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Ill or just old? Towards a conceptual framework of the relation between ageing and disease

Ill or just old? Towards a conceptual framework of the relation between ageing and disease Background: Is this person ill or just old? This question reflects the pondering mind of a doctor while interpreting the complaints of an elderly person who seeks his help. Many doctors think that ageing is a non-disease. Accordingly, various attempts have been undertaken to separate pathological ageing from normal ageing. However, the existence of a normal ageing process distinct from the pathological processes causing disease later in life can be questioned. Discussion: Ageing is the accumulation of damage to somatic cells, leading to cellular dysfunction, and culminates in organ dysfunction and an increased vulnerability to death. Analogously, chronic diseases initiate early in life and their development is slow before they become clinically apparent and culminate in disability or death. The definition of disease is also subject to current opinions and scientific understanding and usually, it is an act of individual creativity when physical changes are recognised as symptoms of a new disease. New diseases, however, are only rarely really new. Most new diseases have gone undiagnosed because their signs and symptoms escaped recognition or were interpreted otherwise. Many physical changes in the elderly that are not yet recognised as a disease are thus ascribed to normal ageing. Therefore, the distinction between normal ageing and disease late in life seems in large part arbitrary. Summary: We think that normal ageing cannot be separated from pathological processes causing disease later in life, and we propose that the distinction is avoided. ered normal in elderly people. Today, it is recognised as Background Is this person ill or just old? This question reflects the pon- an outcome of atherosclerosis and a principal cause of car- dering mind of a doctor while interpreting the complaints diovascular disorders that necessitates proper treatment, of an elderly person who seeks his help. Should the com- also in the very old [2]. Furthermore, it is confusing that plaints be explained by the normal ageing process or is the description of normal ageing as a series of cumulative, there a disease as yet undiagnosed? Many attempts have universal, intrinsic and deleterious changes [3], also been undertaken to separate pathological ageing from applies to many chronic diseases [4]. normal ageing. The distinction, however, has remained unclear as it appears to be dependent on current opinions The aim of the present paper is to explore the relation and the extent of our scientific understanding [1]. Isolated between ageing and disease late in life. To that end, we systolic hypertension, for example, has long been consid- provide the biological definition of ageing, comment on Page 1 of 6 (page number not for citation purposes) BMC Geriatrics 2003, 3 http://www.biomedcentral.com/1471-2318/3/7 A B CD E F G The Figure 1 biological mechanism underlying ageing The biological mechanism underlying ageing The quadrangle (A) represents the human body. Extrinsic and intrinsic stressors cause injury (B). Subsequently, several mechanisms repair the injury, but the repair is not complete because of its high metabolic costs (C). As a consequence, damage accumulates (D-G), and cells, tissues, and organs decline in function. the definition of disease, and present a conceptual frame- necessary to produce offspring. Therefore, the somatic work of the ageing process that can be applied in clinical maintenance of the body is not complete, and, as a conse- medicine. This framework can help doctors in under- quence, there is permanent damage. standing the physical changes that they observe in elderly patients without having to decide whether their patient is The definition of disease ill or just old. Defining disease is difficult. New diseases continually arise [1]. Usually, it is an act of individual creativity when Discussion certain physical changes are recognised as symptoms of a The biological definition of ageing new disease. A disease is more easily accepted as such Ageing is defined as those processes in an organism that when it has therapeutic consequences. New diseases, increase the mortality risk as a function of time [5]. This however, are only rarely really new. Most new diseases definition seems rather simplistic and it looks as if all key have gone undiagnosed because their signs and symp- parameters of ageing are ignored by it. However, the toms escaped recognition or were interpreted otherwise. reverse is true. Imagine that the mortality risk does not Many physical changes in the elderly that are not yet rec- increase with age. In that case, living cautiously and avoid- ognised as a disease are thus ascribed to normal ageing. In ing accidents would imply eternal life. However, death is the past, this has not only happened to isolated systolic a fact of life and over the years the mortality risk inevitably hypertension but also, for example, to osteoporosis. increases despite all our efforts to prevent it. Therefore, the distinction between normal ageing and dis- ease late in life seems in large part arbitrary [8]. The biological process that underlies ageing is an accumu- lation of damage to somatic cells (figure 