"Starve a fever and feed a cold": feeding and anorexia may be adaptive behavioral modulators of autonomic and T helper balance.

Anorexia is a common symptom accompanying infections, but the teleology of the phenomenon remains unexplained. We hypothesize that anorexia may represent a prehistoric behavioral adaptation to fight infection by maintaining T helper (Th)2 bias, which is particularly vital in fighting bacterial pathogens. Specifically, we propose that anorexia may avert the reduction of Th2/Th1 ratio by preventing feeding-induced neurohormonal and vagal output from the gut. Emerging evidence suggests that the vagal and neurohormonal output of the gut during feeding promotes Th1 function, which is desirable in fighting viral infections. Since fever may be an adaptation to fight bacteria and "colds" are generally viral in origin, the adage "starve a fever and feed a cold" may reflect a sensible behavioral strategy to tilt autonomic and Th balance in directions that are optimal for fighting the particular type of infection. The ability to modulate T helper balance through the neurohormonal and autonomic axis by adjusting food intake may be the mechanism behind other unexplained clinical observations such as the improved outcomes of ICU patients after enteric versus parenteric feedings. Compared to the prehistoric period when bacterial infection was commonplace, the anorexic response may be less adaptive today when viruses and cancers have become common triggers of anorexia. By promoting host anorexia, cachexia, and insomnia, cancers and viruses can deter behaviors such as digestion and sleep that would raise vagal and Th1 activity against tumors and viruses. Hydration and sleep, unexplained but widely accepted recommendations for flu patients, may also work by promoting vagal and Th1 functions. Modulating feeding, hydration, and sleep may prove beneficial in treating other conditions associated with abnormal autonomic and Th balance.

Clinical benefits of hydration and volume expansion in a wide range of illnesses may be attributable to reduction of sympatho-vagal ratio.

Hydration and volume expansion regimens are widely thought to offer symptomatic benefit in many human ailments. Many varied theories for the phenomenon exists such as decreased blood viscocity in cardiac disease, dilution of toxins in cancer, and cleansing effect on airways in asthma. While it is plausible that disparate mechanisms are involved in different conditions, we propose an alternative, unifying hypothesis that many of the clinical benefits of hydration and volume expansion are partly related to reduced sympatho-vagal ratio. Hypovolemia triggers baroreceptor-mediated sympathetic response and neurohormonal activation to promote fluid retention. Emerging evidence suggests that many diseases including cardiovascular, neurologic, gastrointestinal, metabolic, inflammatory, thrombotic, viral, and oncologic conditions are manifestations of abnormal sympathetic bias and associated T helper 2 bias. Hypovolemia-induced sympathetic activation, especially if baroreceptor dysfunction is involved, can worsen these conditions. Hydration and volume expansion may lower sympatho-vagal ratio, thereby tempering a wide variety of clinical conditions linked directly or indirectly to adrenergia including, but not limited to, acute coronary syndromes, asthma, cancer, and stroke. Interestingly, isotonic or hypertonic hydration, rather than a low-salt diet, may be a counterintuitive potential strategy to treat some cases of hypertension associated with dehydration and autonomic dysfunction. In contrast to the putative causal relationship between them, perhaps hypertension and end-organ damage represent independent consequences of dysfunctional sympathetic and neurohormonal activation. Venipuncture enables faster volume expansion but may also be a source of sympathetic hyperactivity. Oral hydration may additionally promote vagal tone by triggering gastric distension, a benefit not offered by intravenous fluids. The empiric benefits of hydration and volume expansion portend novel methods to treat a wide range of clinical conditions through pharmacologic or electrical modulation of cardiovascular or gastrointestinal baroreceptors.

Pineal attrition, loss of cognitive plasticity, and onset of puberty during the teen years: is it a modern maladaptation exposed by evolutionary displacement?

