Econstudentlog

Biodemography of aging (II)

In my first post about the book I included a few general remarks about the book and what it’s about. In this post I’ll continue my coverage of the book, starting with a few quotes from and observations related to the content in chapter 4 (‘Evidence for Dependence Among Diseases‘).

“To compare the effects of public health policies on a population’s characteristics, researchers commonly estimate potential gains in life expectancy that would result from eradication or reduction of selected causes of death. For example, Keyfitz (1977) estimated that eradication of cancer would result in 2.265 years of increase in male life expectancy at birth (or by 3 % compared to its 1964 level). Lemaire (2005) found that the potential gain in the U.S. life expectancy from cancer eradication would not exceed 3 years for both genders. Conti et al. (1999) calculated that the potential gain in life expectancy from cancer eradication in Italy would be 3.84 years for males and 2.77 years for females. […] All these calculations assumed independence between cancer and other causes of death. […] for today’s populations in developed countries, where deaths from chronic non-communicable diseases are in the lead, this assumption might no longer be valid. An important feature of such chronic diseases is that they often develop in clusters manifesting positive correlations with each other. The conventional view is that, in a case of such dependence, the effect of cancer eradication on life expectancy would be even smaller.”

I think the great majority of people you asked would have assumed that the beneficial effect of hypothetical cancer eradication in humans on human life expectancy would be much larger than this, but that’s just an impression. I’ve seen estimates like these before, so I was not surprised – but I think many people would be if they knew this. A very large number of people die as a result of developing cancer today, but the truth of the matter is that if they hadn’t died from cancer they’d have died anyway, and on average probably not really all that much later. I linked to Richard Alexander’s comments on this topic in my last post about the book, and again his observations apply so I thought I might as well add the relevant quote from the book here:

“In the course of working against senescence, selection will tend to remove, one by one, the most frequent sources of mortality as a result of senescence. Whenever a single cause of mortality, such as a particular malfunction of any vital organ, becomes the predominant cause of mortality, then selection will more effectively reduce the significance of that particular defect (meaning those who lack it will outreproduce) until some other achieves greater relative significance. […] the result will be that all organs and systems will tend to deteriorate together. […] The point is that as we age, and as senescence proceeds, large numbers of potential sources of mortality tend to lurk ever more malevolently just “below the surface,”so that, unfortunately, the odds are very high against any dramatic lengthening of the maximum human lifetime through technology.”

Remove one cause of death and there are plenty of others standing in line behind it. We already knew that; two hundred years ago one out of every four deaths in England was the result of tuberculosis, but developing treatments for tuberculosis and other infectious diseases did not mean that English people stopped dying; these days they just die from cardiovascular disease and cancer instead. Do note in the context of that quote that Alexander is talking about the maximum human lifetime, not average life expectancy; again, we know and have known for a long time that human technology can have a dramatic effect on the latter variable. Of course a shift in one distribution will be likely to have spill-over effects on the other (if more people are alive at the age of 70, the potential group of people also living on to reach e.g. 100 years is higher, even if the mortality rate for the 70-100 year old group did not change) the point is just that these effects are secondary effects and are likely to be marginal at best.

Anyway, some more stuff from the chapter. Just like the previous chapter in the book did, this one also includes analyses of very large data sets:

The Multiple Cause of Death (MCD) data files contain information about underlying and secondary causes of death in the U.S. during 1968–2010. In total, they include more than 65 million individual death certificate records. […] we used data for the period 1979–2004.”

There’s some formal modelling stuff in the chapter which I won’t go into in detail here, this is the chapter in which I encountered the comment about ‘the multivariate lognormal frailty model’ I included in my first post about the book. One of the things the chapter looks at are the joint frequencies of deaths from cancer and other fatal diseases; it turns out that there are multiple diseases that are negatively related with cancer as a cause of death when you look at the population-level data mentioned above. The chapter goes into some of the biological mechanisms which may help explain why these associations look the way they do, and I’ll quote a little from that part of the coverage. A key idea here is (as always..?) that there are tradeoffs at play; some genetic variants may help protect you against e.g. cancer, but at the same time increase the risk of other diseases for the same reason that they protect you against cancer. In the context of the relationship between cancer deaths and deaths from other diseases they note in the conclusion that: “One potential biological mechanism underlying the negative correlation among cancer and other diseases could be related to the differential role of apoptosis in the development of these diseases.” The chapter covers that stuff in significantly more detail, and I decided to add some observations from the chapter on these topics below:

