REVIEWS PHYSIOLOGY 31: 392–397, 2016. Published October 5, 2016; doi:10.1152/physiol.00013.2016 Evolutionary Medicine: The Ongoing Evolution of Human Physiology and Metabolism The field of evolutionary medicine uses evolutionary principles to understand Frank Rühli,1 Katherine van Schaik,1,2 and Maciej Henneberg1,3 1 Institute of Evolutionary Medicine, University of Zurich, Zurich, Switzerland; 2Harvard Medical School and Harvard Department of the Classics, Harvard University, Cambridge, Massachusetts; and 3Adelaide Medical School, The University of Adelaide, Adelaide, Australia frank.ruehli@iem.uzh.ch changes in human anatomy and physiology that have occurred over time in response to environmental changes. Through this evolutionary-based approach, we can understand disease as a consequence of anatomical and physiological “trade-offs” that develop to facilitate survival and reproduction. We demonstrate how diachronic study of human anatomy and physiology is fundamental for an increased understanding of human health and disease. Adaptations of the Human Body Humans are animals, and, like the animals we study, we possess bodies that change in response to the features of our external and internal environments. We have done much to affect our interactions with these environments: we have insulated our bodies from climate, produced and chemically processed our food (for example, through fermentation or additives), removed much of the disease causes we might encounter (for example, parasites and bacteria), and, with the help of technology, have learned to repair our bodies (prosthetics) to increase our physiological performance both physically (eyeglasses and hearing aids) and mentally (medications to enhance concentration). Although it may sometimes be difficult to identify precisely the nature of the relationship between our environments and our bodies, and to demonstrate why and how the human body changes, we can at least observe how it has changed over the last few millennia. A classic example of the relationship between health and the evolution of the human body involves osteoarthritis and the development of erect bipedal locomotion. Progressive degenerative arthritic changes in the spine and lower limb are a biomechanical consequence of upright posture and locomotion (2, 20, 23). Another relatively more recent example of human evolution, the appearance of multiple renal arteries and veins, involves modern populations rather than past populations. It suggests that there are now, more so than in the past, alterations of embryonic development that affect the ascent of the kidneys from their initial position (31). Changes in macroscopic traits over time can be studied through examination of skeletal human remains, mummies, the fossil record, and patient’s records and images. Furthermore, such changes at the macroscopic or morphological 392 level could reasonably be assumed to mirror changes at the microscopic or metabolic level. For example, micro-evolutionary trends of human hormones and their impact on human morphology have already been proposed (27, 28). Evolution of various biological characteristics proceeds at various rates in various populations in different periods. The direction and speed of such evolution depend on disturbances in homeostasis. Although mutations occur at fairly stable rates, natural selection, especially in its purging form, is becoming relaxed as a result of decreasing mortality and controlled fertility (30). The relationship between evolution and human physiology-and the evidence that evolution continues to affect human physiology—means that research in physiology should engage with evolutionary perspectives and hypotheses. This paper highlights important evolutionary alterations of human physiology, both in the past and in the present, a topic that is a core part of the interdisciplinary research field of evolutionary medicine (also called Darwinian medicine). Study of the formation of human physiology in the past yields a clearer understanding of the etiology of many current challenges to human health and wellness (FIGURE 1). Furthermore, study of the evolution of disease could facilitate improved methods to address these challenges, from the research bench, to the patient’s bedside, to the offices of lawmakers seeking improved public health strategies. Evolutionary Medicine and Selected Physiological Processes Evolutionary medicine has been defined as a research field applying evolutionary principles to understand human health and disease, and the mechanisms that change health and disease over time (32). Its theoretical concepts are primarily based on established and well known principles 1548-9213/16 ©2016 Int. Union Physiol. Sci./Am. Physiol. Soc. Downloaded from journals.physiology.org/journal/physiologyonline (054.163.042.124) on May 27, 2020. REVIEWS and terminology used in evolutionary biology and genetics. These include major forces of evolution: mutations, natural and sexual selection, inbreeding, assortative mating, gene flow, and genetic drift. Also relevant for evolutionary medicine are the effects of epigenetic and physiological adaptability to general and local environmental factors. Human