Version 4.

1 Cancer and the social induction of aging

Rodrick Wallace Deborah Wallace Division of Epidemiology The New York State Psychiatric Institute July 25, 2011
Nature Precedings : hdl:10101/npre.2011.6146.1 : Posted 25 Jul 2011

Abstract
Age has long been known as the primary population risk factor for cancer. We suggest that the observed disparities in hormonal cancers by ethnicity, gender, and other indices of social structure and power relationships, imply a dierential aging by psychosocial and environmental exposures, in the context of cross-generational epigenetic heritage. A relatively simple model of malignancy regulation illuminates the cellular root of induced aging, and explains the decline in cancer rate with extreme old age via telomere shortening. We nd that the multifactorial determinants of the disorder cannot be eectively addressed by small molecule interventions at the individual level, but must involve comprehensive prevention strategies that lessen exposure to policies and cultural practices that accelerate senescence in vulnerable or targeted populations. Key Words: health disparities, hormonal cancer, psychosocial stress, spontaneous symmetry breaking.

Introduction

Like Alzheimers disease, the principal risk factor for cancer is age. Figures 1 and 2 display aggregated cancer incidence by age cohort in the US and in the Miyagi Prefecture of Japan (NIA, 2011; Arbeev et al., 2005). Cancers of the breast and prostate hormonal cancers however, show large disparities by ethnicity and economic class in incidence among young adults, stage at presentation, and mortality rate (e.g. Parker et al., 1998; HHS, 1998). Although certain genetic alleles predispose individuals to higher susceptibility for these cancers (e.g., Gong et al., 2002 for prostate cancer), recent changes of incidence and mortality in time and geography indicate genes alone do not explain the expressed population-level patterns. At present, AfricanAmerican women under age 35 suer an approximately twofold higher age-specic rate of breast cancer, compared to white women, and the mortality rate is about three times
Box 47, 1051 Riverside Dr., New York, NY, 10032. lace@pi.cpmc.columbia.edu

Figure 1: Aggregated age-specic cancer rates for the USA. While undierentiated by cancer and/or social classication, an overall sigmoidal structure is evident. The downturn after age 82 is real and will be addressed using a telomere shortening argument.

wal-

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Figure 2: Adapted from gure 1 of Arbeev et al. (2005). Cancer indigence rates for males in the Miyagi Prefecture of Japan. Again, the downturn at very old age is evident.

velopment in which a de-facto aging rate can be driven by psychosocial and other environmental exposures, with possible eects across generations via epigenetic mechanisms (e.g., Wallace and Wallace, 2010). We propose, then, an approach that more fully integrates the biocultural processes that shape the development of humans, their cancers, and dierentials in both their susceptibility and pathways of disease progression. We begin with Nunneys (1999) evolutionary history of cancer, as opposed to more conventional local evolutionary dynamic theories of tumorigenesis within an organism (e.g., Bertram, 2001). Nunneys analysis suggests that in larger animals, whose lifespans are proportional to about the 4/10 power of their cell count, prevention of cancer in rapidly proliferating tissues becomes more dicult in proportion to their size. Cancer control requires the development of additional mechanisms and systems to address tumorigenesis as body size increases a synergistic eect of cell number and organism longevity. As Nunney puts it, This pattern may represent a real barrier to the evolution of large, long-lived animals and predicts that those that do evolve... have recruited additional controls [over those of smaller animals] to prevent cancer. Nunneys work implies, in particular, that dierent tissues may have evolved markedly dierent tumor control strategies. All of these, however, are likely to be energetically expensive, permeated with dierent complex signaling strategies, and subject to a multiplicity of reactions to signals. For modern humans, large animals whose principal selective environment is other humans, this suggests a critical role for the signal of psychosocial stress, as mediated by a local sociocultural network, i.e., an embedding cognitive social structure linked to a cultural practice and history. Contemporary evolutionary anthropology (e.g., Durham, 1991; Richerson and Boyd, 2005) emphasizes that culture, largely dening what social relations are particularly helpful or stressful, has become inextricably intertwined with human biology. The seminal study by Forlenza and Baum (2000) suggests that psychosocial stress is a very strong signal indeed and severally aects the stages of mutation control: immune surveillance, both DNA damage and repair, apoptosis, and rates of somatic mutation.

