Two groups at particular risk in this regard are adolescents within 2 years of menarche and women with inter-pregnancy intervals <18 months; both groups may have low nutrient reserves (King 2003). This underscores the importance of optimal nutritional status of women, from the preconception period and throughout pregnancy, detailed in a recent publication by the International Federation of Gynecologists and Obstetricians (FIGO), on optimal pregnancy outcomes and the prevention of low birth weight as well as defects such as neural tube defects (NTD) (Hanson et al. 2015). Current research interest is also turning to the role of the father's nutritional status/diet in influencing pregnancy outcomes, reflected in identified paternal epigenetic contributions in animal models (Siklenka et al. 2015; Donkin et al. 2016) as well as humans (Govic et al. 2016).

#### **2.1.1 Birth Defects**

In spite of the progress made in the prevention of neural tube defects worldwide, there are still approximately 300,000 infants born annually with neural tube defects (Christianson et al. 2006). Although the impact of folic acid fortification of the food supply has successfully lowered the incidence in the United States, there are still babies being born with neural tube defects. The latest Centers for Disease Control and Prevention data show the estimated prevalence has decreased from 10.7 per 10,000 live births in 1995–1996 (pre-fortification) to 6.5 per 10,000 in 2009–2011 (post-fortification) and that about 1326 fewer infants have been born over this 3-year period with a neural tube defect (Williams et al. 2015). However, Hispanic babies are affected disproportionately (4.17/10,000 live births) compared to either non-Hispanic Blacks (2.64/10,000) or Whites (3.22/10,000) (CDC, 2015; Parker et al. 2010), indicating that either this population is not being reached (e.g., only wheat flour, not corn, is fortified) or there are other factors in play such as genetic predispositions or other environmental exposures. In the case of Mexican-American women, there is some evidence that fumonisins, mycotoxins that contaminate corn, may be involved in the etiology (Missmer et al. 2006).

Incomplete uptake of folic acid, either from fortification or supplements (or folate from food), is suggested by recently published data (Tinker et al. 2015) from the 2007 to 2012 National Health and Nutrition Examination Survey (NHANES), which showed that 23% of women of childbearing age have red blood cell (RBC) folate concentrations below the recently established World Health Organization (WHO) recommended cutoff (i.e., 400 ng/mL or 906 nmol/L) for the prevention of neural tube defects (WHO 2015). On the other hand, another study has reported that one in ten women took folic acid supplements that exceeded the tolerable upper limits for that vitamin (Hoyo et al. 2011); more research into the possible effects of too much folate is also needed.

Even considering incomplete protection from dietary folate deficiencies in spite of the fortification program, not all cases of neural tube defects are preventable by folic acid alone (Heseker et al. 2009), indicating that there are other factors involved. Using the data (*n* = 954 with neural tube defects; *n* = 6268 controls) from the National Birth Defects Prevention Study (1997–2005), it was found that other micronutrients, related to methylation or oxidative pathways, in addition to folate and betaine, when present at higher levels in the maternal diet (thiamin, iron, and vitamin A), were associated with a decrease in anencephaly among some groups of women. In others, higher intakes of thiamin; riboflavin; vitamins B6, C, and E; niacin; and retinol were associated with decreased risk of spina bifida (Chandler et al. 2012). Vitamin A deficiency during pregnancy has also been associated with congenital diaphragmatic hernia (Beurskens et al. 2013).

Other birth defects, including cardiac anomalies, limb defects, cleft lip, and/or palate, have been prevented by provision of folate alone (Berry et al. 1999) or, in combination with other vitamins, urinary tract defects and congenital hydrocephalus, according to a meta-analysis (Goh et al. 2006).

Further evidence for the importance of other micronutrients has come from data collected by the Hungarian periconceptional service between 1984 and 1994 (Czeizel et al. 2004). In a randomized controlled trial (RCT) to test the efficacy of a multivitamin supplement containing folate (0.8 mg) in the prevention of neural tube defects, researchers were surprised to find that not only were neural tube defects reduced by about 90%, but there was a very significant reduction (21 per 1000 population versus 41 per 1000 population) in the incidence of other major anomalies as well, notably cardiovascular anomalies and urinary tract defects (Czeizel 2009). Even when the neural tube defect cases were removed, the results remained statistically significant. The Hungarian group has published several articles examining folate with and without multivitamin supplementation and, based on their results, has strongly recommended that folate be recognized as preventing cardiovascular malformations as well as neural tube defects (Czeisel 2011) and that multivitamins be included in periconceptional supplements (Czeizel and Bánhidy 2011).

The US Public Health Service currently recommends that women capable of becoming pregnant consume 400 *μ*g of folic acid daily. Based on correlational data from Irish and Chinese studies (Cordero et al. 2015), the WHO recently recommended levels of maternal RBC folate >400 ng/ml in order to reduce the risk of neural tube defects. To determine optimal levels for supplementation to prevent birth defects, one approach would be to quantify the daily dietary amounts necessary to achieve a level in whatever biological sample is typically used to measure the status of the nutrient. For example, the next step in this case would be to examine the dietary intake necessary to produce those protective RBC folate levels.

In recognition of the importance of folate and zinc to the processes involved in cell division and DNA synthesis and that alcohol interferes with the metabolism of each of these nutrients, as well as providing calories devoid of any nutrients, it is not surprising that a recent publication (Young et al. 2014) has explored the nutritional etiology of fetal alcohol syndrome. Young and his colleagues provide a review of the current state of research on the effects of alcohol on folate and zinc metabolism, along with some of the other nutrients known to be essential to successful reproduction—vitamin A, docosahexaenoic acid (DHA), choline, vitamin E, and selenium—that have been studied in animal models in relation to fetal alcohol syndrome. The question these authors pose is an interesting one: What is the potential of preventing or at least mitigating the severity of the disorder, by providing nutrient supplementation for pregnant women who drink?

These findings provide support for the importance of optimal preconception nutritional status to long-term health development. According to the life course health development principles, we would predict that further research will implicate yet other nutrients and their interactions with the intrauterine environment in the development of a variety of birth defects. Even for conditions such as fetal alcohol syndrome, no single risk factor (such as alcohol) is likely to fully explain the development and severity of birth defects.

The complexity of intrauterine environmental interactions between nutrition and alcohol is further illustrated in a Danish National Birth Cohort study that found a lack of effect of mild to moderate alcohol intake (one to eight drinks/week; one drink = 12 gm pure alcohol) during early to midpregnancy on children's intelligence, executive function, or attention at age 5 (Kesmodel et al. 2012). It is possible that adequate nutritional status was a protective factor in these women. Although diet was considered in the study as a possible "confounding factor" (Olsen et al. 2001), the focus was on fish (omega 3s), iron, and breastfeeding. They did not evaluate how diet as a whole might have been a protective factor; the women sampled were largely middle class and so may be expected to have had adequate diets. Further research into diet as a protective factor among women who are moderate drinkers, as well as the implications of higher nutrient supplementation in an attempt to potentiate the damage to their fetuses in those whose alcohol intake is heavy is needed, particularly to confirm positive results, to determine optimal amounts of nutrients and types of nutrients that should be provided, and to investigate the collective effects of multiple-nutrient supplementation.

#### **2.1.2 Low Birth Weight**

Low birth weight has long been recognized as a risk factor for mortality and neurodevelopmental problems (Hack et al. 1995). When the infant is small for gestational age—that is, born either before or at term and weighing less than expected for his/her fetal "age"—it suggests that the fetus was malnourished in utero. Full-term low birth weight has an incidence of 5% of live births in the United States and is considered a proxy for intrauterine growth retardation (CDC 2011). Among women underweight preconceptionally, the prevalence of low weight gain during pregnancy is 23%, preterm birth 15%, and low birth weight 10%.

In 2009, the Institute of Medicine issued updated guidelines for weight gain during pregnancy based on World Health Organization body mass index categories (IOM 2009). (There were not enough data to recommend guidelines for adolescents, and this is an area needing to be examined.) A recommended action was to continue services, where needed, into the postpartum period to prepare women for the next pregnancy, assuring good nutrition and adequate weight gain. A recent meta-analysis has suggested that there are protective effects of maternal overweight or obesity on risk of delivering low birth weight infants, both in developed and developing countries, but especially the latter. However, there was also an increased risk of having an infant of very low birth weight (<1500 g) or extremely low birth weight (<1000 g); the heavier the woman, the higher the risk (McDonald et al. 2010). This seeming contradiction may be explained by a high risk for malnutrition due to a lack of micronutrients in obese women, as reported by Bodnar and Parrott (2012) and referenced earlier.

Two recent reviews of the potential effects of maternal multiple-micronutrient supplementation, as opposed to folate or iron alone, have clearly shown that there is a significant benefit on decreasing the incidence of low birth weight and babies born small for gestational age (Haider and Bhutta 2012; Zerfu and Avele 2013). Both reports recommend amassing more evidence through future, larger trials before moving to a universal policy change, as well as further studies to determine the optimal dosage and mix of the micronutrients to promote the best pregnancy outcomes.

The scope of this chapter does not extend to the examination of the literature concerning the many individual nutrients, or other environmental and social factors, that have been associated with the incidence of low birth weight. However, because of the current burgeoning interest in the effects of vitamin D beyond bone health (also related to undernutrition and deficiency in circulating concentrations of maternal vitamin D) (Javaid et al. 2005, 2006), it is worth mentioning that a recent study found an association between maternal vitamin D levels at 26 or fewer weeks of gestation and growth measures of newborns; serum vitamin D levels were positively related to birth weight and head circumference and negatively associated with the risk of an infant being born small for gestational age (Gernand et al. 2013).

#### **2.1.3 Developmental Origins of Adult Disease**

We now know that the embryo is particularly susceptible to "nutrient-induced adaptations in gene expression" (Waterland and Garza 1999). These adaptations, or developmental plasticity, have been defined as the ability of a single genotype to give rise to several different phenotypes which, teleologically speaking, allows organisms to adapt to their surrounding environmental conditions more rapidly than possible with evolutionary changes (Duncan et al. 2014). Some have suggested that the term "plasticity" was used to describe epigenetic phenomena before we had an understanding of epigenetics (Jablonski 2012). Whatever these phenomena are called, and some have suggested the term "evo-devo" (Jablonka 2012), there can be negative implications for life course health development when the prenatal and postnatal environmental conditions are dissimilar.

Beginning with the epidemiological observations of David Barker and his colleagues in England linking low birth weight to earlier adult mortality (Barker et al. 1989, 1993) and the subsequent fetal origins of adult disease hypothesis (Barker 1995), the consensus now is that undernutrition during the early stages of pregnancy results in epigenetic adaptations which prepare the fetus for survival in an extrauterine life where the environment is lacking in sufficient nutrients to support optimal development. If the infant, born with a low birth weight, is then exposed to an environment of plenty, there is a mismatch between the metabolic adaptations that took place prenatally and the demands of the extrauterine environment which can result in later chronic disease (Gluckman et al. 2008). For example, if the kidney develops with fewer nephrons in response to prenatal deprivation, the well-nourished adult may later be predisposed to hypertension (Stein et al. 2006). Christian and Stewart (2010) have published a conceptual framework (Fig. 2) that illustrates the pathways by which various organ systems may be affected by maternal micronutrient deficiency.

Barker's early hypothesis regarding the negative, lifelong consequences of poor nutrition during pregnancy, in spite of a presumably postnatal normal diet, has been supported by retrospective observations of life course health development of children prenatally exposed to starvation during the brief (6 months), but severe, Dutch famine during the winter of 1944–1945 when the Nazis laid siege to western Holland. Not only were these children more likely to experience coronary heart disease, decreased renal function, and decreased glucose tolerance in adulthood (Roseboom et al. 2006), but their offspring are shorter and heavier, which demonstrates the transgenerational effects of early nutritional insults on future health outcomes (Painter et al. 2008). This is possibly due to epigenetic changes occurring in fetuses exposed to the famine, which are then transmitted across generations (Tobi et al. 2009).

Similar findings of long-term health effects resulting from exposure to starvation during the developmental period have resulted from investigations following the Chinese famine of 1959– 1961 during the "Great Leap Forward" (Huang et al. 2010). Over 35,000 young women (average age 32 years), exposed during this period, were studied. In the 1958 and 1959 cohorts, postnatal exposure (1.5–3 years of life) was associated with reduced height, increased body mass index, and a threefold increase in the odds of hypertension for the 1958 cohort. Body mass index increased for the same postnatal exposure for the 1957 cohort, but decreased for the 1960–1961 cohorts for those exposed during pregnancy and infancy. The authors note the young age of the subjects and hypothesize that later in life there might have been more significant effects. Interestingly, they also document negative effects on economic productivity as measured by labor and earning findings.

