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Home , Famine, Thrifty gene hypothesis

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30 Beyond Feast–Famine: Brain Evolution, Human Life History, and the Christopher W. Kuzawa

EXPLAINING THE MODERN METABOLIC 2008). The idea that and related diseases result DISEASE : THE THRIFTY GENOTYPE from a “discordance” or “mismatch” between our HYPOTHESIS AND ITS LIMITATIONS ancient genes and our rapidly changing lifestyle and is now widely accepted, and it seems clear that Today, more than 1 billion people are overweight or obesity must be more common today in large part obese, and the related condition of cardiovascular dis- because we are more and expending less than ease (CVD) accounts for more than any other our ancestors traditionally did (Eaton and Konner, cause (Mackay et al., 2004). Why this epidemic of 1985; see Chapter 28 of this volume). Despite the intui- metabolic disease has emerged so rapidly in recent tive appeal of these ideas, the hypothesis is not without history is a classic problem for anthropologists con- limitation. For one, it helps explain why we gain weight cerned with the role of culture change in disease in a modern environment of nutritional abundance, transition (Ulijaszek and Lofink, 2006). In 1962, the but says very little about the syndrome of metabolic geneticist James Neel proposed an explanation for this changes that account for the diseases that accompany phenomenon that looked for clues in the “feast– obesity (Vague, 1955; Kissebah et al., 1982). While famine” conditions that he believed our nomadic, for- excess weight gain in general is unhealthy, it is specif- aging ancestors faced in the past. Given the unpredict- ically deposition in the visceral or abdominal region ability of resources in natural ecologies, Neel that accounts for the bulk of its adverse effects on suggested that a “thrifty” capable of effi- health. Visceral fat has unique metabolic properties ciently storing excess dietary energy as body fat when that contribute to states like insulin resist- food was abundant would have provided a survival ance when deposition in this depot is excessive advantage during later periods of shortage. In the wake (Reaven, 1988; Wellen and Hotamisligil, 2003). The of the rapid dietary and lifestyle change in recent gen- simple idea that our bodies are famine adapted may erations, and the comparatively slow pace of genetic help explain why we are prone to gaining weight when change, these foraging-adapted genes would now be we eat too much, but it says little about the metabolic “rendered detrimental by progress” (Neel, 1962), symptoms that make weight gain unhealthy. leading to obesity and diabetes. While a useful way to The sole focus of the hypothesis on genes is also think about obesity generally, variations on this idea outdated in light of newer evidence that biological sus- have been proposed to help explain the high rates of ceptibility of developing these adult diseases is also metabolic disease among populations believed to have elevated among individuals who experienced poor experienced especially severe nutritional conditions in during early life (Barker et al., 1989; Gluck- the past, including the diabetes-prone Pima Indians of man and Hanson, 2006). A large research literature has the American Southwest (Knowler et al., 1982), and demonstrated that the body’s responses to early life several groups of South Pacific Islanders who have nutrition subsequently influences that individual’s risk among the highest rates of obesity in the world (Dowse for developing adult diseases like diabetes and CVD, and Zimmet, 1993; McGarvey, 1994). a process described as nutritional “programming” The thrifty gene hypothesis was one of the first uses (Lucas, 1991) or “induction” (Bateson, 2001). For of evolutionary reasoning to shed light on a human instance, CVD and the rate of CVD mortality in adult- disease, and is thus a classic example of evolutionary hood are inversely related to size at birth – a measure or “Darwinian” medicine (see Nesse and Williams, of fetal nutrition – in places like the UK, Sweden, 1994; Stearns and Koella, 2008; Trevathan et al., India, and the Philippines (Kuzawa and Adair, 2003;

Human Evolutionary Biology, ed. Michael P. Muehlenbein. Published by Cambridge Press. # Cambridge University Press 2010.

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16

14

12

10

8

% body fat 6

4

2

0

Cat Pig Rat Lamb Calf Foal Mouse Rabbit Human Fur seal Baboon Caribou Sea LionsReindeer Hamster Guinea Harppig seal Black bear Elephant seal 30.1. Percentage of body fat at birth in mammals. Adapted from Kuzawa (1998).

