The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59:B543-B546 (2004)
© 2004 The Gerontological Society of America
Debates
The Close Relationship Between Biological Aging and Age-Associated Pathologies in Humans
Robin Holliday
Sydney, Australia.
Address correspondence to Robin Holliday, 12 Roma Court, West Pennant Hills, Sydney, NSW 2125, Australia. E-mail: randl.holliday@bigpond.com
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Abstract
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In the last 100 years, there has accumulated a vast amount of information about the changes that accompany aging in a wide range of animal species. At the same time, there has been extensive documentation of the onset and characteristics of age-associated pathologies of humans and other mammals. It is argued that the totality of all this information is interrelated and provides a very extensive description of the deleterious changes in molecules, cells, tissues, and organs, which accompany both aging and many age-associated diseases. The accumulation of damage is in DNA, proteins, membranes, and organelles, as well as the formation of insoluble protein aggregates. The evolved design of many organ systems, such as the cardiovascular system, the brain, and the eye, are incompatible with indefinite survival. The eventual failure to maintain the integrity of tissues and organs is the end result of the multiple causes of aging.
IN the 20th century, there was a diverse range of experimental studies on the biological processes of aging in a wide variety of animal species, from unicellular organisms to humans [see reviews (1–5)], and this research will obviously be expanded in this century. Also, there were enormous advances in biomedical research, which includes detailed documentation of those human pathologies that are age-associated. Major examples of these are cardiovascular and cerebrovascular disease, type II late-onset diabetes, osteoporosis and osteoarthritis, dementias, carcinomas, kidney failure, and the deterioration of hearing and vision [see reviews (6,7)]. The issue is whether the study of biological aging is distinct from the study of age-associated disease, or whether, as I will argue here, there is considerable overlap between them. If so, then any comprehensive description of aging in humans (and many other mammals) should also encompass age-associated pathologies. In this context, it should be noted that most reviews of biological aging (in the work cited) do not include or assess the importance of the research on these diseases.
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EXPERIMENT AND OBSERVATION
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During aging there are innumerable documented changes at the cell, tissue, and organ level. These studies have used the experimental methods of biochemistry, physiology, genetics, endocrinology, and immunology, and, more recently, the increasing exploitation of the latest procedures in molecular biology. Many changes in proteins, RNA, DNA, lipid membranes, and organelles have been documented. There are well-known biomarkers of aging, such as cross-linking of collagen, the accumulation of AGEs (advanced glycation end products), and lipofuscin, and mutations in the DNA of mitochondria. The latter and much else is evidence of damage induced by reactive oxygen species (ROS). Also, there are changes in chromosomes and their genes. All these will have effects on cells and therefore on tissue and organ function. In addition, there are studies on homeostasis, in the broadest sense, which includes short- and long-range interactions between different cells, tissues, and organ systems.
The evolved design of many human organs exposes them to cellular damage, and repair of this damage, or cell renewal, may be ineffective. I can cite only a few examples here. The walls of the major blood vessels lose elasticity through the cumulative cross-linking of collagen and elastin. This has the effect of gradually increasing blood pressure during aging, and this may also affect kidney function. Abnormalities in lipid metabolism results in the deposition of atherosclerotic plaques on the inner wall of arteries, and damage to arteries can lead to the formation of dangerous blood clots. The heart itself has limited capacity for repair, and muscle cells are not replaced. The heart is a very efficient pump, but it cannot be expected to last indefinitely, and eventually valves and other structures deteriorate. All these damaging effects can lead to cardiovascular disease (broadly known as "heart disease"). Proteins that are not regularly replaced are slowly and progressively modified by a variety of postsynthetic chemical changes, including oxidation, glycation, deamidation, and cross-linking, as well as partial denaturation. For example, the crystallin of the eye lens is laid down early in life, and cannot be replaced. It gradually loses elasticity and transparency, and the latter leads to the formation of cataracts. Most tissues have proteases that remove abnormal proteins, and this can, in some cases, produce a steady state, but in other instances, high molecular weight end-products may accumulate. This is seen in the retina of the eye, where the continual turnover of light receptor elements throughout life often leads to the build up of secondary lysosomes and other granular material in the pigmented epithelial layer below the rods and cones. This, in turn, results in mild or severe retinopathy, a well-known disability of old age.