In a study of adults exposed as infants to undernutrition before, during, and after the Biafran famine of 1967, both women and men experienced a higher prevalence of overweight, hypertension, and impaired glucose tolerance at 40 years of age (Hult et al. 2010). This reinforces the above findings suggesting that fetal and infant undernutrition are closely associated with the development of chronic disease as adults and that nutritional challenges in early life can result in changes to epigenetic regulation of genes which are detectable up to 60 years later (Lillycrop 2011).

#### **2.2 Growth and Obesity**

#### **2.2.1 Growth**

Although adequate, if not optimal, nutrition is recognized universally as being important to growth and life course health development, nutritional evaluations are rarely considered in population-based studies because of the difficulties (i.e., time intensity, expense) in collecting the dietary and/or biochemical data that would reflect the inadequacies in dietary intake and/or decreases in nutrient stores that precede growth faltering, as the body adapts to the decreased nutrient intake. This continuum in nutritional status from optimal health to overt disease is depicted in Fig. 3, which also shows the typical measures used in assessing nutritional status, as well as their level of sensitivity. Dietary assessment is the most sensitive in predicting, and therefore preventing, nutritional problems, followed by biochemical assessment, a measure of nutrient stores. As these assessments are rarely included, many studies of children's health development use growth as a proxy for nutritional status. Although growth is a clinical/ functional measure of nutritional status, it is not ideal, because it follows the usually chronic insufficient/poor nutrient intake which results in decreased nutrient stores. However, growth remains the most widely used and reported indicator of nutritional status and, if measurements are carefully taken, can be useful in monitoring growth rates in children or assessing nutritional health in populations.

#### **Sensitivity of Measures of Nutritional Status**

**Fig. 3** Continuum of nutritional status and sensitivity of assessment methods to detect risk/signs of malnutrition

Reduced stature caused by a combination of poor diet and disease burden in childhood, called "net nutrition" by some (Steckel 1995; Silventoinen 2003), is modifiable. Data from the Organization for Economic Cooperation and Development (OECD) have shown an increase in stature, generally attributed to the improvement in net nutrition, for most of the 34 member countries (OECD 2009), although there do seem to be upper limits to growth potential, as evidenced by the apparent plateauing of the increases seen in the Dutch population (Schönbeck et al. 2012). Interestingly, the United States has not shown the same gains as the other countries (Komlos 2008), a finding not likely explained by the influx of immigrants of short stature (OECD 2009).

The Institute of Nutrition of Central America and Panama in Guatemala conducted a study from 1969 to 1977 in which women and children in entire villages were exposed to supplemental nutrition; findings showed significant improvements both in children's stature and in pregnancy outcomes in intervention, compared with control villages (Martorell 1992; Martorell et al. 1995). Follow-up studies (1988–2007) showed that the nutritional intervention for girls also increased the body size of their offspring, again demonstrating the intergenerational effects of nutritional status (Behrman et al. 2009).

The idea that there is a universal potential for growth, regardless of the environmentally sensitive phenotypic expression of that potential, led to a study (1997–2003), sponsored by WHO, of the growth of infants and children from six different continents who were healthy at birth and breastfed for at least 6 months (the Multicentre Growth Reference Study). The results strongly suggested that all human infants, regardless of racial or cultural background, have the genetic potential to achieve similar stature under optimal conditions (de Onis et al. 2004). These findings were considered robust enough for the WHO to adopt them as universal reference data for growth (WHO 2006); the international WHO Child Growth Standards, from 0 to 5 years of age, are now used in more than 140 countries worldwide (de Onis et al. 2015). In the United States, the Centers for Disease Control and Preventions have recommended their use for children 0–2 years, recognizing that the growth of breastfed infants should be the standard (Grummer-Strawn et al. 2010).

Data from the INTERGROWTH-21st Project (the International Fetal and Newborn Growth Consortium for the 21st Century), which assessed fetal growth and newborn size among healthy pregnant women in eight urban populations (Brazil, China, India, Italy, Kenya, Oman, the UK, and United States), have provided similar international convergence in growth potential. From 2009 to 2013, assessments of over 4600 women with problem-free pregnancies (out of 60,000) were done using ultrasound measurements at 5-week intervals from week 14 to delivery. Again, similar results in growth across ethnicities and countries suggested that most of the variation in the average size of babies born in different places around the world is due to nutritional and other socioeconomic and healthcare differences (Villar et al. 2014a). Thus, these data, representing optimal fetal growth, have been used to construct fetal growth charts to be used universally, in conjunction with the WHO charts, as a clinical tool to assess maternal, fetal, infant, and early childhood health and nutritional status on both the individual and population-based levels (Chatfield et al. 2013; Papageorghiou et al. 2014). For the newborn standards, meticulous measurements of weight, length, and head circumference for more than 20,000 babies born between 33 and 42 weeks' gestation during the same study were used to generate the charts, representing the first international standards for newborn growth under optimal conditions during pregnancy (Villar et al. 2014b).

#### **2.2.2 Obesity**

As the world goes through a "nutrition transition" from inadequate food to relative overabundance, adaptation to poor diets of a different sort in an age of "overnutrition" has no evolutionary precedent. Physiological constructs have been programmed from Paleolithic times, when we were hunters and gatherers, to conserve energy as fat in times of plenty to serve as energy stores for periods of relative food scarcity. At that time and up until the last century, most humans were very active physically and, because of their highenergy needs, consumed enough food to meet micronutrient needs as well. Today, a sedentary lifestyle means that we must be selective about our food choices to meet micronutrient needs with a lower energy intake. In fact, obese people may also be malnourished even while exceeding their energy needs if their diets are nutrient poor.

This double burden of malnutrition presents interesting challenges, with regard to which nutrients to supplement for optimal birth outcomes, when overweight or obese mothers coexist with underweight children in the same household. Until recently, the double burden was considered a phenomenon more common in lowand middle-income countries. However, data from the Danish National Birth Cohort studies reveal that obese women have a higher risk of micronutrient deficiencies (Bodnar and Parrott 2012). These data demonstrate that micronutrient deficiencies associated with pregnancy in overweight/obese women are becoming increasingly an issue in both affluent and lower- and middleincome countries and may further negatively impact birth outcomes, particularly the incidence of preeclampsia and low birth weight (Darnton-Hill and Mkparu 2015), and may explain the apparent contradiction mentioned earlier with regard to obesity being at the same time a potential protective factor for birth weight, but also a risk factor (McDonald et al. 2010).

There are many causes underlying the current worldwide "obesity epidemic," including many that are based in cultural, social, and political as well as biological factors. Genetics, epigenetics, and even causes related to the microbiome (discussed later in the chapter) are currently being studied intensely. However, the bottom line is that obesity is caused by increases in dietary energy (much of it nutrient-poor food) that is not compensated for by increased energy output.

Paradoxically, the increasing concern about obesity and its role in the predisposition to metabolic disease has resulted in the growing interest in the developmental origins of health and disease, discussed earlier.

The Newborn Epigenetics Study, a federally funded research project based at Duke University, is studying how pre- and postnatal environmental exposures, including nutrition, affect the epigenome, with a special interest in obesity. A paper, recently published by this group, examined the potential associations between DNA methylation patterns in newborns and parental preconception obesity and found that hypomethylation of the IGF2 gene in newborns is associated with paternal obesity (Soubry et al. 2013). The contribution of the father to pregnancy outcomes—mentioned earlier with regard to folate—is an area of research that has potentially important implications for the public health community with regard to the development of new and different population intervention strategies.

While an inverse relationship between total serum vitamin D and increased adiposity has been established in children, adolescents, and adults, the relationship between neonatal adiposity and vitamin D status has only recently been investigated. Researchers found that infants born to lean mothers had a third higher amount of vitamin D compared to infants born to obese mothers (Josefson et al. 2012). Obese women in this study transferred less vitamin D to offspring than normal weight women, despite similar serum levels, possibly due to sequestration of this fat-soluble vitamin in their adipose tissue. These findings underscore the evolving relationships between maternal obesity, vitamin D nutritional status, and adiposity in the neonatal period that may influence subsequent childhood and adulthood vitamin D-dependent processes (Josefson et al. 2012).

#### **2.3 Neurological Development**

The brain continues to grow rapidly after birth for the first 2–3 years of life, coinciding with a high iron requirement. Iron deficiency is the most prevalent nutritional problem worldwide, because after 6 months of age, even breastfed infants need an additional source of iron (WHO 2011). Multiple studies, dating back to the mid-twentieth century, have investigated the effects of iron deficiency and iron deficiency anemia on the development of infants and young children, which support the claim that there is a causal relationship between iron deficiency anemia and poor performance on measures of psychomotor and cognitive development, particularly when the anemia is severe (McCann and Ames 2007). In cases in which a child is iron deficient but not anemic, the findings are equivocal (Sachdev et al. 2005; Szajewska et al. 2010).

Other nutrient deficiencies in early childhood can also impact the ability to learn and affect school readiness, which in turn can alter lifelong achievement and increase inequalities in life course health development (WHO 2011). The importance of folate and iron to brain formation has already been mentioned. Another animal study has shown that offspring of pregnant rats fed a mildly zinc-deficient diet, compared to those of controls and supplemented rats, showed decreased learning and memory ability that was reflected in changes in the morphology of the hippocampus (Yu et al. 2013).  Unfortunately, the placental transport of vitamin C is not active, and it appears to be insufficient in the case of vitamin C deficiency (Norkus et al. 1979). In animal models, even marginal vitamin C deficiency in the mother stunts the development of the fetal hippocampus, the important memory center, permanently impeding optimal development of the brain even if guinea pig pups were given vitamin C after birth. (Tveden-Nyborg et al. 2012). This study has implications for the 10–20% of all adults in the developed world with vitamin C deficiency, including the most vulnerable populations who already suffer from health and socioeconomic disparities and who may also have poor dietary habits and perhaps smoke cigarettes, both of which increase the risk of vitamin C deficiency (Montez and Eschbach 2008).

Polyunsaturated fatty acids are essential nutrients for humans; omega-3 (synthesized from linolenic acid) and omega-6 (synthesized from linoleic acid) long-chain polyunsaturated fatty acids are involved in the development and maturation of neuronal structures, serve as structural and functional components of cell membranes, and are precursors of eicosanoids, which exert hormonal and immunological activity. The central role of the omega-3s DHA and eicosapentaenoic acid (EPA) in the development and functioning of the brain has met with growing research interest with regard to neurological development in children, including visual acuity (Schuchardt et al. 2008). In early studies, when it was recognized that infant formulas were lacking in DHA and EPA, it was shown that retinal development (Birch et al. 1992) and visual evoked potentials (Faldella et al. 1996) in very low birth weight infants were improved if they were supplemented with these omega-3 fatty acids. The effects of supplementation on visual acuity in term infants has also been shown (Birch et al. 2005), but not consistently. In addition, the effects of oral supplementation of omega-3 fatty acids during pregnancy on early childhood development, especially visual, were inconclusive (Gould et al. 2013). In a meta-analysis of 12 studies (1949 infants up to 12 months of age), omega-3 supplementation of infant formulas appeared to have possible effects on visual acuity as measured by evoked potential for infants 2 months of age and by behavioral methods at 12 months (Qawasmi et al. 2013). In another meta-analysis conducted by the same authors evaluating the effects of omega-3 supplementation of infant formula, no effects on general cognition were identified (Qawasmi et al. 2012).

Omega-6 fatty acids are also essential, but their metabolites are more inflammatory than those of omega-3, and some researchers believe that the ratio of omega-6 to omega-3 fatty acids that are consumed fall within a range of 1:1–1:4 (Lands 2005). Others believe that a ratio as high as 4:1, which is thought to approximate the ratio obtained in the diets, rich in animal meat and seafood, of our earliest ancestors, is still healthy (Simopoulos 2002). Currently, typical Western diets provide dramatically higher ratios of between 10:1 and 30:1, which may be of concern (Hibbeln et al. 2006; Schuchardt et al. 2010). The significance of these findings has been related to current dietary practices that result in an increased intake of omega-6 precursors (vegetable oils, processed and fast foods, meat) over those of omega-3 (fish, nuts, legumes).

