The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59:B568-B572 (2004)
© 2004 The Gerontological Society of America
Aging: The Reality
The Multiple and Irreversible Causes of Aging
Robin Holliday
Sydney, Australia.
Address correspondence to Robin Holliday, 12 Roma Court, West Pennant Hills, Sydney, NSW 2125, Australia. E-mail: randl.holliday{at}bigpond.com
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Abstract
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At the end of the 20th century, scientists have revealed the biological causes of aging, and why it is so widespread among animals. It has also become apparent why different mammalian species have very different longevities. Aging is accompanied by changes in a wide range of cells, tissues, and organs. These include damage in DNA, proteins, membranes, and organelles, as well as the accumulation of high molecular weight insoluble aggregates. The multiple phenotypic changes that accompany aging show that there must also be many different causes. The failure to maintain a steady-state level of damage is the result of a limit to the resources that can be used to preserve the integrity of the soma. For each species, there is a tradeoff between what is invested in reproduction and what is used to maintain its cells, tissues, and organs. The failure of maintenance is irreversible, although longevity may be modulated under certain circumstances, such as dietary restriction accompanied by a loss of fertility.
IN 1996, in the forward to the book Advances in Anti-Aging Medicine, Ronald M. Klatz writes: "Within the next 50 years or so, assuming an individual can avoid becoming the victim of major trauma or homicide, it is entirely possible that he or she will be able to live virtually forever" (1). I believe this is a statement that well illustrates the widespread misunderstanding of what constitutes human aging. At the end of the 20th century, three books were published: Why and How We Age (2), Why We Age (3), and Understanding Ageing (4). These titles are entirely appropriate because, just a few years ago, scientists realized for the first time that they understood the biological reasons for the existence of aging, and also knew a great deal about the changes that accompany aging. Each of the authors obviously presents his particular viewpoint, but taken together they provide a strong biological argument that should be satisfying to scientists, even though there are many who wish to think otherwise, and like Dr. Klatz, believe that aging is just another problem that can be "solved" by medical or other treatments. In the following discussion, the main focus is on the aging of mammalian species.
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THEORIES AND CAUSES
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Throughout the 20th century, a large number of theories of aging have been proposed (5). In many cases, a theory is proposed because it is assumed, explicitly or implicitly, that there is one major cause of aging, and the theory aims to explain that cause. The proposer also usually implies that other theories are inadequate or incorrect. The fact is that the information that has gradually accumulated about aging shows that there is some validity to several of the major theories. Taken together, these illustrate the central feature of aging: that it is not a single process but instead a series of processes occurring during the inevitable decline of many normal body functions during the progressive senescence that leads to death. To illustrate this, it is necessary to briefly summarize these theories and refer to some published evidence that supports them.
- One of the earliest theories was that aging is due to accumulated mutation or damage in genes and chromosomes. We now know that both somatic mutation and chromosome changes accumulate during aging (6,7).
- A related and now popular theory is that reactive oxygen species (ROS) produced during radiation can damage DNA, proteins, membranes, and organelles (8).
- One likely target for ROS is mitochondrial DNA. Many deletions in mitochondrial DNA have been detected by molecular techniques as cells age, and it is not surprising that mitochondrial defects have been proposed to be a major cause of aging (9,10).
- There is much evidence that the amino acids of long-lived proteins undergo a variety of abnormal chemical changes, including oxidation, glycation, deamidation, racemization, abnormal phosphorylation, or methylation, as well as partial denaturation of the protein molecule itself. Some altered proteins accumulate as aggregates, such as advanced glycation end products (AGEs), in lipofuscin or in secondary lysosomes, which are not easily degraded. Not surprisingly, it has often been proposed that these changes are an important cause of aging (11,12).
- There are mechanisms to ensure the accuracy of synthesis of DNA, RNA, and proteins, but if these break down, from any of several causes, then the cell is on a downward path that cannot be reversed.
