AND THE DISEASES OF OLD AGE
Leonard Hayflick, Ph.D.
Professor of Anatomy,
Department of Anatomy
School of Medicine
University of California at San Francisco,
The Sea Ranch, CA 95497; USA
“MODULATING AGING AND LONGEVITY”
S. I. S. Rattan, Editor
Kluwer Academic Publishers; 2003, pp. 1-15
Written on September 15, 2002
Revised for the Internet on February 26, 2004
Running Title: “Modulating Aging, Longevity Determination, and the Diseases of Old Age”
Copyright ©: September 2002 by Leonard Hayflick
No discussion of aging can be productive without a clear definition of what the communicator means by “aging” and by other terms that are central to understanding in this field. Failure to do so has, and still is, creating enormous confusion, futility to effectively communicate, and inability to grasp the fundamental differences between aging, the determination of longevity, and age-associated diseases.
There is probably no other scientific discipline in which there is such widespread lack of agreement on what is meant by the most elemental words in the field. This failure to agree on the definitions of basic vocabulary mirrors the present diffuse and chaotic state of the field itself. The practitioners of what is commonly called aging research, many of whom are aware of this problem, have not yet become sufficiently motivated to rectify the situation. The problem is further compounded by the ease with which neophytes can enter this field and become recognized as aging researchers.
Because no experiment can be done in the absence of a temporal variable, it is arguably true that all biological research is research on aging. This common impression has attracted researchers to the field who have no understanding of its fundamental concepts and even less understanding that there is a lack of agreement by established practitioners on the definition of common terms used. In order to avoid these pitfalls and to attempt clear communication, I will define my terms rigorously here and, in the process, not only reveal why misunderstandings of fundamental concepts persist in this field but why longevity determination and the diseases of old age can and are being modulated and why the fundamental processes of aging cannot be modulated.
If our understanding of the fundamental processes of aging biogerontology) is to advance, it will not only be necessary to distinguish it from geriatric medicine (the diseases and pathologies of old age) but it will also be necessary to distinguish aging from the concept of longevity determination. The failure to make these distinctions has contributed significantly to the frequent erroneous interpretation of research data that is replete in this field. The failure to make the distinction between aging and longevity determination, is particularly pervasive by those who use invertebrate models, where research data interpreted to bear on aging, in fact, should be interpreted to bear upon our knowledge of longevity determination. Additional confusion frequently is added to the mix when research findings that are applicable to the diseases of old age are interpreted to advance our knowledge of the aging process.
Aging can be defined as a disorder that occurs at many levels of biological organization of which the most fundamental is molecular. Although the disorder or changes that occur over time at the atomic level generally are ignored by biogerontologists they are the cornerstone of quantum mechanics.
Aging in living things is a stochastic process that occurs after reproductive maturation and results from increasing random, systemic, molecular disorder [1-3]. It is no different in its fundamental aspect of increasing loss of molecular fidelity from the aging phenomenon as it occurs in the entire non-biological world.
The scientific literature is replete with examples of age-related declines in protein synthesis and degradation , loss of DNA fidelity , and effects with age of oxidative stress on molecular fidelity . Many of the chance events that initiate this loss of molecular integrity and result in the subsequent aging process have been extensively catalogued .
It is difficult not to be impressed with what appears to be the fundamental inability of animals that reach a fixed size in adulthood to maintain the fidelity of their molecules after reproductive success. This systemic increase in molecular disorder leads to the inescapable conclusion that the sum of all these decrements is the etiology of the resulting age changes that have been defined in other terms at higher levels of organization.
We spend the first twenty-five years or so of our lives producing, ordering, and replacing our molecules with the greatest likelihood of absolute fidelity. Through natural selection, the fidelity of anabolic processes is maintained by the efficiency of turnover and repair until reproductive success or our species would vanish. Natural selection has favored energy states that differ for each species because the molecules in each species need only to maintain their fidelity long enough to guarantee reproductive success. The energy states that have been achieved at the time of reproductive success will then indirectly govern subsequent post-reproductive longevity. After reproductive success, there is no species survival value in maintaining those energy states indefinitely. Consequently, the random downward spiral of molecular disorder results in changes at increasingly higher levels of organization in cells, tissues, and organs, each of which reveals a catalogue of decrements that we label as age changes. These events occur in spite of the existence of well-known repair processes because repair processes themselves are as vulnerable to the loss of molecular fidelity as are their target molecules. Chance events that create molecular disorder certainly occur during development but repair mechanisms must overcome these or the species would vanish. However, after reproductive success the balance of molecular disorder shifts to exceed the capacity for repair, and thus the process of aging is initiated in those animals that reach a fixed size in adulthood.