1) [6]. Several Conceptual framework intrinsic and extrinsic stressors may lead to injuries of the From an epidemiological point of view, diseases can best body. Well-known examples are the free oxygen radicals be explained by the accumulation of component causes. produced by the oxidative metabolism and infections that Component causes are part of a conceptual framework emerge from the environment. Although most of the that originally has been developed by Rothman [9]. A suf- injury is repaired, the repair is often not complete because ficient cause is defined as an event or a state of nature that of the high metabolic costs associated with it [6]. High initiates or permits a sequence of events that inevitably metabolic costs reduce the resources available for other results in an effect [9]. However, most causes with medical essential functions of the organism, such as reproductive relevance are not sufficient in themselves but components capacity [7]. From an evolutionary point of view, a spe- of a sufficient cause (figure 2). A component cause thus cies' best survival strategy is to limit the investment of reflects what is generally called a risk factor. An effect resources in the repair of injuries to the amount that is occurs according to the principle that a specific combina- Page 2 of 6 (page number not for citation purposes) BMC Geriatrics 2003, 3 http://www.biomedcentral.com/1471-2318/3/7 Sufficient cause I Sufficient cause II Sufficient cause III I H ED HG J G A C A F A F B B Th Figure 2 e distinction between component causes and sufficient causes The distinction between component causes and sufficient causes Sufficient causes I and II have five component causes each and sufficient cause III has seven component causes. The component causes are depicted as A to J. All three sufficient causes share the component causes A and B, that can be interpreted as shared risk factors if the sufficient causes have distinct effects (adapted from Rothman, 1976 [9]). tion of component causes must be present to complete a these changes are interpreted as a disease whereas others sufficient cause. are interpreted as normal ageing. An effect, or a disease, can be explained by different com- Death can be explained by a line of reasoning similar to binations of component causes (figure 2). Each combina- the one that has been put forward here to explain the tion constitutes another sufficient cause. Sufficient causes physical changes with ageing (figure 3). Death has several that have the same effect may share some of their compo- sufficient causes. Since their origin is complex, most suffi- nent causes. cient causes of death are likely to consist of a large number of component causes. At puberty, when the mortality risk On the other hand, some component causes may be part is lowest, there are only a few component causes. As we of different sufficient causes, each having its own distinct grow older, the sufficient causes that constitute the vari- effect. In medicine, this phenomenon is recognised as dif- ous causes of death are step by step completed. Every new ferent diseases sharing the same risk factors. For example, component cause increases the chance of completing one smoking is not only a component cause of atherosclerosis, of the sufficient causes. The model thus explains the it is also a component cause of lung cancer. The specific increased mortality risk in old age, the hallmark of ageing combination with other component causes determines [5]. which effect becomes clinically apparent. Example: unsteadiness, gait disorders, and death At a certain point, some of the necessary component Unsteadiness is a common complaint in elderly people, causes to complete a sufficient cause may be missing [9]. and, in most cases, it cannot be ascribed to one factor. However, the missing component causes can be accrued Therefore, let us suppose that someone has accumulated over time. It is this gradual accumulation of component the following component causes (illustrated in figure 3): causes that provides a model to understand the physical A, a stooped posture; B, polyneuropathy; C, high-heeled changes that occur with ageing. The more component shoes; D, an impaired vision; and E, a clavus under the causes accumulate throughout a lifetime, the more suffi- sole of the foot. Let us also suppose that these five factors cient causes will be completed. As a consequence, the are sufficient to cause a feeling of unsteadiness. Then, it number of physical changes grows with increasing age becomes clear why the purchase of other footwear, the (figure 3). Depending on our scientific insights, some of acquirement of new glasses or the removal of the clavus is Page 3 of 6 (page number not for citation purposes) BMC Geriatrics 2003, 3 http://www.biomedcentral.com/1471-2318/3/7 Accumulation of component causes A to E ED Sufficient cause I e.g. unsteadiness completed A C Further accumulation of component causes F to H HG Sufficient cause II completed e.g. gait disorder A F Further accumulation of component causes I and J I H Sufficient cause III J G e.g. death completed A F Conceptual sc Figure 3 heme of ageing as the accumulation of component causes throughout life Conceptual scheme of ageing as the accumulation of component causes throughout life Ageing starts with the accumulation of component causes A–E. The presence of these five component causes completes