higher (Shavers et al., 2003). For prostate cancer, AfricanAmerican men have a two-fold higher mortality rate, and 50 % higher incidence rate, than their white counterparts (Sarma and Schottenfeld, 2002). Currently, via cultural blinders reinforced by pressure from the research funding stream, ideologies of individualism permeate US biomedical and scientic thinking, and, except for some pious lip service, policy interest in health dierentials has waned. In its stead, the life style doctrine predominates: people get sick because they dont take responsibility for their own health. The connection between diet and breast cancer was an often-cited example of how life style aects health. Nonetheless, a large and growing literature on determinants of risk behaviors has explored the bases of life style decisions and found them rooted in social and economic processes (e.g., Bursik, 1986; Fullilove and Fullilove, 1989; Kane, 1981; Wallace et al., 1996; Wallace and Fullilove, 1999). The literature is too extensive to fully review here. Many of the risk behaviors associated with AIDS, drug abuse, and violence, are known to be coping mechanisms driven by frustration, pain, deprivation, humiliation, and danger (e.g., Ben-Tovin et al., 2002; Wallace et al, 1996). The particular modes of coping spread, rst between social networks and then within social networks by branching processes (Latkin et al., 1999). What is perhaps the classic study of drug use, The Heroin Epidemics, clearly described all these contagious small-scale processes (Hunt and Chambers, 1976). Risk behaviors may explain part of the pattern in hormonal cancers. Such behaviors, however, may not fully account for population dierentials in hormonal cancer incidences and mortality rates, and certainly do not explain the overall dominant effect of aging in cancer incidence. Given the powerful patterns of gures 1 and 2, we will explore a model for cancer de2

Spontaneous symmetry breaking with age

The basic mechanism is explored in gure 3, where an initial cell in a particular tissue undergoes division, from state S0 into two possible nal states, Sn for a normal process, and Scan for an abnormal state likely to lead to a cancerous proliferation. The regulatory system, a sophisticated process of chemical cognition in the sense of Atlan and Cohen (1998), can determine an average distance D between what has been

Nature Precedings : hdl:10101/npre.2011.6146.1 : Posted 25 Jul 2011

Figure 3: Developmental paths for a dividing cell lead either to its normal form Sn , with average distortion from an expected conguration of D = 0, or, via a set of pathological tracks, to a cancerous form having D > 0, by some appropriate measure. The full and dotted lines represent high probability paths. The lled triangular zone represents the vast majority of low probability nonsense developmental path- Figure 4: Dynamics of the probability of cancerous proliferaways. tion as a function of age for two de-facto aging rate parameters, k. The basic idea is that, for humans, k depends on individual exposures to environmental or psychosocial stresses produced by cell division and what should have been the outcome, via something much a rate distortion argument (e.g., over the life course, as aected by possible epigenetic herWallace and Wallace, 2010). The regulatory apparatus acts in itage across generations. As the regulatory machinery ages a cognitive manner to repair/eliminate cells that deviate from out, cancer probability rises according to a roughly sigmoidal the set of pathways leading to the condition D = 0. It seems curve. likely that the exact form of D, and the chemical processes that measure it, may be of little importance, via the powerful necessary conditions arguments of the Rate Distortion Theorem (Cover and Thomas, 2006). The mathematical parallel is the way that long sums of stochastic variates converge on the Normal distribution via the Central Limit theorem. In fact, Wallace et al. (2003) give a purely information-theoretic cast to the cancer problem, an approach that we try to simplify here. The model we invoke is analogous to a spontaneous symmetry breaking in Landaus sense (Landau and Lifshitz, 2007; Pettini, 2007): With increasing age, the regulatory apparatus corrodes, becoming progressively less eective in containing cancerous proliferation. This is taken as equivalent to raising the temperature of a physical system so that increasing numbers of symmetries of a Hamiltonian become accessible. By analogy, then, the probability of the distortion measure Di , P [Di ], becomes

where k is a socially-determined scaling constant, T is temporal age, and Dj any measure of average distortion from the normal cellular conguration for the cell conguration j. For the two-state system of gure 3 this gives

P [Cancer] = (2)

exp[Dcan /kT ] , 1 + exp[Dcan /kT ]