A review of studies considering the significance of polyunsaturated fatty acids related to the development of behaviors in older children has found equivocal evidence in support of an association, although numerous observational studies have shown a link between omega-6 to omega-3 imbalances and some developmental disorders, including attention deficit hyperactivity disorder (ADHD) and autism (Schuchardt et al. 2010). In an RCT, conducted by Vaisman et al. (2008), among 60 children, aged 8–13, with impaired visual sustained attention, an improvement in performance test scores was seen in those supplemented with either EPA or EPA plus DHA compared to those receiving the placebo. Frensham and coworkers (2012) suggest that among children and adolescents, the greatest benefits of omega-3s in the diet are seen in trials with durations of at least 3 months and in subgroups of children with low socioeconomic status, learning disabilities, and ADHD or ADHD-type symptoms, which might explain the reported discrepancies.

#### **2.4 Immune Function and Oxidative Stress**

With respect to the development of the immune system, animal models show that exposure to omega-3s during gestation and lactation resulted in a more permeable gut, allowing new substances to pass through the lining and into the bloodstream more easily (De Quelen et al. 2011). The new substances then trigger the fetal immune response and the production of antibodies. This results in the potential for a more developed and mature immune system with better immune function, which could be important for the prevention of allergies as a child develops. Supporting this is a recent periconceptional multi-micronutrient supplementation intervention (vs. placebo) with malnourished Gambian women which led to differential methylation of genes, some of which were associated with the immune function, in their offspring at birth, and also at 9 months of age (Khulan et al. 2012).

Zinc has been shown to be required for the activation of at least 300 enzymes and for the gene expression of nearly 2000 transcription factors (Prasad 2012). It serves as an intracellular signaling molecule, playing an important role in cell-mediated immune function and oxidative stress (Prasad 2009). An estimated 17% of the global population is at risk for inadequate zinc intake, ranging from 8% in high-income regions to 30% in South Asia (Wessells and Brown 2012). Provision of zinc supplementation has been shown to decrease oxidative stress markers and inflammatory cytokines (Prasad 2008a, b). This is an interesting example of the dependence, as described by Hambidge (2000), of many metabolic processes important to life course health development, including the immune system, on the presence of a trace mineral. Certainly, the role of zinc, and other trace elements once thought to be insignificant, needs further investigation.

#### **2.5 Healthy Aging**

The aging process begins before birth with epigenetic changes that affect gene regulation. In addition to fundamental changes in organ structure, it has also been increasingly demonstrated that epigenetic mechanisms, which are susceptible to the presence or absence of certain nutrients during critical growth periods, establish long-lasting patterns of gene expression. Some of these have been discussed earlier in the chapter. The nutrient needs of individuals over 50 have only recently been explored; the oldest age category in the last edition of the Recommended Dietary Allowance (RDA), published in 1989, was 50 and over (Food and Nutrition Board 1989). This was largely because the studies carried out to determine nutrient needs used young subjects and were focused on deficiencies and extrapolating beyond the age of 50 was not deemed reasonable. With an aging population and an increased interest in the relationship between nutrition and chronic disease, there were calls to determine the RDAs for older adults (Russell 1997). In the newly defined series, the Dietary Reference Intakes, first published in 1997 and updated with regularity, the age categories were expanded to include 50–70 years and 70 and older (Food and Nutrition Board 1997), using data from the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. The following is a brief overview of some of the nutrients that the latest research has shown to be potentially important for healthy aging.

The traditional function of vitamin D is understood to involve the release of 1,25 vitamin D into the circulation, after which its effects are targeted on end organs involved in calcium and phosphorus homeostasis, such as the kidney, intestines, parathyroid, and bone (Jones 2007). However, we now know that there is a vast array of other biological functions in which vitamin D plays a role in and that these functions actually represent the bulk of daily metabolic utilization of vitamin D (Jones 2007; Heaney 2008). The recognition of these new pathways has led to newly ascribed paracrine functions of vitamin D that include multiple organ systems such as the cardiovascular (Heaney 2008; Verstuyf et al. 2010), renal, and immune systems. These systems are believed to activate vitamin D locally, via vitamin D receptors, to regulate cell and tissue growth and differentiation (Falkenstein et al. 2000), as well as to serve as precursors of enzyme cofactors, all integral to the intact functioning of numerous metabolic processes (Heaney 2008; Rostand and Warnock 2008). The widespread presence of vitamin D receptors supports the extensive range of physiological functions of 1,25 vitamin D (Dusso and Brown 1998). As such, vitamin D has a number of important effects on both developmental and lifelong health trajectories.

As an example of the role vitamin D plays in the development of long-term health outcomes, substantial evidence has linked low circulating vitamin D levels to increasing risk and incidence of cardiovascular disease (CVD) (Poole et al. 2006; Wang et al. 2008) and also suggests the possibility that vitamin D repletion may reverse or attenuate what remains the leading cause of mortality in the United States (Ford et al. 2011). In the cardiovascular system, the mechanisms responsible for vitamin D's effects appear to be mediated through the interaction of activated vitamin D with the intracellular vitamin D receptors within vascular smooth muscle, endothelium, and heart muscle cells. These mechanisms serve to modulate key processes involved with the pathogenesis of CVD including vascular inflammation (Rigby et al. 1987), platelet aggregation (Aihara et al. 2004) and vascular smooth cell proliferation, vascular calcification, and more (Artaza et al. 2009, 2010).

Age-related effects of vitamin D include its protective effects against Alzheimer's disease (Annweiler et al. 2012), improved cognitive health in older women (Annweiler et al. 2013), and improved mobility among older adults (Houston et al. 2013). Vitamin D plays an important role in the development and maintenance of muscle mass, particularly in institutionalized elderly, and is recommended for optimal musculoskeletal health (Mithal et al. 2012).

In addition to vitamin D, omega-3 fatty acid intake appears to influence the aging process. Adequate intake of omega-3 fatty acid supplements, to improve the balance of omega-3s to omega-6s, may slow a key biological process linked to aging. Among overweight middle-aged and older adults who took omega-3 supplements for 4 months, the ratio of their fatty acid consumption was altered in a way that helped preserve white blood cell telomeres, which normally shorten during the aging process (Kiecolt-Glaser et al. 2013). The improved omega ratio also resulted in reduced oxidative stress, caused by free radicals in the blood by about 15% compared to those in the placebo group. Other benefits of omega-3 intake for older adults include its putative role in the prevention of dementia and predementia. In the results from a meta-analysis of more than 2200 elderly subjects and matched controls with cognitive deficits, the latter had lower serum levels of EPA, DHA, and omega-3 fatty acids, while serum levels of EPA alone were significantly lower in those with pre-dementia. This indicates that EPA might not only be a disease state marker but may indicate increased risk for cognitive impairment as individuals age (Lin et al. 2012). All of these studies demonstrate that omega-3 fatty acid intake across all phases and stages of the life course is important and has the potential to alter health development outcomes, although there is some controversy regarding whether or not the omega 6/omega 3 ratio is important (Willett 2007).

There is also some evidence that vitamin E, with its antioxidant properties, may protect against memory loss in older adults. In a prospective study carried out in Finland, a sample of 140 over 65-year-olds with no memory impairment at the onset of the study was followed for 8 years, during which time it was found that higher total serum levels of vitamin E (alpha-tocopherol), as well as the other forms of the vitamin, seemed protective against memory disorders (Mangialasche et al. 2013). A recent study, using a zebra fish model, showed that a diet deficient in vitamin E—equivalent to a human lifelong deficiency—resulted in about 30% lower levels of DHA phosphatidylcholine (DHA-PC), which is a part of the cellular membrane in every brain cell or neuron, indicating that DHA-PC may be a good predictor of a higher risk for Alzheimer's disease (Choi et al. 2015). A recent meta-analysis found that patients with Alzheimer's disease, compared with cognitively intact elderly controls, had significantly lower plasma alphatocopherol concentrations (Lopes da Silva et al. 2013).

A recent large RCT involving over 500 patients with mild to moderate Alzheimer's disease at 14 Veterans Affairs medical centers found that 2000 IU/day of alpha-tocopherol compared to a placebo resulted in a slower cognitive functional decline (Dysken et al. 2014). Although supplements have been found to have benefit in slowing Alzheimer's disease progression, they do not seem to prevent Alzheimer's disease occurrence (Traber 2014). Because 96% of adult women and 90% of men in the United States do not receive adequate levels of vitamin E in their diet (Choi et al. 2015), it would seem that additional studies are needed to explore further risk reduction related to the development of cognitive impairment.

Further evidence of the preventive value of folate in reducing the risk of cardiovascular disease and stroke has been provided by recent studies. A meta-analysis of eight randomized trials which assessed the use of folic acid supplementation in the primary prevention of stroke showed beneficial effects, especially in trials that lasted longer than 3 years (Wang et al.

2007). The China Stroke Primary Prevention Trial, a large (*n* = 20,702) randomized, doubleblind clinical trial that took place in 32 communities over 5 years, also examined folic acid's effects on cardiovascular disease (Huo et al. 2015). Participants were given either enalapril (a drug used to treat hypertension) alone or in combination with folic acid. The results showed that the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These examples (folate and vitamin E) both illustrate how the accumulation of a lifetime of inadequate intake of a nutrient may contribute to the development of a serious disease and also that improved nutrient intake can result in some degree of amelioration of chronic disease symptoms.

While adequate intake of specific nutrients has been shown to help preserve structure and function of the body with aging, a number of studies in model organisms have also demonstrated the benefits of caloric restriction. A 20–40% reduction in calorie intake reduces levels of insulinlike growth factor I and other growth factors, which has been consistently associated with increased lifespan, and prevents the development of age-associated cardiovascular functional and structural changes (Fontana et al. 2012; Wei et al. 2008). In animal models, caloric restriction is associated with reduced cancer risk (Longo and Fontana 2010), likely through similar mechanisms as described above, in addition to reduction in circulating levels of anabolic hormones, inflammatory cytokines, and oxidative stress markers (Hursting et al. 2003; Fontana and Klein 2007). Further, caloric restriction reduces glucose uptake and lactate concentration, which preserves vascular function. Therefore, the effects of caloric restriction appear to be neuroprotective (increased presence of ketone bodies, improved cerebral blood flow), which seems to play an important role in preserving brain physiology in aging (Lin et al. 2015).

#### **3 The Importance of Food**

#### **3.1 Food Versus Nutritionism**

We have highlighted the importance of individual nutrients to optimal health development. Nonetheless, we must emphasize that focusing on nutrients alone provides an incomplete picture. The tendency to isolate nutrients, to use them to fortify foods, and to manufacture supplements can lead to what Michael Pollan (2008) and others (Lang et al. 2009) have called "nutritionism," or the emphasis on individual nutrients rather than food. The science of nutrition has progressed to the point where we have amassed a great deal of information about nutrients, their metabolic roles, their influence on gene regulation, and ways that the physical and social environments interact with nutritional intake. The complexity of these interactions, which are dynamic, are continuous, and work on multiple levels, is typical of life course health development phenomena.

However, we cannot assume that we have no further discoveries to make regarding the thousands of bioactive compounds contained in food itself. Nutrition science is not yet able to "copy" nature; there remain elements, present in natural foods, that promote health development and which we are still just beginning to understand. An example of this is the ongoing attempt to emulate breast milk in infant formulas as newly recognized components of breast milk are uncovered. In the 1990s, it was shown experimentally that adding additional zinc than that found in breast milk to infant formula improved growth in male infants (Walravens and Hambidge 1976). Further investigation revealed that the zinc in breast milk is more biologically available than that in formula, due to the presence of previously unrecognized factors that enhance its absorption (Sandstrom et al. 1983; Blakeborough et al. 1986). DHA, one of the omega-3 acids, was not added to infant formula in this country until the mid-1990s, although we now know that this compound, present in breast milk, is critical to optimal infant health development. Thus, simply replicating the nutrient composition of breast milk, or of any other naturally occurring foods, cannot replicate all of the potentially bioactive compounds, as it is likely that there are as yet other unknown factors in all foods that positively affect health development.

There has been an evolution in the definition of dietary nutrient sufficiency in the past two decades. The Recommended Dietary Allowances were largely based on empirical criteria that established minimum nutrient requirements by assuming that individual requirements were normally distributed and recommending amounts that would meet the needs of 97.5% (two standard deviations above the mean) of the population. The newer Dietary Reference Intakes (DRI), besides being expanded to include older age categories as mentioned above, are based on the idea that optimal nutrient intakes should be the standard. As a part of establishing the DRI values, upper limits of intake are now also being recommended, along with the Estimated Average Requirement (EAR), recognizing that the new approach could lead to problems with exceeding safe intake level of some nutrients, particularly the fat-soluble vitamins, or nutrients like iron which are not readily excreted (see Fig. 4).