sufficient cause I, resulting in effect I, e.g. unsteadiness. In the following period, the addition of component causes F–H completes sufficient cause II, resulting in effect II, e.g. a gait disorder. The further accumulation of component causes I and J completes sufficient cause III, resulting in effect III, e.g. death (see also the description of the example). Page 4 of 6 (page number not for citation purposes) BMC Geriatrics 2003, 3 http://www.biomedcentral.com/1471-2318/3/7 sufficient for the complaints to disappear. The cause this framework has major implications for the interpreta- becomes insufficient. tion of physical changes in elderly people. Subsequently, the patient may have accumulated the fol- Many doctors think that ageing is a non-disease [14]. lowing new component causes: F, isolated systolic Major textbooks on geriatric medicine and gerontology hypertension; G, periventricular white matter lesions; and explain the occurrence of physical changes in elderly peo- H, global atrophy of the brain. In combination with fac- ple as due to normal ageing or disease [15,16]. The pre- tors A and B, the factors F, G and H complete a sufficient sented conceptual framework makes it clear that a similar cause of an abnormal gait. Some doctors may diagnose a process is causing ageing and disease in the latter part of disease, for example, small vessel disease due to hyperten- life. Therefore, in our opinion, normal ageing cannot be sion. Others may interpret the gait disturbance as an often separated from pathological processes causing disease occurring, normal phenomenon in elderly people, and later in life. As a consequence, we think that making a dis- thus call it a senile gait disorder. However, irrespective of tinction between normal ageing and pathological ageing the interpretation of their cause, all gait disorders in eld- should be avoided. erly people are associated with an increased mortality risk and should therefore be interpreted as abnormal [10]. According to the same reasoning, it is not appropriate to use old-age-specific normal values. The decision whether One day, our patient takes a fall (I) and develops a sub- a body function of an elderly patient is impaired or not dural haematoma (J). The accumulation of these two must be based on the same normal values that are used in component causes completes a sufficient cause of death, young adults. In fact, this idea is not new. and the patient expires. The above example is an illustra- tion of the accumulation of component causes being an Osteoporosis is defined relative to the average bone min- explanation for the occurrence of physical changes, dis- eral density in young adults [17]. This logic is not yet eases and the increase in mortality risk in elderly people. applied in all fields of medicine. For example, some In addition, the conceptual framework makes clear why authors propose lower normal values for haemoglobin some elderly people can be considered to be frail. levels in elderly people [18]. In elderly people, however, all haemoglobin levels below the normal values in young Frailty adults are associated with excess mortality and must thus Frail people may function independently when feeling be considered as abnormal [19]. In the same line of rea- well, but are at high risk of becoming dependent [11,12]. soning, we argue that the definition of normal values for Since many physiological functions decline with increas- cognitive and pulmonary function in the elderly has led to ing age, they have a reduced reserve capacity. One single problematic concepts as late-life forgetfulness and senile factor is then sufficient to cause a cascade of events lead- lung [20,21]. These concepts are used to explain an ing to the deterioration of many body functions, and impaired cognitive or pulmonary function in the elderly eventually death. In the conceptual model, this corre- without referring to disease. In our opinion, this is illogi- sponds to the situation in which several nearly completed cal. There is no good reason why the normal values for sufficient causes share a missing component cause. A sin- functions in young adults are not applied in adults at all gle component cause may complete a series of sufficient ages. causes and will set off several effects. As a consequence, a number of diseases become clinically apparent at the Finally, the presented conceptual framework is in line same time if only one new factor (component cause) is with the observation that frailty is more a constellation of added. many conditions than a discrete clinical entity [22]. Accordingly, frailty is depending on the abundant pres- Implications ence of other risk factors, not on specific risk factors. The presented conceptual framework is an explicit formu- Therefore, we think that it is erroneous to investigate the lation of two common ideas about ageing. First, there is specific risk factors of frailty. With the purpose of prevent- consensus of ageing being associated with the accumula- ing frailty in elderly people, we should investigate the risk tion of damage [4]. Second, it has been recognised that factors (component causes) of diseases in the latter part of chronic diseases initiate early in life and that their devel- life. opment is slow before they become clinically apparent and culminate in disability or death [13]. Both ideas, Summary however, are consistent with the accumulation of compo- The existence of a normal ageing process distinct from the nent causes, physical changes, and diseases later in life as pathological processes causing disease later in life can be has been described in the conceptual framework. As such questioned. Page 5 of 6 (page number not for citation purposes) BMC Geriatrics 2003, 3 http://www.biomedcentral.com/1471-2318/3/7 17. Kanis JA: Assessment of fracture risk and its application to Ageing is the accumulation of damage to somatic cells, screening for postmenopausal osteoporosis: synopsis of a leading to cellular dysfunction, and culminates in organ WHO report. WHO Study Group. Osteoporos Int 1994, dysfunction and an increased vulnerability to death. 