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LIFE EXTENSION FOR THE 21ST CENTURY

As we draw closer to the reality of genetic intervention and life extension, one of the key players in human genome research explores the mythologies and classical failures of those who, in the past, sought their own magical anti-aging elixirs. He also examines the reality of the anti-aging revolution to come.

Adapted from L. Stephen Coles, M.D., Ph.D., Journal of Longevity Research, 1995, Vol.1/No.7, with permission.

In all forms of biomedical research we often ask the question, "How do we know that interesting results obtained in mice will apply to men?" Critical differences in rodent physiology or embryo genesis may trick scientists into a sort of false reasoning by analogy. Professor Roy Walford is the first research scientist to demonstrate convincingly dietary interventions that significantly extend the longevity of mice and apply to humans as well. Ironically, he used himself as a test subject along with seven others, and the data to support this remarkable conclusion happened by accident. This is what my report is about.
Although it has long been known caloric restriction results in increased life span among laboratory animals, we now have supportive evidence that such restrictions regarding calorie intake can also add years to human life, noted Dr. Walford at The 2and Annual Conference on Anti-Aging Medicine and Biomedical Technology for the Year 2010, December 5, 1994, in Las Vegas, Nevada. Dr. Walford based his assertion on the results obtained from an experiment involving eight men and women who spent two years sealed in a closed ecological space known as Biosphere 2 in Arizona. Dr. Walford said the Biosphere experiment provided clear-cut evidence that humans on a calorie-restricted, nutrient-dense diet show the same physiological changes-in cholesterol levels, fasting blood sugar, blood pressure, white blood cell counts, glycated hemoglobin, insulin, and cortisol levels-as do rodents on a similar diet. This strengthens the conclusion that similar age retardation and enhanced disease resistance might also be obtained in humans, providing that they agreed to comply with such a diet, Dr. Walford said.
Yet, one of the reasons why longevity experts are searching for other methods of extending life is that while calorie-restriction may be the first known method used to enhance human life span, its stringency will undoubtedly make it unsuitable for the general population. The good news is that rapid advances in our understanding of the underlying mechanisms of dietary restriction will be forthcoming in the near future. These mechanisms may include (1) the postponement of sexual maturation, (2) the biological clock located along the neuro-endocrine-immune axis, or (3) the free-radical/oxidative-stress damage that occurs secondary to the accumulation of waste products from active metabolism. Thus, the 21st Century may become the century of "the long-lived society."

The Mythologies and Classical Failures of Anti-aging Research

Mythology serves to catalog the dangers involved in a "fruitless" quest for immortality. Mythology tells us the quest for longevity is as ancient as man himself.
Dr. Walford discussed historical myths and classical failures associated with the practice of gerontology. The myths tended to fall into four categories: "Long Ago" (Golden Age); "The Struldbrugg Obsession"; "Far Away" (Shangri-La), and "Contemporary Apologism" (Natural Law).

These Long Ago mythologies include:
- The antediluvian myths, derived largely from the Bible, such as a heavily-armed archangel appointed by God to guard the path to the "second" tree in the Garden of Eden (The Tree of Life). Curiously, the direct descendants of Adam and Eve allegedly all lived to be over 900 years; the eldest of the patriarchs was Methuselah who was supposed to have lived for 969 years.
- The Babylonian epic of Gilgamesh (650 B.C.), one of the earliest myths to explore the theme of the quest-for-immortality.
- The myths of the Egyptian high priests who apparently knew a thing or two about herbs. According to a Hollywood interpretation of the Egyptian Book of the Dead, tree tanna leaves are needed periodically to keep a mummy in hibernation, while nine leaves are needed to awaken him.
- Ahasuerus (Xerxes), the Wandering Jew, who was sentenced to walk the Earth until the Day of Judgement or the Second Coming.
- The Medieval Alchemists (such as Paracelsus, a German-Swiss Physician) who had more to their agenda than just seeking ways to transform base metals into gold.
- Juan Ponce de Leon who sought for the Fountain of Youth in Florida (1513).
- Dracula, of course, who was a well-known successful practitioner of experimental gerontology; (vampires normally subspecialize in hematology!)
- Frankenstein, who, thanks to the wonders of electricity and the skills of the good doctor, overcame the ravages of the grave.
- The Golem (Jewish folklore) in which a rabbi fashions a clay statue and then endows it with life by supernatural means.
- Metropolis in which Maria is transformed by a "mad scientist" into an immortal robot.