The brain is known to have limited capacity for repair. Neurones are progressively lost during aging and cannot be replaced. Defects in protein processing lead to the deposition of amyloid plaques. It is common for individuals of advanced age to lose short-term memory, but this occurs much earlier on in patients suffering from Alzheimer's disease or other dementias. A crucial question is whether the changes seen during advanced age are the same or similar to those seen in early-onset dementias. Certainly there is a steady increase in the symptoms of Alzheimer's disease with age, with roughly a doubling of the incidence for each 5 years of life after the age of 65. This suggests that there is not a defined syndrome, but rather a gradation from early onset to late onset, and late onset may well be labeled as natural aging of the brain. It is doubtful whether the histopathological changes seen are qualitatively different in early-onset and late-onset dementias. It is the rate with which these changes occur that determines whether or not a diagnosis of Alzheimer's disease is made. The brain is dependent on a constant supply of oxygen in the blood, and if that is interrupted, a stroke follows. The age-dependent incidence of this is a classic example of the aging of one organ having disastrous effects on another. In this case, high blood pressure can lead to a brain hemorrhage, and blood clots or detached plaques can block arteries.
The incidence of most cancers rises steeply with age. Epidemiologists have deduced that several successive events must occur in a single cell lineage before malignant tissue is formed. It has therefore been stated that cancer is not related to aging (8). Nevertheless, aging is also a time-dependent process, and probably the summation of innumerable different events. So the time-dependent emergence of cancer des not separate it from other age-associated conditions. Instead, the defenses against successive genetic or epigenetic events eventually fail—in a very small proportion of cells—so that tumors become yet another part of all phenotypic changes seen during aging. In the context of carcinogenesis, it is worth noting that the examination of the structure, properties, and behavior of a particular type of neoplasm may well tell us nothing about aging, but the prior events that eventually gave rise to the tumor are very likely to do so.
Late-onset diabetes is due to abnormalities in insulin and sugar metabolism, which are not yet fully understood, although it is clear that obesity is a predisposing influence. The disease has several serious side effects, some of which are the same as those that occur during normal aging, for example, an increased formation of AGEs. There is also substantial thickening of basement membranes in many locations.
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MULTIPLE CAUSES OF AGING
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The history of gerontology includes a very large number of theories of aging. It is common for the originator of a particular theory to suggest or imply that there is a single cause of aging, because if the theory is correct, then all the changes seen in an aging individual flow from this single cause. It is in fact very unlikely that there is one cause, and very probable that there is some truth in many of the theories. A global view, taking into account the vast amount of information available, strongly suggests that many, if not all, body components are affected during aging, and these changes are the end-result of several or even multiple causes. Again, a few examples will illustrate the point.
It could not be said that the cross-linking of collagen is the same as the postsynthetic changes in the crystallin of the lens, or that the accumulation of AGEs is related to the ROS damage that may produce deletions in mitochondrial DNA. The damage from wear and tear in joints leading to osteoarthritis could hardly be related to the formation of amyloid plaques in the brain. The limited growth potential of many dividing somatic cells could not be the same as the demise of nondividing somatic cells, such as those in the heart or brain. These changes and many others must have distinct chemical and cellular characteristics, and must be occurring independently from one another.