Cognitive plasticity, a developmental trait that promotes acquisition of complex skills such as language or playing musical instruments, diminishes substantially during puberty. The loss of plasticity has been attributed to surge of sex steroids during adolescence, but the phenomenon remains poorly understood. We hypothesize that pineal involution during puberty may contribute to plasticity decay. The pineal gland produces melatonin, the level of which declines dramatically during onset of puberty. Emerging evidence suggest that melatonin may modulate cognitive plasticity, independent of the effects of sex steroids, and low sex steroids and high melatonin may be simultaneously required to maintain cognitive plasticity. Potential mechanisms by which melatonin may modulate plasticity are examined within the sleep and hippocampal long-term potentiation frameworks. Implications for psychiatric conditions that involve sleep disorders and learning dysfunctions such as schizophrenia and autism are discussed, and the potential adaptive roles of postprandial and postcoital sleep are explored. From the Darwinian perspective, development and reproductive maturity may represent distinct phases that require tailored cognitive strategies to maximize fitness. While cognitive flexibility and susceptibility to new skills may be paramount during development, reduced cognitive flexibility and increased cognitive determinism may enable more efficient responses to stimuli during adulthood. Thus, cognitive plasticity and cognitive determinism may represent trade-off adaptations and different dimensions of intelligence. The decline of plasticity and emergence of puberty during the second decade may be relics of prehistoric times when the human lifespan was short and the environment was relatively simple and static. Today, when the environment is more complex and dynamic, and humans are living far longer, the early obsolescence of plasticity during puberty may represent a Darwinian inefficiency exposed by evolutionary displacement. Regulation of plasticity may be a systemic phenomenon, as exemplified by the association of learning disability with allergic conditions, a form of immune plasticity dysfunction. Ramifications for other plastic functions that decline during puberty such as wound healing and hyaline cartilage regeneration are explored. Like the plasticity of immunity and cognition, the plasticity of hyaline cartilage during youth may enable hosts to respond to ecologic opportunities and generate the optimally adapted adult phenotype. Pineal involution may represent a potential target for therapeutic extension or restoration of plasticity after puberty. Extending plasticity may have far-reaching consequences for human evolution.

Debunking a myth: neurohormonal and vagal modulation of sleep centers, not redistribution of blood flow, may account for postprandial somnolence.

It is widely believed that postprandial somnolence is caused by redistribution of blood flow from cerebral to mesenteric vessels after a meal. This belief persists despite its apparent contradiction with a well-known neurophysiologic principle that cerebral perfusion is preferentially maintained under a wide range of physiologic states. For instance, during exercise when a large amount of perfusion is diverted to muscles, blood flow to the brain is maintained. Furthermore, recent evidence suggests that there is no measurable change of blood flow in the common carotid artery during postprandial states. We propose an alternative hypothesis that postprandial release of gut-brain hormones and activation of vagal afferents may play a role in postprandial somnolence through modulation of sleep centers such as the hypothalamus. Feeding alters the milieu of hormones such as melatonin and orexins and also promotes central vagal activation. Emerging evidence suggest that these pathways are also modulators of neural sleep centers. Potential adaptive explanations of postprandial somnolence are explored from a Darwinian perspective.

Maldaptation of the link between inflammation and bone turnover may be a key determinant of osteoporosis.

Currently the etiology of osteoporosis is attributed to various endocrine, metabolic, and mechanical factors. We hypothesize that many cases of osteoporosis are also partially attributable to a maladaptation of the link between inflammation and bone turnover. We explore the spatial and temporal link between inflammation and osteoporosis in conditions such as aging, menopause, reflex sympathetic dystrophy, HIV, pregnancy, transplantation, and steroid administration. While nutritional and mechanical factors clearly play a role in many of these situations, the spatial and temporal concordance of osteoporosis and inflammation is buttressed by emerging molecular evidence. Modern bone biology of humans may reflect dual functional legacies of mineral storage and structural support. Osteoporosis may result from disequilibrium between structural demand for key minerals and their biologic demand during maladaptive states of inflammation.

Modulation of autonomic balance by tumors and viruses.

Autonomic balance, a function generally under host control, is subject to modulation by other signalers. In some cases, modulation of host autonomic function through behavioral and physical stressors exerted by another individual may have negative consequences for the stress recipient by inducing sympathetic bias. Modulation of autonomic function may sometimes benefit one party at the expense of another. Tumors and HIV are examples of illegitimate signalers who may induce host sympathetic bias to promote their own growth and evade host immune surveillance. Paraneoplastic and paraviral syndromes such as hypertrophic osteoarthopathy, QTc prolongation, insomnia, and cachexia could be viewed as epiphenomena related to the tumoral and viral manipulation of host autonomic balance. In a more general framework, other paraneoplastic and paraviral syndromes may represent epiphenomena related to modulation of endocrine, cytokine, and autonomic functions by tumors and viruses to promote their own survival. Spatial distribution of cancers and viruses within the host may reflect affinity for strategic locations that facilitate manipulation of a variety of host functions including autonomic, endocrine, and cytokine regulation. A more general for understanding spatial distribution of diseases based on gradients of autonomic balance in the body are explored. Darwinian perspectives are discussed.