Going back to the "folate story" for another example, one of the objections to universal fortification in the United States was based on the fact that increased folate in the diet has the possibility of masking the pernicious anemia caused by a lack of vitamin B12. Deficiencies of vitamin B12 affect elders for whom its dietary absorption becomes less efficient and, if not recognized, can progress to severe neurological problems. Excess nutrient intake can also be an issue for young children because of the tendency of the food industry to "over-fortify" many of the foods intended for this age group. Most breakfast cereals, for example, have high levels of added nutrients, as do "snack foods," to make them more appealing to parents who often provide "vitamin pill" supplements to their children as well. The influence of excessive levels of certain nutrients on health development is an important area for research.

#### **3.2 Food and Other Bioactive Compounds**

As we delve more deeply into the biochemistry/ metabolism of the individual nutrients, we are simultaneously realizing that our nutritional health depends not only on essential vitamins and minerals, as well as the optimal balance of the macronutrients that fuel our bodies, but also on the other bioactive compounds in our food, commonly referred to as phytochemicals or phytonutrients (Erdman et al. 2007; Beecher 1999). These include important subgroups such as carotenoids and phenolics, which are primarily derived from plant-based foods and are thought to convey

**Fig. 4** Dietary Reference Intakes (Food and Nutrition Board 1997)

important health benefits. While there are more than 600 carotenoids identified in nature, nutrition research has focused primarily on just a handful, alpha-carotene, beta-carotene, betacryptoxanthin, lutein, zeaxanthin, and lycopene, because of their prevalence in both food and the body (Holden et al. 1999; Linus Pauling Institute 2015). Polyphenols are a diverse group of phytochemicals that include many of the molecules that give fruits and vegetables their colors. More than 8000 polyphenols have been distinctly identified to date (D'Archivio et al. 2007; Pandey and Rizvi 2009), and very little is known about the metabolic activity for the majority of them. Flavonoids, the most abundant of the polyphenols in the human diet, are comprised of many subclasses of compounds based on chemical structure (Scalbert and Williamson 2000; Mulvihill and Huff 2010). Flavonoids that have been well explored in the literature include anthocyanidins, found in red, blue, and purple fruits (Erdman et al. 2007) and vegetables, quercetin (Manach et al. 2004), and ellagic acid, primarily found in berries (Beecher 2009; Clifford and Scalbert 2000). Resveratrol, a polyphenol belonging to the group of stilbenoids, is found in the skin of wine grapes, both white and red. However, more frequent maceration in red winemaking allows the resveratrol to be released into red wine at a rate ten times higher than that of white wine.

Both carotenoids and polyphenols have potential health benefits. Carotenoids may reduce the risk for heart disease, particularly from intake of beta-carotene (Mente et al. 2009), while studies on lycopene show potential for the prevention of prostate cancer (Khan et al. 2010). Lutein and zeaxanthin may be instrumental in reducing the effects of oxidative injury that contribute to the development of age-related macular degeneration (Olson et al. 2011). Flavonoids have been studied for their anti-inflammatory characteristics (Garcia-Lafuente et al. 2009), while studies in animal models provide evidence that ellagic acid may reduce DNA damage (Aiyer et al. 2008). Stilbenoids such as resveratrol have been shown in animal models to prevent cancer, increase endurance, and lessen the consequences of obesity, including the loss of insulin sensitivity and increase in mortality rate (Jang et al. 1997; Baur et al. 2006; Lagouge et al. 2006). However, it should be noted that the amounts needed to produce such effects far exceed what could be obtained from usual dietary intake (Walle et al. 2004; Wenzel and Somoza 2005; Vitaglione et al. 2005).

In addition, recent analyses from national food consumption surveys in the United States (Murphy et al. 2012), Korea (Lee et al. 2013), and globally (Murphy et al. 2014) indicate that despite dietary recommendations that underscore the importance of increasing consumption of fruits and vegetables, intakes worldwide are lower than recommended. As a result, the diets of many individuals may be lacking in nutrients and phytonutrients typical of a diet rich in a variety of fruits and vegetables. Each of these studies demonstrates that individuals with the highest intakes of fruits and vegetables also have the highest intakes of phytonutrients, yet the sources of these phytonutrients in each of these studies are derived from just a few types of fruits and vegetables. This means that many of the essential nutrients already mentioned (e.g., vitamins A, C, and E and folate) that also play key roles in supporting optimal health are lacking in the diets of the majority of people. These data underscore one of the reasons why diets domestically and globally are suboptimal; without adequate access to fruits and vegetables, it is not possible to obtain essential nutrients let alone phytonutrients.

Optimizing the intake of specific foods and/or their bioactive components is a reasonable and cost-effective strategy for disease prevention. However, defining "the" ideal food pattern is challenging for a number of reasons including the difficulty in determining the required quantity of a particular food or nutrient to bring about the desired response as well as a host of nutrientnutrient and nutrient-gene interactions that can occur (Milner 2008; Mariman 2008; Ferguson 2009; Ahmed et al. 2009; Simopoulos 2010). Even though there is not sufficient information to formulate the "ideal diet," there is sufficient knowledge to justify a call for future food-oriented health research (Milner 2008). In addition, it is becoming increasingly clear that individuals do not respond identically to the foods they consume. Therefore, as we begin to better understand the critical roles that multiple food components have in regulating cellular events and how these are influenced by genetic and epigenetic events, cultural and lifestyle differences, as well as our individual physical and social environments, the greater is our ability to develop a more individualized or personalized approach to our diets and to optimize our nutritional health (Kannan et al. 2008; da Costa et al. 2007; Kaput 2008). Since those compounds, which are growing in number, have yet to be fully understood, the importance of whole food itself, as opposed to simply the nutrients it provides, is becoming paramount again, as illustrated in Fig. 1.

#### **3.3 Food and the Microbiome**

An important area of emerging research focuses on the relationships between the microbiome and food and is helping to explain why individuals do not metabolize food in the same way. The human microbiome encompasses the collective genetic material of microbial communities found on several different sites on and inside the human body including the nasal passage, oral cavities, skin, urogenital tract, and the gastrointestinal (GI) tract and refers to the genetic information that these microorganisms carry (Ursell et al. 2012). In contrast, the human microbiota consists of 10–100 trillion symbiotic microbial cells, which are found primarily in the gut of every person (Turnbaugh et al. 2007). Evidence for a strong link between a person's microbiota, digestion, and metabolism is increasing. For example, in animal models, dietary changes have led to significant alterations in bacterial metabolism, especially small-chain fatty acids and amino acids, in as little as 1 week (Ley et al. 2008; Martin et al. 2010), and can lead to large changes after only 1 day (Turnbaugh et al. 2009). Perhaps most importantly, the genetic diversity found within our gut microbiota allows us to digest compounds via metabolic pathways not explicitly coded for in the mammalian genome, which greatly increases our ability to extract energy from our diverse diets. Therefore, these pathways are important linkages to understanding the individual differences in nutritional intake and how nutrients are utilized in our bodies to affect our health or risk for disease.

In addition to being an adjunct to the basic function of the human digestive system, the human microbiota have an important influence on the body's physiological, nutritional, and immunological processes and are able to modulate the expression of host genes that regulate diverse and fundamental physiological functions. Some of the ways in which the microbiome affects our health include its role in energy harvest from the gastrointestinal system, vitamin production, development and maintenance of the gut itself, metabolism of drugs and xenobiotics, deconjugation and metabolism of bile acids, and modulation of the immune system (Cerf-Bensussan and Gaboriau-Routhiau 2010; Young 2012; Maynard et al. 2012). However, despite the essential functions provided by the gut microbiome, the composition of each individual's microbiome is distinct (Costello et al. 2009). The individualized nature of the gut microbiome is related to a number of factors, including host genetics, age, diet, and health status and other processes like antibiotic use and birth delivery mode (Spor et al. 2011). To complicate things further, the amount of temporal stability in one's microbiome also appears to be personalized (Flores et al. 2014).

Nevertheless, a number of trends relating the composition of the microbiome to host health are beginning to emerge. In particular, changes in the dominant types of microorganisms living in the human gut have been associated with obesity in adults and model organisms (Backhed et al. 2004; Tremaroli and Backhed 2012; Ley et al. 2005, 2006; Turnbaugh et al. 2006). The relationship of the gut microbiome to obesity has become a focus of research. Although causality between the gut microbiome and obesity has yet to be established, findings from a number of studies suggest that the microbiome of obese individuals has an increased ability to extract energy from food. The gut microbiome has also been suggested to play a role in other inflammatory diseases (e.g., cardiovascular diseases, diabetes, and cancer) through the production of pro-inflammatory compounds that can cause chronic low-grade inflammation (Heilbronn and Campbell 2008; Tremaroli and Backhed 2012; van Olden et al. 2015; Hartstra et al. 2015).

Although several other factors play a role in the pathogenesis of obesity, the composition of the gut microbiome is now considered an important environmental factor and a potential therapeutic target for treatment of obesity (Tremaroli and Backhed 2012; Hartstra et al. 2015). Moreover, recent research suggests that not only are the metabolic products that result from carbohydrate digestion important in the etiology of obesity (e.g., short-chain fatty acids such as acetate, propionate, and butyrate) but that these factors may also have effects on appetite regulation through signaling of the hypothalamic region of the brain (Corfe et al. 2015).

The microbiome not only affects physical health but also our mental health across the life course. Patients with various mental health disorders appear to experience alterations in the stability, structure, and composition of fecal microbiota (Jiang et al. 2015; Mayer et al. 2014a), which in turn affect the severity of their disease. Scientists speculate that alterations in the gut microbiome may play a pathophysiological role in human brain diseases, including autism spectrum disorder, anxiety, depression, and chronic pain through bidirectional signaling between the brain and the gut microbiome involving multiple neurocrine and endocrine signaling mechanisms (Mayer et al. 2014b; Wang and Kasper 2014; Rosenfeld 2015). This research starts to bring together the effects that the microbiome has not only on physical health but also on mental and emotional health.

#### **4 Conclusions and Future Directions**

In this chapter, we have mainly considered population-based issues. However, if diet can be used to alter phenotypic expression of our genes, then nutritionists, food scientists, and physicians may also be able to work together to design personalized diets to prevent disease and optimize health development outcomes.

To affect maximum preventive benefit, dietary changes should begin early in life, ideally with breastfeeding, but, if not, with a formula more closely resembling breast milk than at present. Studies testing this hypothesis have already begun. The European Childhood Obesity Project, which has enrolled 1000 infants from five countries, tested an infant formula lower in protein, to more closely match that of breast milk, against the typically higher protein formula and a breastfed group, and found that the growth pattern of the infants more closely resembled that of the breastfed infants as well as the trajectory on the WHO growth charts referenced on breastfed infants (Koletzko et al. 2009). Given the importance of diet during this sensitive period in life course health development and in response to growing demand, the Agricultural Act of 2014 (Farm Bill) officially called for the Dietary Guidelines for Americans to expand to include infants and toddlers (ages 0–2), as well as women who are pregnant, beginning with the 2020 edition (USDA CNPP 2015). The US Department of Agriculture (USDA), in collaboration with Department of Health and Human Services (DHHS), is currently in the evidence-gathering phase (Jan 2015–Jan 2017) prior to developing a technical report to submit to the 2020 Dietary Guidelines Advisory Committee.

The fact that food is related to our health has always been obvious. However, as we have attempted to show, that relationship is very complex, and our understanding of its importance is growing with technological advancements, both in nutritional science and also in the numerous fields of study that have contributed to our knowledge base. That epigenetic mechanisms are so closely linked to the nutrients in our food (Jimenez-Chillaron et al. 2012) suggests that these mechanisms have allowed us to adjust rapidly to changes in our diet over the course of evolution, modifying the expression of our genes to adapt metabolically to a changing environment.

The effect of environmental stressors, other than nutrition, on inheritable epigenetic changes has been recognized and explored perhaps more fully to date (Jablonka 2012), while the importance of nutrition has been underrated, in spite of the rich literature on the subject (Horton 2008; Hanson et al. 2015)). Thus, we would like to echo Horton (2008), quoted at the beginning of the chapter; because of its key role in promoting optimal life course health development, especially for mothers, infants, and children, nutrition should no longer be "neglected." It is time for the attention of the maternal and child health community to turn toward nutrition, as we would argue, along with FIGO (Hanson et al. 2015), the most important environmental factor in the determination of life course health outcomes. As FIGO now recommends for gynecologists and obstetricians, we all need to "Think Nutrition First" (Hanson et al. 2015).

Areas for further study have been alluded throughout the paper. The long-term consequences of periconceptional nutrition to pregnancy outcomes and early development must be recognized; epigenetic changes during periods of rapid health development can have lifelong effects and intergenerational consequences. At the same time, we know that dietary changes at any time during the life course can ameliorate potentially inimical nutritional status.

