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Low incidence of cardiovascular disease and cancer in old age and decreased immune response
- Jecko Thachil (12 December 2008)
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Blood flow in aging, cancer and cardiovascular disease
- Les O. Simpson (15 December 2008)
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What do doctors die from?
- Georgina Rowan, Sarah Wild, Brian McKinstry (22 December 2008)
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Less cancer in the very elderly may reflect the underlying biology of cancer rather than less efficient diagnosis
- Mark A Vickers (22 December 2008)
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Jecko Thachil, Research Fellow University of Liverpool
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In the journal, Driver et al report a decrease in incidence of cardiovascular disease and cancer late in life with the lifetime risk approaching a plateau in the tenth decade [1]. One of the reasons attributed is the increased resistance to disease in those who survive to old age. Is this increased resistance due to a decreasing inflammatory response which occurs with age? Inflammation has been linked to both atherosclerotic disease and cancer [2, 3, 4]. The first step in atherosclerosis is thought to be endothelial dysfunction and every step in the progression of the plaque represents a different stage in a chronic inflammatory process [2]. Possible causes of endothelial dysfunction include the well known cardiovascular risk factors, hypercholesterolemia and hypertension. However, a study of 571 participants including nearly half who had a history of hypertension, demonstrated that in individuals over the age of 85 years, an elevated blood pressure is not a risk factor for mortality, irrespective of the history of hypertension [5]. Also, another report showed that high total serum cholesterol concentration is not a risk factor for cardiovascular disease in people aged 85 years and on the contrary, it is associated with longevity owing to lower mortality from cancer and infection [6]. Is this lower incidence of cancer and infection and indeed cardiovascular mortality related to the exhaustion of the immune system which occurs in extreme old age? Epidemiological evidence demonstrates a connection between inflammation and a predisposition for the development of cancer. Examples include Helicobacter-associated gastric cancer, chronic colitis fueling the development of colon cancer and the chronic bronchitis of smokers leading to lung cancer. If the immune response to the different inciting factors which cause cancer is not adequate, it may not lead to uncontrolled stimulation of the cells, needed for the development of the malignancies, explaining a lower incidence in older individuals with diminishing immune function. William Osler said over 100 years ago, “Except on few occasions, the patient appears to die from the body’s response to infection rather than from it.” Can we say if the body does not adequately respond to the inflammatory triggers for cancer and cardiovascular disease, they may survive longer? References 1. Driver JA, Djoussé L, Logroscino G, Gaziano MJ, Kurth T. Incidence of cardiovascular disease and cancer in advanced age: prospective cohort study. BMJ 2008 337: a2467. 2. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999; 340: 115-26. 3. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2002; 357: 539–545. 4. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002; 420: 860–867. 5. van Bemmel T, Gussekloo J, Westendorp RG, Blauw GJ. In a population- based prospective study, no association between high blood pressure and mortality after age 85 years. J Hypertens. 2006; 24: 287-92. 6. Weverling-Rijnsburger AW, Blauw GJ, Lagaay AM, Knook DL, Meinders AE, Westendorp RG. Total cholesterol and risk of mortality in the oldest old. Lancet 1997; 350: 1119–23. Competing interests: None declared |
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Les O. Simpson, retired experimental pathologist Dunedin, New Zealand 9077
