(1)
Indian Institute of Science Education and Research Pune (IISER-P), Pune, India
Abstract
At the core of the new paradigm of T2D is the concept that behavioral mechanisms are at the root of and are the drivers of all the endocrine, metabolic, immunological, and neurological changes observed in T2D and its complications. A simple expectation that arises from this concept is that there should be detectable behavioral changes accompanying or actually preceding diabetes. Also one should be able to observe behavioral differences between diabetics and age-matched nondiabetic controls. This has not been looked at seriously because hardly anyone suspected so. The other reason is that the behavior of diabetics is always perceived as normal, and there is no doubt that is it generally “normal” in the sense that it is not what psychiatry calls a disorder. Psychiatry looks at behavioral disorders and is generally not interested in behavioral differences within the “normal and healthy” range of behaviors. Psychologists and ethologists, on the other hand, who are interested in “normal” behavior do not study diabetes. As a result whether diabetics differ in any types of behaviors or personality within the normal range of behaviors was a question almost never addressed so far. The word diabetic personality has occasionally been used and debated [1–3], but this literature does not talk about the kind of personality traits the new paradigm expects. But differences do exist and I will cite one example.
At the core of the new paradigm of T2D is the concept that behavioral mechanisms are at the root of and are the drivers of all the endocrine, metabolic, immunological, and neurological changes observed in T2D and its complications. A simple expectation that arises from this concept is that there should be detectable behavioral changes accompanying or actually preceding diabetes. Also one should be able to observe behavioral differences between diabetics and age-matched nondiabetic controls. This has not been looked at seriously because hardly anyone suspected so. The other reason is that the behavior of diabetics is always perceived as normal, and there is no doubt that is it generally “normal” in the sense that it is not what psychiatry calls a disorder. Psychiatry looks at behavioral disorders and is generally not interested in behavioral differences within the “normal and healthy” range of behaviors. Psychologists and ethologists, on the other hand, who are interested in “normal” behavior do not study diabetes. As a result whether diabetics differ in any types of behaviors or personality within the normal range of behaviors was a question almost never addressed so far. The word diabetic personality has occasionally been used and debated [1–3], but this literature does not talk about the kind of personality traits the new paradigm expects. But differences do exist and I will cite one example.
An interesting two-minute game called ultimatum game involves two-player bargaining. The two players are unknown to each other. One player (player 1) plays the role of allocator, and the other player (player 2) plays the role of recipient. Player 1 is promised some money and is asked to divide it between himself and the other player. The rules stipulate that player 1 must make an offer, and player 2 can either accept the offer or reject it. If player 2 accepts the offer, player 1 receives the promised money and will have to give the offered fraction to player 2. If player 2 rejects the offer, none of them gets any money.
If we assume that each player plays to maximize his benefits, the rational strategies are simple. For player 2, accepting and rejecting are the only two options. Since rejection is bound to give zero returns, accepting any nonzero offer is the only rational strategy. Assuming player 1 knows what is rational for player 2, offering minimum nonzero amount would be the most rational strategy for player 1. However, it is observed that most people do not go by this rationale. In a large number of studies across age groups and cultures, the modal offer is typically 50%, and the mean offer lies between 40 and 50% of the total amount. Although the game is simple to perform and analyze, the interpretation of the results is complex. The surprising agreement about roughly equal sharing has been commonly interpreted as a result of an innate human tendency to appreciate fair and to retaliate unfair decisions [4]. This interpretation is certainly attractive and generally widely agreed. However the demonstration that serotonin [5–7] and testosterone [8, 9] levels affect ultimatum offers has raised other possibilities too. Both serotonin and testosterone are associated with social dominance hierarchy and aggression in diametrically opposite ways. Manipulating brain serotonin levels can change the dominant status and behavior of an individual [10, 11]. It is possible therefore that the ultimatum game offers reflect social hierarchical behavior in some way and not fairness alone. Social factors related to status and hierarchy have also been reported as risk factors for metabolic syndrome [12, 13]. Both serotonin and testosterone play important roles in metabolic syndrome. Chronically elevated serotonin signaling in the hypothalamus induces peripheral insulin resistance [14, 15]. Testosterone levels of diabetics are typically low, and testosterone has a protective role against many pathological consequences of metabolic syndrome [16–18] with the possible exception of advanced stages of nephropathy. Since serotonin is negatively associated with ultimatum offers and testosterone is positively associated [5–9], one may expect that diabetics may give lower offers in ultimatum game.