4(6):368-381. 18. Tietz NW, Shuey DF, Wekstein DR: Laboratory values in fit aging individuals: sexagenarians through centenarians. Clin Analogously, chronic diseases initiate early in life and Chem 1992, 38:1167-1185. 19. Izaks GJ, Westendorp RG, Knook DL: The definition of anemia in their development is slow before they become clinically older persons. JAMA 1999, 281:1714-1717. apparent and culminate in disability or death 20. Blackford RC, La Rue A: Criteria for diagnosing age associated memory impairment: proposed improvements from the field. Dev Neuropsychol 1989, 5:295-306. In addition, the definition of disease is subject to current 21. Verbeken EK: The senile lung. Comparison with normal and opinions and scientific understanding. emphysematous lungs: 2. functional aspects. Chest 1992, 101:800-809. 22. Hamerman D: Toward an understanding of frailty. Ann Intern Based on the above, normal ageing cannot be separated Med 1999, 130:945-950. from pathological processes causing disease later in life, and we therefore propose that the distinction is avoided. Pre-publication history The pre-publication history for this paper can be accessed Avoiding the distinction between normal and pathologi- here: cal ageing has important implications for the clinician. For example, the use of old-age-specific normal values http://www.biomedcentral.com/1471-2318/3/7/prepub appears to be inappropriate. Competing interests None declared. Authors' contributions GI discussed core ideas and drafted the manuscript. RW discussed core ideas and drafted the manuscript. Both authors read and approved the final manuscript. References 1. Rise and fall of diseases:. Lancet 1993, 341:151-152. 2. Staessen JA, Gasowski J, Wang JG, Thijs L, Boissei JP, Coope J, Ekbom T, Gueyffier F, Liu L, Kerlikowske K, Pocock S, Fagard RH: Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet 2000, 355:865-872. 3. Strehler BL: Definitions, criteria, categories, and origins of age changes. In Time, cells, and aging New York: Academic Press; 1962:4-32. 4. Solomon DH: The role of aging processes in aging-dependent diseases. In Handbook of theories of aging Edited by: Bengtson VL, Schaie KW. New York: Springer Publishing Company; 1999:133-149. 5. Finch CE: Introduction. In Longevity, senescence, and the genome Chi- cago: The University of Chicago Press; 1990:3-42. 6. Kirkwood TB, Austad SN: Why do we age? Nature 2000, 408:233-238. 7. Kirkwood TB: Evolution of aging. Nature 1977, 270:301-304. 8. Holliday R: Ageing in the 21st century. Lancet 1999, 354(Suppl):SIV4. 9. Rothman KJ: Causes. Am J Epidemiol 1976, 104:587-592. 10. Bloem BR, Gussekloo J, Lagaay AM, Remarque EJ, Haan J, Westen- dorp RG: Idiopathic senile gait disorders are signs of subclini- Publish with Bio Med Central and every cal disease. J Am Geriatr Soc 2000, 48:1098-1101. scientist can read your work free of charge 11. Brocklehurst JC: The geriatric service and the day hospital. In Textbook of geriatric medicine and gerontology Edited by: Brocklehurst JC. "BioMed Central will be the most significant development for Edinburgh: Churchill Livingstone; 1985:982-995. disseminating the results of biomedical researc h in our lifetime." 12. Rockwood K, Fox RA, Stolee P, Robertson D, Beattie BL: Frailty in Sir Paul Nurse, Cancer Research UK elderly people: an evolving concept. CMAJ 1994, 150:489-495. 13. Fries JF: Aging, natural death, and the compression of Your research papers will be: morbidity. N Engl J Med 1980, 303:130-135. available free of charge to the entire biomedical community 14. Smith R: In search of "non-disease". BMJ 2002, 324:883-885. 15. Miller RA: The biology of aging and longevity. In Principles of ger- peer reviewed and published immediately upon acceptance iatric medicine and gerontology Edited by: Hazzard WR, Blass JP, Ettinger cited in PubMed and archived on PubMed Central WH, Halter JB, Ouslander JG. New York: McGraw-Hill; 1999:3-19. 16. Masoro EJ: Physiology of aging. In Textbook of geriatric medicine and yours — you keep the copyright gerontology Edited by: Tallis RC, Fillit H, Brocklehurst JC. Edinburgh: BioMedcentral Submit your manuscript here: Churchill Livingstone; 1998:85-95. http://www.biomedcentral.com/info/publishing_adv.asp Page 6 of 6 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Geriatrics Springer Journals

Ill or just old? Towards a conceptual framework of the relation between ageing and disease

Izaks, Gerbrand; Westendorp, Rudi
BMC Geriatrics , Volume 3 (1) – Dec 19, 2003
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Springer Journals
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Copyright © 2003 by Izaks and Westendorp; licensee BioMed Central Ltd.