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Unfortunately, the medical profession seem not to recognise the pathogenic potential of impaired blood flow. For that reason it is unlikely that cardiovascular disease will be fully understood or appropriately treated, nor will the aging process or the consequences of cancer be explicable. In 1998, while working at the National Institute of Aging, Ajmani and Rifkind (1) published a seminal paper titled, "Hemorheological changes during human aging." They noted, "The rise in fibrinogen, blood viscosity, plasma viscosity, red cell regidity, fibrin degradation products, and early activation of the coagulation system are some of the most prominent findings." Such changes were considered to be involved in the development of age-related disorders and diseases. Five years later we published a report which showed that the blood of subjects aged between 60 and 96 years had high values for non -discocytic red cells. (2) We had shown earlier that changed red cell shape populations were present in poorly filtrable blood. As it is known that fish oil improves red cell deformability and lowers blood viscosity, there is clinical significance in the findings of Kromhout et al (3) who reported that a daily intake of 34 grams of fatty fish was associated with a 50% reduction in coronary heart disease in a 20 year follow up. It appears that none of these findings have gained clinical acceptance. As early as 1976, Dintenfass(4) had reported that in cancer patients, plasma and blood viscosity was increased and that red cell deformability was reduced. Therefore it seems that cancer is a biphasic disorder. Firstly, cancer invokes changes in the surrounding tissue. Secondly, there is change in the internal environment which alters blood rheology and stimulates change in the shape populations of red cells. Scanning electron microscopy of immediately fixed blood samples from anonymous donors with a variety of tumours and treatments, all showed changes in the shape populations of red cells. When following the progress of a patient after radical mastectomy, it was found that after both radio- and chemo-therapy there were marked increases in some red cell shapes which coincided with an exacerbation of symptoms. During the following week, symptom severity declined in concert with a return towards baseline of the shape changed red cell population. As fish oil has been shown to lower blood viscosity and to improve red cell deformability it is noteworthy that 6 grams daily of fish oil as a dietary supplement greatly reduced symptom severity. Thus it may be possible to improve the quality of life of cancer patients by addressing their blood flow problem. However, reports on these findings were rejected by cancer journals. While the inter-relationships of the age-associated and the cancer- related changes in blood rheology may be complex,it is possible that both changes may be ameliorated by agents such as fish oil which improve red cell deformability and capillary blood flow. Certainly the situation will not improve simply by ignoring the problem. I have attempted to show the extent to which blood flow problems are not recognised in current approaches to chronic disorders in a recently published book. (5) References. 1. Ajmani RS, Rifkind JM. Hemorheological changes during human aging. Gerontology 1998;44:111-20. 2. Simpson LO, O'Neill DJ. Red cell shape changes in the blood of people 60 years of age or older imply a role for blood rheology in the aging process. Gerontology 2003;49:310-5. 3. Kromhout D, Bosochieter EB, Coulander C, et al. The inverse relation between fish consumption and 20 year mortality from coronary heart disease. N Engl J Med 1985;312:1205-9. 4. Dintenfass L. Rheology of blood in diagnostic and preventive medicine. Butterworth and Co., London,1976. Chapter 4. Criteria and values in diagnosis and treatment and prevention of metastasis in neoplastic disease. 5. Simpson LO. Blood viscosity factors - the missing dimension in modern medicine. The Mumford Institute, Highlands, NJ7732, USA, 2008. Competing interests: None declared |
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Georgina Rowan, Foundation Doctor Western General Hospital, Edinburgh. EH4 2XU, Sarah Wild, Brian McKinstry
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Driver et al use a participant group of male doctors to predict general population trends in cardiovascular disease and cancer. However we recently compared causes of death in doctors as described in BMJ obituaries over ten years with 2002 mortality statistics from the Office of National Statistics for England and Wales (1); we found some significant differences between doctors and the general population. Our data included a total of 2275 deaths in doctors and 522720 deaths in the general population. We used proportional mortality ratios (PMR) for our comparison. We found that increased proportions of doctors appear to die from cerebrovascular disease (PMR 1.16, 95% CI 1.03 to 1.32) and cancer (PMR 1.33, 95% CI 1.24 to 1.43) and decreased proportions die from ischaemic heart disease (PMR 0.54, 95% CI 0.48 to 0.61) compared to the general population. Our original area of interest was cholangiocarcinoma which we also found to be a more common cause of death in doctors than in the general population (PMR 3.07, 95% CI 1.79 to 5.30), particularly in hospital doctors. Studies in Britain, Denmark and Finland have shown lower mortality in doctors from cancer and circulatory diseases (including cerebrovascular disease, ischaemic heart disease and peripheral vascular disease) and increased mortality from suicide (2,3,4). An older study from England and Wales showed increased proportions of deaths in doctors attributable to stroke, coronary heart disease and suicide and less from infectious diseases, cancer and accidents (5). Although there are discrepancies between studies this highlights an important limitation in using doctors to demonstrate population trends. References 1.Office for National Statistics. Series DH2 No.28 Mortality Statistics: cause. London: The Office of National Statistics; 2002. 