- There is evidence that the immune system loses efficiency with aging, and this gave rise to the theory that the mechanisms that normally distinguish self-antigens from nonself ones progressively break down. This gives rise to increasing damage to normal cells or tissues, collectively known as autoimmunity, which could adversely affect a variety of normal functions (13,14).
- More recently, it has been realized that epigenetic mechanisms maintain the integrity of differentiated cells. The "dysdifferentiation" theory proposes that changes in the signals, such as DNA methylation, that control the epigenotype, may lose specificity with aging (4). It is known, for example, that genes on the silent X chromosome in female mice become reactivated with age (15).
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MAINTENANCE MECHANISMS
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To understand aging, it is essential to realize that the organism also defends itself by a variety of efficient mechanisms that act to prevent the various processes of aging listed above. These maintenance mechanisms are also listed here.
- DNA repair occurs through a set of highly efficient enzymes that are capable of recognizing abnormalities in DNA and restoring the normal structure. For example, it has been estimated that approximately 10,000 apurinic gaps occur in the genome of each cell per day (16), and almost all of these are repaired. Moreover, if one repair mechanism fails, there are also back-up repair pathways.
- Defenses against ROS, either enzymes that rapidly destroy free radicals or antioxidants that absorb them.
- Proteases exist that can recognize abnormalities in proteins and degrade these molecules. Continual protein turnover is an essential process in all cells with active metabolism.
- The immune system itself is a defense mechanism that can recognize foreign pathogens and parasites. Without it, we would not survive for long.
- Many plants and some animals in normal food contain toxic chemicals, and there is an elaborate detoxification system, especially in the liver, based on monooxygenase enzymes (p450 cytochromes).
- There are many healing mechanisms, most obvious in surface wounds, but also in the clotting of blood and the joining of broken bones and torn ligaments.
- The cell suicide mechanism, apoptosis, can get rid of abnormal or damaged cells that otherwise would be harmful to tissues.
- Mechanisms are in place that ensure physiological homeostasis, that is, the coordinated function of different cells, tissues, and organs. Temperature control is the most important homeostatic mechanism.
- The storage of fat enables an animal to survive periods of inadequate nutrition.
- Many animals spend a considerable amount of time grooming their hair or skin. This removes surface pests, dirt, and debris.
Taken together, a) through j) can be referred to as maintenance mechanisms, and it is these that enable an animal to live long enough to reproduce and care for offspring until they reach adulthood. Collectively, they maintain order and prevent the appearance of disorder. However, they eventually begin to fail, and it is the increasing disorder in cells, tissues, and organs that results in senescence and death. It is important to realize that the failure on one mechanism may lead to a particular phenotype of aging (for example, the failure of DNA repair may result in cancer), whereas the failure of another may have a different effect. This is not only consistent with, but provides the biological basis for, the multiple causes of aging. Finally, it is very clear that the resources an animal invests in maintenance is a considerable proportion of all energy resources, but this proportion varies between species (see below).
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THE EVOLVED DESIGN OF MAMMALS
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Why do maintenance mechanisms eventually fail? To understand this we need to look at the evolved design and architecture of the body. Higher animals are made up of nondividing postmitotic cells and also cells that divide continuously or intermittently. In contrast, the bodies of some of the smaller invertebrates, such as nematode worms and flies, consist of nondividing cells, and cell division occurs only in the germ line of the developing animal. These organisms have a very well-defined life span, because postmitotic cells will sooner or later suffer a lethal event, and they cannot be replaced. For example, a cell may lose normal mitochodrial function with cessation of respiration, it may have a lethal mutation, or lose essential genes through chromosome rearrangement. It may accumulate insoluble protein aggregates or suffer other irreversible damage.