In a comparative study of people with metabolic syndrome (MS) and age-matched controls, as compared to the healthy control group, the MS group deviated significantly from the mode, much of the deviation being towards the left. The mean offer by the MS group (Rs. 202.55) was lower than the control group (Rs. 241.05), and frequency below 50% offer was significantly greater than the control group (χ 2 = 32.01, df = 2, p < 0.001) (Fig. 14.1). The comparison of diabetics and nondiabetics showed similar pattern, and the difference was highly significant (χ 2= 28.42, df = 2, p < 0.001). For other disorders the sample sizes were too small to allow a meaningful statistical test. There was a weak negative correlation between BMI and ultimatum game offers in the pooled data which was nonsignificant.
Fig. 14.1
Behavior of people with metabolic syndrome disorders in ultimatum game: Frequencies of ultimatum offers by people with metabolic syndrome (MS) disorders are depicted in comparison with healthy controls: Data are divided in three categories, namely, modal (50 ± 5%), below modal, and above modal class. MS disorders give significantly lower offers (χ 2= 32.01, df = 2, p < 0.001)
Logistic regression with presence of at least one of the metabolic syndrome disorders as a dependent binary variable and including sex, occupation, BMI, and ultimatum offers revealed that the effects of sex and occupation were nonsignificant, whereas BMI (coefficient β = 0.088, Wald = 3.09, p = 0.078) and ultimatum offer (coefficient β = −0.004, Wald = 3.56, p = 0.059) were marginally significant with overall predictability of the model being 62.4%. Exclusion of BMI from the regression rendered the effect of ultimatum offer significant (Wald = 5.12, p = 0.02) with predictability improving to 68.6%. On exclusion of ultimatum offer, the effect of BMI was nonsignificant and predictability declined to 56.78%. Considering T2D alone the patterns were very similar. Only ultimatum offer significantly predicted T2D in logistic regression (coefficient β = −0.004, Wald = 4.42, p = 0.035), whereas BMI, sex, and occupation did not show significant effects, the predictability of the model being 65.52%. In cross-sectional data ultimatum game offer was a better predictor of diabetes than BMI.
Ultimatum game is generally considered as a “fairness” game. However it would be unfair to jump to the conclusion that people with metabolic syndrome are “unfair” to others. This is because the fairness interpretation of ultimatum game itself can be questioned. People may deviate from the economically rational low offers owing to a number of possible alternative reasons apart from fairness: (1) The offers may represent a valuation of relative social ranking with anonymous person being given a default equal ranking; (2) A high offer may be viewed as a costly signal intended to advertise one’s own status and generosity; or (3) It may be driven by a hidden prediction of repeated and reciprocal interactions. All these explanations can be grouped as social status related explanations as opposed to the economic rationality. It can be perhaps generalized that economic rationality prompts low offers, and social rank-related factors prompt offers substantially higher than the economically rational ones. On this scale diabetics appear to be more inclined towards economic rationality than social rank- or social justice-related factors. We have seen earlier that social ranks play an important role in determining metabolic state. The hormones which have previously been shown to affect economic game behavior are serotonin and testosterone, both of which are known to play a role in social dominance hierarchy [10, 11]. Therefore a plausible explanation of lower hits by diabetics is likely to be related to the social hierarchy factors. It makes sense for a diplomat to be economically rational and care less about aggressive social hierarchical struggle. The results of the survey are therefore compatible with the behavioral origin paradigm of metabolic syndrome. On the other hand there is no a priori reason why “fairness” should be affected in metabolic syndrome disorders.
Of much potential interest is the result that ultimatum game offers are good predictors of T2D and other disorders in a cross-sectional sample. At least in our sample ultimatum offers were a better predictor of diabetes than BMI. This may not be surprising because of two reasons. On the one hand in Indian population, insulin resistance is not necessarily associated with very high BMI [19], and on the other hand, the inadequacy of obesity alone in explaining insulin resistance syndrome is increasingly being recognized.
This small study should therefore stimulate further studies along three paths. One would be to test the robustness of the association of ultimatum game offers with metabolic syndrome cross-culturally, the other to design and standardize a set of tests to cover a wider variety of behaviors that could be markers of metabolic syndrome, and the third to test whether the set of behavioral differences can predict the development of metabolic syndrome disorders in longitudinal studies.
