping of collagen, or else they must receive their nutrients from blood vessels which are wrapped with collagen fibers. In the young body, nutrients easily pass through these barriers into the cells, and wastes easily pass out of the cells into the blood. When the collagen is not excessively crosslinked, materials pass in and out of the cell as easily as Olympic runners leaping hurdles on a track. But as the collagen ages, the course becomes more and more tortuous. Runners have to pass through what comes to be more and more like a jungle-gym. They may get through to the finish-line, but they won’t win any races. The cells become more and more choked off from supply sources, and metabolism slows down. Fewer and fewer biochemical deadlines are met, and disorder increases. Regulatory processes become progressively imbalanced, and death ensues. If we could prevent just the cross-linking of collagen and elastin, a lot of derailed biochemical trains could be put back on their tracks, and we should be able to double our life-expectancy.

Fortunately, we don’t have to wait until the next millennium to be able to slow down, prevent, or perhaps even reverse the excessive cross-linking of collagen. There are steps we can take right now to help stall The Reaper.

A number of antioxidant materials are known, many of which are naturally occurring substances such as vitamins and minerals. Not only is there evidence they can slow down the aging (cross-linking) of collagen and elastin, there is evidence they may have prophylactic value against both cancer and coronary artery disease - two major impediments to the attainment of even the traditional life-span of three-score years and ten. Free-radical mechanisms have been implicated in the build-up of plaque in artery walls - a primary factor in hardening of the arteries and coronary heart disease. In the case of cancer, free-radical processes seem to be involved whether or not the cancer is being induced by tumor viruses or carcinogenic chemicals.

It is now known that one of the major agents involved in the free-radical cross-linking of collagen and other proteins is glucose. This most common of sugars is needed for energy metabolism, and it is probably safe to say that life cannot exist without it. However, it is able to react with amino acids (the building blocks of proteins) to form compounds appropriately called AGEs (Advanced Glycation End products). The reaction is familiar to anyone who has ever bitten into a snow-white apple, set it on the table, and watched it turn brown. Known as the Maillard (or browning) reaction, the sugar is first attached to a protein. Then, rearrangements involving a free-radical mechanism allow the product to link up with a second protein, cross-linking the proteins. Since each protein can react with more than one glucose molecule, it is possible for many proteins to become joined together into an insoluble molecular monstrosity.

Antioxidants to the Rescue
There is evidence that some of the natural antioxidants can reduce the risk of developing heart disease and cancer, and some of these nutrients are known to stimulate the immune system - a system which tends to be one of the major casualties in the battle between the body and its oxidizing environment. Unfortunately, too great a consumption of antioxidants may interfere with one link in the chain of immune defenses, the process whereby certain white blood cells consume and digest (phagocytize) foreign cells such as bacteria or tumor cells. It is a disturbing irony that these cells produce free radicals as a chemical defense against microscopic invaders! Too many antioxidant molecules in the vicinity of these immune cells can neutralize their attempts at chemical warfare.

The two most important of the natural antioxidant vitamins are vitamins that are already being consumed in enormous quantities by health-minded Americans and Europeans: vitamins C and E. Vitamin C is water-soluble, and helps to defuse free radicals in the water compartments of the cell and in body fluids such as blood and urine. Vitamin E is a fat-soluble vitamin, and it helps prevent free-radical damage to cell membranes - sandwich-like structures comprised of lipids (fatty molecules) covered above and below by protein molecules. Since lipids are good electrical insulators, they make up a very large fraction of the molecules found in the brain, where electrical processes are of critical importance. It is in the brain’s lipid structure that vitamin E may be of great value in preventing the buildup of fatty oxidation products such as lipofuscin and ceroid - metabolic garbage that accumulates in nerve and other cells until the cells are killed by the metabolic equivalent of suffocation.

Interestingly, vitamin C is also of great importance in the brain, where vitamin C levels exceed 100-fold their levels in circulating blood. Ever since Nobelist Linus Pauling published his book Vitamin C and the Common Cold, a large number of people (including the author) have been consuming a gram or more of this vitamin per day - not only for its antiviral effect but for its antioxidant and, possibly, its anti-aging effect as well.

Lest my readers rush out and start taking megadoses of vitamins on the premise that “if a little is good for me, a lot is better,” I must caution that with vitamin C as well as with other vitamins and minerals, there may be definite cases in which megadoses are harmful. Persons suffering from certain metabolic disorders such as diabetes and parkinsonism, and particular types of cancer such as melanoma, may actually be harmed by megadoses of individual vitamins. For example, very large doses of vitamin C are thought by some scientists to be able to inactivate the insulin molecule by breaking the sulfur bridges that hold it together. In persons with parkinsonism, large doses of vitamin B₆ may counteract the L-Dopa commonly used in treatment.

