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Life Extension Magazine

LE Magazine September 1995

Achieving Physical Immortality

The Life Extension Foundation's Seven-Part Research Plan
To Enable Us To Live In Good Health For Centuries
By Saul Kent, President, Life Extension Foundation

At The Life Extension Foundation, we believe that many of the stepping stones to physical immortality may already exist. That much of the basic research needed to develop authentic anti-aging therapies may be at our fingertips. And that all we need to achieve an indefinitely extended life span of health and vigor in the foreseeable future is a comprehensive plan to achieve this goal. What follows are some of the details of The Life Extension Foundation's research plan for the achievement of physical immortality!

 

1. Measuring The Rate At Which We Age:
The Search For Biomarkers Of Aging

In order to pursue physical immortality on a reasonable time scale, it is absolutely necessary that we develop valid, reliable, tests to measure the rate at which we age over relatively short periods of time. The failure to develop such "biomarkers of aging" is a major impediment to the development of scientifically verifiable anti-aging therapies.

LEF image The reason we need valid biomarkers of aging is that we have no other way of assessing the effectiveness of potential anti-aging therapies! The only currently accepted method of measuring the rate of aging is the extension of maximum lifespan.

For example, if the maximum lifespan of a strain of mice is about three years of age under natural conditions, and scientists are able to get some of these mice to live for four-to-five years by restricting their food intake, it is convincing evidence that the aging process has been slowed in these mice.

The Problem With Lifespan Studies

The problem with this type of evidence is that it takes an exceedingly long time to develop. A lifespan study in mice, for example, can take 4-5 years. Even if you started the study with adult 12-month-old mice, it would only reduce the length of the study by about a year.

A lifespan study in dogs or cats would take 15-to-20 years. Such a study in monkeys would take at least 30 or 40 years, while a lifespan study in humans could take well over 100 years. Even if you started the study in 60-year-old people, it would still take another 60 years or more before acceptable evidence could be developed that the therapy being studied can slow aging.

The Value Of Tests To Measure Aging

On the other hand, validated tests to measure aging would provide us with an invaluable shortcut to determine the value of potential anti-aging therapies. For example, if we had reliable tests to measure aging over a six month period in mice or a 3-5 year period in humans, we could assess the ability of therapies to slow the aging process quite well over a reasonably short period. This would add immeasurably to our ability to screen a wide variety of therapies for their ability to slow aging in both animals and humans.

The importance of validated tests to measure aging over relatively short periods of time is unquestioned, the only questions that remain are how to validate these tests.

Measuring Functions In Food Restricted Animals

The first thing we need to look at is the only model in which slowing of the aging process is unquestioned--food restriction in laboratory animals. There have been dozens of studies in both rats and mice showing that food restriction extends maximum lifespan.

One of the requisites for a proposed biomarker of aging test would therefore be that the function it measures is altered significantly in food restricted animals compared to normally fed animals.

There are a wide variety of hormone, enzyme, and other functions that change appreciably with advancing age in normally fed animals (and humans). For example, the lens of the eye becomes increasingly opaque with age, which leads to the development of cataracts as we grow older. However, this aging-related change in the lens of the eye is demonstrably slowed in food-restricted animals, which suggests that evaluation of the opacity of the lens of the eye could be a possible biomarker of aging.

Another example of a function that is altered in food-restricted animals is the solubility of collagen, which is a measure of molecular crosslinking in aging tissues. In normally aging animals, collagen becomes progressively more insoluble with advancing age, while in food restricted animals, this progression is significantly slowed.

A few examples of other functions that change appreciably and reliably during aging are blood levels of hormones such as melatonin, DHEA, and thymosin, which decline with advancing age, hormones such as cortisol, which increase with age, lymphokines such as interleukin-6, which increase with age, and enzymes such as choline acetyltransferase (which decline with age) and monoamine oxidase (which increase with age). If these functions are true measures of normal aging, their age-related changes should be significantly altered in food-restricted animals.

The Degree Of Change During Aging

Another requisite for a test to measure aging is that its effect must be measurable over a reasonably short period of time. If the test we propose to measure aging in humans, for example, only changes significantly over a 20-year period, its rate of change is simply too slow to have any practical value. Thus, it is a practical necessity for us to have tests that can be used effectively over a period of only a few years.