Yajnik, 2004; Lawlor et al., 2005). Individuals who 30 were born small also experience durable changes in biological systems that contribute to CVD, as reflected 25 Male in their higher risk of depositing fat in the visceral Female region, or of developing high blood pressure, impaired 20 glucose tolerance or diabetes, or high cholesterol (Adair 15 et al., 2001; Kuzawa and Adair, 2003). When the dietary

intake of pregnant rats and sheep is restricted, their % body fat 10 offspring have much the same set of outcomes as we see in humans born small (McMillen and Robinson, 5 2005; Fernandez-Twinn and Ozanne, 2006). This finding 0 suggests that the body has an ability to induce a “thrifty 0 12243648607284 phenotype” that is better suited to survival in nutrition- Age (months) ally challenging environments. It also illustrates why a 30.2. purely gene-based model of metabolic disease evolution Age changes in percentage body fat in humans. Data from Davies and Preece (1989), pp. 95–97. is incomplete (Hales and Barker, 1992). A third limitation of the thrifty genotype hypothesis is that it merely assumes that famine was the key source of selection on human metabolism without con- mammal studied thus far (Kuzawa, 1998). This is sidering the actual causes of that stress and the ages at followed by a continued period of rapid fat deposition which it is most severe (Kuzawa, 1997). There are during the early postnatal months. In well-nourished reasons to question whether our distant foraging populations, adiposity reaches peak levels during the ancestors experienced a major burden of famine, first year of life before gradually declining to a nadir in which archaeological and contemporary ethnographic childhood, when humans reach their lowest level of data suggest only emerged as an important problem body fat in the lifecycle (Figure 30.2). If the threat of after the evolutionarily recent development of agri- famine is what drove the human tendency to build up cultural subsistence (Cohen and Armelagos, 1984; fat reserves, it is not obvious why children’s bodies Benyshek and Watson, 2006). Given this, famine may should do so little to prepare for these difficult periods. have been a relatively weak force of selection on the The lower priority placed upon maintaining an energy human gene pool (Speakman, 2006). reserve by middle childhood suggests that the back- Additional support for this interpretation comes ground risk of faced by our ancestors – from the growth pattern of body fat in humans, shown “famine” – was small in comparison to the nutritional in Figure 30.1. In humans, body fat makes up a larger stress experienced during the preceding developmental percentage of weight at birth than in any other period. A prereproductive life history stage that does Comp. by: PG1812 Stage : Proof ChapterID: 9780521879484c30 Date:23/3/10 Time:19:49:42 Filepath:H:/ 01_CUP/3B2/Muehlenbein-9780521879484/Applications/3B2/Proof/9780521879484c30.3d