The Struldbrugg Obsession

For another class of myth, Dr. Walford coined the phrase "Struldbrugg Obsession" (a phrase derived from an unfortunate people in Swift's Gulliver's Travels). If you continually age but never die, you get older and older, finally condemned to perpetual frailty and/or senility. According to the Greek legend of Eos and Tithonus, Eos, goddess of the dawn requested Zeus to bestow eternal life on her mortal lover Tithonus. The request was granted, but with a catch-22. Tithonus became more and more decrepit, because she forgot to ask for eternal youth, having asked only for eternal life. (Sigh!) Eventually, Eos had to shut Tithonus away in a room, where he presumably still lies paralyzed and babbling. The 1974 movie Zardoz and the 1992 movie Death Becomes Her explored this theme further, as did Oscar Wilde's, The Picture of Dorian Gray and Aldous Huxley's After Many a Summer Dies the Swan. Unfortunately, certain biologists have been known to shy away from experimental gerontology, perhaps because of an unconscious desire to avoid the Struldbrugg Obsession.

Long Ago

Next are the Hyperborean myths. In other words, Dr. Walford observed, these myths tell us that even if the solution to the problem did not happen a long time ago, it certainly must have been discovered in places far away. For example, Shangri-La is the tale of an intriguing mountain utopia. Greek legend held that those who lived there for thousands of years--free from all natural ills--in a land of perpetual sunshine beyond the North Wind. Real places in which excess numbers of centenarians per capita were supposed to be living include: (1) the isolated village of Vilcabamba, Peru high in the Andes mountains; (2) Azerbaidzhan high in the Caucasus Mountains of Russia; and (3) the Hunza people high in the Karakoram (Himalayan) Mountains of Pakistan. Unfortunately, with the careful investigation by scientific researchers, these claims were subsequently proven to be false.

Contemporary Apologism

As we draw closer to our own time and place, we encounter a number of contemporary myths that Dr. Walford has coined "contemporary apologism or, to put it in popculture terms, the "Star-Trek Inconsistency." In this myth, best illustrated by Star Trek, Captain James Kirk appears to age in precisely the usual way over a 30-year period. Even though we can supposedly travel at warp speeds in the 22and Century and future medicine has provided us with scanners that physicians can point at us to make us instantly better, no progress whatsoever appears to have been made in the longevity sciences. Why not? What people frequently say when confronted with the Star-Trek Inconsistency for the first time is "Yes, you're right! I never thought of that." How can you explain this? It may simply be a failure of nerve on the part of the writers. Or perhaps it's because we have been culturally conditioned to think of life-extension research as a fraudulent scientific activity. In fact, Dr. Walford next listed some of the more recent cases of pseudo-gerontology research that he asserts have given the field a bad name:
- Charles-Edouard Brown-Sequard, a French physiologist who performed testicular implants (1890s),
- Elie Metchnikoff of the Pasteur Institute in Paris who recommended yogurt (1910s).
- Serge Vernoff, a Russian who proposed monkey glands transplants (1920s).
- Alexander Bogomoletz of Kiev, Ukraine who prescribed injections of animal antisera (1940s).
- Paul Neihans, who founded La Prairie Clinic near Geneva, Switzerland to introduce cellular therapy with fetal lamb tissue for the rich and famous (1950s)
- Ana Aslan of Bucharest, Rumania who prescribed procaine in the form of Gerovital H3 (1960s).