The Effect Of Physical Conditioning

One of the pitfalls in our search for valid biomarkers of aging is that some potential measures of aging can be affected dramatically by physical conditioning, which can easily mask their value for aging measurement.

For example, functions such as blood pressure, heart rate, reflexes, and strength can be affected positively by an exercise program at any age. Thus, a sedentary man of 50 with high blood pressure, slowed reflexes, and diminished strength, who embarks upon a regular, exercise program for the first time in his life, will soon find that his blood pressure is lower, his reflexes are faster, and his strength is greater than it was before he started exercising.

If the man continued this exercise program for five years, he would probably exhibit more "youthful" measures of blood pressure, reflexes, and strength at age 55 than he did at age 50. That would not mean, however, that the man was really younger at 55 than he was at 50. What this tells us is that in searching for tests to measure aging--we cannot use functions that are easily affected by physical conditioning,

The Effects Of Diet And Medical Treatment

Another pitfall in the search for biomarkers of aging is the masking effects of diet and medical treatment. Functions such as blood pressure, serum cholesterol levels, serum glucose levels, blood cell counts, and immune cell competence can easily be altered by diet, supplemental nutrients, and drug therapies.

For example, a reduced fat diet lowers cholesterol levels, as does supplementation with niacin, and several cholesterol-lowering drugs. Any function that is so easily manipulated by such interventions cannot be used to measure the aging process, which continues unabated, regardless of the effects of dietary or medical treatment.

Invasiveness And Cost

The less invasive a test is, the easier it is to use on a large-scale basis. In searching for tests to measure the rate of aging, the degree of invasiveness of the test is a significant issue. A small degree of invasiveness, such as using a syringe to obtain a person's blood, is acceptable, but a surgical operation is not. Obtaining bone marrow for example, which involves a painful, invasive process is not appropriate for widespread use,

Cost is also a significant issue. Some tests are so expensive that it's simply not practical to use them on a mass basis. It is thus important, in developing a battery of tests to measure aging, that we use relatively inexpensive tests that are easily affordable for most people.

Promising Biomarkers Of Aging

Now that some of the criteria for valid, reliable biomarkers of aging have been discussed, let's take a look at a few functions that show promise as measures of the rate of human aging.

A Crucial Step In Protein Synthesis

One of the characteristic signs of aging is a decline in protein synthesis in virtually every cell in the body. Proteins are synthesized in cellular "factories" called ribosomes through a complex process that involves a number of critical steps. Scientists have discovered that a compound involved in the protein synthesis process called Elongation-Factor-5 is depleted markedly with age and may be the critical "fault" that leads to the decline in protein synthesis as we grow older. One of the questions that remains is whether we can easily and inexpensively test for Elongation-Factor-5 .

The Anti-Aging Hormone

LEF image-DNA strand Evidence is mounting that melatonin may be the body's own anti-aging hormone. Melatonin has extended lifespan in laboratory animals by 25%, has potent anti-cancer effects, is a highly potent antioxidant, improves the quality of healing, recuperative sleep, and elevates levels of many intrinsic health building substances within the body. Since blood levels of melatonin decrease radically with advancing age, regardless of other conditions, it appears as if the measurement of melatonin levels may be an effective biomarker of aging.

Measuring The Pacemaker Of Aging

Perhaps the most promising biomarker of aging is the length of telomeres at the ends of the chromosomes in the nucleus of our cells. Scientists have shown that, in dividing cells, the gradual shortening of the nucleotide sequences that make up the ends of our chromosomes during cell division is directly correlated with the age related loss of proliferative capacity, which leads to the malfunctioning and eventual death of our cells.

Many scientists now believe that the shortening of telomeres is the pacemaker of aging that determines the rate at which we age. Dr. Michael West of Geron has informed The Foundation that telomere length can be measured relatively easily from skin cells taken from a superficial scraping.

These are just a few suggestions for tests to measure the rate of aging. Whether any of them will prove to be valid, reliable, and practical remains to be seen. What is clearly needed, however, is a solid research program to develop a battery of such tests as soon as possible.

2. Studying The Anti-Aging Effects Of Today's Therapies

There have been a few lifespan studies suggesting that some of the nutrients and drugs that are readily available today may slow aging in humans. There is additional evidence of anti-aging effects for a wide variety of other therapies that have yet to be tested in lifespan studies.