Mammals have vital organs that are largely made up of postmitotic cells, such as the brain and heart, and they cannot be expected to last forever, for the reasons given. Some proteins are laid down early in life, such as the crystallins in the lens of the eye, and cannot be replaced. They gradually accumulate damage which can lead to cataracts. Collagen is the most common protein in the body and its molecules are very long lived. It has been experimentally demonstrated that they become progressively cross-linked, and this necessarily affects the elasticity and resilience of all connective tissues in the body. The structure of vital organ systems, such as the major blood vessels, limits their capacity for self-repair, and eventually accumulating damage leads to the aging of the cardiovascular system. It can be said that this and other nonrenewable organ systems have evolved to "last a life-time." The wearing down of teeth is an instructive example. In many herbivores, they cannot be replaced, and continual grazing can eventually lead to an inability to feed. The teeth are genetically programmed to be a certain size and strength, but they become aged through wear and tear. Thus, both the genetic program and the accumulation of damage are important components of aging.
The aging of dividing cells in the body is more controversial. It seems that all types of dividing cells that have been grown in culture have finite growth potential (17). There was early evidence that fibroblasts from skin biopsies from elderly individuals have less division potential than those from young skin (18), but this result has been disputed (19). However, in the Syrian hamster, it is very clear that skin fibroblasts are running out of division potential as the animals age (20). Also, the rate and efficiency of wound healing declines during aging. The decrease in the immune response may also be due to a reduced capacity of lymphocyte proliferation, and the reduction of muscle volume and strength with age is due to a loss of muscle cells, without their replacement from the division of myoblasts.
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COMPARATIVE STUDIES AND EVOLUTION
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The most telling evidence for a relationship between aging and loss of maintenance comes from comparative studies of different mammalian or bird species. When a specific maintenance parameter is examined, for example, DNA repair, then it is found that long-lived species have more efficient mechanisms than short-lived ones. Holliday (4) lists 15 such studies, and, since then, others have provided additional evidence (21–27). The observations of Barja's group are particularly remarkable because the defenses against ROS in a long-lived bird, the pigeon, are much more efficient than those in the rat, a short-lived mammal of similar size and metabolic rate. A similar difference was found between small long-lived birds (canary and parakeet) and the mouse (25).
This leads in turn to a fundamental question. What sets the efficiency of maintenance and determines the life span of a particular species? This question can only be answered in evolutionary terms, and particularly by the disposable soma theory of aging (28–31). All animals have limited energy resources, which are used as follows:
- For general metabolic processes, common to all species
- Reproduction, including the rearing of offspring and development of these to reproductive age
- Maintenance of the developing and adult organism.
Obviously, the resources not used by a) must be divided between b) and c). This means that the more that is invested in reproduction, the less that is available for maintenance, and vice versa. There is therefore a trade-off between reproduction and longevity. Examination of the life histories of 47 species or genera of mammals showed that this is indeed the case (4,32). Animals such as rodents, which have a very high mortality rate in their natural environments (due to predators, starvation, drought, or disease), also have a very high rate of reproduction, and development to adulthood is rapid. In complete contrast, those that are successful at surviving for long periods (higher primates, pachyderms, and whales) produce few offspring, at widely spaced intervals, and development to adulthood is slow. These species have evolved the longest life spans. Other groups of animals have intermediate rates of reproduction and longevity, but overall there is a clear inverse relationship between these two life history parameters. Many gerontologists have attempted to relate size and metabolic rates to longevity, but bats are always the exception. Most species are small and have high metabolic rates, but they have long life spans, comparable to birds. As expected from the theory, they have a very low rate of reproduction. Their adaptation to flying greatly reduces mortality, and as a result, these species have evolved a long life span with greatly reduced fecundity.
The forces of natural selection can result in either a reduction of longevity of a given species or an increase in longevity. If mortality increases, then a population with genetic variability responds with a faster rate of reproduction and a shorter life span. In contrast, a reduction in mortality in a natural environment will lead to the selection for longer-lived species and a lower rate of reproduction.
The concept of the efficiency of maintenance includes the total of all such mechanisms. In this connection, it is important to realize that it would be pointless to increase (or decrease) the efficiency of one without changing the others in the same direction. In terms of the aging of an animal, it would be pointless to evolve a circulatory system, for example, which is capable of surviving much longer than the brain, or other vital parts of the body. In other words, evolution will ensure that there will be a degree of synchrony in the multiple causes of aging (33).