520 Christopher W. Kuzawa

not prioritize energy storage is difficult to reconcile 100 with the assumption that famine was the major nutri- tional challenge faced by human populations. 80 In this chapter, I review the causes, consequences, and adaptive solutions to the nutritional stress of 60 infancy and childhood in hopes of shedding light on the evolution of human metabolism. Viewing human 40 nutritional stress through a developmental lens helps % RMR to brain identify ages when human metabolism has likely been 20 under strongest selection. I will show how two traits 0 that are central to the adverse health consequences 0 5 10 15 20 of obesity in overnourished adults – visceral fat and Age (years) insulin resistance – likely evolved as components of 30.3. Percentage of resting metabolic rate (RMR) devoted to an energy backup system that reprioritizes the alloca- the brain by age in humans. Data adapted from Holliday (1986). tion of prized energy and glucose during a crisis, thus allowing the body to shunt resources from nonessen- tial functions to critical organs like the brain (for dis- which requires a constant redistribution of ions across cussion of the function of insulin resistance during the cell membrane using energy-dependent ion pumps. pregnancy, see Haig, 1993). Demands placed on this Humans are exceptional in the quantity of this costly system are greater during infancy and early childhood tissue that they must sustain, and it has been estimated than at any other age of the lifecycle, suggesting that that greater than 80% of the body’s metabolism is some of the evolutionary of adult metabolic dis- devoted to the brain in the newborn (Figure 30.3). ease may trace to selection pressures operative during It is a notable feature of human metabolism that early life. In addition, evidence for developmental total metabolic rate measured in adulthood (for plasticity in this backup system and the adult diseases instance, calories expended per day) is not increased that it contributes to suggests that its priorities may be above other mammals of similar body size despite adjusted in response to nutritional and other stressors our highly encephalized state (Armstrong, 1983). experienced early in the life cycle. A developmental Thus, brain expansion must have been matched by a approach to the evolution of human metabolic disease reduction in other energetically expensive tissues underscores the importance of the body’s internal (Armstrong, 1983). Human evolution was marked by strategies of allocating finite resources – in addition a movement to more energy-dense and easy to digest to the external stress of famine – as key to understand- (Leonard and Roberton, 1992, 1994), which may ing the contemporary epidemic of metabolic disease. have allowed a reduction in the size and energy requirements of the metabolically costly gut (Aiello and Wheeler, 1995). This reduction in gut expenditure A DEVELOPMENTAL PERSPECTIVE ON may have helped offset our increased brain needs in ENERGY STRESS IN HUMAN EVOLUTION: adult life (Aiello and Wheeler, 1995), but this seems THE DEVELOPMENTAL BOTTLENECK less likely during infancy and childhood. The size of the brain relative to the body is far larger in the human Humans have been described as naturally obese (Pond, neonate and infant than in the adult, and as a result, 1997), a characterization which is particularly fitting at the body’s total energy requirements are likely elevated birth as human newborns are born with more body fat at this age relative to other similarly sized mammalian than any other species (Kuzawa, 1998). Attempts to and primate newborns (Foley and Lee, 1991). More- explain our unusual “baby fat” have traditionally over, unlike energy expended on other tissues or looked to our hairlessness for clues, and it is widely systems, brain metabolism may not be reduced to con- assumed that natural selection compensated for our serve energy during a period of shortage, but instead loss of fur with a layer of insulative body fat (e.g., must be maintained within narrow limits to avoid per- Hardy, 1960; Morris, 1967). A competing perspective manent damage (Owen et al., 1967). Thus, our large notes that this excess is well-suited to brains impose a double burden on metabolism during serve as a backup energy supply for another distinctive infancy: they increase demand for energy while human trait: our large brains (Kuzawa, 1998). Brains restricting flexibility in metabolic expenditure when have among the highest metabolic rates of any tissue or nutritional supply is disrupted. organ in the body, and they are quickly damaged in the Other factors that are commonly experienced event of even temporary disruption in energy supply. during infancy can impede the supply of nutrients, Neuronal tissues are costly because they must be main- ensuring that negative energy balance is a regular tained in a state far from thermodynamic equilibrium, occurrence at this age in most populations. 