Another antioxidant vitamin is vitamin B₅, calcium pantothenate. In a rather old experiment, ¹ this vitamin (one of the active ingredients in honeybee “royal jelly”) increased the life expectancy of mice twenty percent when fed to them in dosages roughly equivalent to one gram per day for a human. I am unaware of any recent confirmation of this study, but if it is valid and can be extrapolated to humans, it would appear that humans taking megadoses of pantothenate could increase their life-expectancy by about fourteen years!

Not all antioxidants need to be “natural” to be of possible use in fighting the free-radical war. Back in the early ’70s, I had my college biology students do some feeding experiments employing both natural and artificial antioxidants. I had them raise fruit flies on various diets enriched with various antioxidants. They found that vitamin E and BHT - the antioxidant put in cereal boxes - measurably increased life-expectancy. Moreover, the BHT appeared to be better than the natural vitamin! Some authors believe that people can be helped by adding BHT to their yogurt! ² Needless to say, a lot more research must be done before I will endorse that idea. Nevertheless, I have an open mind. The fact that something is “unnatural” is not necessarily a strike against it. After all, “naturalness” inexorably leads to the death of everyone!

While we wait for science to map clearly the pathway to the fountain of youth, what can we do to keep alive? What can we do to “stall The Reaper”? For readers expecting to be told to sleep in magnetized pyramids facing Stonehenge, most of my suggestions will sound disappointingly like common sense. Nevertheless, here they are.

First of all, avoid suicide. That is, don’t give yourself lung cancer by smoking anything. Marijuana depresses not only sexual potency, but the immune response as well. Avoid cirrhosis of the liver by shunning excess amounts of alcohol, but drink a glass of wine a day (unless one is predisposed to alcoholism or suffers from certain metabolic disorders, moderate consumption of wine correlates with reduced rates of atherosclerosis). If you are overweight, shed the excess fat (caution! burning fat produces lipid peroxides, and increases your need for antioxidants) and engage in moderate exercise. (In experiments with animals from roundworms to rats, drastic calorie restriction of diets has resulted in marked increases in longevity, presumably by reducing the amount of peroxides and free radicals generated by eating large amounts of food.) Walking and swimming are fine. Avoid excess exposure to the sun. When you have to be in the sun, use a good sun-screen.

Reduce the amount of fat in your diet. Both animal and vegetable fats peroxidize easily, and they can become carcinogens. Frying and baking are especially hard on fats and render them more harmful. Vegetable fats are more likely to be “unsaturated” - that is, they contain less hydrogen per carbon than do “saturated” fats. The greater your consumption of unsaturated fats, the greater your need for antioxidants - a fact often overlooked by nutritionists who wisely counsel reduction of animal-fat consumption, Since cooking involves heat, and since heat accelerates free-radical formation, avoid overcooking. (But be sure you cook your pork long enough to kill the trichina worms!)

Avoid table sugar (sucrose) as much as possible. Many artificial sweeteners are far safer. Honey and brown sugar are no safer. In fact, brown sugar may be more dangerous, because of the impurities which give it its color! Increase the roughage content of your diet. Reduce consumption of red meats, since they are rich in iron, and iron is a ready catalyst for peroxidation of lipids. Unless you have a specific medical requirement, avoid taking iron supplements.

Begin a life-extension program involving carefully chosen antioxidant vitamins and other substances. This will require the help of a good physician. Since most American-trained doctors have almost no knowledge of nutrition at all, and since most spend more time studying accounting than the physiology of aging, finding a good physician to help you may very well be the most difficult — and most vital — task facing you. But if you want a crack at real immortality - the kind where you get to keep your brain and genitalia — you will not give up until you find one. European doctors tend to know more about preventive medicine than do American doctors, who tend to think only in terms of crisis-intervention, but the situation seems to be improving.

The most important advice I have to offer is use your head. READ! Read everything you can on the subject of life-extension and aging. Unless you are a scientist, you will have to begin with the popular literature first. But once you have mastered the specialized vocabulary, start reading the scientific journals and scholarly books devoted to the physiology and therapy of aging. It is absolutely essential that you proceed beyond the popular literature, lest you be taken in by quacks. There will soon be just as much money in the rejuvenation scam as in the religion scam. Be forewarned!