The random molecular disorder and the diminished physiological capacity that molecular disorder produces are the hallmarks of age changes. As the process accelerates the decrements in physiological capacity that are produced increase vulnerability to predation, accidents, and the diseases and pathologies of old age.
The proof that individual survival beyond reproductive success is unnecessary for species survival is clear. Humans have survived with a life expectation of twenty-five years or less for 99.9 percent of the several million years that we have been a species. No prehistoric human remains have been found to be older than about 50 years. If the time in which the human species has existed could be imagined on a twenty-four hour time scale, aging as a process that most people in developed countries experience would occur only a few seconds before midnight.
There is an almost complete absence in the biogerontological literature of an appreciation that the process of aging is identical, in principle, in both the animate and inanimate worlds. That is, the random loss of energy necessary to maintain molecular structure and function defines the aging process in all matter. Furthermore, the processes by which inanimate objects are formed, with or without human intervention, are analogous to the developmental processes that occur in biological material. Thus, in both animate organisms and inanimate objects the elements of design, materials used, and construction and repair processes all conspire to influence the potential longevity of each.
Species survival depends on a sufficient number of members living long enough to reproduce and, if necessary, to raise progeny to independence. Natural selection favors animals that have greater survival skills and, especially, redundant physiological reserve in vital organs beyond the minimum needed to survive the damage that might be exacted by predators, disease, accidents, or environmental extremes. Thus, selection for physiological capacity, beyond the minimum required for life, increases the chances for animals to survive long enough to achieve reproductive success just as redundant vital systems in complex machines, better insures that they will reach their goals. The amount of excess physiological capacity, like the amount of redundancy engineered into space vehicles, not only better insures that the essential goal will be reached but, when it is reached, it indirectly provides the potential for continued longevity beyond the primary goal [1-3, 8]. The level of physiological capacity reached at the time of reproductive success in living things is the determinant of their potential longevity. It is conceptually and biologically different from the aging process.
Longevity determination in living material is not a random process. It is governed by the amount of excess physiological capacity reached at the time of sexual maturation that, through natural selection, was achieved to better guarantee survival. Thus, the determination of longevity is not directly determined by the genome but is only indirectly determined. Longevity can be thought of as a by-product, or as an incidental consequence, of the primary purpose of genome activity -- to govern those events that take an organism from conception to reproductive success. Aging, on the other hand, involves the loss of fidelity that occurs in these pre-existing molecules, or their turnover replacements, and can be thought of as the process that works against longevity determination. Weakened members of a species will be culled by the forces of natural selection because living long beyond reproductive success has diminishing value for the survival of a species. Species survival is optimized when energy is spent to guaranty reproductive success rather than spending it on increasing individual longevity.
It is for this, and other reasons, that biogerontologists are asking the wrong question: “Why do we age?" The right question is: “Why do we live as long as we do?"
Longevity determination in higher animals has been a profoundly neglected area of research. One class of animals that may provide some answers to the determination of longevity are those animals that do not reach a fixed size in adulthood and age slowly or not at all. If these animals do age, the process is either negligible or it occurs below the limits of detection. Representative animals of this class include some tortoises, many sport and cold-water deep-sea fish, some amphibians, and the American lobster. Even telomerase expression, the hallmark of immortal cells, has been found at extraordinarily high levels in all the cells of negligibly aging animals like the American lobster (Homarus americanus) and the rainbow trout (Onchorhynchus mykiss)[9,10]. Whether these animals age at all, and the reasons for this, have been almost entirely neglected. These animals are not immortal because, like animals that do age, there is a constant threat of disease, predation, and accidents [3, 11]. The time is long overdue for more intense study of the phenomenon of negligible aging.
IV. GENES DO NOT GOVERN AGING
Aging is not a programmed process governed directly or entirely by genes [1-3]. It is mostly those who work with invertebrates who have interpreted their findings to involve genes in the aging process. They have failed to appreciate that the genes that they have identified are involved in longevity determination and not in aging.
Genes are not involved in aging because they have not been shown to affect, reverse, or arrest the inexorable expression of molecular disorder that defines aging. Few, if any of the alleged aging studies on invertebrates have employed an experimental design in which organisms having the aging phenotype have been subjected to some variable that has been shown to reverse or arrest that phenotype. Most of the studies on invertebrates are more accurately interpreted to impact on our understanding of longevity determination because the experimental results have almost universally revealed an affect on physiological capacity or developmental events that occur well before the aging process begins. The interpretation that gene manipulation has resulted in a delay in the appearance of the aging process is more accurately interpreted to be the result of increasing physiological redundancy, improved repair processes, or the betterment of any other variable that results in the greater likelihood that an animal will reach reproductive success.