The truth is that the vast majority of potential anti-aging therapies have never been tested in lifespan studies for their effect on the rate of aging. Moreover, there has not yet been adequate lifespan testing of the three promising therapies--deprenyl, melatonin, and coenzyme-Q10 for which lifespan studies have been conducted.

Among the promising anti-aging therapies that have yet to be tested in lifespan studies are DHEA (a lifespan study is underway), acetyl-l-carnitine, phosphatidylserine, thymosin, n-acetyl-cysteine, estrogen, growth hormone, aminoguanidine, hydergine, vinpocetin, piracetam, zinc, selenium, and arginine.

The Lifespan Studies Project

A major step forward in our quest for physical immortality would be a comprehensive lifespan studies project in which every promising anti-aging therapy would be tested in lifespan studies in large numbers of laboratory animals. We need to test each potential anti-aging therapy in young, middle-aged, and old animals, and we need to test combinations of these agents in order to discover the most potent anti-aging therapies.

When a battery of validated anti-aging tests becomes available, these tests should be used to screen promising therapies for any indication of anti-aging effects. The most promising of these therapies should then be tested in large-scale lifespan studies in animals and--if they are safe--in large-scale clinical studies in humans.

3. More Sophisticated Drug Delivery Systems

If we want truly effective anti-aging therapies capable of radical life extension, we need highly sophisticated, interactive drug delivery systems that release and inhibit neurotransmitters, hormones, enzymes, and other vital substances, according to the changing needs of our bodies.

An example of the sophistication of our internal control systems is the variable release of insulin and glucagon from the pancreas in response to varying blood levels of glucose (blood sugar). After you eat a meal, your pancreas secretes insulin to control and help process the extra glucose in your bloodstream. When your blood glucose level drops too low, on the other hand, your pancreas releases glucagon to stimulate glucose production.

More Complex Interactions

In women, estrogen plays a vital role in maintaining bone strength, sexual functioning, and reproduction. In doing so, it interacts in a highly complex manner with vital substances such as progesterone, luteinizing hormone, follicle-stimulating hormone, dopamine, serotonin, and calcitonin.

Recent studies show that estrogen may play an essential role in learning, memory, and information processing in the brain (in both men and women) through interaction with acetylcholine and other neurotransmitters. Moreover, there is evidence that estrogen may have other anti-aging effects in addition to its rejuvenating effects in post-menopausal women.

Mimicking The Body's Own Drug Delivery Systems

A critical need in our quest for physical immortality is drug delivery systems that mimic the body's own systems. What we need are small implantable systems as responsive to our needs as endocrine organs such as the pancreas, ovaries, pineal gland and pituitary gland. We need systems that normalize the activity of, or replace, our endocrine glands as they atrophy, wear out, and become increasingly dysfunctional with advancing age.

Fortunately, we already have companies such as Alza Pharmaceuticals, which have made an excellent start in developing steady state drug delivery systems. Such companies are already on the way to developing the kind of high-tech drug delivery systems we will need to extend the human lifespan.

4. The Life Extension Net

Now that The Internet has been developed, we need to use its awesome communications power to further progress towards physical immortality. We need to set up Life Extension Net, which would be designed to integrate existing knowledge in every scientific field related to life extension in order to accelerate progress in extending the human lifespan.

Life Extension Net would include scientists and physicians engaged in life extension research, lay people on life extension programs, INFOrmation scientists to collect and analyze data generated within the system and to search for related findings from other data bases, and journalists to communicate the advances developed through the system to people throughout the world.

The Rules Of The Publishing Game

When scientists publish their research results in peer-reviewed journals, it enables their findings to be scrutinized by other "qualified" scientists before being revealed to the public. This process protects against the release of premature or inappropriate findings. It is strengthened by the policies of publications such as the New England Journal Of Medicine, which threaten to withhold publication from scientists who reveal "too much" of their early results to other media sources.

The problem is that the career advancement of scientists depends to a great extent on reports of their studies being published in peer-reviewed journals. As a result, these rules foster secrecy among scientists who fear having their research results stolen, and delay the public release of lifesaving findings. In fact, some findings weren't published until years after being discovered.

Changing The Rules Of The Game

In setting up Life Extension Net, scientists need to be persuaded to reveal their research findings on the Net as they develop--without waiting for final results or formal peer review. The purpose of soliciting ongoing input from scientists would be to foster progress among all scientists engaged in similar research and to provide for the earliest possible release of potentially beneficial findings. The release of findings from scientists at private companies will be constrained, of course, by the need for patent protection before revealing their findings on Life Extension Net.