Along these same lines, Betty Friedan recounts in her recent best-selling book The Fountain of Age that many of the attendees of a meeting of the American Gerontological Society, at which Dr. Walford also spoke, found the very idea of anti-aging research to be "strangely threatening." Indeed, it was felt that such research could possibly lead to a "Gerontological Winter." "Of course," said Dr. Walford, "such an idea is absolute baloney."
Why are we so hung up on the validity of gerontology research? The answer may lie in the fact that "thinking about death is unpleasant." Therefore, we've skillfully invented ways to avoid thinking about it. The long list of false myths and failed searches has conditioned us to trivialize the quest for immortality into a form of "apologism." Apologism, of course, is the categorical belief that longevity research must fail in principle. Objections come in many forms:

- Religious--dabbling in prolongevity research is against divine will, the natural order, fate, destiny, the mysterium tremendum, or whatever. All these arguments should be dismissed as "begging the question." Of course the ultimate theological finesse is the claim that such research is unnecessary because "death is not the end!" This is a hard argument to refute;

- Ennui--living too long will make us listless or bored to death. (I strongly doubt this will be true for most of us);

- Darwinian--successful immortality research will interfere with natural evolution. Such arguments neglect to mention that we've already interfered with Nature pretty well already. We've obviously spread our human presence into every nook and cranny of the earth and made a large number of "annoying" species extinct while endangering many others in the process;

- Stagnation--if essentially everyone is old, society will lose its capacity to innovate.

Famous apologists throughout history include Aristotle, Titus Lucretius, Marcus Tullius Cicero, and Marcus Aurelius. Conversely, Roger Bacon, Francis Bacon, Paracelsus, Rene Descartes, and Benjamin Franklin have composed powerful prolongevity arguments. More recently, Alan Harrington's The Immortalist begins "Death is an imposition on the human race and is no longer acceptable." Obviously, there are a variety of opinions on this subject.
Another more insidious form of contemporary apologist literature documents just how many old people are highly accomplished in their respective professions, not just consigned to nursing homes, with the implicit aim of helping us feel good about growing old--the rationalization of transforming an apparent necessity into a virtue. No matter how inferior one may consider it, the horror-story literature cited earlier at least has the virtue of serving to warn us that those who seek to intervene in their mortal destiny will be punished by a greater spiritual power for their hubris. The lesson is that those who strive to contradict the classic Aristotelian syllogism starting with the premise "All men are mortal" will ultimately meet a fate worse than death.
All of this mythology is due for a radical shake-up according to Walford. It's time to appreciate the implications of the immortalist doctrine before we are caught by surprise. Significant progress in gerontology is happening as we speak, and it is likely to reach fruition in our own lifetimes. Just because we haven't done it, doesn't mean it can't be done. Maybe it's just that no one has done it yet.

Realities of Life Extension

Dr. Walford next asked the question: "How can we know if we've succeeded?" The answer is complicated by the difference between "average life expectancy" and "maximum life span" for any given species. If all we do is increase average life expectancy without increasing maximum life span, sometimes called "curve-squaring" or "rectangularizing" interventions, we will hot have achieved our ultimate goal, as worthwhile as that might be. A true "right-shift" of the mortality curve, sometimes called "span extending" interventions, is really what is sought. Therefore, for any given species, only a complete, time-consuming, life-span experiment is sufficient to answer this sort of question. Furthermore, a sufficient number of animals must be enrolled into each group (experimental and control) to establish the results as statistically significant, which makes this form of experiment expensive as well as time consuming for the experimenter.

"Upregulating" Genes or, Of Flies and Men

Orr and Sohal's genetic-manipulation experiments with Drosophila (fruit flies) reported last year in Science were cited by Walford as the first "opening of the door" in the right direction. They "upregulated" superoxide dismutase and catalase genes in certain artificially-mutated strains of fruit flies and saw an unprecedented increase in maximum life span. Although Prof. Michael Rose of UC Irvine, another well-recognized researcher in fruit-fly longevity, has challenged the methodological integrity of the results as claimed, everyone agrees that these experiments must now be carried out with mammals in order for the claims to be acceptable to the larger scientific community--first in rodents and then later in primates. In the mean time, the real question is, "Do right-shifting methods obtained in one part of the phylogenetic zoological tree generalize to other parts?" There are enough idiosyncratic differences in the metabolic physiology of insects to cast suspicion on any attempt to claim more than what was observed with the species in question.