Discovery of Genes Controlling Aging
The existence of “suicide genes” has been proven beyond any room for doubt - at least at the cellular level. It has been known for many years that embryonic development is accompanied by the “programmed death” of large numbers of cells. Called apoptosis in the technical language of cell biology, scheduled death of particular cells allows for the movements and migrations of other cells as they seek out the positions they will occupy in the mature body. It has been discovered also that the body has an apoptotic defense system for fighting viral infections and stopping cancer before it can get out of control. In the case of cancer defense, apoptosis causes the self-destruction of cells before they can start proliferating. Cancers develop when something interferes with the signalling system that “decides” when apoptosis-triggering genes need to be activated. An enormous amount of medical research is now being carried out to discover drugs that can induce apoptosis where needed, drugs that can turn on suicide genes. Once this is all sorted out, we should also be able to deal with the reverse problem: turning off suicide genes being activated in tissues that we don’t want to lose, e.g., healthy brain tissue.

Concerning the discovery of genes associated with the aging process in general, the last two years have produced so many discoveries in so many different areas that it is hard to know how to deal with it all. Earlier I noted the curious phenomenon of sudden aging in salmon. It has recently been discovered that in brown trout (a close relative of the salmon) fish possessing a particular form of a gene for the enzyme lactic dehydrogenase (Ldh-5) develop a giant, “ferox” body form - and live about five times longer than the smaller trout which have a “normal” form of the gene. ³ If this could be extrapolated to humans, we would expect a “ferox human” to live 350 years!

In the tiny roundworm Caenorhabditis elegans, a bunch of genes have been discovered which can greatly affect the life expectancy of the humble creature. ⁴ Mutations in these genes have been produced that can greatly increase longevity by - you guessed it! - increasing resistance to free radicals, ultraviolet light, and other stressors. The first of these, age-I, has been identified with the enzyme phosphatidylinositol 3-kinase and produces a life expectancy about double that of worms possessing the normal form of the gene. Another mutation, daf-2, affects a gene resembling that for the insulin receptor and may provide an explanation for the increase in longevity associated with food restriction in many animal species. A number of so-called “clock mutations” have also been discovered in this worm that can increase life expectancy. The first of these, clk-1, encodes a protein that indirectly regulates the transcription of genes controlling energy metabolism. Combinations of these mutations, such as daf-2 with clk-l, increase longevity five-fold! Would human analogs of these mutations give us life expectancies of 350 years? Gene switching that causes these worms to go into a sort of slow-motion dauer state resembling hibernation can increase longevity eight-fold - the equivalent of 560 years in humans! ⁵

A rather startling discovery was made in June of 1998 when it was learned that transplanting the human gene SOD1 into the nerve cells of fruitflies could increase life-spans as much as 40 percent. ⁶ Significantly, the enzyme encoded by this gene is superoxide dismutase, which has the job of chemically disarming superoxide, a particularly dangerous free-radical form of oxygen. (In recent years, health-food stores have been selling capsules of superoxide dismutase - ostensibly for its antioxidant properties. However, the enzyme is a protein; when taken by mouth it can be expected to be digested before it can do any good. Buying such a preparation is, in my opinion, a waste of money.)

The importance of enzymes able to disarm free radicals was underscored late in August of 1998 when Naoaki Ishii of Tokai University Medical School in Japan discovered a mutation in a C. elegans gene called mev-l which causes worms to die sooner when exposed to excess oxygen. ⁷ The mutation allows excessive production and build up of free radicals in mitochondria, the powerhouses of cells.

Moving up to mammals, in November of 1997, Tokyo researcher Makoto Kuro-o and colleagues reported the discovery of a mouse gene they called klotho, named after Klotho, one of the Fates of Greek mythology. ⁸ A defect in this gene produces a syndrome resembling human aging, including a short lifespan, infertility, arteriosclerosis, skin degeneration, osteoporosis, and emphysema.
The genetic basis of Wemer’s progeria, mentioned earlier, has been found to involve a gene resembling those encoding enzymes known as DNA helicases. ⁹ Mutations leading to loss of function of this gene impair DNA replication or repair - producing the premature aging phenomena associated with this fortunately rare disease. Significantly, this gene mutation is also associated with a rapid decrease in the length of telomeres - long DNA structures at the ends of chromosomes that seem to be the functional equivalents of the caps placed at the ends of shoelaces to prevent fraying and unraveling.