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born with a naı¨ve adaptive immune system, and must and periods of negative energy balance therefore come into contact with (and be infected by) decline to a small fraction of their high prevalence specific pathogens to acquire the repertoire of anti- during the postweaning period. Because older children bodies necessary to protect us from future . are far less likely to have to rely upon energy reserves Initially, newborns enjoy immune protection from for survival, it is easy to see why the human body several maternal sources. The first is in the form of places lower priority on maintaining sizeable body fat maternal immunoglobulin G (IgG) antibodies acquired stores by this age. across the placenta. In addition, exclusively breast-fed Thus, the unique energetic stressors of early life infants are shielded from exposure to pathogens, and have left an imprint on the developmental pattern of also enjoy passive immune protection from maternal fat deposition in humans, represented by intensive secretory antibodies (sIgA) in breast milk. As a result, investment in the tissue in the run-up to the stresses newborns are often quite healthy in the early postnatal of weaning, and a gradual decline in the priority given months. However, both sources of passive immune to maintaining this reserve at older and more resilient protection eventually wane. As energy requirements ages. But this merely shows that the body is prioritiz- outstrip the supply capacity of breast milk by roughly ing the allocation of energy to an energetic buffer. This 6 months of age, less sterile complementary foods must energy backup must have also been accompanied by be introduced, and infectious disease becomes the evolution of an efficient distribution and delivery unavoidable in all but the most sanitary environments. system. Because the brain accounts for 50–80% of the These childhood infections, in turn, are a source of body’s energy usage during the first few years of life, nutritional stress, and indeed, it is primarily through we should expect that this delivery system – human their effects on nutritional status that they comprom- metabolism – will be organized around the goal of ise health and contribute to mortality during infancy ensuring a constant supply of energy to this fragile and childhood (see Scrimshaw, 1989, for review). Once and costly organ. The availability of dietary nutrients sick, a child loses appetite and this may be com- is variable and often unpredictable, and as we will see pounded in some cultures by the withholding of food next, human metabolism manages this risk by rapidly by caretakers (Scrimshaw, 1989). The common diar- modifying energy allocation in response to changes in rheal diseases reduce nutrient absorption and diges- intake and expenditure. Multiple cues signaling nutri- tion, while the fevers associated with many viral tional stress induce a similar response that achieves a infections can increase metabolic rate and thus energy common end: stored are mobilized for use, while expenditure. The specific symptoms may vary by ill- glucose is spared for the brain at the expense of less ness, but the pattern of nutritional depletion that critical functions like muscle. accompanies infections has the effect of suppressing immune function, leaving the infant more prone to future infection and a compounding cycle of nutri- TISSUE-SPECIFIC INSULIN RESISTANCE tional stress (Pelletier et al., 1995). AS A LIFE HISTORY STRATEGY The human infant thus faces a profound energetic dilemma: at precisely the age when they are most Although long-term changes in fat stores are moni- dependent upon provisioning by caretakers to main- tored by the brain through the effects of fat-derived tain the high and obligatory energy needs of their large hormones like leptin, short-term changes in energy brains, they are likely to be cut off from that supply metabolism are regulated in a more distributed fashion chain as a result of illness and the nutritional stresses by organs like the pancreas, and also by the tissues of weaning. It is this confluence of factors, and the themselves, which alter their own uptake and use of synergy between nutritional stress and compromised glucose in response to changes in circulating hormones immunity, that accounts for much of the high infant and the supply of nutrients. A sudden glut of glucose or mortality in many societies (Pelletier et al., 1995). other substrate in the blood stream is sensed by the beta Natural selection likely favored neonatal adiposity as cells of the pancreas, which secrete insulin into the a strategy to prepare for these difficult periods. It is circulation. Insulin stimulates glucose uptake by tissues easy to imagine how infants with a genetic predispos- throughout the body, initiating a negative feedback pro- ition to deposit copious quantities of energy as fat prior cess that helps re-establish normal basal glucose con- to weaning would be better represented among the centrations. The tissues that are not responsive to subset who survive to adulthood to reproduce and pass insulin are few, but prominently include the organ most on their genes (Kuzawa, 1998). vulnerable to energy shortage – the brain (Seaquist It is important to note that these sources of energy et al., 2001). While this may at first seem paradoxical, stress have largely receded by mid childhood: children this tissue-specific pattern of insulin sensitivity provides have already acquired antibodies against the major the body with the ability to modify partitioning of glu- pathogens that they are likely to confront. As a result, cose between the brain and other tissues by increasing Comp. by: PG1812 Stage : Proof ChapterID: 9780521879484c30 Date:23/3/10 Time:19:49:44 Filepath:H:/ 01_CUP/3B2/Muehlenbein-9780521879484/Applications/3B2/Proof/9780521879484c30.3d