Hypertrophic osteoarthropathy may be a marker of underlying sympathetic bias.

Hypertrophic osteoarthropathy (HOA) is a condition that accompanies many seemingly unrelated diseases. It is commonly associated with various clinical conditions such as pregnancy, aging, pulmonary diseases, cancers, and other systemic illnesses. The condition has been attributed to various causes such as platelet abnormalities, hormonal disturbances, and cytokine dysfunction, but the exact underlying mechanism has been elusive. We propose a unifying hypothesis that activation of the adrenergic system is the common thread that links all of the disparate clinical associations of hypertrophic osteoarthropathy. In diseased states, autonomic stimulation may occur as a result of chemoreceptor activation in response to acidosis, hypoxia, or hypercapnia. Examples include sleep apnea, congestive heart failure, renal failure, and tumor-induced hypoxia. In this setting, clinical signs of HOA may be a marker of underlying autonomic dysfunction. Autonomic stimulation may also occur as a normal part of pregnancy or as an abnormal component of aging. The exact pathway linking adrenergic excess to HOA remains to be clarified, but a plausible scenario based on current molecular evidence is offered.

Modulation of host immunity by HIV may be partly achieved through usurping host autonomic functions.

Modulation of host immunity has been observed in human immunodeficiency virus (HIV) infections. HIV is believed to influence host immunity through a variety of mechanisms including direct effects on host T cell survival, indirect effects on cytokine profile through modulation of immune cells, and modulation of endocrine functions that affect immunity such as steroids. We hypothesize that HIV infection may also alter host immunity through modulation of host sympatho-vagal balance. Specifically, we propose that HIV drives autonomic balance towards sympathetic bias, which can contribute to a T helper (Th)2 type immunity. A variety of paraviral syndromes associated with HIV infection such as QT prolongation, cachexia, cardiomyopathy, and lipodystrophy are consistent with evidence of autonomic dysfunction. Immunomodulatory effects of autonomic dysfunction toward Th2 bias are presented. A plausible mechanism by which HIV can influence autonomic balance through hypothalamic manipulation is offered. Shift to Th2 dominance is associated with HIV disease progression and can be viewed as a viral adaptation to promote its own survival. Autonomic remodeling by HIV may exemplify this phenomenon. Our hypothesis has implications for treatment of HIV and its associated syndromes.

Temporal variation of autonomic balance and diseases during circadian, seasonal, reproductive, and lifespan cycles.

Many diseases show patterns of temporal variation that remain unexplained. We hypothesize that oscillation of autonomic balance over different time intervals plays a role in these variations. In the Darwinian struggle, organisms must perform various functions related to fitness such as survival, energy acquisition, and reproduction in a prioritized fashion. Autonomic systems enable differential allocation of effort to various functions under different conditions, some of which vary in patterns that are predictable such as circadian, menstrual, seasonal, and life cycles. For many species, daytime functions such as seeking food and avoiding predators are achieved with sympathetic activity while night-time functions such as internal processing are achieved with parasympathetic activity. For organisms that maintain thermal homeostasis year-round, cooler temperature seasons may demand sympathetic bias to drive adaptive thermogenesis. Reproduction may necessitate autonomic shift to sympathetic bias during the luteal phase and pregnancy to modulate immune balance towards a more tolerant Th2 bias. Many diseases including infectious, cardiovascular, inflammatory, pulmonary, metabolic, fertility, oncologic, and neurologic conditions also show variation in prevalence over these cycles. The co-variation of autonomic balance and diseases over time intervals suggests that autonomic balance, by its direct effects as well as its indirect effects through modulation of T helper immune balance, plays an under-recognized role in diseases. The theory is extended to the co-variation of autonomic balance and diseases over the lifespan. Termination of organisms during senescence, achieved by emergence of autonomic imbalance and other systemic dysfunctions, is explored from a Darwinian perspective.

Menstrual variation of autonomic balance may be a factor in exacerbations of certain diseases during the menstrual cycle.