It has long been known that the telomeres are associated with the ability of cells to reproduce in tissue-culture situations. Most cells, when placed in culture, are able to divide just so many times. After a certain number of generations, the cells “senesce,” decline, and die. Other cells - cancer cells, for example - seem to be able to reproduce forever in culture. Somehow, the changes that converted normal cells into cancer cells “immortalized” them. It is now fairly well established that the difference between mortal and immortal cell lines involves changes in telomere maintenance. Each time that an ordinary cell divides, its telomeres become a bit shorter. Finally, the telomere is too short to protect the chromosome to which it is attached; rather soon the chromosome breaks down. In tumor cells, however, the telomeres do not become progressively shorter, due to the presence of an enzyme called telomerase. Active in the early embryo and germ cells, the gene encoding telomerase is usually turned off during the developmental process - effectively limiting the number of times particular cell lines will be able to reproduce. In cancers, however, the gene somehow gets switched on again - allowing the telomeres to be continuously repaired and granting unlimited reproductive potential to the cells that contain them.

The practical significance of this is obvious: we need to find ways to inhibit telomerase in cancer cells (to prevent their unbridled replication) and we need to find ways to activate it in, say, nerve and muscle cells, in order to allow such cells to reproduce so they can replace cells lost to the ravages of disease or aging. Hardly a week goes by without someone, somewhere in the world, filing for a patent on a drug or gene-therapy procedure intended to control telomerase.

Progress in the Reversal of Aging
Although it has been known for a long time that the aging process can be slowed down by such stratagems as caloric restriction of diets and consumption of antioxidants, the Holy Grail of aging research has always been the discovery of agents capable of reversing the chemical ravages of old age. It would appear that we are now beginning to drink the rejuvenating waters of that otherwise mythical cup. Research during the last decade or so has struck where aging hits hardest: the free-radical mediated glucose cross-linkage of collagen and other proteins. It has been discovered - and now confirmed by dozens of experiments - that a simple molecule known as aminoguanidine can inhibit the formation of AGEs. ¹⁰ Having more nitrogen atoms than carbons in its structure, aminoguanidine looks like it would more likely be a rocket fuel than a medicine! Yet it seems to be relatively nontoxic and very effective in blocking glucose cross-linkage of proteins. There is even some indication that it can undo cross-linkage that has already occurred - thus actually reversing aging’s chemical curse. ¹¹ While the jury is still out on this aspect of aminoguanidine’s utility, it seems clear that compounds related to it will be found that will do this safely and without harmful side-effects.

Although some clinical trials are now in progress that employ aminoguanidine as an antiaging and antidiabetic agent (the high levels of glucose in diabetes accelerate the aging process), the compound is not yet approved by the FDA for human use. Until such approval is forthcoming, we shall have to do with some natural substances that seem to be able to do the same thing, albeit less effectively for the most part. Most readily available is L-lysine, a common amino acid which is available at any drug store. ¹² One can take several grams per day of this simple nutrient without likelihood of harm. However, it is about an order of magnitude less potent than aminoguanidine.

Other anti-AGE natural substances are the polyamines spermine, spermidine, and putrescine. ¹³ Occurring naturally in seminal fluid, it may be that these substances have some role in maintaining sperm cells as the quintessence of rejuvenation. Although the ability of these substances to prevent glucose cross-linking, it is not yet known if it is safe to consume large amounts of these substances for prolonged periods of time.

Rutin, a flavonoid found in buckwheat and many other plants, also has been shown to prevent AGE formation and may be of value in treatment of diabetes. ¹⁴ But more exciting is the discovery that forms of vitamins B₁ and B₆ may be more effective than aminoguanidine for this purpose. ¹⁵ Thiamine pyrophosphate (a form of vitamin B₁) and pyridoxamine (a form of vitamin B₆) in in vitro studies (test-tube studies) have been found to inhibit AGE formation involving human hemoglobin, bovine serum albumin, and the important enzyme RNase A. At present, these particular forms of vitamins are not very easy to find, and we may have to wait for some time until these specifically anti-AGE forms are mass-produced by the vitamin suppliers.

Finally, there are compounds being studied that facilitate the removal of AGEs that have already formed. If you will, these are agents that help aging cells put out the garbage or take out the trash. The first such compound of which I am aware is FFI, which goes by the jaw-breaking chemical name of 2-(2-furoyl)-4(5)-(2-furanyl)-1H-imidazole. ¹⁶ It is claimed to be effective in removing accumulated AGEs from tissues. Further corroboration is, of course, required.