Hungry Mice Live Longer

Dr. Walford then explained that caloric restriction experiments repeated in his laboratory at the University of California at Los Angeles on congenic colonies of mice and rats over the last two decades show that significant benefits can be obtained when animals are rigorously maintained on a calorie-restricted, but nutrient-rich, diet throughout their lives. Furthermore, these effects are directly proportional to the degree of restriction (up to a certain point). That is to say, maximum life span is extended more and more as the level of restriction is increased from 10 percent to 20 percent, to 50 percent, and even to 60 percent! More than that, however, and the effects of real starvation set in, causing a plateau and then a decline in benefits. Paul Segall of the University of California at Berkeley has shown that reproductive competence is also extended proportionally.
Dr. Walford then presented laboratory data in rodents to show that blood cholesterol and fasting blood sugar are both decreased in calorically restricted animals. Also, physical skills, like "log rolling" in water were preserved in tact in the mice. Finally, intellectual skills, like running a maze, were preserved at youthful levels in mice 39-40 months old, the equivalent of 90 to 100 years for humans. Walford showed photographic evidence for a more youthful appearance in a group of experimental vs. control mice that was conspicuous, even to a casual observer. Therefore, the data demonstrate that the long-feared Struldbrugg Obsession is actually contradicted for these animals. They live longer and remain youthful at the same time!
When all the mice had died of whatever causes, autopsies were performed on both the restricted and control groups with the overall effects summarized as follows:

- decreased cardiovascular disease

- decreased cancer

- decreased diabetes

- decreased autoimmune disease

Moreover, the average age of onset of these diseases, when they did occur, was postponed. Finally, rodent laboratory results revealed a favorable alteration in a wide variety of biochemical, immunological, and physiological (endocrinological) measurements.

Biosphere 2

How do we know that similar results will obtain in humans? The recently-completed two-year $100 million experiment conducted on three acres of desert near Tucson, Arizona by eight humans (4 men and 4 women [all unmarried]) inadvertently shed some light on this question. Biosphere 2 was created to be a tightly sealed (less than 10 percent atmospheric leakage per year compared to a 25 percent per day exchange in a typical closed office building) environment with the aim of prototyping a hypothetical space colony to see if a small number of humans could be fully self-sufficient over a long period of time without direct human contact with the outside world (except for energy [electricity] and bilateral information transfer [cable TV, phone lines, etc.]). According to the ground rules, there was to be an absolutely minimal transfer of physical molecules during the experiment. (However, when one of the women lost the tip of her finger in threshing-machine accident early on, she was released for reattachment microsurgery outside the biosphere and then readmitted a few days later.) The biosphere was further subdivided into separate physical habitats: ocean, rainforest, savanna, desert, and human living quarters, as well as an infrastructure subunit underneath. The human living quarters included sleeping quarters, a kitchen/dining area, library, workshops, a medical facility equipped with minimal operating room, laboratory equipment (gas chromatograph, microscope, etc.), x-ray, and dental equipment, while the infrastructure subunit included all the equipment needed to recirculate air and trap excess carbon dioxide. It was sort of like "the Garden of Eden located on top of an aircraft carrier," said Dr. Walford. One of the habitats included goats, chickens, and pigs. Agriculture, however, was the primary means of generating food.
Because they couldn't grow as much food as they projected they would be able to, they were forced onto a calorie-restricted dietary regime of about 1,800 calories per person per day. This was really quite little, considering the amount of physical work they had to do to grow the crops they needed. The physically demanding workload had to be shared by all (sort of like sending university intellectuals into the fields during the Chinese Cultural Revolution), and it added up to more than 65 hours per week per person! Everyone had to learn how to thresh wheat, butcher animals, cook for eight persons, etc. Dr. Walford, as the resident physician, was not excepted from this rigorous work schedule, even though he was the oldest member of the team at 67. At one point he injured his back, and it took a long time to recover. (Dr. Walford admitted, however, that, beyond working in the "fields," one of his more onerous tasks, as a pathologist, was the retaking of his general medical-board exams for the State of Arizona!)
However, as Walford showed in photographs taken at the end of the experiment, all of the biospherians looked like they had come through a "concentration-camp" experience. Nevertheless, they were otherwise healthy and happy. The men lost 18 percent of their normal body weight, while the women lost 10 percent, just the point where bone resorption would normally begin to take place, given that one wasn't overweight to begin with. There was no evidence of starvation, however. For example, there was no peripheral edema, and none of the females experienced amenorrhea (loss of their menstrual periods), even though this would have been expected under the same weight-loss circumstances without the rigorous daily activities.