Just as a blueprint is vital to manufacture a complex machine and contains no information to cause the aging of that machine, the genome is critical for biological development but unnecessary to direct the aging of that animal. Both machine and animal eventually fail as a result of increasingly irreparable loss of molecular fidelity, which in living systems increases vulnerability to predation, accidents, or disease and in inanimate objects increases vulnerability to analogous failures in some vital component.
Another argument against the direct role of genes in programming the aging process is that animals do not age at the same rate, even when inbred, nor are the patterns of age changes identical in each identical twin or other identical multiple births. When the random events characteristic of aging are compared with the orderly, virtually lock-step, changes that occur during genetically driven embryogenesis and development, that orderliness and precision stands out in stark contrast to the quantitative and qualitative disorder of age changes . The variability in the manifestations of aging differs greatly from animal to animal within a species but the variability in developmental changes differs trivially. Humans from conception to adulthood are virtually identical in respect to the timing of the stages involved in biological development but from about thirty on, age changes produce profound biological heterogeneity .
The faulty interpretation that gene manipulation in invertebrates can arrest the aging process has been extrapolated by authors in both the lay and scientific press as potentially applicable to higher organisms including humans. This has resulted in the belief that in a short time our increasingly better understanding of the genome and proteomics will permit humans to modulate their own aging processes through gene manipulation. This erroneous conclusion has been reached simply because there has been a failure to appreciate the critical distinction between the processes of longevity determination and aging. Even if the determinants of human longevity could be manipulated using genetic engineering, the results have the potential to produce an enormous array of unintended consequences that will be discussed subsequently.
V. AGING AND AGE-ASSOCIATED DISEASES
Aging is not a disease. This distinction is central to understanding why the resolution of the leading causes of death in old age -- cardiovascular disease, stroke, and cancer, will tell us little about the fundamental biology of age changes. The resolution of all three causes will only result in an increase of about fifteen years in human life expectation . Then, aging, or the inexorable loss in physiological capacity that underlies the cause of these pathologies will be revealed as the leading cause of death. For the first time in human history, most people will be found to die of old age.
The resolution of age-associated diseases will advance our knowledge of the aging processes to the same extent that the resolution of pediatric-associated diseases such as poliomyelitis, acute lymphocytic leukemia, Wilms’ tumors, and iron deficiency anemia increased our knowledge of childhood development. That is, no increase occurred at all.
Aging is not a disease because, unlike any disease, age changes
(1) occur in every animal that reaches a fixed size in adulthood;
(2) cross virtually every species barrier;
(3) occur in all animals that reach a fixed size in adulthood and only after sexual maturation;
(4) occur in animals removed from the wild and protected by humans, even when that species has not been known to experience aging for thousands or even millions of years;
(5) increase vulnerability to death in 100 percent of the animals in which it occurs; and
(6) occur in both animate and inanimate objects.
Today, the study of age-associated diseases and the manipulation of biological development in lower life forms dominate what is assumed to be the field of aging research. Neither research area will provide insights into the aging process. One example of this misunderstanding is that more than half the budget of the National Institute on Aging in the United States is spent on Alzheimer’s Disease research, yet motor vehicle accidents cause twice as many deaths  and from age 65 on, Alzheimer’s Disease is not even one of the five leading causes of death . The likelihood of dying from Alzheimer’s disease is 0.7 percent  and the complete resolution of this disease will add about 19 days onto average life expectation . Nor will that accomplishment advance our knowledge of the fundamental biology of aging.
In the minds of the public, policy makers and many biomedical scientists, no one suffers or dies from aging. We suffer and die from the diseases associated with the aging process. Yet, age changes increase vulnerability to everything that is written on the death certificates of the elderly.
No one over the age of, say, 75 has or will die from what is written on his or her death certificate. Death results from the inevitable increase in systemic molecular disorder that living long enough incurs. That disorder, when it occurs in vital systems simply increases vulnerability to whatever was, or will be, written on death certificates.
Because there are multiple pathologies in older people the true cause of death is rarely known. Because there are few autopsies, and little research, the cause of most deaths in old age is still hidden in the proverbial “black box.” The numbers of autopsies that have been done on the elderly have continued to decrease in the last few decades. In those rare instances where autopsies have been performed on a large number of old people, the findings have shown that from 40 to 50 percent of the causes of death appearing on the death certificates have been inaccurate [14 - 16]. In the most recent study of 93 postmortem examinations done in an Israeli hospital over a twenty-year period, 42 percent of the causes of death written on the death certificates were incorrect . Over this twenty-year period the rate of autopsies dropped from 2.8 percent to 0.25 percent. These findings should raise considerable concern for the many political, economic, actuarial, and scientific decisions that, without benefit of autopsy, may have a forty-percent error rate.