anatomy and physiology are regarded as evolutionary trade-offs, consequences of adaptation of the human body to its living circumstances. The goal of evolutionary medicine studies is to use this evolutionary biology-based framework to decipher both proximal and ultimate causes of alterations in human health and disease. There are many examples of studies that address the relationship between evolution and physiological processes, including research about functional alleles. For example, the persistence of lactase in adults is a result of the relatively recent dependence of some human populations on unprocessed milk (34). Other studies have suggested that the number of amylase gene copies increased as a result of agricultural production supplying abundant complex carbohydrates (24). The relationship between hemoglobinopathies and exposure to malaria is well known (26). Additional examples that illustrate the relationship between evolution and physiological processes are human adaptations in oxygen saturation as a consequence of living at high altitude (40), and even adolescent growth spurts, since not all societies through human history seem to have experienced this phenomenon (1, 36). Hormones provide a particularly nuanced and complex example of the intersection between physiology, evolution, and human history. Consider sex hormones in women: Modern females at healthy body weights (i.e., not over- or under- weight) who live in developed nations reach their first ovulatory period at an average age ⬃12.5 yr (7) and reach menopause at the average age (for this same demographic) of 51 yr (14). Evidence suggest that changes in diet, the introduction of birth control methods, and reductions in the average number of children born per woman have led to changes in estrogen levels. These changes in estrogen levels could in turn lead to alterations in metabolism (16). Furthermore, it is increasingly becoming clear that neuro-hormonal axes, in particular those systems regulated by dopamine and thyroid hormones, are more responsible for the evolution of human mental abilities than changes in brain anatomy (25). Such changes in brain physiology could have enabled better cognition and thus improved behavioral adaptations and potentially an increased proclivity toward reward- and pleasure-seeking behavior. Biological Rhythms and Their Adaptation Biological rhythms exist in many mammals, including humans, and may be understood as evolutionary adaptations to regularly changing environmental conditions. Prominent among those are diurnal rhythms of rest and activity. Humans are diurnal, so their bodies must be prompted to activity during daylight and to rest at night. Diurnal rhythm is neuro-hormonally regulated, with the melatonin secreted by the pineal gland playing a primary role. Since humans need to sleep several hours out of every 24 hr, maintenance of the diurnal rhythm is crucial for health and normal functioning. Secretion of melatonin is cyclical and can be altered by changing light exposure and activity patterns (9). Substance abuse FIGURE 1. Pictorial summary of the evolutionary etiology of selected pathologies PHYSIOLOGY • Volume 31 • November 2016 • www.physiologyonline.org Downloaded from journals.physiology.org/journal/physiologyonline (054.163.042.124) on May 27, 2020. 393 REVIEWS Humans’ desire to light their world artificially, without the light of the sun, has existed for a long time. The recent discoveries of Homo naledi deep in the cave system in South Africa may indicate that humans were already using artificial light over 2 million years ago (3), and the oldest use of fire has been suggested to have occurred at least 1.5 million years ago (6). In the 19th century, humans became more adept at creating artificial light when they invented light sources (kerosene, gas, electricity) that could imitate more effectively the brilliance of daylight. Bright television, computer, and smartphone screens mean that, today, our eyes are exposed to more bright lights, more often, than has previously been the case in human history. This is contributing to disturbances in sleep and wakefulness (17). Whether and how this change might contribute to long-term neuro-hormonal changes, both on the individual and on the species level, remain to be seen. Recent research has indicated that women involved in night-shift work are at greater risk for cardiovascular disease (35), suggesting that alterations to circadian rhythm could have the potential to contribute to some kind of evolutionary change. Cycles on a broader scale–that is, annual cycles– are less conspicuous in humans than in other animals but are nonetheless present. Manifestations of annual rhythms include different rates of fertility and mortality, depending on the season, and correlations between body size and month (or season) of birth (21, 38). These differences may represent evolutionary adaptations themselves, or they may be the consequence of different access to resources during particular times of the year. At the very least, such data indicate the ongoing relationship between human physiology and the external environment. Aging Vasculature: An Evolutionary Perspective Global vascular