All data, findings, and ideas introduced on the network would be recorded in chronological order to make it possible to identify the contribution of each scientist to every advance that occurs as a result of network collaboration. These records would be used to give every contributing scientist the credit he or she deserves when the final report is published in a medical journal. Hopefully, this will end the concern of some scientists that their ideas might be stolen if they participate.

It is also hoped that--in the interest of more rapid progress in medicine--the editors of peer reviewed journals would permit scientists to participate in Life Extension Net without penalizing them. If they wished to, in fact, the journals could become vital participants in the give-and-take of network interaction... perhaps by providing referees to moderate debates about important issues.

Realistic Clinical Trials

One of the potential benefits of Life Extension Net will be the opportunity to conduct realistic clinical trials that generate vast amounts of data on a continuing basis for every therapy used in medicine. These trials will eventually replace today's controlled clinical trials as the sine qua non for the scientific evaluation of medical therapies.

Today's controlled clinical trials force all patients to submit to the exact same experimental regimen for the identical period of time. Such trials normally test only one experimental agent at a time and expose half the patients to a placebo instead of an active drug. In short, the controlled clinical trial is conducted in a highly artificial manner that seriously distorts its results.

On Life Extension Net, clinical trials could be conducted using patients receiving individualized treatment from their own physicians. lnstead of forcing patients to follow the same protocol, scientists on The Net--with access to patients around the world--could group together subjects of similar age, sex and other personal characteristics, who all follow the same protocol because it's the best treatment for them as individuals.

Physicians treating patients in the field would follow uniform data entry on computer programs designed by experts in the field. These programs would generate compatible data from physicians around the world, which would then be analyzed to yield useful findings and conclusions.

If enough physicians would submit medical data to The Net, we could generate large-scale, never-ending clinical trials for every therapy on Earth. These studies would provide us with perpetual evaluation of the safety-and-effectiveness of promising anti-aging therapies, which would fuel an explosion of new knowledge about how to extend our lives in good health.

Communicating The Results Of Net Research

There would be several ways of communicating the results of Life Extension Net research. First would be that all data, ideas, findings, conclusions, and speculations generated on The Net would be available to all Net participants--either for their own information, or as raw material for studies.

Second would be scientific papers, reports, talks, and symposia produced from The Net's data base--either by scientists conducting research on The Net or by generalists who use the data for insights about the nature of aging, methods of extending lifespan, or ideas about future research.

Third would be reports, stories, TV shows, movies, and computer programs produced by journalists for the general public. These reports would offer direct help to people who want to live longer now, and would seek to stimulate public support for more research.

5. The Human Anti-Aging Genome Project

The Human Genome Project is one of the most ambitious and highly publicized research projects in history. By setting aside a billion dollars to identify and map the 100,000 or so genes that make up the human genome, the U.S. government has recognized the preeminent role that genes play in our lives, as well as the huge medical potential of genetic engineering.

LEF image-molecule The time is ripe for a more focused project to identify and discover the mechanisms of action of the genes involved in the aging process, with an eye towards manipulating them to extend the human lifespan. Evolutionary evidence suggests that relatively few genes determine the length of our lifespan...perhaps no more than 1% of the genome, either by causing the breakdowns associated with aging, or the production of substances that prevent the breakdowns of aging.

The Human Anti-Aging Genome Project is a major part of The Foundation's plan for the achievement of physical immortality. Learning more about the genes involved in health and longevity will pay big dividends in the development of potent, new, anti-aging therapies. Several companies are now delving into the genetic control of aging, including Geron Corporation, which has an entire laboratory to search for, identify, characterize, synthesize, and manipulate aging-related genes.

6. Aging Control By Manipulating Atoms

If genes are the biochemical entities that control our life processes, atoms are the basic building blocks of matter--including the cells within our bodies. If it proves difficult to gain total control over aging through genetic engineering, there's an exciting new science called Nanotechnology which will, eventually, allow us to gain total control over aging atom-by-atom through the use of highly advanced, super-tiny, therapeutic systems introduced into our bodies to repair our deteriorating cells, tissues, and organs!

A nanometer is a billionth of a meter, and Nanotechnology involves the design, engineering, and construction of machines that work at sizes of a billionth of a meter or even smaller. A technology capable of operating at such incredibly small sizes would be able to repair virtually any type of damage to our bodies, including the damage caused by aging.