More than 75 percent of all human deaths in developed countries now occur in those over the age of 75. If the causes of these deaths are resolved, we will not become immortal, but we will have revealed how death occurs in the absence of disease. What will be found is that the underlying cause of these deaths is the inexorable loss of physiological capacity that results from increasing molecular disorder in the cells of vital organs. This is the hallmark of aging, and it will appear on all death certificates once the present leading causes are resolved.
Both lay and science policy makers, properly impressed with the future demographics of the graying of all economically developed countries, are basing important policies and decisions on a flawed understanding of what constitutes aging research and what the results of that research might accomplish. Regrettably, most biomedical scientists also do not seem to understand this fundamental distinction. The evidence for this is clear. There is an almost universal belief in biomedical research that borders on a mantra in which it is stated that “the greatest risk factor for the leading causes of death in humans is aging.” Yet, inexplicably, the resources devoted to understanding the aging process are microscopic compared to the resources devoted to the resolution of the leading pathologies which all agree have their origins in the aging process. The present enormous imbalance in resources available to study the fundamental aging process compared with the resources available to study the derivative pathologies will continue until this illogical reasoning becomes better appreciated. The greatest risk factor for all of the leading causes of death will be better understood when we have an answer to the core question: “Why are old cells more vulnerable to pathology than are young cells?”
Understanding how the molecules of an old cell differ from those in a young cell and why those changes lead to pathology has the potential to increase our understanding of the etiology of cancer, cardiovascular disease, stroke, and even age-related accidents because the etiology of all of these conditions are rooted in the differences.
VI. AGING IS AN ARTIFACT OF CIVILIZATION
Aging is a phenomenon unique to the human species because it is a consequence of implementing our advancing knowledge of predator and accident avoidance, hygiene, and biomedicine. Aging will also occur in those animals that we choose to protect like our pet, zoo, and domestic animals because we apply to those animals the same principles of hygiene, biomedicine, and protection from accidents and predators that we have applied to ourselves. The resulting increase in the numbers of older people in developed countries is, to a large extent, an unintended consequence of these advances and an artifact of human civilization [1-3, 18].
Humans, and the animals we choose to protect, are the only species in which large numbers experience aging. Furthermore, old humans, or old animals, are not essential for the survival of any species. The evidence for this is that humans have had a life expectation at birth of thirty years or less for more than 99.9 percent of the time that we have inhabited this planet. The rarity or non-existence of old humans is evident from the study of prehistoric human remains. None have revealed individuals older than about fifty years of age. There appears to be no selective advantage favoring the survival of old animals or old humans.
Members of exotic feral animal species, who for millions of years have not experienced aging, reveal those changes when protected by humans as pets or in zoos. It would be difficult to explain how evolution could have selected for a process like aging that could be made to appear in all members of a species after, perhaps, millions of years of suppression. Because modern humans, unlike feral animals, have learned how to escape death long after reproductive success, we have revealed a process that, teleologically, was never intended for us to experience. One might conclude, therefore, that human aging is an artifact unique to our civilization.
A. Modulating the Diseases of Old Age
Clearly, the elimination of or delay in the appearance of potentially fatal diseases can and does increase the length of human life. That, plus efforts made to avoid accidents, are the approaches that have yielded the greatest -- and the only -- effects on extending human longevity. The evidence for how disease elimination or reduction has influenced life expectancy is best illustrated by realizing that it was the virtual elimination of acute infectious diseases that resulted in the increase of about 27 years in life expectation that occurred in developed countries within the last century . An increase of that magnitude and within that period of time has not occurred in any other century, nor is it probable that it will ever happen again.
21 of the 27-year increase in life expectation that occurred during the Twentieth Century took place during the first 70 years. Only a six-year increase in life expectation occurred in the following 27 years . For an increase of even 10 more years in human life expectation to occur in the United States in the next 50 years, mortality rates will have to decline to a level that has never before been achieved .
In order to achieve a life expectation greater than 100 it will be necessary to eliminate all mortality risks from 1995 levels before age 85 . The 1995 death rates would have to decline by more than 50 percent at every age in order for life expectancy to reach 85 years in the United States . Even among Japanese women who are the longest lived sub-group in the world, total mortality at every age would have to drop 20 percent in order to raise life expectancy by two years from its current 83 years. The mortality reductions at every age required to achieve a 1-year increase in life expectancy at birth today are more than twice those needed to achieve the same gain early in the 20th Century . It is not possible to reach life expectations of 100 or more unless the method will not only completely eliminate all causes of death currently appearing on death certificates but will also include an intervention to slow or stop the fundamental aging process. Thus, the approximate 25-year increase in life expectancy that occurred in the United States from [1900 - 2000] will be impossible to achieve in the 21st Century, if ever.