disease burden (including cardiovascular, peripheral vascular, and neurovascular diseases) is great and growing, and it is a major cause of death worldwide in both developed and developing nations (22). Much research has focused on identifying causes of vascular damage and ways to prevent or to reverse pathological degeneration of and damage to vessels (22). As is the case in other chronic degenerative conditions (e.g., osteoporosis, neuro-degeneration), vessels “age” through lack of maintenance (33). In the second half of the 20th century, much scientific research linked problems with vascular maintenance and with plaque accretion to diet and lifestyle. In the 21st century, however, new research began to suggest other ways of considering etiologies of 394 vascular disease. These studies found that diet was less important than other issues, such as the integrity of the human immune system and the role of inflammation in chronic disease (22). Paleopathological data–specifically, study of the occurrence of cardiovascular disease in mummies from four different pre-modern time periods and locations– suggested that the modern sedentary lifestyle and lipid-rich diet may not be as responsible for cardiovascular disease as previously thought. Evidence of prominent plaques was found, for example, in the abdominal vessels of an Unangan (Aleutian Islands) woman who lived in the 19th century CE and died in her late 40s; in an Egyptian woman in her late 40s who died in an unknown era during the Pharaonic period; in an Ancestral Puebloan woman in her late 40s who died between 1500 BCE and 500 CE; and in a woman from ancient Peru, 200 –900 CE, who died in her early 40s. Similar evidence of vascular disease was found in the remains of male mummies as well, and at other places in the vasculature, such as the carotid arteries (33). Such paleopathological findings suggest the limitations in our understanding of the etiologies of what might be considered a “normal” part of human aging. Integument and Interaction With the Surrounding Environment Human integument, consisting of epidermis, dermis, and subcutaneous adipose tissue, is the largest single organ of the body. Besides providing mechanical and biological protection, it plays an active role in thermoregulation by affording insulation and enabling heat dissipation. Unlike the integument of our closest primate relatives, human skin possesses relatively small hairs that are incapable of providing thermal insulation. Instead, it has been suggested that human body hair evolved not to provide insulation but to enhance detection of ectoparasites (11). Other changes in the human body over time have worked to protect against heat loss, including differences in humans’ surface area-tobody volume ratio that varies with latitude (4). Loss of effective hair cover by humans also resulted in the development of the layer of melanin in the basal stratum of the epidermis. This layer protects deeper layers of skin against ultraviolet radiation (5). Amounts of melanin differ widely among individuals and among populations, with most of this variation emerging as a consequence of long-term evolutionary adaptations to different levels of UV radiation in different areas of the world (8). A degree of physiological adaptability is demonstrated by the phenomenon of skin tanning: melanogenesis in the skin is increased in response to exposure to UVB light. Together, genetic PHYSIOLOGY • Volume 31 • November 2016 • www.physiologyonline.org Downloaded from journals.physiology.org/journal/physiologyonline (054.163.042.124) on May 27, 2020. REVIEWS adaptation to the area of origin and the process of tanning produce protection against the UV radiation that may destroy the living cells of the dermis. Similarly, melanin accumulation in the iris protects eyes against destructive UV radiation, and lighter-colored irises tend to be more frequent among populations in latitudes that receive less intense UV radiation (18). Migration of individuals with lighter skin to areas of more intense sun exposure can lead to increased incidence of skin cancer; migration of individuals with darker skin to higher latitudes can contribute to the development of vitamin D deficiency (10). Evolutionary Perspectives of Homeostasis The human body is a complex system resulting from genetic, epigenetic, and external factors, and in normal conditions there is an energy homeostasis. However, alterations of our gene pool (i.e., relaxed natural selection leading to accumulation of regularly appearing random mutations), influences on epigenetic level (e.g., extent of DNAmethylation), or environmental factors (diet, lifestyle) can lead to disturbances of homeostasis. Stress in any form– eustress or distress– can lead to physiological adaptation and thus can result in a selective advantage or disadvantage of certain traits. For instance, the flight or fight response, understood and correctly described even in ancient times (12), is in modern society rarely necessary in its original sense. A biochemical and physiological basis for its development and evolution can now be indirectly assessed by measuring cortisol levels in hairs of mummies (37). This type of analysis