“Studying the role of the p53 gene in the connection between cancer and cellular aging, Campisi (2002, 2003) suggested that longevity may depend on a balance between tumor suppression and tissue renewal mechanisms. […] Although the mechanism by which p53 regulates lifespan remains to be determined, […] findings highlight the possibility that careful manipulation of p53 activity during adult life may result in beneficial effects on healthy lifespan. Other tumor suppressor genes are also involved in regulation of longevity. […] In humans, Dumont et al. (2003) demonstrated that a replacement of arginine (Arg) by proline (Pro) at position 72 of human p53 decreases its ability to initiate apoptosis, suggesting that these variants may differently affect longevity and vulnerability to cancer. Van Heemst et al. (2005) showed that individuals with the Pro/Pro genotype of p53 corresponding to reduced apoptosis in cells had significantly increased overall survival (by 41%) despite a more than twofold increased proportion of cancer deaths at ages 85+, together with a decreased proportion of deaths from senescence related causes such as COPD, fractures, renal failure, dementia, and senility. It was suggested that human p53 may protect against cancer but at a cost of longevity. […] Other biological factors may also play opposing roles in cancer and aging and thus contribute to respective trade-offs […]. E.g., higher levels of IGF-1 [have been] linked to both cancer and attenuation of phenotypes of physical senescence, such as frailty, sarcopenia, muscle atrophy, and heart failure, as well as to better muscle regeneration”.

“The connection between cancer and longevity may potentially be mediated by trade-offs between cancer and other diseases which do not necessarily involve any basic mechanism of aging per se. In humans, it could result, for example, from trade-offs between vulnerabilities to cancer and AD, or to cancer and CVD […] There may be several biological mechanisms underlying the negative correlation among cancer and these diseases. One can be related to the differential role of apoptosis in their development. For instance, in stroke, the number of dying neurons following brain ischemia (and thus probability of paralysis or death) may be less in the case of a downregulated apoptosis. As for cancer, the downregulated apoptosis may, conversely, mean a higher risk of the disease because more cells may survive damage associated with malignant transformation. […] Also, the role of the apoptosis may be different or even opposite in the development of cancer and Alzheimer’s disease (AD). Indeed, suppressed apoptosis is a hallmark of cancer, while increased apoptosis is a typical feature of AD […]. If so, then chronically upregulated apoptosis (e.g., due to a genetic polymorphism) may potentially be protective against cancer, but be deleterious in relation to AD. […] Increased longevity can be associated not only with increased but also with decreased chances of cancer. […] The most popular to-date “anti-aging” intervention, caloric restriction, often results in increased maximal life span along with reduced tumor incidence in laboratory rodents […] Because the rate of apoptosis was significantly and consistently higher in food restricted mice regardless of age, James et al. (1998) suggested that caloric restriction may have a cancer-protective effect primarily due to the upregulated apoptosis in these mice.”

Below I’ll discuss content covered in chapter 5, which deals with ‘Factors That May Increase Vulnerability to Cancer and Longevity in Modern Human Populations’. I’ll start out with a few quotes:

“Currently, the overall cancer incidence rate (age-adjusted) in the less developed world is roughly half that seen in the more developed world […] For countries with similar levels of economic development but different climate and ethnic characteristics […], the cancer rate patterns look much more similar than for the countries that share the same geographic location, climate, and ethnic distribution, but differ in the level of economic development […]. This suggests that different countries may share common factors linked to economic prosperity that could be primarily responsible for the modern increases in overall cancer risk. […] Population aging (increases in the proportion of older people) may […] partly explain the rise in the global cancer burden […]; however, it cannot explain increases in age-specific cancer incidence rates over time […]. Improved diagnostics and elevated exposures to carcinogens may explain increases in rates for selected cancer sites, but they cannot fully explain the increase in the overall cancer risk, nor incidence rate trends for most individual cancers (Jemal et al. 2008, 2013).”

