Critical Reflection

INVITED REVIEW

Nutrition in early life and the programming of adult disease: a review S. C. Langley-Evans

School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, UK

Keywords

cardiovascular disease, foetal programming,

metabolic syndrome, obesity, pregnancy,

weaning.

Correspondence

S. C. Langley-Evans, School of Biosciences,

University of Nottingham, Sutton Bonington

Campus, Loughborough LE12 5RD, UK.

Tel.: +44 (0)115 9516139

Fax: +44 (0)115 9516122

E-mail: [email protected]

How to cite this article

Langley-Evans S.C. (2015) Nutrition in early life

and the programming of adult disease: a review.

J Hum Nutr Diet. 28 (Suppl. 1), 1–14

doi:10.1111/jhn.12212

Abstract

Foetal development and infancy are life stages that are characterised by

rapid growth, development and maturation of organs and systems. Variation

in the quality or quantity of nutrients consumed by mothers during preg-

nancy, or infants during the first year of life, can exert permanent and pow-

erful effects upon developing tissues. These effects are termed

‘programming’ and represent an important risk factor for noncommunica-

ble diseases of adulthood, including the metabolic syndrome and coronary

heart disease. This narrative review provides an overview of the evidence-

base showing that indicators of nutritional deficit in pregnancy are associ-

ated with a greater risk of type-2 diabetes and cardiovascular mortality.

There is also a limited evidence-base that suggests some relationship

between breastfeeding and the timing and type of foods used in weaning,

and disease in later life. Many of the associations reported between indica-

tors of early growth and adult disease appear to interact with specific geno-

types. This supports the idea that programming is one of several cumulative

influences upon health and disease acting across the lifespan. Experimental

studies have provided important clues to the mechanisms that link nutri-

tional challenges in early life to disease in adulthood. It is suggested that

nutritional programming is a product of the altered expression of genes that

regulate the cell cycle, resulting in effective remodelling of tissue structure

and functionality. The observation that traits programmed by nutritional

exposures in foetal life can be transmitted to further generations adds

weight the argument that heritable epigenetic modifications play a critical

role in nutritional programming.

Introduction

Research over a period of several decades has identified

associations between anthropometric measurements at

birth and disease in later life (Barker, 2006; Langley-

Evans & McMullen, 2010; Gluckman et al., 2011). The

epidemiological studies describing such associations have

led to the assertion that factors in the maternal environ-

ment influencing growth and development can also alter

tissue function, such that adult physiology reflects the

early-life experience. Work with experimental models

has confirmed that nutrition in early life has the capac-

ity to permanently establish physiological and meta-

bolic states that effectively determine the risk of diseases

that occur with ageing (Langley-Evans & McMullen,

2010).

The evidence linking nutrition in early life to health in

adulthood now forms a cornerstone of health promotion

and public health nutrition programmes globally. A 2009

report recognised and promoted the importance of foetal

and early-life nutrition and its relationship with lifelong

health. This report found compelling evidence for a role

of early-life nutrition in setting the risk of conditions

including coronary heart disease, type-2 diabetes, osteo-

porosis, asthma, lung disease and some forms of cancer

(British Medical Association, 2009). These findings were

further backed by the 2011 report of the UK Scientific

Advisory Committee on Nutrition, which recommended

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Journal of Human Nutrition and Dietetics

a strategy to promote, protect and support breastfeeding

and to optimise the diets and body composition of young

women (Scientific Advisory Committee on Nutrition,

2011). In 2012, the WHO published global targets and

recommendations for the nutrition of mothers, infants

and young children with the aim of reducing the preva-

lence of low birth weight (World Health Organization,

2012).

The concept of early-life programming

The term ‘programming’, originally coined by Lucas

(1991), is used to describe the process by which exposure

to specific environmental stimuli or insults, during criti-

cal phases of development, can trigger adaptations that

result in permanent changes to the physiology of the

organism (Gluckman & Hanson, 2004; Gluckman et al.,

2011). In other words, when a developing foetus or infant

is subject to external challenge, the physiological adapta-

tions that occur to ensure survival may leave behind a

permanent memory of that exposure.

Programming is a consequence of the plasticity of cells

and tissues during development, which permits the devel-

oping embryo or foetus to respond to their current envi-

ronment. For most types of cell, plasticity is a short-lived

characteristic that is a feature only of the embryonic and

foetal stages. In some cell types, the adaptive capacity

remains present throughout life. For example, the human

immune system can respond to infection by a previously

unencountered pathogen and the B-lymphocytes that dif-

ferentiate during that response remain available to com-

bat any subsequent infection by that organism

(Gluckman et al., 2011). The majority of tissues retain

plasticity only during the periods of embryonic and foetal

development. As a result, these are considered to be the

critical developmental phases during which perturbation

of normal processes and hence programming of human

health and disease by nutrition may occur.

A key process through which the environment encoun-

tered during early life may determine lifelong physiologi-

cal and metabolic function, and hence disease risk, is

likely to be through the remodelling of organs and tissues

(Langley-Evans, 2009). All tissues have a structure that

relates to their function, with functional units that are

required to mediate physiological function. For example,

in the pancreas, the functional unit required for mainte-

nance of insulin synthesis and secretion is the islet. Simi-

lar to most human systems, the pancreas is fully formed

by the time of birth and the number of islets is set in ute-

ro (Snoeck et al., 1990). Subtle developmental exposures

that result in fewer islets being formed may have no

immediate impact upon pancreatic function but make an

age-related decline in metabolic regulation more likely. As

described below, the same principle applies to other

organs and tissues (Langley-Evans et al., 1999) and,

hence, factors that determine the quality of the intrauter-

ine environment can modify tissue structure and are

effectively risk factors for noncommunicable diseases of

adulthood.