can lead us to estimate general physiological stress levels, further enhancing our knowledge of the kind of physiological stress that could be related to the heightened levels of inflammation described in the previous section discussing causes of vascular disease. Physiological adaptations to a way of life characterized by hunting and gathering, instead of the relatively stable food supplies that the development of agriculture facilitated, explain human metabolism and our physiological tendency to store excess calories as energy-rich fat to combat potential times of scarce resources. This also at least partially explains the human preference for fatty, energy-rich food. Today, when food is readily available and minimal effort is required to obtain it, the physiological system that encouraged survival in times of famine is now contributing to obesity and its associated pathologies (13, 16). Consider also the biomolecular aspect of human metabolism. Hunter-gathering humans were accustomed to eat large amounts of protein (for ex- ample, when a large animal was killed) with some degree of regularity, although probably with fairly long gaps of time in between kills. With this diet characterized by large loads of protein, interspersed with plant foodstuffs, the human metabolic system became effective at acquiring energy from digested amino acids that had to be deaminated before being broken down into pyruvates used in the citric acid cycle. Any surpluses of the products of deamination were effectively stored in adipose tissue by subjecting amino acid-derived pyruvates to de novo lipogenesis (13, 16). When the human diet began to include larger quantities of carbohydrates and fats with the advent of agriculture and pastoralism, easily digestible and easily absorbed compounds were preferentially used to fuel the citric acid cycle. Meat requires more time for digestion: with sufficient energy gains from carbohydrates and fats, the products of protein digestion were stored as fat in adipose tissue, besides providing essential amino acids for specific processes. This situation persists today, with meat added to otherwise energetically sufficient meals, fueling the obesity epidemic (13, 16). Understanding of the evolutionary aspects of eating behaviors and metabolism can contribute to efforts to reduce the prevalence of obesity and related pathological conditions. It is important to emphasize, as this evolutionary perspective reminds us, that obesity is not “pathological,” in the sense that it is a normal outcome of a metabolic process that evolved to guarantee energy stores. Certainly, there are many pathological sequelae of FIGURE 2. Correlation of the prevalence of the Type 1 and Type 2 diabetes mellitus with the opportunity for natural selection in 118 countries based on the data provided by the International Diabetes Federation and the WHO Logarithmic scales. Opportunity for natural selection in a given country is measured as the ratio (1 ⫺ Ibs)/Ibs, where Ibs is the Biological State Index. The Biological State Index of a given population expresses a probability of an individual passing her/his genes to the next generation under the conditions of mortality and fertility prevailing in this population. The lower the ratio, the less opportunity for selection exists. For calculations for the Biological State Index and the application of WHO and International Diabetes Federation, see Refs. 19, 30, and 39. PHYSIOLOGY • Volume 31 • November 2016 • www.physiologyonline.org Downloaded from journals.physiology.org/journal/physiologyonline (054.163.042.124) on May 27, 2020. 395 REVIEWS obesity, including joint damage and insulin resistance, and the evolutionary aspects of insulin have recently been addressed. A study of 118 countries, for which data about diabetes mellitus type 1 (DM-1) were available from the International Diabetes Federation (19), suggested a statistically significant relationship between the prevalence of DM-1 and the relaxation of selection, when controlling for other variables such as income and urbanization (39) (FIGURE 2). However, the physiological origin of obesity is in the human body’s carefully evolved systems of energy storage and homeostasis, and understanding this origin should augment research about prevention and treatment of obesity-related conditions like DM-1. Medical treatment seeks to address both symptoms and causes of pathological conditions, with causes being the preferred target of treatment when feasible. Evolutionary medicine explicitly addresses the causes of human physiology–and human pathophysiology–from their origins. Obesity is an example of a condition with pathological outcomes that resulted from normal physiological processes. Considered as a consequence of this normal metabolic process, “obesity” is a more complex physiological condition than the term “disease” implies. 396 We thank Francesco Galassi and Corina Steiner (Institute of Evolutionary Medicine, University of Zurich) for technical assistance. Funding for this research was provided by Mäxi-Foundation. No conflicts of interest, financial or otherwise, are declared by the author(s). 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