We also know that mammals have very different life spans, but the same or similar changes are occurring at very different rates. A specific well-documented example is the occurrence of mutations in the HPRT (hypoxanthine phosphoribosyl transferase) gene in lymphocytes in mice and humans. In both species, a similar increase in mutations throughout the life span is seen, but because the life spans differ by 30-fold, the actual rate of mutation is much higher in the mouse (9,10). The same applies to the events that give rise to tumors in humans and mice or rats (11,12). A strong argument can be made that the life span is determined by the resources invested in the maintenance of cells and tissues [reviewed in (13,14)]. Increased longevity can evolve by increasing the stability of cellular components, and also by improving repair and replacement mechanisms. These include defenses against damaging agents such as ROS, or toxic chemicals in the diet, better recognition and breakdown of abnormal proteins, and more efficient DNA repair, and other mechanisms [reviewed in (3)]. The evolutionary forces that result in the increase or decrease in life span must be acting on all processes of aging. This is achieved by natural selection, but there would be no evolutionary advantage in increasing, say, the longevity of the cardiovascular system, while allowing a more rapid deterioration of some other organ system. The advantage is gained only if all age-associated changes occur with broad synchrony (15). Genetic factors will strongly influence such synchrony, and it is these on which natural selection will act. Nevertheless, given genetic variability, there will be individuals who are more prone to this or that disease, and perhaps less prone to others. It is well known that there are mutant genes that predispose an individual to develop early cancers, whereas other families may be almost cancer free. Another example is familial Alzheimer's disease. It is also established that long life itself runs in families. Thus, although there may be broad synchrony in the onset of age-associated changes, there is also detectable genetic variation, so that this synchrony breaks down. It is often in this situation that an early-onset change is labeled as a disease, and some will say that it is distinct from the very same changes that may occur in other individuals at a later age. Nevertheless, the actual pathological deterioration that is occurring at the cell and tissue level are more common than not, just the same; only their timing is different. Down's syndrome is instructive: These individuals have an unbalanced genome and normally develop age-associated diseases such as Alzheimer's and several other signs of premature aging much earlier than individuals with balanced genomes (16). The breakdown of cellular maintenance occurs more quickly, but its effects are not distinguishable at the pathological level.
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THE ORIGIN AND TREATMENT OF AGE-ASSOCIATED PATHOLOGIES
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It is generally agreed that the obvious features of the aging phenotype are the end result of events that may be occurring much earlier on. The clinician or geriatrician is presented with a tissue or organ defect that is pathological, and therefore treated as a disease. Appropriate treatment is applied, which may or may not be successful. A major part of biomedical research is to devise better treatments, and also better diagnoses. However, if we want to prevent the onset and progression of the disease in question, we need to know the causes of the deterioration at the biochemical, molecular, or genetic level. This is certainly within the province of gerontology. That is why I have argued elsewhere that the study of aging, gerontology, should be a central discipline in clinical medicine, because it is far better to understand the origins of each age-associated pathology and devise means of preventing its onset, than it is to treat it after it appears (17). Treatment is often expensive, and it can also be counterproductive; if a problem in one organ system is cleared up, it may soon be followed by the deterioration of another.
Textbooks that document the features of age-associated pathologies are describing the end result of one or many processes of aging, but for the most part, they are not concerned with the underlying causes of the abnormalities seen in cells, tissues, or organs. Moreover, clinicians become highly specialized in the diagnosis and treatment of specific age-related disease. Those that specialize in osteoporosis seem to have little in common with those who are experts in vascular disease, or dementias, or oncology, and so on. Unfortunately, most of these specialists have little, if any, interest in aging per se. If they had more interest in the origins of the particular condition, then they would have to learn much more about the damaging events that occur early on, and eventually give rise to a diagnosable age-associated phenotype. In a word, they would have to take an interest in gerontology. In contrast, I think gerontologists should pay more attention to the problem of age-associated human disease, and the expense it imposes on health care services.
In conclusion, we can say that an understanding of aging involves the study of all those mechanisms that preserve and maintain cells and tissues, and why they may eventually break down. The study of the breakdown itself and the immediate consequences are also part of gerontology. Finally, when the problems get more severe, pathological changes become discernable. Gerontologists have been traditionally interested in describing the complex phenotypic changes that accompany senescence in experimental animals, and if they do this, they should also have at least an equal interest in the same changes in humans.