522 Christopher W. Kuzawa

30.4. How body fat and insulin resistance protect the brain. During a crisis, stored triglycerides are broken down into free fatty acids (FFA) and glycerol. Glycerol enters the liver as a gluconeogenic substrate, thus Infection, increasing the pool of available glucose. Free fatty acids Starvation, Inflammatory enter the liver where they are converted to ketone Energy stress cytokines (+) bodies, which the brain uses as a substitute energy ketones substrate. Free fatty acids also induce insulin resistance (+) in the liver and muscle, which spares glucose for the Lipolysis brain. When the nutritional stress is caused by infection, inflammatory cytokines reach the liver and also spare FFA glucose by inducing insulin resistance in liver and muscle. Body fat Liver glycerol GLUCOSE visceral fat FFA (–)

insulin resistance

Muscle

or decreasing insulin-mediated glucose uptake in eventually deplete – its production of insulin in type II the periphery (e.g. muscle, liver, body fat). diabetes (formally noninsulin dependent diabetes, or How this system of resource partitioning works is adult-onset diabetes). However, adopting instead the well illustrated by cases of accidental insulin overdose. perspective of a young organism managing a finite When insulin-dependent diabetics inject themselves energy supply, insulin resistance in a tissue-like skeletal with too much insulin, this can be fatal, because it muscle allows the body to shift its priorities of glucose “overfeeds” the insulin-sensitive periphery, leaving allocation – away from peripheral tissues and toward nothing to fuel the insulin-independent brain (Waring the fragile and energy demanding brain (Figure 30.4). and Alexander, 2004). Reducing insulin-mediated uptake in the periphery has the opposite effect, as it reduces glucose use in tissues like muscle, leaving HOW VISCERAL FAT AND INSULIN more to be delivered to the brain. The body has two RESISTANCE HELP PROTECT THE means of decreasing peripheral glucose use to spare BRAIN DURING A CRISIS the brain when confronted with nutritional stress. The first is to reduce insulin production, which reduces Given these design features, it is not surprising that glucose uptake in the periphery. Secondly, the body insulin resistance is triggered during states associated can influence where glucose is used with greater preci- with negative energy balance, such as starvation, infec- sion by increasing or decreasing insulin sensitivity on a tion, or trauma (Jensen et al., 1987; Childs et al., 1990). tissue-by-tissue basis. Skeletal muscle is a key player in During a fast, free fatty acids (FFA) are first mobilized this flexible system. Because it is the largest consumer from the metabolically active visceral adipose depot, of glucose, the body’s response to changes in energy which is secreted into the portal circulation that drains status prominently involves modulating muscle glucose into the liver. Fat mobilization from this depot is uptake by changing insulin sensitivity in this tissue. The achieved by innervation of the tissue by sympathetic brain is an important arbiter of this response. The brain nerve fibers and, unlike other fat depots, these effects may not be insulin sensitive, but it does express insulin are relatively insensitive to the anti-fat mobilizing receptors and can also sense the adequacy of the supply effects of insulin (van Harmelen et al., 2002; Hucking of glucose that it receives. In the event that cerebral et al., 2003). The liver interprets the sudden appear- glucose flux is attenuated, the brain helps ensure its ance of FFA in the portal circulation as a signal that the own glucose supply by inducing peripheral insulin body is being forced to mobilize fat from this depot, resistance via effects on the sympathetic nervous and reprioritizes metabolism to protect the supply of system and other pathways. In addition to these direct glucose to the brain. This is achieved by increasing effects of the brain, some of the change in glucose hepatic glucose production while also inducing insulin partitioning is co-ordinated directly by the affected resistance in the liver and in skeletal muscle, thus peripheral tissues, as discussed in greater detail below. reducing glucose uptake (Kabir et al., 2005). In add- From the perspective of adult metabolic disease, ition, FFA in the circulation are taken up to be used as this reduced insulin-stimulated uptake of glucose by energy by tissues like muscle, which directly induces skeletal muscle forces the body to increase – and insulin resistance (Roden et al., 1996). Comp. by: PG1812 Stage : Proof ChapterID: 9780521879484c30 Date:23/3/10 Time:19:49:45 Filepath:H:/ 01_CUP/3B2/Muehlenbein-9780521879484/Applications/3B2/Proof/9780521879484c30.3d