A number of other behavioral differences between diabetics and nondiabetics are expected but have not been tested. These include physical risk taking, readiness for adventure, and tolerance to physical discomfort. Specific situational tests need to be designed where there can be two alternative solutions possible for solving a given problem, one involving physical aggression and the other involving social manipulation. The prediction of course is that diabetics would avoid the soldier solution and prefer a diplomat solution.
If these tests demonstrate a behavioral difference, the question of cause–effect relationship would still remain. Are the behavioral differences caused by diabetes or are these behaviors a risk factor for diabetes? This question can only be answered through longitudinal studies where a series of behavioral studies are performed on a cohort, and the cohort is then monitored for several years to see who develops insulin resistance or related phenomenon.
Leaving the question to researchers of whether diabetics differ from nondiabetics in behavior and whether behavioral differences precede or follow diabetes, I would now proceed to reframe the central concept of the new paradigm of T2D in a slightly different perspective and explore the possibility that the concept is much broader and goes beyond T2D and encompasses a wider range of disorders, particularly the ones that have become common suddenly with modern urban lifestyle. The broader concept can be called behavioral deficiency disorders. The mainframe argument of behavioral deficiency disorders goes in the following sequence:
1.
We evolved as hunter-gatherers, and a number of behaviors evolved with us as adaptive behaviors for a hunter-gatherer life.
2.
Every behavior is linked with some neuroendocrine pathway(s).
3.
Therefore chronic deficiency of particular behaviors can affect specific neuroendocrine pathways affecting its downstream links and thereby eventually leading to endocrine, metabolic, immunological, and other functional disorders.
4.
Just as dietary deficiencies are best treated with dietary supplementation, the best treatment for behavioral deficiencies would be behavioral supplementation.
Traditional medicine identifies many different types of dietary deficiencies, but the concept of behavioral deficiencies is nonexistent in current medicine. Much is talked about Paleolithic diet, but the importance of Paleolithic behavior remains largely unrecognized. This should not be too surprising because of two main reasons. One is that epidemiologically behavioral deficiency disorders appear to have become common fairly recently. Most of the disorders that we will list below as possible behavioral deficiency disorders have suddenly become common throughout the world in the last 2–3 generations, and their prevalence is rapidly on the rise. This is because it is only the modern urban life which has created these deficiencies. So it is only recently that any serious research could focus on these. In comparison, dietary deficiencies have been with us for a few thousand years, perhaps beginning with agriculture. As a result research on dietary deficiencies has a much longer history. Also the concept of relation of diet with health is very old although specific vitamins and other essential nutrient deficiencies and their effects were discovered only in the last two centuries. The other reason for the failure to identify behavioral deficiency disorders is the Cartesian body–mind division implicit in medicine. Behavior is thought to be more related to the mind than the body. The “mind” is rarely a part of research of biochemists. Psychiatry deals with the mind and brain, but it becomes active only when there is a perceived “behavioral disorder.” The behavioral disorders handled by psychiatry are rather extreme cases and have always been treated as “defects.” As a result the behavior–biochemistry connection in normal life has been largely neglected. Behavioral ecologists on the other hand could have been quicker to make these connections, but they never consider medicine as their field. This segmentation of science and the extremely myopic view in each segment have prevented science from identifying the logical and obvious possibility of behavioral deficiency disorders.
I have so far discussed T2D, hypertension, hypercholesterolemia, atherosclerosis, and CVD typical of the modern lifestyle as behavioral deficiency disorders, although I did not use this word so explicitly before. All the details that were discussed in the last few chapters can be summarized in this new phrase: behavioral deficiency disorder. We have seen the pathways by which deficiency of soldier behaviors can lead to some of the typical modern “lifestyle” disorders. This may not be a complete list. This is only a beginning of a new concept which we may expect to develop further with more research inputs.
The list of behavioral deficiencies that I can currently identify can be summarized by the acronym PARALISIS, summarizing deficiencies of (1) physical aggression; (2) agility and rapid action; (3) romantic love, sex, and reproductive functions; (4) adventure; (5) exposure to the little creatures around; (6) injury proneness; (7) serenity and solitude; (8) intellectually intensive activities; and (9) sun, heat, and other skin exposures.
1.
Physical aggression: Through the entire book, we have been looking at what the deficiency of physical aggression can cause. Almost the entire pathophysiological picture of T2D can be explained by deficiency of physical aggression. But how and when did we develop this deficiency and why are its effects apparent only in the modern urban lifestyle?