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Medicine & Public Health; Geriatrics/Gerontology; Aging; Rehabilitation
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1471-2318
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10.1186/1471-2318-3-7
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14683526
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Abstract

Background: Is this person ill or just old? This question reflects the pondering mind of a doctor while interpreting the complaints of an elderly person who seeks his help. Many doctors think that ageing is a non-disease. Accordingly, various attempts have been undertaken to separate pathological ageing from normal ageing. However, the existence of a normal ageing process distinct from the pathological processes causing disease later in life can be questioned. Discussion: Ageing is the accumulation of damage to somatic cells, leading to cellular dysfunction, and culminates in organ dysfunction and an increased vulnerability to death. Analogously, chronic diseases initiate early in life and their development is slow before they become clinically apparent and culminate in disability or death. The definition of disease is also subject to current opinions and scientific understanding and usually, it is an act of individual creativity when physical changes are recognised as symptoms of a new disease. New diseases, however, are only rarely really new. Most new diseases have gone undiagnosed because their signs and symptoms escaped recognition or were interpreted otherwise. Many physical changes in the elderly that are not yet recognised as a disease are thus ascribed to normal ageing. Therefore, the distinction between normal ageing and disease late in life seems in large part arbitrary. Summary: We think that normal ageing cannot be separated from pathological processes causing disease later in life, and we propose that the distinction is avoided. ered normal in elderly people. Today, it is recognised as Background Is this person ill or just old? This question reflects the pon- an outcome of atherosclerosis and a principal cause of car- dering mind of a doctor while interpreting the complaints diovascular disorders that necessitates proper treatment, of an elderly person who seeks his help. Should the com- also in the very old [2]. Furthermore, it is confusing that plaints be explained by the normal ageing process or is the description of normal ageing as a series of cumulative, there a disease as yet undiagnosed? Many attempts have universal, intrinsic and deleterious changes [3], also been undertaken to separate pathological ageing from applies to many chronic diseases [4]. normal ageing. The distinction, however, has remained unclear as it appears to be dependent on current opinions The aim of the present paper is to explore the relation and the extent of our scientific understanding [1]. Isolated between ageing and disease late in life. To that end, we systolic hypertension, for example, has long been consid- provide the biological definition of ageing, comment on Page 1 of 6 (page number not for citation purposes) BMC Geriatrics 2003, 3 http://www.biomedcentral.com/1471-2318/3/7 A B CD E F G The Figure 1 biological mechanism underlying ageing The biological mechanism underlying ageing The quadrangle (A) represents the human body. Extrinsic and intrinsic stressors cause injury (B). Subsequently, several mechanisms repair the injury, but the repair is not complete because of its high metabolic costs (C). As a consequence, damage accumulates (D-G), and cells, tissues, and organs decline in function. the definition of disease, and present a conceptual frame- necessary to produce offspring. Therefore, the somatic work of the ageing process that can be applied in clinical maintenance of the body is not complete, and, as a conse- medicine. This framework can help doctors in under- quence, there is permanent damage. standing the physical changes that they observe in elderly patients without having to decide whether their patient is The definition of disease ill or just old. Defining disease is difficult. New diseases continually arise [1]. Usually, it is an act of individual creativity when Discussion certain physical changes are recognised as symptoms of a The biological definition of ageing new disease. A disease is more easily accepted as such Ageing is defined as those processes in an organism that when it has therapeutic consequences. New diseases, increase the mortality risk as a function of time [5]. This however, are only rarely really new. Most new diseases definition seems rather simplistic and it looks as if all key have gone undiagnosed because their signs and symp- parameters of ageing are ignored by it. However, the toms escaped recognition or were interpreted otherwise. reverse is true. Imagine that the mortality risk does not Many physical changes in the elderly that are not yet rec- increase with age. In that case, living cautiously and avoid- ognised as a disease are thus ascribed to normal ageing. In ing accidents would imply eternal life. However, death is the past, this