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Similar changes in how the body uses glucose are tissue, which saves the more easily metabolized and seen in response to the stress of infection or trauma. desirable energy substrate of glucose for use by the The body’s first response to an infection includes brain. As peripheral insulin resistance helps the body inflammation, which helps mobilize immune and non- control where glucose is used, it seems likely that these immune resources as a first line of defense against general features of human metabolism were forged in tissue invasion and injury (Fernandez-Real and Ricart, the evolutionary crucible of early life nutritional stress. 1999, 2003). Inflammation is initiated in the liver in As emphasized above, the challenge of fueling the response to signals indicating tissue injury, such as the brain, and thus the need to reduce insulin-mediated appearance of that signal the presence of bac- uptake in the periphery during undernutrition or infec- teria, or by molecules called cytokines produced by tion, is most acute, common, and life-threatening at immune cells like macrophages. Interestingly, in obese this age. The need to buffer brain glucose must place individuals visceral adipose tissue is an important an important constraint on any response to nutritional source of these cytokines, which, like FFA, are secreted stress during fetal life, infancy, and early childhood, from fat cells into the portal circulation where they when the brain demands the equivalent of50% or more of induce a similar constellation of changes in energy the body’s total available energy (e.g. Childs et al., 1990). metabolism as they reach the liver (Tsigos et al., 1999). Why these overfilled fat cells secrete proinflam- matory cytokines is currently a focus of intensive HOW PRENATAL NUTRITION HELPS FINE research, and there are interesting leads. One is that TUNE THE SETTINGS OF THE BODY’S adipocytes and the immune cells that secrete inflam- ENERGY BACKUP SYSTEM matory cytokines (macrophages) are closely related cells that share similar patterns of gene expression As previously alluded to, there is now a great deal of (Wellen and Hotamisligil, 2003). It is also of interest evidence that individuals born small have higher risk of that fat cells secrete some cytokines as they swell in developing conditions like diabetes and CVD. The pre- size, perhaps helping the cell avoid overfilling or rup- sent discussion provides an opportunity to speculate turing (McCarty, 1999). Regardless of the mechanism on the function of these biological changes, for they underlying the inflammatory effects of excessive body prominently involve resetting how the body prioritizes fat, it seems very likely that these cells are now sending traits like visceral adiposity and insulin resistance signals that, in the past, would have been reliable indi- (for a review see Kuzawa et al., 2007). Although most cators of infection or trauma rather than obesity. It is human research in this field has documented relation- ironic to think that the metabolism of the overfed ships between early life nutrition and metabolic dis- individual today, whose swollen fat cells produce high ease risk factors in later childhood, adolescence, or levels of cytokines, may be tricked by their obesity into adulthood, a handful of studies have now investigated sensing an inflammatory challenge or threat, inappro- these same outcomes in infants and young children – priately initiating the same constellation of metabolic the age when the allocation of scarce glucose may be adjustments designed to cope with starvation or most critical for survival, and thus, when these meta- infection. bolic pathways may have been under particularly What is clear is that multiple signals of nutritional strong evolutionary pressure. What these studies find stress or trauma – whether FFA or cytokines – help link is that, compared to their age mates who were better- the highly labile fat depot of the abdomen with nourished prior to birth, individuals born small tend to metabolic adjustments co-ordinated by the liver put on more visceral fat and become more insulin (Figure 30.4). Not unlike the effects of FFA in the portal resistant as they gain weight (Soto et al., 2003; Ibanez circulation, these cytokines induce a state of peripheral et al., 2006). Metabolic changes in glucose use and insulin resistance, while also mobilizing FFA stored in visceral fat are already detectable in the first year of visceral fat for use as energy. These FFA also bathe the life, showing that a body with a prior history of liver, and thus further contribute to insulin resistance prenatal nutritional stress is not only prone to adult through the pathways described above (Pickup and disease, but also handles its energy and substrate Crook, 1998; Orban et al., 1999). differently during late infancy and early childhood. The evolutionary perspective adopted here, empha- Why the body adopts this strategy when prenatal sizing the importance of the brain metabolism and the nutrition is scarce is uncertain, but two possibilities pattern and sources of nutritional stress, helps clarify seem plausible. Firstly, glucose-sparing adjustments the logic underlying metabolic adjustments that lie at could be important for protecting the brain during the heart of the metabolic syndrome: when the body is prenatal life when intrauterine nutrition is comprom- confronted with a challenge to energy balance, such as ised (Hales and Barker, 1992). The challenge of pro- starvation or infection, the less critical, peripheral tecting the brain, as outlined above, does not begin at tissues shift to using fats mobilized from adipose birth, and nutritional shortfall in utero can result when Comp. by: PG1812 Stage : Proof ChapterID: 9780521879484c30 Date:23/3/10 Time:19:49:47 Filepath:H:/ 01_CUP/3B2/Muehlenbein-9780521879484/Applications/3B2/Proof/9780521879484c30.3d