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NONPATHOLOGICAL CHANGES DURING AGING
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No one doubts that many of the changes seen during normal human aging are not life threatening. The greying, whitening, or loss of hair are normal features of aging, and so is the wrinkling of skin. The gradual loss of accommodation of the lens of the eye is not a disease, although it is treated by providing spectacles. Also, the wear and tear of teeth with age is not regarded as pathological, and can be repaired by dental treatment. There is a progressive decline in the ability to hear high frequency sound, and the gradual loss of muscular strength is troublesome rather than pathological. Nevertheless, there are ambiguities in deciding what is and what is not a pathological condition. The example of loss of muscular strength is part of normal aging, but the decline in bone strength is osteoporosis, clearly understood to be an abnormal condition, if not a disease. Moreover, loss of muscle strength leads to uncertainty in movement, and a fall may result in a broken hip. This break is much more likely if the individual has osteoporosis. Thus, different age-associated changes may interact with one another, with deleterious outcomes, and sometimes in ways that are not immediately obvious. The dividing line between what is and what is not pathological is not always clear. Wrinkling of the skin is a normal component of aging, but other changes also occur, such as "age spots" (possibly clones of altered cells), and much more seriously, carcinomas and melanomas. Also, the healing of wounds gradually gets less efficient, and in some cases, skin ulcers may develop that do not heal at all. I have not previously mentioned the gradual decline in the efficiency of the immune system during aging, an intrinsic change that may only become important if it makes aged individuals more susceptible to exposure to infectious diseases such as pneumonia and influenza, and possibly with a reduced capacity to retard tumor growth.
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CONCLUSIONS
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In summary, we can say that the treatment of age-associated disease in humans is part of medical practice and geriatrics, and it is not gerontology, Nevertheless, the detailed studies of the development and progress of each disease, documented in a vast biomedical literature, provides a description of the outcome of a change or set of changes that are one part of the aging itself. In some cases, this documentation may well have revealed the earliest changes in the development of the disease, and therefore the underlying biochemical, physiological, or molecular events. The study of these events are certainly within the province of gerontological research, and this may ultimately lead to their prevention. The distinction between age-related changes that are not pathological and those that are pathological is not at all fundamental. It is more that some of these changes are not life threatening, whereas others certainly are. This is to be expected, when so many of these alterations in phenotype are occurring with broad synchrony, as the maintenance of cells, tissues, and organ systems gradually breaks down during the course of aging.
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Footnotes
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Decision Editor: James R. Smith, PhD
Received October 9, 2003
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References
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- Comfort A. The Biology of Senescence. 3rd Ed. London: Churchill Livingstone; 1979.
- Finch CE. Longevity, Senescence and the Genome. Chicago: Chicago University Press; 1990.
- Holliday R. Understanding Ageing. Cambridge: Cambridge University Press; 1995.
- Hayflick L. How and Why We Age. 2nd Ed. New York: Ballantine; 1996.
- Austad SA. Why We Age. New York: John Wiley; 1997.
- Grimley Evans J, Franklin Williams T, Beattie BL, Michel JP, Wilcock GK. Oxford Textbook of Geriatric Medicine. Oxford: Oxford University Press; 2000.
- Ratnaike RN, ed. Practical Guide to Geriatric Medicine. Sydney: McGraw-Hill; 2002.
- Peto R, Parish SE, Gray RG. There is no such thing as ageing, and cancer is not related to it. IARC Publications. 1977;58:23-53.
- Morley AA. Somatic mutations and ageing. Ann NY Acad Sci. 1998;854:20-22.[Medline]
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- Holliday R. Neoplastic transformation: the contrasting stability of human and mouse cells. In: Lindahl T, ed. Genetic Instability and Cancer. New York: Cold Spring Harbor Laboratory Press; 1996:103–115.
- Kirkwood TBL. Evolution of ageing. Mech Ageing Dev. 2002;123:737-745.[Medline]
- Holliday R. Modulation of longevity by natural selection. In: Rattan SIS, ed. Modulating Aging and Longevity. The Netherlands: Kluwer Academic Publishers; 2003:17–26.
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- Martin GM. Genetic syndromes in man with potential relevance to the pathology of aging. In: Bergsma D, Harrison DE, eds. Genetic Effects on Aging. New York: Alan Liss; 1978:5-39.
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