Exacerbation of certain medical conditions during specific phases of the menstrual cycle has long been recognized. Mechanisms of the cyclic variations are poorly understood, but are often attributed to fluctuations in reproductive hormones. We hypothesize that normal variations in autonomic balance during the menstrual cycle, which likely evolved as adaptations for reproduction, may contribute to catamenial variations in diseases independent of hormonal variations. Emerging evidence suggests that autonomic balance shifts towards sympathetic bias during the second half of the menstrual cycle. This shift can be seen as an evolutionary adaptation to address the immunologic and physiologic demands for successful implantation and gestation. Through direct modulation of lymphoid system and activation of the cortisol pathway, sympathetic bias promotes a shift to relative T helper (Th)-2-biased immunity which may favor maternal tolerance of the embryo by attenuating Th-1-mediated interference of implantation. Immune variance during the menstrual cycle has been implicated in menstrual fluctuations of many diseases, but until now the immune variance has been attributed to female hormonal changes. We propose that shifts in autonomic balance independently contribute to fluctuations in diseases by modulating the immune system. Still further, we propose that many other diseases fluctuate due to the direct nervous system actions of shifts in autonomic balance. Our hypothesis portends new therapeutic paradigms based on cyclical modulation of autonomic balance to address catamenial variations of medical conditions.

Immunomodulatory function of seminal catecholamines may be an adaptation for reproduction.

Catecholamines are found at high concentrations in seminal fluid. The exact functional significance of seminal catecholamines is unknown. We hypothesize that seminal catecholamines perform important immunomodulatory functions that support reproductive success. Specifically, we propose that catecholamines contribute to a local adaptive shift of T helper (Th) balance to Th2 dominance in the maternal reproductive tract to enable the gametes, and possibly the nascent zygote, to evade immune surveillance of the female. Our hypothesis suggests that the Th2 effects of catecholamines are independent of the direct immunomodulatory effects of seminal cytokines such as prostaglandin E2 and transforming growth factor beta1. Potential immunomodulatory functions of other seminal constituents such as aldosterone, oxytocin, vasopressin, and angiotensin remain unexplored and represents a topic of future interest. Seminal stress hormones may play a role in mating dynamics since alpha males typically live in a state of high hormonal stress, Mating with adrenalized alpha males may represent an adaptive Darwinian strategy by females to maximize their reproductive fitness.

Autonomic dysfunction may be an under-recognized cause of female fertility disorders.

Female conditions of impaired fertility comprise a heterogeneous group of disorders that are attributed to various anatomic, hormonal and immunologic disturbances. We hypothesize that autonomic dysfunction may be a previously unrecognized factor in female fertility disorders. Emerging physiologic and molecular evidence suggests that autonomic balance varies during normal menstrual cycles with a shift to sympathetic bias during the luteal phase. Furthermore, many diseases associated with autonomic dysfunction show catamenial variations in patterns consistent with a shift to sympathetic bias occurs during the second half of normal menstrual cycles. The shift to sympathetic bias during the normal luteal phase may be an evolutionary adaptation to address the immunologic and physiologic demands for successful implantation and gestation. Through direct modulation of the lymphoid system and activation of the cortisol pathway, sympathetic bias promotes a shift to relative T helper (Th)-2 biased immunity which may favor maternal tolerance of the embryo by attenuating Th-1 mediated interference of implantation. Indeed, a growing body of evidence has implicated abnormal Th balance in fertility disorders, but the link has been attributed to factors other than autonomic function, such as hormonal factors. After implantation, maternal sympathetic bias may further support gestation through physiologic changes necessary to maintain placental perfusion pressure. We propose that insufficient shift to sympathetic bias during the luteal phase, which manifests in inadequate shift towards Th-2 bias and down-regulation of Th-1 function, may be the mechanism of impaired fertility in certain patients. Our hypothesis portends new potential methods to treat fertility disorders by modulating autonomic balance.

Many diseases may reflect dysfunctions of autonomic balance attributable to evolutionary displacement.