It is abundantly clear that the elimination of the present age associated chronic diseases, or slowing the rate of their appearance, will indisputably increase the length of human life. And, in fact, the number of years of additional life that the elimination of each will produce has been determined. Eliminating the major cardiovascular disease as a cause of death will increase life expectancy at birth in the U.S. by 6.73 years, eliminating stroke will produce an increase of 0.068 years; the resolution of cancer as a cause of death will result in an increase of 3.36 years; while eliminating all accidents will result in an increase of 0.92 years . The elimination of all other causes of death will result in an increase in life expectancy of about 4.26 years . Thus, although these numbers are not strictly additive (the resolution of one cause of death will increase the number of years gained by the resolution of the remaining causes of death) the elimination of all causes of death currently written on death certificates will result in an increase in life expectation of about fifteen years.
Significantly, the United States Department of Health and Human Services and its subsidiary units does not accept “aging,” “natural causes,” or “old age” as a valid cause of death in its statistical summaries. Regardless of the precise number of years gained if all causes of death currently written on death certificates are resolved, we will not become immortal but we will succumb to the inexorable increase in molecular disorder that defines the aging process. The cause of death will then be universally attributable to the aging process and, perhaps, more accurately described as loss of physiological function in some vital organ.
All successful biomedical research, and its implementation, results in adding time up to the fifteen-year limit of what remains for extending human life expectation by intervening in causes of death attributable to disease and accidents. In order to achieve life expectancies in excess of fifteen years it will be necessary to modulate the aging process and or the processes of longevity determination.
The eventual loss of fidelity in most organic biological molecules is inevitable. In this respect even the dogma of the immortality of the germ plasm is suspect. We know of no immortal organic biological molecules . The only biological property that is long lasting on an evolutionary time scale is the information that is transmitted by the genome but even that information is subject to mutation or change. Indeed, mutation is one of the few universal properties of life. In addition to the physical problem of intervening in a process in which energy states have been disturbed in, perhaps, billions if not trillions of molecules, there are the ethical and practical problems that would occur if it would become possible to arrest, prevent, or reverse the aging process in humans. This issue will be discussed subsequently.
Although biological aging occurs in an open system, it is equivalent to an expression of the Second Law of Thermodynamics or “increasing entropy.” Because aging is not a disease, the concept of seeking a remedy for it is tantamount to seeking a remedy for embryogenesis of child or adult development. Furthermore, there is the complication that there exist thousands of manifestations of the aging process that few would consider to be pathologies or diseases in need of a cure. Emergency Room personnel would not look kindly on patients who seek admission because of complaints that their hair is turning gray, wrinkled skin has just been observed, reaction time has increased, short-term memory losses have been noted, or that the 25 year-old Olympic champion sprinter arrived to say that he/she could no longer reach the running speed that, at age 19, won the gold.
These examples are representative of the hundreds of thousands of systemic losses in molecular fidelity that lead to age changes and that are not pathologies in need of treatment. But, when molecular disorder occurs in cells or cell products that are part of vital systems and accumulate sufficiently to increase vulnerability to pathology, a trip to the Emergency Room may indeed become a necessity.
The inexorable loss in molecular fidelity that defines aging can either lead to changes that may be an affront to vanity, inconvenient, or simply uncomfortable. When the same kind of molecular mischief occurs in the cells of vital organs and then leads to an increase in vulnerability to disease or pathology, treatment is required because life may become threatened.
Because of the randomness of the underlying molecular process in which molecular fidelity decreases, the rate of loss varies from cell to cell, tissue to tissue, and organ to organ, making us what is analogous to a clock shop where there is little probability that all clocks are measuring time identically. The difference in rates of cell aging usually results in a few human tissues or organs containing the weakest links and whose failure ultimately leads to death. This condition, in which the rates of biological deterioration differ among tissues and result in only a few that contain the weakest link, is analogous to what occurs in the aging process of the components of complex inanimate objects like automobiles.
It is not difficult to understand why an automobile of a particular make, model, and year of manufacture will have a greater probability of failing because of a particular weak link, like, for example, the electrical system. In another car of similar manufacture but different year or model, the cooling or exhaust system will age fastest and become the most probable system to fail first. There is inevitably a weakest link in the probability of component failure in groups of similar complex entities. To engineers, the time when the weakest link fails is called the Mean Time to Failure (MTTF). For a cheap car, it might be four or five years and for United States citizens born today it is about 76 years. In developed countries, the weakest links in humans are the vascular system and the cells in which cancer is most likely to occur. The aging process increases vulnerability in those cells that, in humans, are the weakest links and increase vulnerability to the pathologies that we recognize as the leading causes of death.