2.Juel K, Mosbech J, Hansen ES. Mortality and causes of death among Danish medical doctors 1973-1992. International Journal of Epidemiology 1999; 28: 456-460. 3.Carpenter LM, Swerdlow AJ, Fear NT. Mortality of doctors in different specialities: findings from a cohort of 20000 NHS hospital consultants. Occupational and environmental medicine 1997; 54 (6): 388- 395. 4.Rimpela AH, Nurminen MM, Pulkkinen PO, Rimpela MK, Valkonen T. Mortality of doctors: do doctors benefit from their medical knowledge? The Lancet 1987; 1(8524): 84-87 5.King H. Health in the medical and other learned professions, Journal of chronic disease 1970; 23: 257-281. Georgina Rowan, Foundation Doctor Sarah Wild, Senior Lecturer in Epidemiology, University of Edinburgh Brian McKinstry, Reader in Primary Care Research at the Centre for Population Health Sciences University of Edinburgh Competing interests: None declared |
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Mark A Vickers, Professor of Applied Medicine University of Aberdeen, AB25 2ZD
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The article by Driver et al provides further evidence that cancer rates plateau and may even decline in the very elderly. Richard Doll and Peter Armitage first observed that the incidence of most cancers increases as a 4th-5th power of age and, in a seminal paper (1) from 1954 (2), deduced that cancer may be a multistep process with 5-6 rate limiting steps. If this relationship were followed in older ages, the incidence of cancer in the 90-99 age group would be approximately double that in the 70-79, and the data of Driver et al imply that the diagnosis of half of all cancers are therefore missed in this age group. The authors conclude that 'people aged 80 and older have a substantial amount of undiagnosed disease'. I would like to suggest an alternative explanation. The mutation rate at individual oncogenic loci is so low that multiple rate limiting mutations are difficult to accommodate in multistage models. Doll and Armitage themselves recognised this problem and subsequently developed a two stage model (3), but this never gained such influence as their original model. More recent recogniton that oncogenic mutations arise in stem cells, which are rare and slowly dividing have accentuated this problem (4). Indeed, these factors imply that cancer may only be caused by a single mutation. If this mutation led to a slowly exponentially-expanding clone, a 4th-5th power age specific incidence rate may result (5). In this scenario, the age specific incidence results from the inherent variability in stem cell division rates. However, at more advanced ages, this model predicts that the incidence should eventually level out reflecting the underlying single order kinetics arising from a constant stem cell mutation rate (6). Thus the fascinating epidemiological observation of a constant age specific rate, which is also observed in experimental animals (7), may provide a deeper insight into the pathogenesis of cancer. 1. R A Weiss. Multistage carcinogenesis. British Journal of Cancer (2004) 91, 1981–1982. 2. Armitage P, Doll R (1954) The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer 8: 1–12 3. Armitage P, Doll R (1957) A two-stage theory of carcinogenesis in relation to the age distribution of human cancer. Br J Cancer 11: 161–169 4. Vickers M, Brown GC, Cologne JB and Kyoizumi S (2000) Modelling haemopoietic stem cell division by analysis of mutant red cells. British Journal of Haematology 110:54-62. 5. Vickers MA (2007) JAK2 V617F positive polycythemia rubra vera maintained by ~18 stochastic stem cell divisions/year, explaining age of onset by a single rate limiting mutation. Blood 110:1675-1680. 6. Vickers M, Jackson G and Taylor P (2000) The incidence of acute promyelocytic leukemia appears constant over most of a human lifespan, implying only one rate limiting mutation. Leukemia 14:722-726. 7. Pompei F, Polkanov M, Wilson R. Age distribution of cancer in mice: the incidence turnover at old age. Toxicol Ind Health. 2001;17:7-16. Competing interests: None declared |
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