It is not difficult to perceive that until modern times, the importance and frequency of aggressive neuromotor actions have not changed in human history in spite of going through major transitions such as hunter-gatherer to agricultural and agricultural to urban life. Unlike many popular perceptions, hunter-gatherer life is not full of violence. Most hunter-gatherer societies are generally peace loving with occasional intergroup tensions and rarely actual wars. The main aggressive neuromotor actions are not because of wars, they are most frequent during day-to-day foraging. Both hunting and gathering have aggressive neuromotor actions. Aggression in hunting does not need any elaboration, but gathering exercises also involve digging, cutting, throwing, and other aggressive actions. Other day-to-day maintenance activities such as cutting wood for fire, mending houses, and making tools also involve a number of aggressive actions. This did not change with agriculture. Even in a peaceful agricultural society, aggressive actions are involved in digging, cutting, driving animal-drawn carts, controlling animal herds, and driving away birds and nuisance animals like foxes and jackals. Even in urban life, as long as there was the use of firewood, wood cutting was necessary. Manual cutting, grating, dough mixing, and other cooking preparations did involve aggressive neuromotor actions. Whether good or bad, punishing a child with a quick spank was a routine. The games children played were more of rough and tumble type. Social signaling among friends could easily involve some aggressive actions like a forceful stroke on the back or a mild punch on the arm.
All these mild and minimum aggressive actions are also lost in the modern mechanized, mannerized, automated, and comfortable urban life. Modern life is not free of violence, but modern violence too is aggression deficient. Pulling the trigger of a revolver and pressing a button of a remote control bomb are examples of nonaggressive violence. Even spanking our own children has vanished from our lives now. The nature of games that children play has also changed substantially. Parents are overanxious that their kids do not engage in aggression even while playing. The disappearance of aggression at an early age may be one of the reasons why T2D and other disorders have started appearing at an earlier age now. Aggressive actions have almost disappeared from social signaling as well since they are being considered increasingly uncivilized. This is where extreme deficiency of aggression accumulated over decades of life might start showing its effects. If this is true, then participation in even mildly aggressive exercises or sports would be able to prevent most of the modern lifestyle disorders. Unfortunately sports have become a specialist and highly competitive activity. It has not remained a frequent and casual activity. Parents like their kids to participate in some sport only to excel. While excelling is good, the other side of the coin is that it discourages a larger proportion of individuals who do not excel. So a very small proportion of youngsters actively engage in sports, others remain passive spectators.
2.
Agility and rapid action: We talked a lot about aggression since there are substantial data on the physiological effects of aggression. That does not mean that aggression is the only or the most important behavioral deficiency. A number of others are indicated here about which there is suggestive evidence, but researchers have mostly neglected them mainly owing to the lack of a paradigm that recognizes their importance. But the difference between a soldier and diplomat lifestyle is not restricted to the presence and absence of aggression. There are a number of other components of soldier life that may be equally important.
Rapid action is one such possibility. Although very little research has gone into it, there is a demonstration that hyperinsulinemia is associated with downregulation of quick preattentive neuronal responses and enhancement of some of the slower cognitive responses [20]. This is clearly a soldier–diplomat difference. Rapid and complex nerve–muscle coordination (NMC) action is required in hunting, fighting, or explosive sports. The cerebellum is responsible for such coordination. There is some evidence indicating that the neurodegenerative changes in the aged individuals are more due to cerebellar degeneration than cortical degeneration [21, 22]. This might mean that deficiency of complex NMCs is the ultimate cause of neurodegenerative disorders. This is currently only a speculation but it looks promising and warrants research.
3.
Romantic love, sex, and reproduction: Although romantic love, sex, and reproduction have very different connotations, they form a continuum, and therefore, here we group them together. Romantic love increases NGF levels, and NGF deficiency is one of the important contributors to degenerative nerve disorders. Affectionate body contact behavior stimulates oxytocin release which is believed to be a stress-protecting hormone. We have noted before the many protective effects of male and female sex hormones against oxidative damage, apoptosis, and many of the diabetic complications [23–26]. Mating is shown to upregulate BDNF in the brain [27]. In females, EGF levels go up in pregnancies and remain higher than baseline after pregnancy as well [28]. Thus there are many indications that the trio of romantic love, sex, and reproduction has a number of beneficial effects on health. It is also known that castration induces obesity and insulin resistance in rats [29, 30]. Many contraceptive measures are known to have components of metabolic syndrome as their side effects [31, 32]. But whether the altered nature of love, sex, and their relevance to reproduction in the modern society has anything to do with the cluster of modern diseases is an open question so far largely ignored by the scientific community.