has not only happened to isolated systolic a fact of life and over the years the mortality risk inevitably hypertension but also, for example, to osteoporosis. increases despite all our efforts to prevent it. Therefore, the distinction between normal ageing and dis- ease late in life seems in large part arbitrary [8]. The biological process that underlies ageing is an accumu- lation of damage to somatic cells (figure 1) [6]. Several Conceptual framework intrinsic and extrinsic stressors may lead to injuries of the From an epidemiological point of view, diseases can best body. Well-known examples are the free oxygen radicals be explained by the accumulation of component causes. produced by the oxidative metabolism and infections that Component causes are part of a conceptual framework emerge from the environment. Although most of the that originally has been developed by Rothman [9]. A suf- injury is repaired, the repair is often not complete because ficient cause is defined as an event or a state of nature that of the high metabolic costs associated with it [6]. High initiates or permits a sequence of events that inevitably metabolic costs reduce the resources available for other results in an effect [9]. However, most causes with medical essential functions of the organism, such as reproductive relevance are not sufficient in themselves but components capacity [7]. From an evolutionary point of view, a spe- of a sufficient cause (figure 2). A component cause thus cies' best survival strategy is to limit the investment of reflects what is generally called a risk factor. An effect resources in the repair of injuries to the amount that is occurs according to the principle that a specific combina- Page 2 of 6 (page number not for citation purposes) BMC Geriatrics 2003, 3 http://www.biomedcentral.com/1471-2318/3/7 Sufficient cause I Sufficient cause II Sufficient cause III I H ED HG J G A C A F A F B B Th Figure 2 e distinction between component causes and sufficient causes The distinction between component causes and sufficient causes Sufficient causes I and II have five component causes each and sufficient cause III has seven component causes. The component causes are depicted as A to J. All three sufficient causes share the component causes A and B, that can be interpreted as shared risk factors if the sufficient causes have distinct effects (adapted from Rothman, 1976 [9]). tion of component causes must be present to complete a these changes are interpreted as a disease whereas others sufficient cause. are interpreted as normal ageing. An effect, or a disease, can be explained by different com- Death can be explained by a line of reasoning similar to binations of component causes (figure 2). Each combina- the one that has been put forward here to explain the tion constitutes another sufficient cause. Sufficient causes physical changes with ageing (figure 3). Death has several that have the same effect may share some of their compo- sufficient causes. Since their origin is complex, most suffi- nent causes. cient causes of death are likely to consist of a large number of component causes. At puberty, when the mortality risk On the other hand, some component causes may be part is lowest, there are only a few component causes. As we of different sufficient causes, each having its own distinct grow older, the sufficient causes that constitute the vari- effect. In medicine, this phenomenon is recognised as dif- ous causes of death are step by step completed. Every new ferent diseases sharing the same risk factors. For example, component cause increases the chance of completing one smoking is not only a component cause of atherosclerosis, of the sufficient causes. The model thus explains the it is also a component cause of lung cancer. The specific increased mortality risk in old age, the hallmark of ageing combination with other component causes determines [5]. which effect becomes clinically apparent. Example: unsteadiness, gait disorders, and death At a certain point, some of the necessary component Unsteadiness is a common complaint in elderly people, causes to complete a sufficient cause may be missing [9]. and, in most cases, it cannot be ascribed to one factor. However, the missing component causes can be accrued Therefore, let us suppose that someone has accumulated over time. It is this gradual accumulation of component the following component causes (illustrated in figure 3): causes that provides a model to understand the physical A, a stooped posture; B, polyneuropathy; C, high-heeled changes that occur with ageing. The more component shoes; D, an impaired vision; and E, a clavus under the causes accumulate throughout a lifetime, the more suffi- sole of the foot. Let us also suppose that these five factors cient causes will be completed. As a consequence, the are sufficient to cause a feeling of unsteadiness. Then, it number of physical changes grows with increasing age becomes clear why the purchase of other footwear, the (figure 3). Depending on our scientific insights, some of acquirement of new glasses or the removal of the clavus is Page 3 of 6 (page