We have also emphasized that the focus of the "power" of nutrition for life course health development has moved from the centuries-old attention paid to food, to elucidating, during the past century, an understanding of the role of specific nutrients and other bioactive components in food, and now back to food itself as the source of as yet unknown, but potentially important, other health-supporting elements (Fig. 1). The effects of food as translated through the microbiome is an emerging area of research that is likely to affect how we think about the composition and quantity of the food in our diet and the consequences for life course health development at all levels, from physical to mental and emotional health. It is, therefore, essential that access to enough food and the appropriate quality foods be available to all populations to afford the opportunity for optimal health development.

The recognition of nutrition as a central environmental determinant that all investigators should include in their assessment of life course health development and promotion is now becoming more widespread. Therefore, we invite and embrace other disciplines and health professionals to gain a better understanding of the centrality of nutrition and to work together in an effort to optimize population and individual health.

While more extensive than this chapter has space to allow, it bears mention that it is expected that the outcomes of research into the role of nutrition in life course health development would be further translated into priority-setting strategies for both practice and policy development. One current jumping-off point is the recent development of a healthcare system which promises to provide coverage for most Americans. This provides policy-makers, as well as healthcare professionals, an opportunity to switch from a focus on secondary prevention and treatment to a concentration on primary prevention. This should begin, we would argue, with optimizing diets, taking advantage of the current trend among consumers to recognize food as an avenue to health. In addition, recent clinical interventions, such as physicians offering patient's prescriptions to purchase healthy foods, would be a part of such a conversation (Brody 2014), as would the new recommendation by the American Academy of Pediatrics that pediatricians screen families with children for evidence of food insecurity (2015), given the impact of nutrition on health development. Other practice-oriented efforts such as authorizing reimbursement for nutrition services in multiple settings, including those providing primary preventive (e.g., inter-conception care) as well as secondary preventive care (e.g., diabetes) and placing more importance on educating healthcare providers in the basics of nutrition science, would go a long way to improving service delivery and promoting health development across the life course.

With respect to the food industry, broadly speaking, it would be important for those professionals to work collaboratively with academics and governmental agencies to translate academic insights into innovative solutions and agreed-upon regulations, for the benefit of the public's health, with a greater focus on health development as well as food safety. Laws taxing foods containing excessive amounts of sugar and/or fat as well as legislative collaboration between governmental organizations such as USDA, National Institutes of Health (NIH), and Maternal and Child Health Bureau/Health Resources and Services Administration (MCHB/HRSA) around nutrition issues could also support positive changes to the healthcare system as a whole but also to the greater public through crosscutting policy efforts.

#### **5 Key Research Priorities**

#### **5.1 Basic Mechanisms**

#### **5.2 Clinical Research**

concepts translate into population screening for prevention.

• Explore the effects of subclinical nutrient deficiencies, as well as potential effects of supplements exceeding the tolerable upper limits for individual nutrients.

#### **5.3 Population/Epidemiologic Research**

#### **5.4 Data and Methods Development**

#### **References**

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**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

## **How Socioeconomic Disadvantages Get Under the Skin and into the Brain to Influence Health Development Across the Lifespan**

Pilyoung Kim, Gary W. Evans, Edith Chen, Gregory Miller, and Teresa Seeman

#### **1 Socioeconomic Disadvantages and Health Across the Lifespan**

Socioeconomic disadvantage (SED) has adverse impacts on physical (Adler and Rehkopf 2008; Blair and Raver 2012; Braverman and Egerter 2008; Cohen et al. 2010; Poulton et al. 2002) and psychological (Adler and Rehkopf 2008; Bradley and Corwyn 2002; Grant et al. 2003) health development. SED is similar to low socioeconomic status (SES) which is based on occupation, income, and education or a composite of more than one

P. Kim (\*)

G.W. Evans Department of Design and Environmental Analysis, Department of Human Development, Cornell University, Ithaca, NY, USA e-mail<EMAIL_ADDRESS>
E. Chen • G. Miller Department of Psychology and Institute for Policy Research, Northwestern University, Evanston, IL, USA e-mail<EMAIL_ADDRESS><EMAIL_ADDRESS>
#### T. Seeman

David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA, USA e-mail<EMAIL_ADDRESS>
of these indicators (McLoyd 1998). However, we conceptualize SED more broadly than socioeconomic status to also include subjective perception of social position and contextual indicators of disadvantage, such as neighborhood deprivation. One of the most commonly used SED indicators is poverty, which is calculated using income that falls below an annually adjusted federal poverty line. Some studies suggest independent effects of different SED variables, but each variable tends to be highly correlated with the others; thus, it is often nearly impossible to disentangle independent effects. Therefore, in this chapter, we will review findings on different SED variables but discuss the impact of SED inclusively. In adulthood, SED is assessed based on factors in an individual's own background such as income, occupation, and education level, whereas in childhood, SED is typically assessed based on these factors for the parents.

SED is a widely recognized concern because long-lasting adverse effects on health have been robustly and consistently reported throughout the lifespan (Chen et al. 2007; Chen et al. 2002; Cohen et al. 2010; Evans and Kim 2010; Seeman et al. 2010) . With respect to psychological health development, exposure to SED has been associated with poor language, cognitive deficits, and behavioral problems during childhood (Blair and Raver 2012; Brooks-Gunn and Duncan 1997; Evans 2004; Evans and Kim 2013; McLoyd 1998). In adolescents, SED has been associated

Department of Psychology, University of Denver, Denver, CO, USA e-mail<EMAIL_ADDRESS>
with higher rates of psychopathology including substance abuse, disruptive behaviors, and depression (Doan et al. 2012; Fauth et al. 2007; Goodman et al. 2005; Sariaslan et al. 2014). In adulthood, individuals with SED exposure are more likely to exhibit reduced productivity at work, increased involvement in crime, as well as higher rates of mental illness (Duncan et al. 2010; Lorant et al. 2003; Ross 2000).

SED has also been associated with physical health development. In infancy, SED is linked to higher infant mortality and negative birth outcomes (Brooks-Gunn and Duncan 1997; Metcalfe et al. 2011). In childhood and adolescence, SED is associated with higher risk for asthma, dental problems, and physical inactivity (Chen et al. 2004; Miller and Chen 2013). Individuals exposed to SED are more frequently sick, and they die early, with higher morbidity and mortality rates throughout adulthood. Adults exposed to SED have higher rates of cancer, cardiovascular disease, and diabetes (Seeman et al. 2001). Finally, childhood SED exposure has long-lasting impacts on both psychological and physical health development after accounting for adult exposure to SED (Cohen et al. 2010; Danese and McEwen 2012; Evans et al. 2012).

Elevated levels of stress have been identified as a primary mediating mechanism underlying the effects of SED on health development. Childhood SED such as family poverty is associated with greater exposure to stressors such as harsh parenting, exposure to violence, separation from the parent, lower school quality, negative peer relations, substandard housing, pollutants, noise, and crowding (Evans 2004). Neighborhood deprivation is associated with lack of access to physical and cultural resources such as fresh fruits and vegetables, open space and other recreational amenities, libraries, and transportation, as well as greater exposure to violence and crime (Meijer et al. 2012). Adulthood SED is also associated with financial hardship, perceived discrimination, lack of control and reward at work, and job insecurities (Ferrie et al. 2002; Matthews and Gallo 2011). Moreover, one of the distinct characteristics of being exposed to SED is that individuals with SED are far more likely to experience multiple stressors over long periods of time. Chronic and severe levels of stress exposure immobilize the individual's ability to cope with stressors (Blair et al. 2011; Evans and Kim 2013; Wadsworth and Compas 2002).

#### **2 Neurobiological Mechanisms of Stress Regulation**

The next step in linking SED and health development is building an understanding of relevant neurobiological mechanisms. Chronic exposure to cumulative risk factors associated with SED can cause dysfunction in the brain and physiological systems, which in turn increases risks for psychological and physical illnesses. Neurobiological mechanisms of stress highlight three brain regions for their key roles in stress perception, appraisal, and regulation – the amygdala, hippocampus, and medial prefrontal cortex. These brain regions regulate the physiological stress systems, particularly the hypothalamus-pituitary-adrenal axis and autonomic nervous system, which lead to physical responses to stress such as "fight or flight" (Ulrich-Lai and Herman 2009).

#### **2.1 Brain**

The amygdala is a key region for detecting threats or potentially threatening information from the environment (Rodrigues et al. 2009). When an individual experiences actual or anticipated threats, the amygdala signals the paraventricular nucleus of the hypothalamus which then activates two primary physiological stress systems, the hypothalamus-pituitary-adrenal axis and the autonomic nervous system. Activation of the hypothalamus-pituitary-adrenal axis increases glucocorticoid (cortisol in humans) secretion and autonomic nervous system activation, including release of epinephrine and norepinephrine (Ulrich-Lai and Herman 2009). Long-term exposure to stressors perceived as stress can cause changes in microstructure and function of the amygdala, leading to neurogenesis and synaptogenesis (Davidson and McEwen 2012; Tottenham and Sheridan 2009). These changes may lead to hyperactivity of physiological stress regulation and increased behavioral reactivity to stress (Rodrigues et al. 2009).

The hippocampus is important for memory formation but also for stress regulation (Jacobson and Sapolsky 1991; McEwen 2001). While the amygdala rapidly activates the physiological stress system, the hippocampus plays a regulatory role by decreasing glucocorticoid secretion. This, in turn, leads to recovery of the hypothalamus-pituitaryadrenal axis activation to baseline. The hippocampus has a rich distribution of glucocorticoid receptors; therefore, its structure and function are particularly vulnerable to increased stress hormone level exposure. Exposure to chronic stress injures the microstructure and function of the hippocampus by retraction of apical dendrites and a reduction in spine density (McEwen 2001). The impact is further exacerbated because impaired hippocampal function reduces glucocorticoid negative feedback or regulatory functioning, which in turn leads to higher cortisol levels.

The prefrontal cortex is involved in excitatory and inhibitory physiological stress systems. The prefrontal cortex interacts with the amygdala and hippocampus, with the medial prefrontal cortex inhibiting both hypothalamus-pituitary-adrenal and autonomic stress responses by suppressing amygdala activation (Kalisch et al. 2006; Radley et al. 2006). On the other hand, the orbitofrontal cortex is involved in appraisal of emotional information and activates both hypothalamus-pituitary-adrenal and autonomic stress responses by increasing activity in the amygdala (Milad and Rauch 2007). Exposure to chronic stress impairs the medial prefrontal cortex through structural atrophy and suppression of neurogenesis while increasing dendritic connections of neurons in the orbitofrontal cortex (Davidson and McEwen 2012). Behaviorally, prefrontal cortex dysfunction contributes to difficulty in regulating emotional distress. Indeed, increased amygdala and orbitofrontal cortex activation and decreased hippocampal and medial prefrontal cortex activation are neural risk markers for many mental illnesses such as depression, anxiety, and antisocial behaviors (Coccaro et al. 2007; McEwen 2005; Mervaala et al. 2000; Shin et al. 2006). Similarly, abnormal brain morphometry typically assessed by gray matter volumes, cortical thickness, or white matter structure in the amygdala, hippocampus, and medial prefrontal cortex has also been associated with a range of psychiatric disorders (Phan et al. 2009; Price and Drevets 2012).

The three brain regions discussed above − amygdala, hippocampus, and prefrontal cortex – have been intensely examined in animal studies because of their role in stress regulation and vulnerability to chronic stress exposure. In humans, other brain regions also play an important role in responding to stress, and these too can be affected by chronic stress exposure. Rather than directly influencing human physiological stress responses, these brain areas communicate with and therefore influence the medial prefrontal cortex, hippocampus, and amygdala. The first of these neural networks is the lateral prefrontal cortex and anterior cingulate cortex, which are involved in executive function, decision-making, and self-regulation (Kalisch 2009; Kalisch et al. 2006; Ochsner et al. 2012). Activation in these regions suppresses amygdala activity by supporting cognitive reappraisal strategies and attentional control to help people cope with stressful situations. Chronic stress exposure has been shown to alter microstructure and function in this network, which contributes to difficulties in executive function (Holmes and Wellman 2009).

The second network of neural regions involved in human stress and coping includes the insula, superior temporal gyrus, temporoparietal junction, and posterior cingulate cortex, brain areas which are centrally related to social cognition (Uddin et al. 2007). In humans, most everyday life experiences take place in social contexts, and these brain regions are involved in processing crucial social information such as others' mental states, thoughts, and intentions. Language is also critical for communication during social interactions and likely contributes to coping processes such as cognitive appraisal. Therefore, brain regions involved in language production and comprehension, including Broca's area, Wernicke's area, and the angular gyrus, have also been examined by human stress researchers. Lack of cognitive and social stimulation has been associated with impaired functions in these networks (Adolphs 2001; Hackman and Farah 2009).