Your Prospects For Physical Immortality
With reasonably good luck and careful management, you can survive to the year 2010. If you can live that long, scientific progress in the interim should have advanced to the point where it can keep you going until you’re 140. If civilization still exists at that time, and if science has not been eclipsed by religion, you should be able to renew your lease as often thereafter as you wish. To an extent far greater than you may have dared to hope, it’s up to you. You don’t need help from the man who wears high-pointed hats and lace-fringed dresses. Barring accidental causes of death, immortality is within your reach.

No day goes by without another scientific paper reporting some progress in the war against aging, the war on death itself. In hundreds of journals, in over a dozen languages, the battle is enjoined. The New Day may dawn too late for some of my readers and for me, but not necessarily.

The Brave New World of immortality may very well number some of us among its citizens. The question, “How will you spend eternity?” may assume an important new meaning very soon. John Donne’s heroic “Death, thou shalt die!” may prove to be a boast more solid than skeptics have hitherto allowed!

But time is of the essence: time is the stuff that life is made of. The longer we delay our decision to do what already is possible, the fewer of us may hope to succeed where Ponce de León failed. We do well to remember the lines of Omar Khayyám:

A Moment’s Halt - a momentary taste

Of Being from the Well amid the Waste -

And Lo! - the phantom Caravan has reached

The Nothing it set out from - Oh, make haste!

* * *

The Bird of Time has but a little way

To flutter - and the Bird is on the Wing.

REFERENCES
¹ Cited by Durk Pearson and Sandy Shaw in Life Extension (Warner books, 1982).

² Ibid.

³ Finch, Caleb E., and Rudolph E. Tanzi, “Genetics of Aging,” Science, 17 October 1997,278:407-411.

⁴ Finch, op. cit.

⁵ Wade, Nicholas, “Tiny worm May Offer Lessons on Longevity,” The New York Times, 15 August 1997, p. A8.

⁶ Associated Press, “Fly’s Life Prolonged By a Human Gene,” The New York Times, 3 June 1998, p. A17.

⁷ “Roundworm Gene May Be Key To Aging,” The Columbus Dispatch, 23 August 1998, p. 6B.

⁸ Kuro-o, Makoto, et. al., “Mutation of the mouse klotho gene leads to a syndrome resembling ageing,” Nature, 6 November 1997, 390:45-51.

⁹ Finch, op. cit.

¹⁰ Brownlee, Michael, et al., “Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking,” Science (1986), 232:1629-32; Ulrich, Peter C. and Anthony Cerami, “Amino acids useful as inhibitors of the advanced glycosylation of proteins” (patent) PCT Int. Appl., WO 9314750 A2, 49 pp.

¹¹ Brownlee, Michael, “Phamacological modulation of the advanced glycosylation reaction,” Prog. Clin. Biol. Res. (1989), Vol. date 1988, 304 (Maillard React. Aging, Diabetes, Nutr.), 235-48.

¹² Cerami, Anthony, Peter Ulrich, and Michael Brownlee, “Method and agents containing aminoguanidine, K-hydrazinohistidine, and lysine for inhibiting protein aging in animals and foodstuffs” (patent) Eur. Pat. Appi. EP 222313 A2870520, 32 pp.

¹³ Charonis, Aristidis S., Leo T. Furcht, et al., “Protective role of polyamines in modifications of basement membrane macromolecules in diabetes” (patent) PCT Int. Appi., WO 9412464 A1 940609,19 pp.

¹⁴ Odetti, Patrizio R., et al., “Prevention of diabetes-increased aging effect on rat collagen-linked fluorescence by aminoguanidine and rutin,” Diabetes (1990), 39(7):796-801.

¹⁵ Booth, A. Ashley, et al., “Thiamine pyrophosphate and pyridoxamine inhibit the formation of antigenic advanced glycation end-products: comparison with aminoguanidine,” Biochem. Biophys. Res. Commun. (1996), 220(l):113-19.

¹⁶ Mallon, Veronica, “Compositions and methods for elimination of advanced glycosylation endproducts (in vivo)” (patent), PCT Int. Appl., WO 9706819 A1 970227,55 pp.

Formerly a professor of biology and geology, Frank R. Zindler is now a science writer. He is a member of the American Association for the Advancement of Science, the New York Academy of Sciences, The Society of Biblical Literature, and the American Schools of Oriental Research, He is the editor of American Atheist.