Nanotechnology is more than a pipe dream. Scientists can already manipulate atoms to some degree through instruments such as the Scanning Tunneling Microscope and the Atomic Force Microscope, and Nanotechnologists such as Dr. Ralph Merkle of the Xerox Palo Alto Research Center in California are currently designing Nanotechnology systems.

Scientists involved in Nanotechnology predict that full-fledged, computerized, Nanophysicians capable of restoring us to permanent youth, health, and vigor will likely become available at some point in the 21st century. It will probably be at least 50-75 years before Nano-Therapeutic-Systems will be available, but it could be sooner if enough research money is invested in the field of Nanomedicine.

7. Suspended Animation: The Time Machine

Some of us alive today will never grow old and will go on to live in good health for centuries, but most of us who've already grown older than we'd like, are going to need help to survive long enough to take advantage of the anti-aging technologies of the future.

The best answer for those of us faced with death before the advent of Super Medicine is Suspended Animation--the cryopreservation of our bodies at ultra-low temperatures for the purpose of future revival. Being placed into Suspended Animation will be like entering a time machine that will send us rocketing into the future in the pursuit of physical immortality!

Today's methods of cryopreservation are imperfect, however pioneering research to perfect Suspended Animation is now being conducted at a high-tech California company called 21st Century Medicine, Inc. The Foundation has invested money in this company, which also will be conducting lifespan experiments to test the anti-aging effects of promising life extension therapies.

Suspended Animation is the Life Extension Science we'd most like to avoid if possible. Our objective is to stay alive, to conquer aging, and to continue to live in super-good health for centuries to come! We trust that you share this goal, and we want you to know that we're doing everything we can to help you in your personal quest for an extended healthy lifespan!

Geron Sells Asian Rights To Anti-cancer Research

We've carried several reports about the exciting advances in cellular aging made by scientists at Geron Corporation in Menlo Park, California. They've discovered an "immortalizing" enzyme called telomerase which is present in virtually every type of cancer cell, but is not found in normal cells. Telomerase controls the "clocking" mechanism that determines the lifespan of dividing cells by maintaining the DNA structures (telomeres) at the ends of chromosomes, the loss of which (during cell division) gradually weakens the chromosomes, leading, eventually, to the massive cell death involved in aging.

These discoveries point the way to the possibility of novel anti-cancer therapies based upon the development of inhibitors of telomerase, which would, presumably, transform cancer cells back into normal cells with normal mortality. On the other hand, the development of a method to enable telomerase (or an analog) to slow, stop, or reverse the senescence of dividing cells could be a highly effective way of controlling aging and, possibly, treating age related diseases such as Alzheimer's and Parkinson's disease.

Geron's telomerase findings have caused tremendous enthusiasm in the cancer research community, which has been hungering for an exciting new approach to the treatment of cancer for many years. Despite billions of dollars of money spent on cancer research since 1971 when President Nixon declared "war on cancer", there have been few advances in the treatment of this dreaded disease. Even worse has been the realization that more people have and are dying of cancer today than in 1971. Robert Weinberg, Ph.D. of MIT, a pioneer in the molecular understanding of cancer, believes that "Telomerase represents the most exciting opportunity to arise in the cancer field in recent years."

Japanese Company Validates Geron's Findings

The value of Geron's findings has been validated by a new collaborative agreement with Kyowa Hakko Kogyo, Ltd, the number one oncology company in Japan, with annual sales in excess of $3 billion. Kyowa Hakko is headquartered in Tokyo and has more than 6,500 employees.

The agreement, which covers Japan and other major Asian countries, provides for payments to Geron of up to $30 million for research and development milestones. Geron will receive royalties on product sales and Kyowa Hakko will receive manufacturing and marketing rights in Asia for any anti-cancer therapies developed from further research by Geron. Kyowa Hakko has the responsibility of funding clinical trials for these therapies in Asia. Geron retains all remaining worldwide rights to any such anti-cancer therapies and total worldwide rights for any therapies it develops to treat aging and any of the other diseases of aging.

We will continue to update you on the latest developments at Geron and other companies with innovative approaches to the control of aging and age-related diseases. We believe that Geron's research holds the greatest promise of providing the first definitive therapy to extend maximum lifespan in humans.