number not for citation purposes) BMC Geriatrics 2003, 3 http://www.biomedcentral.com/1471-2318/3/7 Accumulation of component causes A to E ED Sufficient cause I e.g. unsteadiness completed A C Further accumulation of component causes F to H HG Sufficient cause II completed e.g. gait disorder A F Further accumulation of component causes I and J I H Sufficient cause III J G e.g. death completed A F Conceptual sc Figure 3 heme of ageing as the accumulation of component causes throughout life Conceptual scheme of ageing as the accumulation of component causes throughout life Ageing starts with the accumulation of component causes A–E. The presence of these five component causes completes sufficient cause I, resulting in effect I, e.g. unsteadiness. In the following period, the addition of component causes F–H completes sufficient cause II, resulting in effect II, e.g. a gait disorder. The further accumulation of component causes I and J completes sufficient cause III, resulting in effect III, e.g. death (see also the description of the example). Page 4 of 6 (page number not for citation purposes) BMC Geriatrics 2003, 3 http://www.biomedcentral.com/1471-2318/3/7 sufficient for the complaints to disappear. The cause this framework has major implications for the interpreta- becomes insufficient. tion of physical changes in elderly people. Subsequently, the patient may have accumulated the fol- Many doctors think that ageing is a non-disease [14]. lowing new component causes: F, isolated systolic Major textbooks on geriatric medicine and gerontology hypertension; G, periventricular white matter lesions; and explain the occurrence of physical changes in elderly peo- H, global atrophy of the brain. In combination with fac- ple as due to normal ageing or disease [15,16]. The pre- tors A and B, the factors F, G and H complete a sufficient sented conceptual framework makes it clear that a similar cause of an abnormal gait. Some doctors may diagnose a process is causing ageing and disease in the latter part of disease, for example, small vessel disease due to hyperten- life. Therefore, in our opinion, normal ageing cannot be sion. Others may interpret the gait disturbance as an often separated from pathological processes causing disease occurring, normal phenomenon in elderly people, and later in life. As a consequence, we think that making a dis- thus call it a senile gait disorder. However, irrespective of tinction between normal ageing and pathological ageing the interpretation of their cause, all gait disorders in eld- should be avoided. erly people are associated with an increased mortality risk and should therefore be interpreted as abnormal [10]. According to the same reasoning, it is not appropriate to use old-age-specific normal values. The decision whether One day, our patient takes a fall (I) and develops a sub- a body function of an elderly patient is impaired or not dural haematoma (J). The accumulation of these two must be based on the same normal values that are used in component causes completes a sufficient cause of death, young adults. In fact, this idea is not new. and the patient expires. The above example is an illustra- tion of the accumulation of component causes being an Osteoporosis is defined relative to the average bone min- explanation for the occurrence of physical changes, dis- eral density in young adults [17]. This logic is not yet eases and the increase in mortality risk in elderly people. applied in all fields of medicine. For example, some In addition, the conceptual framework makes clear why authors propose lower normal values for haemoglobin some elderly people can be considered to be frail. levels in elderly people [18]. In elderly people, however, all haemoglobin levels below the normal values in young Frailty adults are associated with excess mortality and must thus Frail people may function independently when feeling be considered as abnormal [19]. In the same line of rea- well, but are at high risk of becoming dependent [11,12]. soning, we argue that the definition of normal values for Since many physiological functions decline with increas- cognitive and pulmonary function in the elderly has led to ing age, they have a reduced reserve capacity. One single problematic concepts as late-life forgetfulness and senile factor is then sufficient to cause a cascade of events lead- lung [20,21]. These concepts are used to explain an ing to the deterioration of many body functions, and impaired cognitive or pulmonary function in the elderly eventually death. In the conceptual model, this corre- without referring to disease. In our opinion, this is illogi- sponds to the situation in which several nearly completed cal. There is no good reason why the normal values for sufficient causes share a missing component cause. A sin- functions in young adults are not applied in adults at all gle component cause may complete a series of sufficient ages. causes and will set off several effects. As a consequence, a number of diseases become clinically apparent at the Finally, the presented conceptual framework is in line same time if only one new factor (component cause) is with the observation that frailty is more a constellation of added. many conditions than a discrete clinical entity [22]. Accordingly, frailty is depending on the abundant pres- Implications ence of other risk factors, not on specific risk factors. The presented conceptual framework is an explicit formu- Therefore, we think that it is erroneous to investigate the lation of two common ideas about ageing. First, there is specific risk factors of frailty. With the purpose of prevent- consensus of ageing being associated with the accumula- ing frailty in elderly people, we should investigate the risk tion of damage [4]. Second, it has been recognised that factors (component causes) of diseases in the latter part of chronic diseases initiate early in life and that their devel- life. opment is slow before they become clinically apparent and culminate in disability or death [13]. Both ideas, Summary however, are consistent with the accumulation of compo- The existence of a normal ageing process distinct from the nent causes, physical changes, and diseases later in life as pathological processes causing disease later in life can be has been described in the conceptual framework. As such questioned. Page 5 of 6 (page number not for citation purposes) BMC Geriatrics 2003, 3 http://www.biomedcentral.com/1471-2318/3/7 17. Kanis JA: Assessment of fracture risk and its application to Ageing is the accumulation of damage to somatic cells, screening for postmenopausal osteoporosis: synopsis of a leading to cellular dysfunction, and culminates in organ WHO report. WHO Study Group. Osteoporos Int 1994, dysfunction and an increased vulnerability to death. 4(6):368-381. 18. Tietz NW, Shuey DF, Wekstein DR: Laboratory values in fit aging individuals: sexagenarians through centenarians. Clin Analogously, chronic diseases initiate early in life and Chem 1992, 38:1167-1185. 19. Izaks GJ, Westendorp RG, Knook DL: The definition of anemia in their development is slow before they become clinically older persons. JAMA 1999, 281:1714-1717. apparent and culminate in disability or death 20. Blackford RC, La Rue A: Criteria for diagnosing age associated memory impairment: proposed improvements from the field. Dev Neuropsychol 1989, 5:295-306. In addition, the definition of disease is subject to current 21. Verbeken EK: The senile lung. Comparison with normal and opinions and scientific understanding. emphysematous lungs: 2. functional aspects. Chest 1992, 101:800-809. 22. Hamerman D: Toward an understanding of frailty. Ann Intern Based on the above, normal ageing cannot be separated Med 1999, 130:945-950. from pathological processes causing disease later in life, and we therefore propose that the distinction is avoided. Pre-publication history The pre-publication history for this paper can be accessed Avoiding the distinction between normal and pathologi- here: cal ageing has important implications for the clinician. For example, the use of old-age-specific normal values http://www.biomedcentral.com/1471-2318/3/7/prepub appears to be inappropriate. Competing interests None declared. Authors' contributions GI discussed core ideas and drafted the manuscript. RW discussed core ideas and drafted the manuscript. Both authors read and approved the final manuscript. References 1. Rise and fall of diseases:. Lancet 1993, 341:151-152. 2. 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Bloem BR, Gussekloo J, Lagaay AM, Remarque EJ, Haan J, Westen- dorp RG: Idiopathic senile gait disorders are signs of subclini- Publish with Bio Med Central and every cal disease. J Am Geriatr Soc 2000, 48:1098-1101. scientist can read your work free of charge 11. Brocklehurst JC: The geriatric service and the day hospital. In Textbook of geriatric medicine and gerontology Edited by: Brocklehurst JC. "BioMed Central will be the most significant development for Edinburgh: Churchill Livingstone; 1985:982-995. disseminating the results of biomedical researc h in our lifetime." 12. Rockwood K, Fox RA, Stolee P, Robertson D, Beattie BL: Frailty in Sir Paul Nurse, Cancer Research UK elderly people: an evolving concept. CMAJ 1994, 150:489-495. 13. Fries JF: Aging, natural death, and the compression of Your research papers will be: morbidity. N Engl J Med 1980, 303:130-135. available free of charge to the entire biomedical community 14. Smith R: In search of "non-disease". BMJ 2002, 324:883-885. 15. Miller RA: The biology of aging and longevity. In Principles of ger- peer reviewed and published immediately upon acceptance iatric medicine and gerontology Edited by: Hazzard WR, Blass JP, Ettinger cited in PubMed and archived on PubMed Central WH, Halter JB, Ouslander JG. New York: McGraw-Hill; 1999:3-19. 16. Masoro EJ: Physiology of aging. In Textbook of geriatric medicine and yours — you keep the copyright gerontology Edited by: Tallis RC, Fillit H, Brocklehurst JC. Edinburgh: BioMedcentral Submit your manuscript here: Churchill Livingstone; 1998:85-95. http://www.biomedcentral.com/info/publishing_adv.asp Page 6 of 6 (page number not for citation purposes)

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