In sum, animal and human research consistently highlights the significant role of the amygdala, hippocampus, and medial prefrontal cortex in stress reactivity and regulation. In human research, these three key regions are interconnected with other neural networks integrally involved in higher-level thought, including the executive function network (the lateral prefrontal cortex and anterior cingulate cortex), the social cognition network (insula, superior temporal gyrus, and posterior cingulate cortex), and language regions (Broca's area, Wernicke's area, and the angular gyrus). The three key regions work together with these other networks to process information from positive and negative experience and decide appropriate responses.

#### **2.2 Physiological Systems**

When individuals are exposed to stress, information is initially processed and evaluated in the brain, which then activates the primary physiological stress systems, the hypothalamus-pituitary-adrenal axis, and autonomic systems. To activate the hypothalamus-pituitary-adrenal axis, signals from the amygdala cause the paraventricular nucleus of the hypothalamus to release corticotropin-releasing hormone and arginine vasopressin, which trigger secretion of adrenocorticotropic hormone from the pituitary gland. The adrenocorticotropic hormone then causes release of glucocorticoids, cortisol (stress hormone) in humans, by the adrenal cortex. Increased cortisol increases blood pressure and heart rate and stimulates anti-inflammatory and immunosuppressive actions.

The autonomic nervous system includes both the sympathetic and parasympathetic nervous systems. The sympathetic branch of the autonomic nervous system provokes immediate changes such as increased heart rate and blood pressure, representing a "fight-or-flight" response to threat. Neuroendocrine biomarkers for these systems include glucocorticoids (cortisol) for the hypothalamus-pituitary-adrenal axis and epinephrine and norepinephrine for the autonomic nervous system. Increased cortisol levels suppress inflammatory cytokines. Thus hypothalamuspituitary-adrenal axis dysregulation can lead to inflammatory system dysregulation. Biomarkers of inflammatory system dysregulation include interleukin-6, tumor necrosis factor alpha, C-reactive protein, and insulin-like growth factor-1.

Dysregulation of hypothalamus-pituitaryadrenal axis and autonomic nervous system activation can also suppress and disrupt metabolic processes. Biomarkers of metabolic system dysfunction include low levels of high lipoprotein cholesterol and high levels of low-density lipoprotein cholesterol, triglycerides, glycosylated hemoglobin, glucose, and insulin. Additionally, adiposity as indicated by body mass index and waist-to-hip ratio are potentially downstream indicators of stress dysregulation. The primary stress response systems increase blood pressure and heart rates and thus elevate risk for cardiovascular disease. Biomarkers include systolic and diastolic blood pressure, as well as heart rate (Krantz and Falconer 1995).

The allostatic load model proposes that exposure to chronic stress may cause wear and tear in one or more primary stress regulatory systems (the hypothalamus-pituitary-adrenal axis and autonomic nervous system) and subsequently in secondary physiological stress systems (metabolic processes, inflammatory and immune responses, and cardiovascular responses). Compromised functioning across these multiple physiological systems from chronic environmental demands may lead to long-term damage. Dysregulation of multiple physiological systems, indexed by allostatic load, is a powerful predictor for health development outcomes and adults, including cardiovascular disease, diabetes, as well as cognitive impairment and premature mortality. SED has also been studied for links to allostatic load because SED increases exposure to repeated, severe, and chronic stressors, which elevate allostatic load over the lifespan (Gruenewald et al. 2012; Seeman et al. 2010).

**Fig. 1** Conceptual model for chapter

#### **3 Overview of SED and Neurobiological Impacts Over the Life Course**

In this section of the chapter, we review current understanding of the effects of SED on neurobiological stress regulatory across the lifespan including (1) how childhood SED affects childhood neurobiological systems, (2) how adulthood SED affects adult neurobiological systems, and (3) how childhood SED affects adult neurobiological systems. Within each temporal focus, we review literature on the brain and physiological systems. Brain regions of interest include the hippocampus, amygdala, prefrontal cortex, and other related regions. We reviewed both structural and functional variations that have been associated with SED. Relevant physiological systems include the hypothalamus-pituitary-adrenal axis, sympathetic nervous system, cardiovascular responses, inflammatory and immune responses, and metabolic processes, as well as allostatic load. When available, the findings on the relations between the brain and physiological systems are also reviewed.

Following this overview of the literature on SED and neurobiological systems, we discuss the literature on life course health development principles (see Halfon and Forrest 2017). In particular, we discuss the multilevel and multidimensional interactions between neurobiological and environmental mechanisms underlying the associations between SED and health development. Finally, we discuss ways in which current scientific understanding of the effects of SED on human biology provides information for interventions and policy from a life course health development perspective (Figs. 1 and 2).

#### **4 Socioeconomic Disadvantages (SEDs) and Neurobiological Mechanisms During Childhood**

#### **4.1 Brain: Structure**

There is a fast-growing body of literature on the effects of SED on the developing brain suggesting that childhood SED has negative impacts on brain development from infancy to late adolescence. We will discuss recent literature on the development of both brain structure and function in the context of SED exposure in the hippocampus, amygdala, and prefrontal cortex.

In the hippocampus, SED is associated with alterations in its structure across developmental stages (Hanson et al. 2011; Noble et al. 2015). Importantly, these effects have been documented not only in the USA but internationally as well (Jednorog et al. 2012). In a longitudinal study, family income was inversely associated with bilateral hippocampus gray matter volumes in children at age 9. This link was mediated by exposure to stress, both caregiving quality and stressful life events, assessed 3 years earlier (Luby et al. 2013). Another study suggests that reduced hippocampal volume is associated with increased externalizing of

**Fig. 2** A summary of socioeconomic disadvantages (SEDs) and neurobiological mechanisms across lifespan (*SEDs* socioeconomic disadvantages; *PFC* prefrontal cor-

tex, *SNS* sympathetic nervous system; *HPA* hypothalamus-pituitary-adrenal)

behavioral problems (Hanson et al. 2014). The reduced volumes in the hippocampus mediated the links between early life adversity and behavioral problems at school including problems with teachers and disruptive behaviors (Hanson et al. 2014).

Amygdala structure has been associated with major chronic stressors in early life such as maternal deprivation (Tottenham and Sheridan 2009). However, the patterns of the associations between early adversity and amygdala structure appear to be more complex compared to the patterns found in the hippocampus. Among children in middle childhood and early adolescence, SED was associated with reduced amygdala gray matter volumes (Hanson et al. 2014; Luby et al. 2013), whereas among children in middle childhood to late adolescence, SED was associated with increased amygdala gray matter volume (Noble et al. 2012). Others have failed to demonstrate the links between SED and amygdala structure (Hanson et al. 2011). More developmental research is needed to identify what SED factors may be associated with different developmental trajectories of the amygdala. Consistent with life course health development principles (see Halfon and Forrest 2017), work to date suggests that both timing and duration of SED exposure are critical for understanding SED impacts on amygdala structure and function.

The prefrontal cortex and other regions for language and social cognition are affected by exposure to SED. Only one study has examined the effects of family income on brain structure in the first years of life (Hanson et al. 2013). Longitudinal analyses revealed that infants from low-income families had lower gray matter volumes in the frontal and parietal lobes compared to their counterparts from mid- and high-income families. Moreover, the low-income infants had more dampened brain growth trajectories compared to mid- and high-income infants: although the brain volumes were comparable during the first year of life, by 3–4 years of age, low-income children showed significantly reduced volumes compared to high- and midincome children. The reduced volume in the frontal lobe, a brain area involved in cognitive control, was associated with more externalizing behaviors, but not with internalizing behaviors. In another study with children aged 4–18, SED based on income and education was associated with cortical thinning in the prefrontal cortex, particularly in the right anterior cingulate cortex and left superior frontal gyrus, regions that are important for behavioral regulation and executive functions (Lawson et al. 2013). This study also provided evidence that changes due to stress exposure are not linear based on age. In the low SES group, from ages 5–17, gray matter volumes decreased in the inferior and superior temporal gyri, areas involved in language development and cognitive controls. On the other hand, in the high SES group, gray matter volumes in these areas increased over time (Noble et al. Noble et al. 2012b). Given that the pruning process occurs mid- to late adolescence (Giedd 2004), the rapid decline in gray matter volume in the low SES group may limit normal development in the prefrontal cortex. This may be further associated with compromised cognitive functions. In middle childhood, SED was linked to reduced gyrification in the medial prefrontal cortex, indicating delayed maturation (Jednorog et al. 2012).

Finally, a recent study demonstrated a robust association among SED, cortical structure, and cognitive function throughout childhood (age 3–20) (Noble et al. 2015). In the sample of 1099 participants, family income was associated with increased cortical surface area as well as thickness. The gradient relations between family income and cortical surface area were quadratic so that the children of the lower-income families were more affected by income changes compared to the children of the higher-income families. The differences in the cortical surface explained the lower neurocognitive abilities among low-income children. Similar findings that support the role of cortical structure differences in the income-achievement gap were recently reported in a smaller sample of adolescents (Mackey et al. 2015).

#### **4.2 Brain: Function**

Existing evidence suggests the effects of SED on whole-brain functioning can start very early in life. A longitudinal study demonstrated that both income and maternal education were positively associated with maturity of the sensorimotor network (primary sensorimotor/auditory) and default mode network at 6 months of age (Gao et al. 2014). At 6 months, babies can sit up and interact more extensively with their environment; therefore, these brain networks may support sensorimotor exploration and a sense of agency. Delayed development in these networks due to exposure to SED during the first year may portend adverse long-term impacts on child health development.

The impact of childhood SED on prefrontal cortex functioning and its role in cognitive development have been examined extensively in the literature, whereas the effects on hippocampal and amygdala functions are less understood. One study focused on the associations between SED and hippocampal function and included both objective measures of SES and maternal subjective ratings of social standing (Sheridan et al. 2013). Interestingly, perceived social standing, but not income or education, was associated with hippocampal function. Among children 8–12 years old, higher perceived social standing was associated with greater hippocampal activation during a memory encoding task. This finding highlights the importance of examining subjective and objective social standing in relation to brain development over the life course.

The role of SED exposure in amygdala functioning is not well understood. In adolescents, low SES was associated with increased amygdala responses to angry faces (Muscatell et al. 2012), which suggests greater neural sensitivity to negative emotional information in social contexts. In a longitudinal study, early adversity including low family income in infancy was associated with reduced functional connectivity between the amygdala and prefrontal cortex in female adolescents (Burghy et al. 2012). This reduced connectivity, which may be related to difficulties in emotion regulation, was further associated with higher anxiety symptoms.

The impact of SED exposure on the prefrontal cortex and other neural regions associated with cognitive functions has been detected during the first few years of life. Six- to eight-month-old infants from low-income families exhibited reduced gamma band power in the frontal lobe compared to infants from high-income families, after controlling for several covariates such as exposure to smoke (Tomalski et al. 2013). Reduced gamma power may be an early risk marker for poor attentional control and delayed language development, both of which are more prevalent in low SES children (Hackman and Farah 2009; Hoff 2006). This link between SES and frontal lobe development was found in older children as well. Low SES was associated with less mature EEG activity patterns in the frontal lobe across ages 4–6 (Otero et al. 2003; Otero 1997).

In middle childhood, SED exposure was associated with prefrontal cortex activity and executive functioning. Children 7–12 years old performed a target detection task designed to probe cognitive flexibility and working memory, which is related to lateral prefrontal cortex activation (Kishiyama et al. 2009). Lower SES children showed reduced prefrontal cortex activation compared to children of high SES families, indicating delayed prefrontal cortex development and increased risks for delay in executive function. Sheridan et al. (2012) examined the link between SED and neural activation for executive functioning among 8–12-year-old children (Sheridan et al. 2012). Interestingly, low SES children showed greater, rather than reduced, activation in right middle frontal gyrus compared to high SES children. Although there were no behavioral performance differences by SES, in low SES children, increased activation in the right middle frontal gyrus was associated with better accuracy. Therefore, low SES children may have to recruit this region more strongly than high SES children in order to perform at the same level. Additionally, low SED adolescent girls exhibited increased activation in the anterior cingulate cortex during an inhibition control task, which indicated ineffective recruitment of the brain region for behavioral performance (Spielberg et al. 2015).