Biomolecules, like the proteins that constitute most of our tissues, are extraordinarily complex entities. The cause of the molecular disorder that characterizes the aging process is the inevitable loss of energy necessary to maintain the structural and functional integrity of virtually all molecules that are synthesized during life. The fidelity of this vast array of biomolecules can last from pico seconds to several thousand years after death in the case of some molecules like DNA and millions of years in the case of bone.
The likelihood that human intervention in the aging process might be possible is presently thought by many to be restricted to manipulating the only process known to do so in lower animals. Yet, even that process is subject to the fog of interpretation. The process is Caloric Restriction (CR). Although demonstrated in many species, including its likely occurrence in non-human primates, it has yet to be demonstrated to occur in humans .
Even if it is applicable to humans, there is an alternative interpretation of the commonly accepted dogma that CR modulates the aging process or the determination of longevity. That alternative is based on the fact that most of the dietary-restricted animal experiments use control animals that are fed ad libitum or some arbitrary reduction of this quantity; what may have been discovered is not that restricted animals live longer but that their longevity more closely resembles that of feral animals. Thus, what might have been discovered is not that caloric restriction increases longevity but that overfeeding is life shortening. One is led to conclude that calorie restricted animals are a more accurate representation of the length of life of feral animals.
We do not know what the usual caloric intake is of feral animals whose laboratory counterparts are being studied. Thus, any assumption about what constitutes a proper control is suspect. Consequently, what are thought to have been the experimental animals in Calorie Restriction studies become the controls and what are thought to have been the controls become the experimental animals. Indeed, there is preliminary evidence that captive feral rodents placed on a calorie-restricted diet do not show an increase in mean longevity. However, it was found that the longest lived animals (about 10 percent) were calorie restricted [S. Austed, Personal Communication].
The only known way that the aging process can be circumvented in inanimate objects is by the replacement of old parts with new. Although parts replacement is possible in organisms including humans, the only certainty is that replacing old organs with young organs increases life expectancy. This result is no different from the many other medical, hygienic, and safety procedures that have been implemented to avoid or postpone death. None treat the fundamental process of aging. Furthermore, the replacement of one’s brain with that of another, even if possible, would result in the loss of self-identity, thus defeating the purpose of extending life. Some computer futurists have claimed that circumventing the aging process might some day be done by uploading the contents of a brain to a storage device and then downloading the contents to a young brain that has been erased. However, no consideration has been given to the complaint that might be expressed by the owner of the younger brain, the contents of which are about to be deleted. Nevertheless, these kinds of thought experiments that involve parts replacement all result in the same dilemma: The original identity of any object -- animate or inanimate -- will be lost as we approach or even succeed in the complete replacement of all of its parts. Thus, full replacement of all parts results in a different object.
In summary, there is little likelihood that the fundamental aging process will ever be capable of modulation by human intervention. Our present ignorance of the process is so great and the resources available for its study so small that the likelihood of an intervention is, in my view, close to zero. Our knowledge of the multiple trillions of molecules that might be involved in the process and how they might be replaced or repaired is too primitive to expect that we will have the ability to intervene in the foreseeable future. In fact, intervention may border on the impossible because the aging process is fundamental to all matter, living or dead. Finally, modulating the aging process also has an enormous array of unintended consequences that will be discussed subsequently.
The likelihood of reversing or slowing the determinants of longevity are at least as daunting as would be attempts to modulate the aging process. The determinants of longevity are dependent on the physical and chemical state of molecules reached at the time of sexual maturation and that provide all of the physiological capacity that exists at that age. Thus, any effort to modulate the process at later ages would depend upon restoring molecules in an older individual that could be identified as “old” to their former youthful state. As with the aging phenomenon, the complexity of intervening in the determination of longevity is further compounded by the probability that the molecular changes that occur may not only be qualitative but also quantitative.
In spite of the monumental difficulties of modulating longevity determination in an aged organism, it has been achieved by the manipulation of genes very early in the developmental stages of some invertebrates (for examples, see [23, 24]). This kind of gene manipulation, even if it was possible to do in humans, is unlikely to be practiced, if for no other reason than because of the insurmountable ethical considerations.
Notwithstanding these considerations, it is likely that a natural increase in the human lifespan is presently occurring; but it is occurring on an evolutionary time scale and thus so slowly that our ability to detect it could only be made after millennia of careful record keeping. This belief is based on persuasive evidence in the fossil record that suggests that the life spans of most animal species increase as evolution proceeds .
VIII. UNINTENDED CONSEQUENCES OF MODULATING HUMAN LONGEVITY
Although it is indisputable that human intervention in slowing or eliminating the diseases of old age has occurred with a resulting increase in longevity, there is no evidence that humans have ever developed an intervention that has perturbed either the processes of aging or longevity determination . And, the likelihood that it will ever become feasible to perturb either process is, as indicated previously remote, if not impossible.