524 Christopher W. Kuzawa

fetal demand for energy outstrips maternal supply stress, thereby increasing survival and thus genetic across the placenta (Harding, 2001). By this reasoning, fitness. Because the nutritional stress of weaning then, an adjustment made in utero to boost immediate occurs prior to reproductive maturity, it represents a survival may have unintended side-effects after birth “developmental bottleneck” through which any meta- (Hales and Barker, 1992). bolic genes must first pass before being passed on to The second and not mutually exclusive possibility offspring (Kuzawa, 1998). This selection would help is that some of the adjustments have been shaped for ensure that traits that increase early life survival would benefits accrued after birth (Gluckman et al., 2005). To stabilize into the pattern of human ontogeny across the extent that poor prenatal nutrition or maternal many generations of differential survival. I have argued stress are correlated with the world that the fetus will that body fat, especially the rapidly mobilized visceral be born into, these signals could allow it to modify the fat depot, and the ability to reprioritize glucose alloca- priorities of energy use, including the settings of this tion by inducing insulin resistance, may be two backup system, to match the severity of postnatal examples of metabolic traits that could be beneficial nutritional stress or challenge that it is likely to face to an infant faced with the challenge of buffering its (for more on fetal nutrition as an anticipatory cue see most critical functions like the brain during the Bateson, 2001; Kuzawa, 2005; Wells, 2007; Kuzawa, common nutritional stressors confronted at this age. 2008). These adjustments could help the infant manage The developmental influences on these metabolic its precarious metabolic state and survive this traits show that the genes favored by natural selection developmental bottleneck of early life nutritional stress do not determine the organism’s metabolic state in a when conditions are difficult. But this shift in meta- simple one-to-one fashion. Not only does adult health bolic priorities would also have the effect of accentu- depend upon the interaction between one’s genome ating the metabolic derangements that accompany and lifestyle, as long appreciated, but the body also weight gain when nutrition is chronically abundant. appears to have a capacity to adjust the settings and When a previously undernourished body is confronted priorities of its metabolism in response to early nutri- with excess nutrition, a strategy of prioritizing visceral tional experiences and to cues conveyed by the mother fat deposition and sparing glucose becomes a liability, across the placenta. These biological responses may be increasing risk of developing the metabolic syndrome, viewed as examples of the well-known importance of diabetes, and CVD as an adult. In other words, if there developmental plasticity as a mode of human adapt- are “thrifty genes” they code not for static properties ability (Lasker, 1969; Frisancho, 1993; also see Chap- but for flexible strategies, or reaction norms. This abil- ter 2 of this volume). Organisms must cope with ity to flex may help match the body’s metabolism to ecological and social change on a variety of time scales, nutritional stress early in life, but this may plant the spanning rapid and reversible changes (e.g., breakfast seeds for metabolic diseases caused when nutrition is followed by a fast until lunch) to much longer trends chronically abundant later in life. that take years, decades, generations, or longer to unfold (e.g., extended , migrating to a new ecology, an ice age) (Potts, 1998). Genes are effective BEYOND FEAST–FAMINE: FRAGILE BRAINS at tracking the slowest, most gradual changes in ecol- AND METABOLIC PLASTICITY ogy and diet, while homeostasis buffers rapid and reversible changes. Developmental adjustments made In proposing the thrifty gene hypothesis, Neel made in response to early life nutrition operate on an inter- the elegant point that we gain insights into modern mediate time scale, allowing the organism to change its human diseases by reconstructing the environments settings more rapidly than could be achieved by nat- and stressors that our ancestors faced, as this provides ural selection, but in a fashion that is more durable and a sense for what our bodies and biology are designed to stable than what the body achieves via homeostasis expect. I have tried to show how we can approach (Kuzawa, 2005). human metabolism from a developmental perspective In this sense, our may not be all that to hone this exercise in reverse-engineering. Rather different from other systems that have a capacity to than inferring past selection from the default clinical adjust long-term settings to local conditions via devel- perspective of adult obesity or diabetes, the develop- opmental responses, illustrated classically by the mental approach developed in this chapter began by important effects of developmental experience on isolating ages of high mortality to identify when systems like the brain, the immune system, and the metabolism is most critical for survival. Identifying skeleton. Many of the body’s systems are built from a the sources of nutritional stress at the ages of peak genetic architecture that evolved through natural selec- nutritional mortality provides clues into the types of tion, but that – by design – rely upon information about biological responses or strategies that would have been local ecology acquired during early development to available to natural selection to work around this complete their construction. 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Beyond Feast–Famine: Brain Evolution, Human Life History, and the Metabolic Syndrome 525