Neural activations for attention control are also associated with SED exposure in children. In both early childhood (Stevens et al. 2009) and adolescence (D'Angiulli et al. 2008; D'Angiulli et al. 2012), low SES children showed reduced responses to target stimuli and increased responses to distractor stimuli. This pattern of neural activation may contribute to poor suppression of responses to distracting information and less filtering of irrelevant information. In adolescence, low SES was also associated with noisier and inefficient neural responses to auditory stimuli compared to mid-SES (Skoe et al. 2013). Such altered neural responses may require low SES children to exert more effort in order to perform at the same levels as their high SES counterparts, which suggests that SED reduces the overall adaptability and threatens the long-term heath development of these children.

Given consistent evidence of delayed language development in low SES children, the impact of SED exposure on brain regions involved in language development has been examined. Among kindergarteners, neural activations during a phonological awareness task of discriminating rhymed monosyllabic words versus nonwords were assessed (Raizada and Kishiyama 2010). Phonological processing is a critical, underlying process in reading acquisition. Children with high family SES exhibited left inferior frontal gyrus specialization, which is important for language development, while children of low family SES were less likely to exhibit such specialization. On the other hand, in middle childhood (ages 7–11), low SES background was associated with increased, not reduced, activations in left fusiform regions during a reading task, which was further associated with better phonological skills within the low SES group (Noble et al. 2006). Fusiform activation is thought to support visual word recognition, but it is not typically associated with effective phonological skills. Middle SES background was associated with increased activation in the perisylvian and superior frontal regions, typical activation regions for language skills. However, among low SES children, perisylvian and superior frontal region activation was less likely to be shown during a reading task. These results show complex associations between brain activations and development in the context of SED.

#### **4.3 Physiological Systems**

The sympathetic nervous system is commonly assessed by resting blood pressure, blood pressure reactivity, and blood pressure recovery in response to an acute stress exposure in children and adolescents. In children, SED is associated with dysregulation of the sympathetic nervous system marked by elevated resting blood pressure and heightened blood pressure reactivity to stress (Chen et al. 2004; Gump et al. 2007; Jackson et al. 1999; Kapuku et al. 2002).

On the other hand, in adolescence, the associations between SED and blood pressure are not consistent or in the opposite direction from childhood. Some researchers have failed to find a consistent association between SED and resting blood pressure during adolescence (Chen et al. 2002). A particularly interesting longitudinal study showed that maternal education was inversely related to childhood resting blood pressure at ages 7 and 9 years, but then had no association among 11- and 15-year-olds (Howe et al. 2013). When exposed to an acute stressor, SED adolescents exhibit dampened rather than elevated blood pressure reactivity (Evans and Kim 2007; Musante et al. 2000). Other studies have failed to reveal any association between SED and blood pressure reactivity in adolescents (Chen et al. 2002). One reason for less consistent findings with blood pressure in adolescence is an increased significance of peer and school environment relative to the family environment during adolescence. For example, neighborhood SED but not family SED was significantly associated with elevated ambulatory blood pressure in adolescents (McGrath et al. 2006). Although it is not consistently found, researchers identified slower blood pressure recovery – blood pressure taking longer to come back to baseline – after lower SES adolescents were exposed to acute stress (Evans et al. 2007; Walter and Hofman 1987). Epinephrine, a hormone that regulates the sympathetic nervous system, was elevated overnight among 9-year-olds exposed to SED (Evans and English 2002; Evans and Kim 2007). SED also reduced expressions of genes regulated by catecholamines in children with asthma, suggesting dysregulation of the sympathetic nervous system (Chen et al. 2009).

Cortisol, a hormone marker of the hypothalamus-pituitary-adrenal axis, is dysregulated in children and adolescents exposed to SED. SED is associated with elevated baseline levels of cortisol during childhood (Essex et al. 2002; Evans and English 2002; Flinn and England 1997; Gustafsson et al. 2006; Lupien et al. 2001; Lupien et al. 2000) and adolescence (Evans and Kim 2007) although Lupien et al. (2001) found that by age 12, SES is no longer related to baseline cortisol levels. The longer children experience poverty, the higher the cortisol level (Blair et al. 2013). In a particularly noteworthy study, Chen et al. (2010) examined salivary cortisol every 6 months for a 2-year period among a group of adolescents. Saliva readings were taken throughout the day. Overall levels were higher among youth from low-income families and, of particular interest, rose faster as the adolescent matured. Children exposed to SED in middle childhood also exhibited heightened reactivity to an acute stressor (Gump et al. 2009). Similar to the findings on blood pressure, neighborhood SES predicted higher cortisol reactivity in adolescent boys (Hackman et al. 2012). These same authors, however, also found a more rapid return of cortisol levels to baseline in relation to residence in more deprived neighborhoods: a result opposite to what one would expect.

Research also suggests that alleviation of SED can improve hypothalamus-pituitary-adrenal axis regulation in early childhood. Fernald and Gunnar (2009) evaluated the impacts of a conditional cash transfer program on assessments of cortisol during a visit to children's homes. In this experimental program, low-income families are randomly assigned to receive cash in exchange for compliance with better health care for their child (e.g., nutrition supplements, physicals, child health education) plus more school attendance, or they are enrolled in a control group. The amount of cash transfer is considerable, averaging between 20 and 30% of a household's annual income. The results showed that primary school-aged children in the income supplement program had lower overall levels of salivary cortisol if they also had a depressed mother. For low-income families in which the mother was not depressed, there were no impacts of additional income on cortisol levels.

Higher obesity rates are found in children exposed to SED. Obesity is associated with malfunctioning of the metabolism system. Metabolic dysregulation is most commonly indexed by high levels of lipids, low glucose tolerance, and high body mass index (BMI) which is an indicator of adiposity. Children exposed to SED show higher BMI (Shrewsbury and Wardle 2008; Sobal and Stunkard 1989). In an interesting study, Hargreaves et al. (2013) examined childhood obesity (≥ 95th% for age and gender) using four different UK national birth cohorts to illustrate secular trends from 1999 to 2009. Occupational level of the head of household was inversely related to obesity, and the degree of inequality rose 25% over the decade. Some researchers find that the link between SED and adiposity is stronger in younger children, females, and Caucasian children. It is also worth noting that when excess adiposity is defined in terms of obesity (typically >95th percentile for age and gender) rather than by actual BMI, the SES trends are stronger and more consistent.

When metabolic dysregulation was examined across childhood and adolescence, exposure to SED from birth to age 9 years was associated with high BMI at age 9 and also a steeper trajectory of weight gain over the next 8 years (Wells et al. 2010). Howe et al. (2013) tracked the same birth cohort over time and found that whereas there were no differences in BMI in relation to SES prior to age 4, around 60 months of age, clear SES differences emerged and continued to widen up to age 10, the end of their study.

A smaller number of studies have examined weight at different ages during development in relation to childhood SES. Kakinami et al. (2013b) took these early life course analyses a step further by generating poverty trajectory classes from birth to obesity assessments at ages 6, 8, 10, and 12 years among a large, representative sample of children from the province of Quebec. They found four classes: always poor, never poor, increased likelihood of poverty over time, and decreased likelihood of poverty over time. The largest differences occurred between the stable poor and the stable, nonpoor groups, but the effects took time to emerge. For age- and gender-adjusted BMI, the stable poverty group had higher BMI percentiles than the stable, nonpoor group at ages 10 and 12 years. Thus, at 6 and 8 years old, there was no link between duration of early poverty and BMI. For the likelihood of being overweight or obese (≥BMI 85th %), differences emerged by age 8 and continued through to age 12. Two other aspects of their data are noteworthy in thinking about health development. First, the older the child, the greater the impact on weight. Second, they also found elevated risk of greater weight in the group with decreased likelihood of poverty over time (i.e., started out poor but became nonpoor) relative to the stable nonpoor group, but did not find this for the opposite trajectory where children started out nonpoor but became poor. Thus, there is evidence that early poverty exposure has long-lasting impacts, regardless of subsequent upward mobility even among children. All of these effects remained with statistical controls for current income, birth weight, and parental weight.

The effects of SED may begin very early in life. Klebanov et al. (2014) showed that lowerincome households have lower-weight infants at birth, a common finding in the literature on SES and birth weight (Spencer 2000). However, Klebanov and colleagues then showed that weight gain was faster in infants from low-income households in comparison to those from middle-income households. Low birth weight babies are at risk for more rapid weight gain because of maternal efforts to help the baby become healthier, leading to overfeeding as well as biological compensatory mechanisms within the baby herself that alter metabolism in order to gain weight.

Glucose metabolism is reduced in children exposed to SED, which contributes to the risk for obesity and metabolic system dysregulation. Several SED variables have been associated with dysregulated glucose metabolism. The National Health and Nutrition Examination Survey (NHANES) data, a nationally representative US dataset, revealed family income was inversely associated with glycosylated hemoglobin levels among children from age 1 to 19 (Seeman et al. 2010). Low parental education was also inversely associated with several metabolic markers including total cholesterol and the ratio of low- to high-density lipoproteins (Leino et al. 1996). Neighborhood deprivation was also associated with dysregulation of the metabolic system including higher low-density lipoproteins, triglycerides, as well as body fat among children aged 9–15 (Gliksman et al. 1990). Kakinami et al. (2013a) conducted a longitudinal study among children beginning at birth until age 10 years old. Poverty exposure was defined in terms of both timing (birth to age 2, 3–6, 7–10 years) and duration (number of age periods [0–3] with poverty exposure). Poverty timing and duration were each linked with elevated triglycerides and insulin with in-depth controls for a host of sociodemographic and physical variables, including family histories of pertinent diseases. Interestingly, for triglycerides, the duration of poverty exposure was most important, whereas for insulin, timing mattered, with exposure from birth to two most consequential. High-density lipids were also reduced by poverty exposure but once the covariates were included in the model, this effect was no longer significant.

Children exposed to SED exhibit elevated inflammatory responses. Chen and colleagues (Chen et al. 2003; Chen et al. 2006) examined the role of childhood SED exposure in inflammation and immune responses particularly among children with asthma. Asthma has a strong association with SED exposure, and the risk of asthma is related to dysregulation of inflammatory response. Among children and adolescents with asthma, low neighborhood SES was associated with increased cytokine responses to allergens (Chen et al. 2003; Chen et al. 2006). On the other hand, in healthy children, no association between neighborhood SES and inflammatory responses was found. Chronic exposure to low SES across ages 1–9 was associated with increased immune responses measured by interleukin-6 production, but a trajectory of initially low SES followed by upward mobility was associated with normal immune responses (Azad et al. 2012).

Inflammatory responses are regulated by gene expression of T cells. Among children with asthma, SED was associated with overexpression of T-cell genes that are involved in chemokine activity and responses to wounds (Chen et al. 2009). This was due to decreased activity of the transcription factors cyclic AMP-binding protein, AP1, and nuclear factor Y as well as increased activity of genes regulated by the proinflammatory transcription factor, nuclear factor kappa-B. Such findings suggest gene and inflammatory pathways linking SED and immune dysfunction among children. Childhood SES was further associated with the genetic mechanisms of inflammatory responses. Low family SES was associated with increased levels of messenger RNA for TLR4, a receptor involved in inflammatory response regulation in adolescence (ages 13–19) (Miller & Chen 2007b). The higher levels of TLR4 suggest leukocyte inflammatory responses to endotoxins, thus greater susceptibility to pathogens such as the cold virus. In addition to objective SED indicators, perceived level of SED was associated with higher proinflammatory biomarkers, IL-6, and TNF-α soluble receptor 2 (sTNFR2) in white, but not black, adolescents (Pietras and Goodman 2013).

When these different physiological systems are considered together in a cumulative fashion, SED is associated with higher allostatic load, indicating chronic wear and tear on physiological stress regulatory systems. Evans and colleagues demonstrated that exposure to chronic stressors including poverty is longitudinally associated with higher allostatic load in middle childhood and early adolescence (Evans 2003; Evans et al. 2007). Longer periods of living in poverty since birth was also associated with high allostatic load at age 13 (Evans 2003; Evans et al. 2007). Although literature on SED and allostatic load in childhood is limited, others have also uncovered significant links between SED and allostatic load in children and adolescents (Goodman et al. Goodman et al. 2005b). In adolescence, neighborhood poverty more significantly predicted higher allostatic load than family poverty (Brody et al. 2014). Using the nationally representative data of the NHANES, researchers also showed that the link between SED and allostatic load is greater in African Americans compared to white and Hispanic adolescents (Rainisch and Upchurch 2013). However, the relative advantages in the white and Hispanic adolescents became smaller as they grew older. The evidence on separate stress systems and allostatic load reveal mechanisms by which SED alters the physiological stress regulatory systems, which may further diminish the ability to cope with stress and increase risks for physical and mental illnesses.