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HOW MANY GENES?
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The isolation of mutants of experimental organisms with increased or decreased life span has lead many investigators to conclude that aging is determined by a few genes. This conclusion requires careful scrutiny. One fact that has to be taken into account is the potential pleiotropy of single gene effects. The premature aging syndrome in humans known as Werner's syndrome is due to a mutation in a gene specifying a DNA helicase (34). This may be akin to throwing a spanner in the works, since an important defect in DNA metabolism may be central to all metabolism, and the result is multiple effects on the aging phenotype. Similarly, a single mutation that increases life span may have pleiotropic effects. For example, it could slow down metabolic rate and therefore have an effect such as a reduction in temperature, which increases life span in animals such as nematodes and flies; or the mutation might reduce fertility and allow more resources to be channeled into maintenance. Mutations of either type are unlikely to survive in a natural environment.
Single-gene changes that increase life span can be compared to the well-known effect of calorie restriction in increasing the life span of mice or rats. Calorie restriction also greatly reduces fertility, and it is likely that the effect is an evolutionary adaptation that would enable an animal to survive over a period of limited food—when it would be fruitless to attempt to reproduce—until such time when adequate food becomes available (35,36). The animal's response to shortage of energy is to channel more into maintenance and less into reproduction. It is not difficult to envisage one or a few genes that would switch an animal into a calorie-deprived condition, which in this case would be irreversible.
The true number of genes involved in the determination of longevity is likely to be very large. Each maintenance mechanism depends on a large number of genes, for example, DNA repair has multiple pathways and each pathway depends on several enzymes. It is also now known that there are close interrelationships between DNA repair and the cell cycle. It would be damaging for a cell with unrepaired DNA lesions to attempt to divide, so such division only occurs when DNA repair is complete, apart from the special case of error-prone repair. There are many genes involved in other maintenance mechanisms, such as proteolysis, defense against ROS, the immune system, detoxification, and so forth. The conclusion must be that a very large number of genes control or determine, in one way or another, the efficiency of cell and tissue maintenance. All these genes contribute, to a greater or lesser extent, to the maximum longevity of the organism in a favorable environment. The very existence of multiple maintenance mechanisms also means that they act as different defenses against the multiple causes of aging.
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CONCLUSION
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In the last few decades, the expectation of human life at birth has been steadily increasing in developed countries, and also in many developing ones, owing to the improvement in the diagnosis and treatment of age-associated disease. This can be regarded as a modulation of longevity and not a change in maximum life span. We can expect that better diagnosis and treatment of age-related diseases will further increase expectation of life, but the prediction by Klatz (1) of potential immortality is completely unreal. It is possible, however, that means may become available for further manipulation of the expectation of life, but only at the expense of other aspects of human existence. Such manipulations are likely to be far from desirable. Less food, more sleep, reduced energy and vigor, slower metabolism, greater lethargy, and reduced libido and sexual activity might all significantly increase longevity, but how many would make that choice? In other words, there would have to be a trade-off between increased longevity and quality of life, just as we see in calorie-restricted animals.
Few would disagree that aging is characterized by its complexity, and all manners of changes occur in cells, tissues, and organs. These affect DNA, RNA, proteins, membranes, organelles, and the many interactions between different parts of the body. All these known changes can only be reasonably interpreted in terms of multiple causes of aging, and when we consider the evolved design of the mammalian organism, it is also apparent that many components inevitably have finite survival time. Possibly, a single cause could be reversed or eliminated, but with our current knowledge of aging, it has become entirely fanciful to believe in the combined removal of all causes.
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Acknowledgments
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I thank Suresh Rattan for drawing my attention to some important recent publications.
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Footnotes
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Decision Editor: James R. Smith, PhD
Received August 25, 2003
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Abstract
Theories and Causes