4.
Adventure: Voluntarily participating and enjoying an activity involving potential physical risk is adventure. The words “physical risk” are important since it necessarily excludes metabolically risky behaviors such as alcoholism or smoking. It also excludes social or business risks. Adventure is another behavior differentiating soldier life from diplomat life. Again there is little research on the metabolic or endocrine effects of adventure except the demonstration that adventure triggers NGF secretion. NGF can effectively prevent neurodegenerative disorders, and therefore, there can be a strong connection between adventure and long-term health. Interestingly, in one study, not only participation in adventure but even the thought of participating in adventure triggered salivary NGF secretion [33]. Unfortunately this study does not estimate other growth factors. NGF is most likely to have an adaptive role in adventure since adventure anticipates injuries and NGF is necessary for regeneration and healing. By the same logic, adventure should also trigger other growth factors such as EGF. Since both aggression and adventure anticipate injuries, many of their immunologic and metabolic effects could be similar. But this has not been tested so far. Again this is not at all difficult to test, just that the paradigm was absent, and so researchers did not think of looking at it.
5.
Little creatures around: One major deficiency of modern urban life is contact with a wide variety of small and large creatures including microbes, animals, and plants. This contact certainly affects immunity and may also influence many other aspects of physiology.
Growing evidence suggests a role of intestinal bacterial flora in obesity [34–37]. This parallels the effects of intestinal microorganisms on brain and behavior. Although surprising at the first glance, there is good evidence that intestinal bacteria affect emotional behavior and central GABA receptor expression [38]. It would not be surprising if it is not a one-way traffic. I would expect behavior to affect intestinal flora too since behavior affects immunity in many ways (Chaps. 8 and 11), and mucosal immunity is likely to be a critical determinant of the resident flora. Thus, the 4 Bs, namely, brain, behavior, BMI, bacteria, could be in a complex interacting loop that we have not sufficiently understood as yet, but there is strong evidence pointing in that direction.
Allergic diseases including asthma or hay fever are less common in a farm environment than in an urban environment [39–44], and this is most likely to be an effect of early life exposure to common microorganisms associated with soil and animals. Early life overexposure to antibiotics also increases the risk of asthma [45]. There is a widely discussed and debated “hygiene hypothesis” which states that early life exposure to a diversity of microorganisms is protective against allergic diseases, and the current increase in the incidence of allergies and asthma is a product of growing in a too hygienic environment. Substantial data support the hygiene hypothesis, although the mechanisms are debated [46–50]. Even type 1 diabetes is included under the hygiene hypothesis by some [51]. There are possible links with type 2 diabetes as well. Arthropod bites and stings have anti-inflammatory properties. I suspect them to be immune redistributors rather than being anti-inflammatory. Frequent exposure to insect bites is likely to drive the innate immune cells peripheral thus ameliorating one of the main pathophysiological processes of T2D (see Chap. 8).
Why do I call deficiency of exposure to the natural biota a behavioral deficiency rather than an environmental factor? The reason is simple. Soil and its microbial and insect flora are generally abundant everywhere even in urban environments. However, people’s attitude to look at it is widely different. Playing in mud could be a routine for farmers’ children, while in urban culture, typically, mud is treated as dirt and children are discouraged from playing in it. This is a behavioral rather than environmental difference.
6.
Injury proneness: We have already argued before that anticipation of injuries by aggression or adventure stimulates EGF and NGF secretion [52–55]. In addition there can be proneness to injuries independent of both aggression and adventure. Simply walking through a dense forest or thorn scrub that involves neither, one can get many minor pricks and scratches on the skin. Traditional cooking also involves frequent minor injuries. These minor injuries attract innate immune cells of the body and help normalize their distribution within the body. They also stimulate the expression of PPARs and some of the growth factors that have effects on insulin and insulin sensitivity. A major change in the frequency of minor injuries characterizes modern urban life. Again we do not have studies to evaluate to what extent this actually matters.
7.