#### **5 SED and Neurobiological Mechanisms During Adulthood**

#### **5.1 Brain: Structure**

The impact of socioeconomic disadvantage on adult brain structure has been researched less than in children. Existing studies suggest that disadvantages in adulthood are associated with aberrant structure in brain regions involved in language, executive functions, and emotion regulation. It should be noted, however, that while adults living in SED are more likely to have experienced similar disadvantages in childhood, most studies do not control for childhood SES or the trajectories of SED that span childhood, adolescence, and adulthood. Therefore, it is difficult to disentangle the timing effects of SED when understanding the effects on brain and physiological systems. Herein, noting this limitation, we review studies examining the crosssectional association between adult SED and neurobiological dysfunctions in adulthood.

Exposure to disadvantages, particularly low educational attainment, has consistently been associated with reduced hippocampal volume. Among cognitively healthy seniors, low SES was associated with impaired neural anatomy including reduced white matter integrity in the hippocampus (Piras et al. 2011; Teipel et al. 2009). Among individuals from a wide age range (18– 87 years), fewer years of education was also associated with a smaller hippocampus (Noble et al. Noble et al. 2012a). The association between SED and hippocampus structure starts at age 35, showing a decline in this area. Evidence of associations between adult SED and amygdala structure is limited, but SED was related to smaller amygdala structure in adulthood (Noble et al. Noble et al. 2012a), which may also be associated with mood dysregulation among adults exposed to SED.

SED exposure has also been linked to changes in regions involved with cognitive functioning. Among men aged 35–64, high neighborhood deprivation was associated with smaller cortical volume and thinning in the language-related Wernicke's and Broca's areas, as well as smaller cortical surface area in the frontoparietal regions, which are implicated in cognitive control (Krishnadas et al. Krishnadas et al. 2013b). In a sample of more than 300 brains of seniors (average age of 76), low educational attainment was associated with reduced gray matter volumes in the left temporoparietal area and in the bilateral orbitofrontal cortex (Foubert-Samier et al. 2012). In young adult participants, low subjective ratings of social standing using the MacArthur Scale of Subjective Social Status were associated with smaller gray matter volumes in the anterior cingulate cortex, but not in the hippocampus and amygdala (Gianaros et al. 2007). Standard SES, based on objective measures of income, education, and occupation, was not associated with gray matter volume in the anterior cingulate cortex.

The structural integrity of the brain in the context of SED has also been examined. Healthy adults aged 30–50 years were examined for the effects of SED on the fractional anisotropy of white matter tracts, which represents the integrity of neural circuits across different regions (Gianaros et al. 2013). All three SED indicators – education, income, and neighborhood quality – were associated with reduced white matter integrity, assessed by the fractional anisotropy, reflecting axonal caliber, myelin thickness, or fiber coherence (Jung et al. 2010) throughout the brain. In another study, neighborhood deprivation alone was also associated with a less efficient and noisier neural network among men aged 35–64 (Krishnadas et al. 2013a). When both young adults and elders were compared, education attainment was not associated with brain structure in young adults but was positively associated with white matter integrity in seniors age 65 and above (Johnson et al. 2013). Reduced white matter integrity in the bilateral superior frontal gyrus was further associated with poor working memory performance in seniors with low educational attainment.

Several studies examined the role of physiological systems in the link between SED and the adult brain. In particular, the role of inflammation dysfunction has been highlighted as a mediator of the relations between SED and brain. The inflammation factor mediates the links between neighborhood deprivation and reduced cortical thickness in key language regions, including the left Wernicke's area (Krishnadas et al. Krishnadas et al. 2013b). Inflammatory dysfunction (C-reactive protein) and metabolic dysregulation (adiposity) were also examined as a physiological risk marker of cardiovascular diseases. Inflammatory factors mediated the link between SED and adiposity, and adiposity was further associated with reduced integrity of neural circuits (Gianaros et al. 2013).

#### **5.2 Physiological Systems**

There is relatively robust evidence on sympathetic nervous system dysregulation in conjunction with adult SED exposure. Several studies have shown that SED is associated with higher resting blood pressure. High resting blood pressure contributes to greater risks for cardiac diseases from young to late adulthood. In developed countries like the USA, Canada, and the UK, evidence is stronger and more consistent than in developing countries (Colhoun et al. 1998; Kaplan and Keil 1993). Neighborhood SED is also associated with higher resting blood pressure among adults in many studies (Chaix et al. 2010; Chaix et al. 2008; Cozier et al. 2007; Cubbin et al. 2000; Diez-Roux et al. 2000; Harburg et al. 1973; McGrath et al. 2006).

Several other markers of sympathetic nervous system dysfunction have been found among adults exposed to SED. SED was associated with dampened blood pressure reactivity to stress (Steptoe et al. 2002a; Steptoe et al. 2003) and reduced heart rate variability (Hemingway et al. 2005; Sloan et al. 2005). Individuals exposed to SED are also less likely to exhibit the normal overnight dip in blood pressure, which is a risk marker for cardiovascular diseases (Spruill et al. 2009; Stepnowsky et al. 2004). One intriguing explanation for these nighttime effects could be sleep disturbance, which appears to be more common among lower SES adults (Buckhalt 2011). In addition, SED was associated with higher norepinephrine and epinephrine levels among adults (Cohen et al. Cohen et al. 2006a; Janicki-Deverts et al. 2007; Seeman et al. 2004).

Cortisol, a hormone index of hypothalamuspituitary-adrenal axis activation, has a natural diurnal rhythm throughout the day. The level is highest immediately after awakening, and then it sharply decreases and continues to decrease until it gradually increases overnight. Hypothalamus-pituitary-adrenal axis dysregulation is indicated by lower levels of cortisol awakening response and dampened and slower decreases during the day. This has been demonstrated in several developed countries, across different ages of adulthood. Lower levels of awakening cortisol and slower decline during the day both result in overall elevated levels of cortisol in the system (Cohen et al. 2006; Cohen et al. 2006a; Li et al. 2007). SED-exposed adults are more likely to exhibit these circadian patterns (Adam and Kumari 2009; Brandtstädter et al. 1991), indicating dysregulation of the hypothalamus-pituitary-adrenal axis. In the context of low SES, compared to younger adults, older adults exhibited higher circadian levels overall (Karlamangla et al. 2013). In addition, when cortisol level was assessed using overnight urinary sampling, the accumulated level of cortisol was higher in SED-exposed adults compared to non-SED-exposed adults (Gruenewald et al. 2012).

Extensive evidence shows that SED is associated with elevated levels of inflammation among adults. Low socioeconomic status variables such as low education attainment, lower class occupation, and low income have been associated with higher levels of C-reactive protein, interleukin-6, and fibrinogen (Alley et al. 2006; Brunner et al. 1996; Brunner et al. 1997; De Boever et al. 1995; Gruenewald et al. 2009; Hemingway et al. 2003; Ishizaki et al. 2000; Jousilahti et al. 2003; Kivimaki et al. 2005; Koster et al. 2006; Loucks et al. 2006; Lubbock et al. 2005; McDade et al. 2006; Owen et al. 2003; Panagiotakos et al. 2004; Petersen et al. 2008; Pollitt et al. 2007, 2008; Rathmann et al. 2006; Steptoe et al. 2003; Steptoe et al. 2002; Wamala et al. 1999; Wilson et al. 1993). Neighborhood poverty is also associated with higher levels of C-reactive protein and interleukin-6 (Gallo and Matthews 2003). Markers for long-term upregulation of proinflammatory cytokines including tumor necrosis factor-α and interleukin-1 receptor antagonist and hemostatic factors such as factor VII, von Willebrand factor, and plasminogen activator inhibitor-1 have also been identified among SED individuals (Steptoe et al. Steptoe et al. 2002b; Wamala et al. 1999). Elevations in inflammatory markers suggest poor immune response regulation, which increases the risk for greater inflammatory reactions to pathogens and irritants and thus portends eventual morbidity (Gruenewald et al. 2012).

Consistent findings on SED and increased markers of metabolic malfunction, higher fasting/ postload glucose, and higher fasting triglycerides were shown in adults with SED (Brunner et al. 1997; Matthews et al. 1989). Higher levels of lowdensity lipoproteins and lower levels of high-density lipoproteins have also been found in SED adults relative to their more advantaged peers (Matthews et al. 1989; Wamala et al. 1997). Not surprisingly, SED adults have higher rates of diabetes (Everson et al. 2002; Guize et al. 2008; Lidfeldt et al. 2007; Maty et al. 2005; Maty et al. 2008) and other metabolic illnesses including hypertension, obesity, dyslipidemia, and hyperglycemia (Brunner et al. 1997; Chichlowska et al. 2009; Loucks et al. 2007; Wamala et al. 1999).

Taken together, there is evidence for links between SED exposure and physiological stress dysregulation across the adult lifespan. Such evidence is reflected in the association between SED and allostatic load in adulthood. Both individual SED variables such as occupation, income, and education level as well as neighborhood SED exposure have been associated with elevated allostatic load (Bird et al. 2010; Crimmins et al. 2009; Geronimus et al. 2006; Karlamangla et al. 2005; Merkin et al. 2009; Schulz et al. 2012; Seeman et al. 2008; Singer and Ryff 1999). Higher allostatic load predicts elevated morbidity and mortality (Juster et al. 2011; Juster et al. 2010).

#### **6 Childhood SED and Adult Neurobiological Mechanisms**

#### **6.1 Brain: Structure**

When the effects of childhood SED exposure on adult hippocampus and amygdala were examined, mixed results were reported. It is important to note that in order to be confident that the relationship between childhood SED and adult neural alterations is not simply reflecting concurrent SED status, these life course studies should examine the association of childhood SED and adult brain independently of adult SED. In a sample of over 200 68-year-old adults in England, childhood exposure to SED at age 11 years was prospectively associated with reduced hippocampal volumes after controlling for adulthood exposure to SED at age 65 (Staff et al. 2012). However, another study provides evidence for the opposite result. Among 403 adults in Australia, aged 44–48 years, the impacts of self-reported childhood poverty exposure as well as financial hardship during the past 12 months on hippocampal and amygdalar volumes were examined (Butterworth et al. 2012). Analysis revealed that the current financial hardship, but not childhood poverty exposure, was associated with reduction in gray matter volumes of bilateral hippocampus and amygdala. However, it should be noted that the study sample was predominantly mid- and high-SES individuals and few individuals from low SES were included. The differences between the two studies may be related to the variance of childhood adversity included in the study samples.

Studies examining the prefrontal cortex and other cortical regions demonstrate that stronger evidence exists for the effects of childhood exposure, rather than adulthood exposure, to SED. In a longitudinal study in Germany, brain structure of 134 young adults was assessed. Early life poverty based on family income at 3 months of age was associated with reduced orbitofrontal gyrus gray matter volume at age 25 (Holz et al. 2015). The reduced orbitofrontal cortex volume further mediated the link between early life poverty and conduct disorders. Exposure to current poverty did not predict the orbitofrontal gyrus volume. Other studies have not directly tested the timing effect of childhood SED by controlling for adulthood SED; however, they suggest that childhood SED contributes to reduced structure in the prefrontal cortex (Cohen et al. Cohen et al. 2006b; Narita et al. 2010).

#### **6.2 Brain: Function**

The effects of childhood SED on the adult brain are better understood in relation to socio-emotional information processing as compared to cognitive processes. This is different from the literature on the effects of SED in adulthood, which is primarily focused on cognitive functions.

Adults who were exposed to childhood SED exhibited greater neural reactivity to negative emotional information in the amygdala, which may indicate elevated stress reactivity. Low subjective ratings of parental social standing, a retrospective report on childhood SED, were associated with greater amygdala response to angry faces, after controlling for adult SES (Gianaros et al. 2008). Adult SES did not predict amygdala response. Lower social status in childhood may be associated with more negative social interactions such as family conflicts and neighborhood adversity which may lead to greater amygdala sensitivity to angry faces. Childhood SED has also been prospectively associated with neural functions for emotion reactivity and regulation in adulthood. In one study, 49 young adults were asked to regulate negative emotions in response to negative images using cognitive strategies (Kim et al. 2013). Family income at age 9 significantly predicted reduced dorsolateral prefrontal cortex and ventrolateral prefrontal cortex activation during emotion regulation. These results were independent of concurrent adult income. Family income at age 9 years was also positively associated with amygdala activation during emotion regulation, which may suggest inefficient suppression of the amygdala for emotion regulation by dorsolateral prefrontal cortex and ventrolateral prefrontal cortex. Moreover, chronic exposure to stress such as family conflicts, violence, and substandard housing quality mediated the links between family income at age 9 and ventrolateral prefrontal cortex and dorsolateral prefrontal cortex activations.