We hypothesize that many ailments are attributable to dysfunctions of autonomic balance. The autonomic system is a primitive, highly-adaptive response system that allows differential allocation of biologic effort under varying conditions. The autonomic system, however, can execute a response that is inappropriate for the system stressor due to evolutionary displacement. Evolutionary displacement is a situation in which a trait that evolved as an adaptive response to certain conditions now faces a new set of conditions. Modern human evolution since the Pleistocene era is characterized by substantial evolutionary displacement, brought on in large part by the accelerating ability of humans to change their own environment. In the setting of evolutionary displacement, previously adaptive systems such as the autonomic system can be rendered unhelpful or even counterproductive. Emergence of chronic conditions, maladaptation of the trauma response, and extension of human lifespan are examples of evolutionary displacements that can induce inappropriate sympathetic bias in hosts. We postulate that many diseases are manifestations of this general phenomenon. Implications for existing and future therapeutic strategies are discussed.

Autonomic dysregulation as a basis of cardiovascular, endocrine, and inflammatory disturbances associated with obstructive sleep apnea and other conditions of chronic hypoxia, hypercapnia, and acidosis.

Obstructive sleep apnea has traditionally been viewed as a structural disease. A multitude of systemic endocrine and cardiovascular abnormalities have been previously attributed to the prevalence of obesity in these patients. A growing body of clinical evidence, however, points to a relationship between sleep apnea and its systemic abnormalities independent of obesity. We hypothesize that this association is based on a maladaptive autonomic response of chemoreceptors, reacting to the hypoxia, hypercapnia, and acidosis of sleep apnea. The elevated sympathetic response triggers an inflammatory cascade that results in a myriad of downstream consequences including insulin resistance, hypertension, diabetes, atherosclerosis and metabolic syndrome. The sympathetic bias and endocrine disturbances may further exacerbate sleep disturbance in a potentially pernicious cycle. Our proposal may extend to any chronic respiratory or metabolic conditions that manifest hypoxia, hypercapnia, and acidosis and elicit a maladaptive autonomic and inflammatory response.

Acute coronary syndromes and heart failure may reflect maladaptations of trauma physiology that was shaped during pre-modern evolution.

We hypothesize that the pathophysiology of many cardiovascular diseases reflects a maladaptation of the triad of trauma response: adrenergia, inflammation, and coagulation. During biologic evolution, trauma has likely been a prevailing factor in natural selection. Components of the trauma triad act to limit hemorrhage, defend wounds against microorganisms, and initiate reconstruction. Response pathways that enable survival after trauma confer obvious adaptive advantages especially if the individual goes on to reproduce. Modern humans have shaped their own ecologic environment in such a way that the incidence of trauma has waned and previously unseen pathologies have emerged. Manifestations of modern diet, changing lifestyles, and extended lifespan have suddenly created new pathologic challenges to our prehistoric physiologic system. During our evolutionary heritage, endothelial injury and end-organ hypoxia were likely exclusively associated with physical trauma and the responses of the trauma triad were appropriate. Today, endothelial injury is more often precipitated by distinctly modern stressors such as hypertension, smoking, diabetes, and dyslipidemia. The once-adaptive trauma response can maladaptively initiate dangerous, self-propelling cycles of adrenergia, inflammation, and coagulation. Acute coronary syndromes perhaps best exemplify this phenomenon. Congestive heart failure, which often ensues, can similarly be seen as a maladaptation of the trauma triad. Whereas end-organ hypoxia was once commonly associated with trauma, now hypoxia is more often attributable to distinctly modern stressors such as pump failure. The fluid conservation and inflammation that results from the trauma triad was clearly adaptive in our prehistoric past, but in congestive heart failure the response is maladaptive, engendering self-propelling exacerbations of pump failure and vascular disease. Our maladaptive trauma response hypothesis portends new diagnostic and therapeutic paradigms for cardiovascular diseases and has ramifications for many other conditions such as stroke, venous thrombosis, vasculitis, aortic disease, arterial disease, pulmonary embolism, and restenosis.

Conditions of aging as manifestations of sympathetic bias unmasked by loss of parasympathetic function.

We propose a unifying hypothesis that many clinical consequences of aging are pleiotropic manifestations of the loss of parasympathetic function that occurs during post-reproductive senescence. The loss of parasympathetic function unmasks the baseline sympathetic bias inherent in the end-organs, resulting in the familiar signs of aging including tachycardia, constipation, insomnia, erectile dysfunction, fluid retention, and systemic inflammation. These consequences in turn may contribute to many of the common diseases associated with aging including type-2 diabetes, Alzheimer's, atherosclerosis, and cancer. Maintenance and restoration of parasympathetic function may enable upstream control over the deleterious aspects of inherent end-organ adrenergic bias.