The following Biosphere 2 human laboratory results were then presented by Walford:

- Blood cholesterol decreased from an average of 198 to something in the range 120 to 125.

- Triglycerides decreased.

- Glycated hemoglobin decreased.

- Fasting blood sugar decreased.

- Insulin levels decreased to less than 5.

- Blood pressure decreased to the range of 95 over 60.

Obviously, we cannot yet measure the increase (or decrease) in life expectancy for these eight humans, since they're all still alive! Further, they were only on this diet for two years, and it is doubtful that they would have wanted to continue on it any longer anyway. And there weren't any sex/aged-matched controls to compare them with. But, for each of the eleven laboratory parameters regularly measured, they were all consistent with the rodent experiments described earlier (in terms of percentage of youthful values). Therefore, at least in so far as nutrient-rich caloric restriction is concerned, it is suggested that the analogy between rodents and humans holds true. We are both mammals, even if it is not the case that we are both primates.

The mechanism of action of nutrient-rich, caloric-restriction interventions in mammals is consistent with various proposed theories of aging, such as the free-radical/oxidative-stress theory, the DNA-repair theory, the neuro-endocrine theory, and the immunological theory. More experiments will have to be conducted to tease out the distinguishing features of each theory subject to dietary restriction.

Walford was sensitive to criticism that he was a radical among serious medical scientists, so on one slide he presented a political spectrum of relative positions which showed him in the middle as a "moderate" with a prediction of "120+" year life span in the next century. On the right-hand side, epitomizing the "conservative" position, was Dr. Leonard Hayflick of the University of California at San Francisco, whose position was described as believing that life-extension was not only impractical, but actually undesirable! On the far left, epitomizing the "radical" agenda was Dr. Marvin Minsky of the Massachusetts Institute of Technology, whose position was described as a complete immortalist, proselytizing a doctrine of molecular nanotechnology that will soon allow for the complete replacement of physical human bodies and brains by robots and computers, as described in a recent Scientific American article.

Social Implications of the Ageless Society

Dr. Walford next asked, "What will the effects be on society that would derive from the discovery of techniques for significantly prolonging human life span?" Gazing into his crystal ball, Walford saw that under the new demographic boundary conditions:

- functional age will no longer be equated with chronological age.

- the pattern of disease will shift from acute to chronic diseases with a resulting refocusing by health-care (and medical-insurance) providers.

- morbidity may be compressed, depending on the degree of rectangularization.

- there will be an opportunity for individuals to indulge in multiple careers. As a corollary, there would be a corresponding remodeling of the educational system, as well as a closing of the so-called "generation gap."

- people will change their political party affiliations more often

- experimental changes in life-styles will take place with a shift toward "values" rather than the achievement of "specific goals."

According to Dr. Walford, there has been almost no professional thinking in the area of speculation as to what would happen of prolongevity research were successful. The work of Dr. Lawrence Koplekoff, an economist at Yale University, was cited as an exception. Dr. Koplekoff predicted that in the next decade "rectangularization-only" interventions (in which the number of old members of the population would increase significantly) would have certain adverse side effects on the U.S. economy. In particular, Dr. Koplekoff forecast a 5 percent decrease in GNP, a 32 percent decrease in new housing starts, a 126 percent increase in unemployment, and a 157 percent increase in requirements for unemployment benefits.
On the other hand, if "lifespan-extending" interventions were to be discovered instead, we could expect positive benefits in the form of a 12 percent increase in capital utilization and a sharply-rising increase in productivity of the labor force.
In terms of the traditional developmental stages of life, Prof. John Riley forecasts a favorable re-integration of many of the economically-dictated phases of social development, including education (during youth), productive work (during middle years), and leisure (during retirement or old age). In other words, individuals would be far more free to move between educational, work, and leisure activities on a full-time basis, as they so desired, rather than being restricted by age and financial circumstances.
Dr. Walford stated in conclusion that for the first time in human history, a significant number of individuals born in the next few years will have the nearly unique opportunity to live in three different centruries: The Twentieth, the Twenty-First, and the Twenty-Second (post 2100). However, if that is really going to happen, we will need to take better care of Biosphere 1 (our own Earth).