Other than the biological considerations of why perturbing either process in humans is unlikely, one must also consider in the abstract what the consequences might be of having that power. The desire to intervene probably originated when prehistoric humans first recognized the phenomenon of aging as undesirable and therefore requiring treatment. The idea has remained unchanged to this day and has given to aging its negative connotation of deterioration, approaching pathology, pain, and death.
Yet, the hundreds of thousands of septuagenarians who follow the sun in their recreational vehicles, no longer have child-rearing responsibilities, possess good health and a modest income will disagree. To them, and others who believe that their intellectual growth doesn't stop, and that the carefree seventies and beyond are the best time of their lives, arresting adult development at an earlier age would be unthinkable.
There is the greater likelihood that it is not the fear of aging but fear of the pathology and pain that precedes approaching death that motivates those who believe that having the power to extend human longevity is desirable. The term "prolongevists" first coined to describe the "… significant extension of the length of life by human intervention..." has precedent over the illogical term "anti-aging" and its 3,500 year-long history has been well described in the monumental work by Gruman .
Prolongevists assume that intervening in the aging process is not only possible but also desirable. Neither is likely. Advocates differ in their beliefs in respect to whether intervention means stopping, slowing, or reversing the process. Stopping, or reversing the process defies fundamental laws of physics and chemistry, and slowing the process is rife with unintended negative consequences. If advocates of intervention would define aging properly and distinguish it from its associated diseases and the process of longevity determination then the folly of intervention should become apparent.
To know what the future societal impact might be of even a fifteen-year increase in life expectation (which is what would occur if all causes of death currently written on death certificates were to be eliminated), one might consider the changes that have occurred from 1931 until the present. During these 70 years an approximate fifteen-year increase in life expectation has occurred . Of the many comments that might be made, three observations are as follows: (1) the increase in the number and proportion of older people; (2) the greater time spent in frailty and dependency in old age; and (3) the political and economic consequences that both of these have had .
In an exercise intended to explore what would occur if tampering with the aging process becomes possible, one might imagine the simplest method: a pill that slows the aging process. The first concern is that those involved in the discovery and the rich and powerful will have earliest, or depending on availability, even the only, access. It is questionable whether these would be the most important to be favored first, or at all. Presumably, the pill would also become available to the antisocial killers, tyrants, and those guilty of genocide along with those who contribute to or benefit human civilization.
Of the many predicaments that could be imagined, one is “When in life would one choose to take the pill?” Before making the decision to administer it in youth, one should be aware of the fact that virtually any age might be chosen and with good reason.
Furthermore, at what age would one choose to have their aging process slowed if they had not yet passed through most ages in order to make an informed decision? Of course, once having passed through the desired age, how then would one reverse time to that earlier and better age? It is also the stuff of science fiction to expect that all of ones fellow humans and the environmental conditions that contributed to that better earlier age would have remained unchanged. And, switching the effects of the pill on or off seems even less realistic. Of the many other bizarre scenarios that could be imagined, it would not be surprising to find families in which children who chose not to take the pill might find themselves biologically older than their parents, who did. Finally, slowing aging is not likely to be an appealing option for a substantial part of the worlds population who find themselves, poor, oppressed, sick, or all three.
We interact with each other to a substantial extent as a function of our perceptions of relative age. The destruction of that relationship would have enormous negative personal and societal consequences.
One might well argue that when it is demonstrated that aging can be stopped, slowed, or reversed in a far less complex entity as one's automobile then attempting it in humans might be taken more seriously. The goal of slowing the aging process also might be viewed in the same light that we view slowing developmental processes. Slow physical or mental development in childhood is viewed universally as a serious pathology. If retarding the mental and physical development of someone from birth to age twenty years, for ten years, in order to gain a decade of additional life, is unattractive then slowing one’s aging processes in later life also will not be attractive and for the same reasons. The probability that either physical or mental development could be slowed independent of the other borders on science fiction.
Yesterdays' prolongevists who searched for the Fountain of Youth, advocated sleeping with young virgins, encouraged monkey testicular grafting, and ate yogurt, simply have been replaced with their modern equivalents and with an equal probability for success. The touting of interventions capable of slowing the aging process will not end because there is too much quick profit to be made by those who have discovered how rich one can get by exploiting the ignorance and gullibility of the public.
As some civilizations have, our society must learn that the phenotype of aging should be valued just as much as is the phenotype of youth. Then the misplaced passion for cosmetic surgery, anti-aging nostrums, and similar snake-oil remedies to arrest aging will be recognized for what they truly are -- at best a cover-up for an irreversible and inexorable process and at worst a delusion and waste of money for the uninformed.
If the main goal of our biomedical research enterprise is to resolve causes of death then every old person present today becomes a testimony to our past successes. Biogerontologists have an obligation to emphasize that the goal of research on aging is not to increase human longevity regardless of the consequences but to increase longevity free from functional disability and dependence.