“[W]e propose that the association between the overall cancer risk and the economic progress and spread of the Western lifestyle could in part be explained by the higher proportion of individuals more susceptible to cancer in the populations of developed countries, and discuss several mechanisms of such an increase in the proportion of the vulnerable. […] mechanisms include but are not limited to: (i) Improved survival of frail individuals. […] (ii) Avoiding or reducing traditional exposures. Excessive disinfection and hygiene typical of the developed world can diminish exposure to some factors that were abundant in the past […] Insufficiently or improperly trained immune systems may be less capable of resisting cancer. (iii) Burden of novel exposures. Some new medicines, cleaning agents, foods, etc., that are not carcinogenic themselves may still affect the natural ways of processing carcinogens in the body, and through this increase a person’s susceptibility to established carcinogens. [If this one sounds implausible to you, I’ll remind you that drug metabolism is complicatedUS] […] (iv) Some of the factors linked to economic prosperity and the Western lifestyle (e.g., delayed childbirth and food enriched with growth factors) may antagonistically influence aging and cancer risk.”

They provide detailed coverage of all of these mechanisms in the chapter, below I have included a few select observations from that part of the coverage.

“There was a dramatic decline in infant and childhood mortality in developed countries during the last century. For example, the infant mortality rate in the United States was about 6 % of live births in 1935, 3 % in 1950, 1.3 % in 1980, and 0.6 % in 2010. That is, it declined tenfold over the course of 75 years […] Because almost all children (including those with immunity deficiencies) survive, the proportion of the children who are inherently more vulnerable could be higher in the more developed countries. This is consistent with a typically higher proportion of children with chronic inflammatory immune disorders such as asthma and allergy in the populations of developed countries compared to less developed ones […] Over-reduction of such traditional exposures may result in an insufficiently/improperly trained immune system early in life, which could make it less able to resist diseases, including cancer later in life […] There is accumulating evidence of the important role of these effects in cancer risk. […] A number of studies have connected excessive disinfection and lack of antigenic stimulation (especially in childhood) of the immune system in Westernized communities with increased risks of both chronic inflammatory diseases and cancer […] The IARC data on migrants to Israel […] allow for comparison of the age trajectories of cancer incidence rates between adult Jews who live in Israel but were born in other countries […] [These data] show that Jews born in less developed regions (Africa and Asia) have overall lower cancer risk than those born in the more developed regions (Europe and America).  The discrepancy is unlikely to be due to differences in cancer diagnostics because at the moment of diagnosis all these people were citizens of the same country with the same standard of medical care. These results suggest that surviving childhood and growing up in a less developed country with diverse environmental exposures might help form resistance to cancer that lasts even after moving to a high risk country.”

I won’t go much into the ‘burden of novel exposures’ part, but I should note that exposures that may be relevant include factors like paracetamol use and antibiotics for treatment of H. pylori. Paracetamol is not considered carcinogenic by the IARC, but we know from animal studies that if you give rats paratamol and then expose them to an established carcinogen (with the straightforward name N-nitrosoethyl-N-hydroxyethylamine), the number of rats developing kidney cancer goes up. In the context of H. pylori, we know that these things may cause stomach cancer, but when you treat rats with metronidazol (which is used to treat H. pylori) and expose them to an established carcinogen, they’re more likely to develop colon cancer. The link between colon cancer and antibiotics use has been noted in other contexts as well; decreased microbial diversity after antibiotics use may lead to suppression of the bifidobacteria and promotion of E. coli in the colon, the metabolic products of which may lead to increased cancer risk. Over time an increase in colon cancer risk and a decrease in stomach cancer risk has been observed in developed societies, but aside from changes in diet another factor which may play a role is population-wide exposure to antibiotics. Colon and stomach cancers are incidentally not the only ones of interest in this particular context; it has also been found that exposure to chloramphenicol, a broad-spectrum antibiotic used since the 40es, increases the risk of lymphoma in mice when the mice are exposed to a known carcinogen, despite the drug itself again not being clearly carcinogenic on its own.