REFERENCES

1. Roy L. Walford, Maximum Life Span (W.W. Norton & Co., New York,; 1983).
2. Roy L. Walford, The 120-Year Diet: How to Double Your Vital Years (Simon and Schuster, New York; 1986).
3. Roy L. Walford and Richard Weindruch, The Retardation of Aging and Disease by Dietary Restriction (Charles C. Thomas, Springfield, Illinois; 1988).
4. Roy L. Walford and Lisa Walford, The Anti-Aging Plan: Strategies and Recipes for Extending Your Healthy Years (Four Walls Eight Windows, New York; 1994).
5. Roy L. Walford, The Interactive Diet Planner for Windows (Longbrook Company, 1015 Gayley Avenue, Suite 1215, Los Angeles, California 90024; 310-392-8208; 1994).
6. Genesis, Chapter 3, Verses 22-24, The Old Testament.
7. Hans Biedermann, Medicina Magica: Metaphysical Healing Methods in Late-Antique and Medieval Manuscripts, Translated from the German (The Classics of Medicine Library, Gryphon Editions, Inc., Birmingham, Alabama, 1978).
8. Gerald J. Gruman, "A History of Ideas about the Prolongation of Life," Transactions of the American Philosophical Society, Vol. 56, No. 9, pp. 1-102 (1966).
9. Jonathan Swift, Gulliver's Travels, Chapter X, pp. 124-129 (Great Books, Chicago, Illinois; 1952).
10. Leonard Hayflick, How and Why we Age (Ballantine Books, New York; 1994).
11. James Hilton, Lost Horizon (1933).
12. James F. Fries and Lawrence M. Crapo, Vitality and Aging: Implications of the Rectangular Curve (W. H. Freeman and Company, San Francisco, California; 1981).
13. Alex Comfort, The Biology of Senescence, 3rd Edition (Elsevier North Holland, Inc., New York; 1979).
14. Betty Friedan, The Fountain of Age (Simon & Schuster, New York; 1993).
15. Betty Friedan, "Why Men Die Young," Playboy Magazine, pp.62-66, 86, 151-152 (April 1995).
16. Alan Harrington, The Immortalist (Random House, New York; 1969).
17. Alex Comfort, Say Yes to Old Age: Developing a Positive Attitude Toward Aging (Crown Publishers, Inc., New York; 1990).
18. Horizons, To Add Another Candle: The Secrets of Living Longer, 30-minute Audio Tape (National Public Radio, 635 Massachusetts Avenue, N.W., Washington, D.C. 20001-3753; November 3, 1992).
19. Arthur L. Caplan, "Is Aging a Disease?" Chapter 12, pp. 195-209, If I were a Rich Man, Could I Buy a Pancreas? and Other Essays on the Ethics of Health Care (Indiana University Press, Bloomington, Indiana, 1992).
20. William C. Orr and Rajindar S. Sohal, "Extension of Life-Span by Overexpression of Superoxide Dismutase and Catalase in Drosophila melanogaster," Vol. 263, pp. 1128-1130, Science (February 25, 1994).
21. Carol Kahn, "Eat Less, Live Longer," Longevity, pp. 46-48, 90-97 (April 1995).
22. Gary Taubes, "Biosphere 2 Gets New Lease on Life from Research Plan," Science, Vol. 267, p. 169 (January 13, 1995).
23. Science, p. 1368 (March 11, 1994).
24. John Allen, Biosphere 2: The Human Experiment (Penguin, New York; 1991).
25. Marvin Minsky, "Will Robots Inherit the Earth?" Scientific American, pp. 108-113 (October 1994).
26. John Riley and Riley, Gerontologist, Vol. 34, pp. 110-115 (1994).

L. Stephen Coles, M.D., Ph.D. Dr. Coles is the founder of the Gerontology Research Group; Los Angeles, California. For more information on his work, please refer to the web site of The Gerontology Research Group or email him at scoles@grg.org;

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