Perhaps the least imperfect goal for which biogerontologists, geriatricians and other biomedical scientists should seek is to resolve all of the conditions that compromise good health regardless of age. By reaching this goal, we will reveal that all subsequent  deaths are caused by decrements in physiological capacity, - the hallmark of aging. The goal then should be for all humans to die of something that they have not previously died of before -- old age.
This, in fact, is precisely the goal that the biomedical research establishment –unwittingly -- has set for itself, because virtually all such research is directed toward the resolution of physical or mental disorders. The resources available to study the underlying aging and longevity-determination processes presently are insignificant.
1. Hayflick, L (1996). How and Why We Age. New York: Ballantine Books.
2. Hayflick, L (1998). How and why we age. Exp. Gerontol. 33:639- 653.
3. Hayflick, L (2000). The future of aging. Nature, 408, 267-269.
4. Gafni, A (2001) Protein structure and turnover In: Masoro EJ and Austed SN, Handbook of the Biology of Aging. pp. 59-83: Academic Press, San Diego, California.
5. Vijg, J and Dolle, MET (2001) Instability of the nuclear genome and the role of DNA repair In: Masoro EJ and Austed SN, Handbook of the Biology of Aging. pp. 84-113: Academic Press, San Diego, California.
6. Tilman, G and Davies, KJA (2001) Oxidative processes in aging In: Masoro EJ and Austed SN, Handbook of the Biology of Aging. pp. 25-58: Academic Press, San Diego, California.
7. Finch, CE and Kirkwood, TBL (2000) Chance, Development, and Aging. Oxford University Press, New York.
8. Hayflick L (2002) Anti-Aging Medicine: Hype, Hope, and Reality. Generations, 25: No.4, 20-26.
9. Klapper W, Kuhne K, Singh KK, Heidorn K, Parwaresch R, and Krupp G (1998) Longevity of Lobsters is linked to ubiquitous telomerase expression. FEBS Lett. 439: 143-146.
10. Klapper W, Heidorn K, Kuhne K, Parwaresch R., and Krupp G. (1998) Telomerase activity in "immortal" fish. FEBS Lett. 434: 409-412.
11. Hayflick L, (2001) Giving chance a chance or, if there are no dice, there is no game. The Gerontologist, 41: 272-275.
12. Anderson RN, (1999) U.S. decennial life tables for 1989-91, Vol. 1, No. 4, pp. 6-8, United States life tables eliminating certain causes of death. National Center for Health Statistics, Hyattsville, Maryland.
13. Hobbs FB and Damon BL (1996) 65+ in the United States. U.S. Bureau of the Census, Current Population Reports, Special Studies, P23-190, pp. 3-9, U.S. Government Printing Office, Washington, D.C.
14. Kohn, R.R., Cause of death in very old people (1982) JAMA, 247: 2793-2797.
15. Patterson DA, Dorovitch MI, Farquhar DL, Cameron HM, Currie CT, Smith RG, and MacLennan, WJ (1992) Prospective study of necropsy audit of geriatric inpatient deaths. J. Clin. Pathol., 45: 575-578.
16. Gee WM, (1993) Causes of death in a hospitalized geriatric population: An autopsy study of 3000. Virchows Arch. 423: 343-349.
17. Leibovitz A, Blumenfeld O, Baumoehl Y, Segal R, Habot B, (2001) Aging Clin. Exp. Res. 13: 406-409.
18. Hayflick L (2000) New approaches to old age. Nature, 403: 365.
19. Crimmins EM, Hayward MD, and Saito Y (1994) Changing mortality and morbidity rates and the health status and life expectancy of the older population. Demography, 31: 159-175.
20. Olshansky SJ, Carnes BA, and Desesquelles, A (2001) Prospects for Human Longevity, Science, 291:1491-1492.
21. Hayflick L (2000) The Illusion of Cell Immortality. Brit. J. Cancer, 83: 841-846.
22. Roth GS, Ingram DK, and Lane MA (1999) Calorie restriction in primates: Will it work and how will we know? J. Am. Geriat. Soc. 47: 896-903.
23. Guarente L (2001) SIR2 and aging -- The exception that proves the rule. Trends in Genetics, 17: 391-392.
24. Kenyon C, Chang J, Gensch E, Rudner A, and Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366: 461-464.
25. Olshansky SJ, Hayflick L, and Carnes BA (June 2002) No Truth to the Fountain of Youth. Scientific American, pp. 92-95.
26. Gruman GJ (1966) A History of Ideas About the Prolongation of Life. Trans. Amer. Phil. Soc., Volume 56, Part 9, Philadelphia, PA; USA.