Many new exposures aside from antibiotics are of course relevant. Two other drug-related ones that might be worth mentioning are hormone replacement therapy and contraceptives. HRT is not as commonly used today as it was in the past, but to give some idea of the scope here, half of all women in the US aged 50-65 are estimated to have been on HRT at the peak of its use, around the turn of the millennium, and HRT is assumed to be partly responsible for the higher incidence of hormone-related cancers observed in female populations living in developed countries. It’s of some note that the use of HRT dropped dramatically shortly after this peak (from 61 million prescriptions in 2001 to 21 million in 2004), and that the incidence of estrogen-receptor positive cancers subsequently dropped. As for oral contraceptives, these have been in use since the 1960s, and combined hormonal contraceptives are known to increase the risk of liver- and breast cancer, while seemingly also having a protective effect against endometrial cancer and ovarian cancer. The authors speculate that some of the cancer incidence changes observed in the US during the latter half of the last century, with a decline in female endometrial and ovarian cancer combined with an increase in breast- and liver cancer, could in part be related to widespread use of these drugs. An estimated 10% of all women of reproductive age alive in the world, and 16% of those living in the US, are estimated to be using combined hormonal contraceptives. In the context of the protective effect of the drugs, it should perhaps be noted that endometrial cancer in particular is strongly linked to obesity so if you are not overweight you are relatively low-risk.

Many ‘exposures’ in a cancer context are not drug-related. For example women in Western societies tend to go into menopause at a higher age, and higher age of menopause has been associated with hormone-related cancers; but again the picture is not clear in terms of how the variable affects longevity, considering that later menopause has also been linked to increased longevity in several large studies. In the studies the women did have higher mortality from the hormone-related cancers, but on the other hand they were less likely to die from some of the other causes, such as pneumonia, influenza, and falls. Age of childbirth is also a variable where there are significant differences between developed countries and developing countries, and this variable may also be relevant to cancer incidence as it has been linked to breast cancer and melanoma; in one study women who first gave birth after the age of 35 had a 40% increased risk of breast cancer compared to mothers who gave birth before the age of 20 (good luck ‘controlling for everything’ in a context like that, but…), and in a meta-analysis the relative risk for melanoma was 1.47 for women in the oldest age group having given birth, compared to the youngest (again, good luck controlling for everything, but at least it’s not just one study). Lest you think this literature only deals with women, it’s also been found that parental age seems to be linked to cancers in the offspring (higher parental age -> higher cancer risk in the offspring), though the effect sizes are not mentioned in the coverage.

Here’s what they conclude at the end of the chapter:

“Some of the factors associated with economic prosperity and a Western lifestyle may influence both aging and vulnerability to cancer, sometimes oppositely. Current evidence supports a possibility of trade-offs between cancer and aging-related phenotypes […], which could be influenced by delayed reproduction and exposures to growth factors […]. The latter may be particularly beneficial at very old age. This is because the higher levels of growth factors may attenuate some phenotypes of physical senescence, such as decline in regenerative and healing ability, sarcopenia, frailty, elderly fractures and heart failure due to muscles athrophy. They may also increase the body’s vulnerability to cancer, e.g., through growth promoting and anti-apoptotic effects […]. The increase in vulnerability to cancer due to growth factors can be compatible with extreme longevity because cancer is a major contributor to mortality mainly before age 85, while senescence-related causes (such as physical frailty) become major contributors to mortality at oldest old ages (85+). In this situation, the impact of growth factors on vulnerability to death could be more deleterious in middle-to-old life (~before 85) and more beneficial at older ages (85+).

The complex relationships between aging, cancer, and longevity are challenging. This complexity warns against simplified approaches to extending longevity without taking into account the possible trade-offs between phenotypes of physical aging and various health disorders, as well as the differential impacts of such tradeoffs on mortality risks at different ages (e.g., Ukraintseva and Yashin 2003a; Yashin et al. 2009; Ukraintseva et al. 2010, 2016).”

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March 7, 2017 - Posted by | books, cancer, medicine, Pharmacology

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