Solitude and serenity: We have seen that population density and its perception affect aggression, social behavior, and reproductive behavior. In a hunter-gatherer society, one is exposed to the wilderness, vast expanses of forest, grassland, deserts, or the sea very frequently and often alone. This happens very rarely in modern urban life. The feeling of being in a serene environment has a number of perceivable effects on feelings and mood, and therefore, it is likely that it has many effects on the endocrine states as well. This appears to have never been studied since the paradigm was nonexistent. There is some literature on loneliness where it is perceived as an entirely negative emotion and a stress [56]. The endocrine effects of an enjoyable and tranquil state of solitude have seldom been studied. I would expect that solitude upregulates adiponectin since adiponectin is a marker of r reproductive strategy. But there can be many other prohealth effects of solitude, and it remains an unexplored area of research.
8.
Intellectually intensive activities: A lot has been talked about the importance of physical exercises. I would like to suggest here that intellectual exercises are equally important. As there has been a reduction in total physical activity with modern urban lifestyle, there is also a reduction in brain activity. A substantial part of the brain work is reduced with reduction in complex nerve muscle coordination activity. The typical hunter- or soldier-related brain activities such as mental mapping and spatial cognition are also reduced substantially. In the soldier to diplomat transition, it is expected that this loss is made up by increase in cognitive activities. In modern life reliance on electronic devices has taken off some of the cognitive activities as well. A reduction in the total brain activity is likely to result into downregulation of glut-1 in the brain capillaries leading to hyperglycemia. It is also possible that NGF and BDNF are downregulated in an inactive brain. These possibilities have not been tested.
9.
Sun, heat, and other climatic exposures: The story of sunlight and vitamin D is well known. Wide cultural differences exist in the perception about exposure to sunlight. Generally people living in cold climates welcome a sunny day and enjoy sunbathing. In tropical countries, there is a reverse trend. In tropical urban environments, avoiding direct exposure to sun has reached such an extreme that there is a paradoxical deficiency of vitamin D in the sunniest places [57–60]. This again is clearly a behavioral rather than environmental deficiency.
The above list of PARALISIS deficiencies is perhaps incomplete. For many, the nature of evidence is currently only suggestive, and therefore, some of them remain only speculations. But speculations stimulate research and therefore need to be respected, simultaneously understanding their limitations. The question to ask further is that if these are the deficiencies, what are the possible disorders caused by these deficiencies and what are the pathways connecting them. We will obviously not talk about T2D and CVD anymore. A number of other diseases that can be primarily behavioral deficiency disorders are as follows:
1.
Cancer: It is well known that cancer cells arise by somatic mutations. However, a single mutation may not be sufficient to make a cell malignant. More than one mutation is involved in carcinogenesis. Since mutation is a rare event, occurrence of many specific mutations that turn a cell cancerous must be extremely unlikely. This is like an old evolutionary debate. A complex structure such as the eye cannot arise by a single mutation. There need to be a series of mutations before a fully functional eye can evolve. This example was used as a procreationist or intelligent design argument. Richard Dawkins and other Darwinians counterargued saying that even intermediate stages in eye development would serve as a primitive eye with a small selective advantage. A small selective advantage can increase the frequency of the primitive eye phenotypes. This forms the platform for further rare beneficial mutations. Since selection is coupled with mutations, the impossible-looking combination of rare mutations can actually materialize. It is likely that the case with cancer is similar. A common feature of a range of carcinomas is abnormal expression of EGF receptor (EGF-R) [61–63]. EGF is an important growth factor for tissue regeneration [64, 65]. As long as EGF levels are normal, the tissue regeneration process will be normal. If a deficiency of EGF arises, the normal cell will have a reduced growth rate, and on this background, a mutant with abnormal expression of EGF-R or autoactivation of EGF-R will get a selective advantage. Since EGF deficiency can arise due to behavioral deficiency, one of the causes of cancer can be behavioral deficiency. A strong support to the behavioral origins of cancer is given by the mice experiments in which mice living in an enriched environment showed reduced tumor growth as compared to mice in traditional cage, and this difference could not be accounted for by total physical activity alone [66]. These experiments monitored BDNF levels and correlated them with tumor suppression. Although these experimenters did not monitor EGF or NGF levels, other experiments have demonstrated that EGF and NGF together stimulate BDNF [67]. It is likely therefore that the difference in the mice in conventional cage versus enriched environment is driven by behavioral differences. Perhaps the link between behavior and cancer goes beyond EGF involving other growth factors and their receptors. The behavior-induced altered distribution of macrophages can affect angiogenesis mechanisms which are known to be important in tumor growth. In short there is sufficient evidence to suspect a link between behavior and cancer, and researchers need to explore this possibility seriously.
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