P [Di ] = (1)

exp[Di /kT ] j exp[Dj /kT ]

a sigmoidal relation. For an arbitrary xed value of Dcan > 0 and increasing age, gure 4 shows the dynamics of cancer expression for the two scaling conditions, k = 1, 2 that represent dierent possible rates of physiological aging with time. Both curves top out at 1/2, but this would represent an extreme condition. Nonetheless, the general principle seems evident. Explaining the downturn at very old age in gures 1 and 2 requires a second step in the model. Following, somewhat, the 3

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Figure 5: Adapted from gure 1 of Eisenberg (2011). Shortening of telomere length with age in humans. Negative numbers are weeks before birth, and positive numbers years after birth. The rate of decline itself declines, leading in the direction of the arguments of Arbeev et al., (2005).

arguments of Eisenberg (2011), telomeres repetitive DNA sequences found at the ends of linear chromosomes play a role in regulating cellular proliferation, and shorten with increasing age in proliferating human tissues. The rate of age-related shortening of telomeres is highest early in life, and decreases with age. Shortened telomeres are thought to limit the proliferation of cells and are associated with increased morbidity and mortality. Figure 5, adapted from Eisenberg (2011), shows telomere length vs. age, as abstracted from a variety of studies. Arbeev et al. (2005) argue, in eect, that k in equation (2) is itself a declining function of time T , having, in their Figure 6: Substituting equation (3) into equation (2) repreapproach, the general form senting the general form of telomere shortening in gure 5 produces a rate model that does indeed begin to decline at the oldest ages. We conjecture that the synergism of psychosocial and environmental stressors, in conjunction with epigenetic heritage across generations, determines k0 and k1 . k = k0 exp[k1 T ]. (3)

Nesting equation (3) in equation (2) produces the general pattern of gure 6, declining at suciently old age. We have, then, produced a relatively simple two-stage conceptual model that reproduces the essential features of gures 1 and 2. The critical parameters k0 and k1 represent aging rates determined by psychosocial and other environmental stressors in the context of possible cross-generational epigenetic inheritance. 4

Discussion and conclusions

An earlier paper examined racial disparities among hormonal cancers in the US, extending the theory of immune cognition to include an elaborate tumor control mechanism constituting the principal selection pressure acting on pathologically mutating cell clones (Wallace et al., 2003). The interplay between them occurs, from that perspective, in the context of an embedding, highly structured, system of culturally-specic psychosocial stress. A classic rate distortion argument found that the larger system of stressors was able to literally write an image of itself onto the disease process, in terms of enhanced risk behavior, accelerated mutation rate, and depressed mutation control. The dynamics of that model were analogous to punctuated equilibrium in simple evolutionary systems, accounting for the often staged nature of disease progression at the individual level. That work found social exposures to be far more than incidental cofactors in human cancer etiology, but rather an essential part of the basic biology of the disorder. The aphorism that culture is as much a part of human biology as the enamel on our teeth seems literally true at a fundamental cellular level. That study, however, ran to 22 equations, involving fairly elaborate mathematical machinery. Here we have reconsidered the problem, examining in particular the large-scale age spectrum of the disorder, as in gures 1 and 2. A relatively simple two-stage nested model accounts in a qualitative manner for the overall cancer/age pattern, in which de-facto aging is determined by the synergism of simple temporal age with patterns of psychosocial and environmental stress, most likely compounded by crossgenerational epigenetic inheritance (e.g., Wallace and Wallace, 2010) that must aect both rates of telomere shortening and the corrosion of tissue-specic tumor regulatory systems. This view reinforces our earlier conclusions that the multifactorial psychosocialneuroimmuno nature of the disorder will not, ultimately, be addressed by small molecule interventions at the individual level, but must involve comprehensive prevention strategies that lessen exposure to policies and practices that accelerate physiological aging among vulnerable or targeted populations. Wallace and Fullilove (2008) show in some detail how serial forced displacement of AfricanAmerican populations, in the context of an ongoing American Apartheid (Massey and Denton, 1998), contributed materially to the failure of AIDS control in the USA. Our analysis suggests the argument might well be extended to patterns of hormonal and other cancers.

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Nature Precedings : hdl:10101/npre.2011.6146.1 : Posted 25 Jul 2011

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