the size, configuration, and attachments of the body’s 4. This chapter argues that developmental adapta- skeletal elements evolved through natural selection tions made by the fetus to nutritional stress could operating on gene frequencies. However, because indi- contribute to a higher risk for diabetes later in life. viduals are idiosyncratic in their behavior and thus the What are these adaptations and how might they be mechanical loadings that they will impose on their beneficial early in life? skeletons, natural selection constructed a system that 5. Chronic diseases often negatively impact health has an exquisite capacity to compensate for biomecha- and survival late in the lifecycle – when one’s nical strain, and to organize developmentally around genome has already been passed on via offspring the pattern of use and disuse in the individual. Perhaps to the next generation. Discuss how selection pres- it should come as no surprise that the body’s priorities sures operating early in the lifecycle might influ- of energy allocation, which are so critical for survival, ence the evolution of diseases with late life negative should have a similar capacity. After all, humans do impacts. not merely vary in their culture, pathogen ecology, and 6. If we ask “What are the causes of the diabetes pattern of physical activity, but also in their diet, nutri- epidemic?”, a public-health or medicine-inspired tional sufficiency, and exposure to metabolically answer to this question might note that many demanding stressors. These physiological and meta- people are eating too much and gaining weight, bolic “loadings” may be hidden from view, but they among other factors, which leads to insulin resist- are just as critical as components of the individual’s ance. What types of answers does an evolutionary adaptive strategy. The ability to adjust metabolic set- approach to this problem inspire, and how are tings to local conditions might help humans prepare they different from a or medical for important adaptive challenges, like the severity of approach? infant and early childhood nutritional stress outlined here. However, this same flexibility may also carry longer-term costs to health in modern environments, ACKNOWLEDGEMENTS especially if -adapted metabolic priorities adopted early in life are later confronted with chronic Dan Benyshek, Dan Eisenberg, Peter Ellison, Lee overnutrition and weight gain (Gluckman et al., 2005). Getler, David Haig, Elizabeth Quinn, Melanie Vento, It remains to be determined which of these ideas and two anonymous reviewers provided helpful com- about the function of these traits are correct in detail. ments on various drafts of this paper. What does seem clear is that our metabolisms are designed to do more than survive the crisis of famine. 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