Trade-off between cancer and aging: What role do other diseases play?: Evidence from experimental and human population studies
Introduction
To compare the effects of public health policies on population's characteristics, researchers estimate potential gain in life expectancy resulted from eradication or reduction of selected causes of death. Keyfitz (1977) estimated that eradication of cancer will result in 2.27 years of increase in male life expectancy at birth (or by 3% compared to its 1964 level). Lemaire (2005) found that potential gain in the U.S. life expectancy resulting from cancer eradication will not exceed 3 years for both genders. Conti et al. (1999) calculated that potential gain in life expectancy resulting from cancer eradication in Italy is 3.84 years for males and 2.77 years for females.
All these calculations assumed independence between causes of death. The use of such an assumption would be completely justified more than a century ago when leading causes of death were infectious diseases. However, for today's populations in developed countries, where deaths from chronic non-communicable diseases took a lead, this assumption is no longer valid. An important feature of such diseases is that they often develop in clusters manifesting a positive correlation with each other. The common opinion was that in case of such dependence the effect of cancer eradication on life expectancy would be even smaller. As Keyfitz (1977) wrote: “since the most common kind of dependence must be a positive one people saved from cancer would be more susceptible to heart and other diseases.”
However, factors associated with increased vulnerability to one disease may, in principle, be protective against other pathology and even favor overall survival and longevity if the protective effect overweighs the detrimental one. If so, then a reasonable strategy would be targeting the risk of death from all causes combined rather than risks of separate diseases independently as it takes place in many of the today's medical programs.
The results of recent studies suggest a number of underlying mechanisms for a possible negative correlation between cancer and several other diseases. One is associated with differential expression of genes involved in apoptotic pathways. For example, genetic variants favoring high intensity of apoptosis in tissues may better protect organism from cancer but instead increase its chances of death from heart disease (in which the amount of cells dying from ischemia is essential for prognosis). Oppositely, genes responsible for the lower levels of apoptosis may contribute to better survival from acute heart disease, but increase chances of death from cancer. Such a trade-off results in a negative correlation between mortality rates from cancer and coronary heart disease (CHD).
The purpose of this article is to show that studying mechanisms of dependence between diseases opens new opportunities for improving human health, as well as for better understanding its connection to aging and longevity. A popular concept about the trade-off between cancer and aging implies that the higher risk of cancer in modern human populations may associate with increased longevity. This is because genetic factors that enhance body's susceptibility to cancer may also decelerate its aging (see van Heemst et al., 2005, Ukraintseva and Yashin, 2005, and references therein). At the same time, there are experimental studies of factors affecting aging/longevity of laboratory animals, in which increased life span is accompanied by the reduction in the cancer risk. Indeed, in experimental rodents, calorie restriction extends maximum life span, while decreases the risk of developing cancer (Weindruch and Walford, 1982, Hursting et al., 2003). The question arises: to what extent can the increases in longevity observed in both human and experimental animal studies be attributed to the effects of deceleration in some fundamental aging process, as compared to the effects of prevention of the occurrence of chronic diseases, or the effects of changing balance between those disease risks that are inherently negatively correlated?
The correlation between causes of death can be evaluated using the U.S. Data on Multiple Causes of Death (http://www.cdc.gov/nchs/products/elec_prods/subject/mortmcd.htm#1999-2002). The importance of such analyses was demonstrated by Stallard (2002) who evaluated associations of diseases and their secular trends by examining statistics on the joint distributions of causes of death for the years 1980, 1990, and 1998. Estimating ratios of observed to expected age-standardized joint frequencies of each pair of 15 selected conditions, he found 57 associations, which were equivalent to a positive correlation of the disease indicator variables. He also demonstrated that Alzheimer's disease (in conditions) accompanies cancer deaths significantly less frequently (up to 5 times) than expected. Stallard argued that any analysis of cause-specific mortality that does not account for the joint occurrence of multiple diseases among elderly decedents, as well as the difficulties inherent in selecting one of these diseases as the underlying cause, will be incomplete.
In this paper, we first review experimental evidence about connection between cancer and aging/longevity in laboratory animals as well as about relationships between cancer and longevity in humans. Then we investigate possible trade-offs among major diseases (causes of death) of the elderly using the Multiple Cause of Death (MCD) data. We evaluate frequencies and associations among the specific diagnoses that appear most often in the death certificates and are overall responsible for the majority of deaths in the U.S., to explore a character of correlations among the causes of death, evaluate their temporal trends, and suggest a plausible interpretation of the findings. The results of this study suggest that understanding mechanisms of trade-offs between major elderly disorders may have important health care applications and be also essential for understanding the effects of aging versus the effects of balancing disease risks/mortalities on longevity.
Section snippets
Evidence of trade-off between cancer and aging in laboratory animals
Studying the role of p53 in the connection between cancer and cellular aging, Campisi, 2002, Campisi, 2003 suggested that longevity may depend on a balance between tumor suppression and tissue renewal mechanisms. Tyner et al. (2002) and Donehower (2002) showed that mice carrying the p53 mutation with a phenotypic effect analogous to the up-regulation of this gene have a lower risk of cancer development but their life span is reduced and accompanied by early tissue atrophy. Long-living mutant
The Multiple Cause of Death (MCD)
The Multiple Cause of Death (MCD) data files contain information about underlying and secondary causes of death in the U.S. during 1968–2004. Totally, they include more than 65 million individual death certificate records. The information available in death certificates includes the date of death, geographic location (region, state, county, division) of death, place of residence (region, state, county, city, and population size), sex, race, age, marital status, state of birth, and origin of
Results of analyses of MCD data
Fig. 1 shows the temporal trends in the proportion of deaths from diseases listed above in Section 3.1.
One can see from this figure that the frequency of death from CHD declined dramatically during the 25-year-period, and the decline was relatively steady during the entire interval. The proportion of deaths from stroke started to decline later, about 10 years ago. Proportions of deaths from diabetes and AD increased over time. Frequencies of death from cancer, asthma, and PD did not show a
Importance of revealing negative correlations among causes of death
The negative correlation between cancer and a number of causes of death described above indicates that individuals susceptible to cancer might in principle be less susceptible to some other diseases. This link suggests a possibility of getting an additional (indirect) contribution to the longevity increase resulting from eradication or reduction mortality from cancer. Indeed, those individuals whose lives were saved from cancer may turn out to be more resistant to other diseases, which would
Acknowledgements
This work was supported by grants 5P01AG008761, R01AG028259, and R01AG027019 from the National Institute on Aging. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health.
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