A diverse range of different stimuli operating during

development may have a programming effect. This review

describes the programming effects of the nutritional envi-

ronment encountered in early life. In addition, any envi-

ronmental factor that might impact upon foetal growth

should be regarded as a potential programming influence,

including smoking, severe psychological trauma, maternal

infection or pharmacological agents (Seckl & Meaney,

2004; Yehuda et al., 2005; Salmasi et al., 2010; Schmiege-

low et al., 2013).

The timing of exposure to potential programming

stimuli may be critical in determining the outcome of the

event. Greatest sensitivity will occur during the periods of

most rapid growth and maturation. For example, the kid-

ney may be most vulnerable during the phase of nephro-

genesis (Langley-Evans et al., 1999). The brain, which has

a critical period of development early in human gestation,

may remain vulnerable for much longer because extensive

growth and development of neural pathways and linkages

extends well into childhood (Plagemann et al., 2000).

Longer periods of exposure may be expected to have an

impact upon a greater range of organs and systems.

Nutritional programming during foetal development

Some of the earliest indications of a relationship between

the intrauterine environment and later health were pro-

vided by ecological studies that showed simple correla-

tions between place of birth and the risk of death from

coronary heart disease and between the risk of death in

infancy and coronary heart disease mortality (Barker &

Osmond, 1987; Osmond et al., 1990). These early indica-

tions were given extra weight through retrospective

cohort studies based upon a population from Hertford-

shire, UK. Records from 16 000 men and women born in

Hertfordshire between 1911 and 1930 included weight at

birth and weight at age 1 year. It was found that,

although mortality rates for all causes were unrelated to

size at birth or in infancy, lower birthweight was associ-

ated with increased coronary mortality (Barker et al.,

1989). Follow-ups of men aged 64–75 years in this cohort indicated inverse associations between weight at birth and

blood pressure (Barker et al., 1990), type-2 diabetes

(Hales et al., 1991) and the insulin resistance syndrome

(Barker et al., 1993). A number of similar studies indi-

cated inverse relationships between lower birthweight

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(but within the normal population range) and disease

outcomes. In one of the largest of these studies, the US

Nurses Health Study, Curhan et al. (1996) collected data

on birthweight from 70 297 women and found that,

among full-term singletons, and after adjustment for

adult body mass index, the risks of coronary heart disease

and stroke were both related to weight at birth (relative

risk estimate 0.85 per kg increase in birth weight). A

lower weight at birth was also associated with higher

blood pressure in adult life. In addition to studies show-

ing relationships between birthweight and disease risk in

adults, a number of reports indicated that disease markers

are elevated in young children subsequent to low birth-

weight (Bavdekar et al., 1999).

Birthweight is not the only measureable feature at birth

that is related to later health and disease. Thinness at

birth (measured as ponderal index; weight/length 3 ) has

been found to be inversely related to risk of type-2 diabe-

tes and glucose intolerance. Eriksson et al. (1999, 2001)

have reported extensively upon two populations born in

Helsinki, Finland (1924–33 and 1933–44). Follow-ups of these cohorts confirmed that stroke and coronary heart

disease mortality were greater with low birthweight. Thin-

ness at birth was also related to risk of coronary heart

disease death type-2 diabetes and metabolic syndrome if

body mass index was high in later childhood (Eriksson

et al., 1999, 2001). Large head circumference in propor-

tion to body length is also a potential disease marker

(Carrington & Langley-Evans, 2006) and, together, these

observations suggest that factors constraining truncal

growth in utero also bring about a programming effect

upon the developing organs, which permanently perturbs

function and redundancy of systems in the face of ageing.

Observations that intrauterine factors were related to

disease in adulthood were explained by the initiators of

the programming hypothesis in terms of deficits in

maternal nutrition. It was argued that, in the early part

of the 20th Century when the Hertfordshire and Helsinki

cohorts were born, the main drivers of poor pregnancy

outcome were poverty and associated undernutrition and

infectious disease among young women. This argument

received some weight with the observation that placental

size was also related to disease outcomes. In children,

blood pressure was positively associated with placental

weight (Moore et al., 1996) and follow-ups of a cohort of

50-year-old men and women found that highest blood

pressure was associated with lower birthweight and a lar-

ger placenta (Barker et al., 1990). Because the placenta is

the primary determinant of nutritional supply to the foe-

tus, it was reasoned that nutritional deficit or excess

could alter the foetal : placental ratio with irreversible

consequences for organ structure (Godfrey et al., 1991).

Animal studies also indicated that lower birthweight was

a frequent outcome of maternal undernutrition (Woodall

et al., 1996). In sheep, maternal undernutrition also

results in placental enlargement, a response that is inter-

preted as an adaptation to maximise transfer of nutrients

from mother to foetus (McCrabb et al., 1991).

To some extent, this argument remains accepted within

the field, although it has to be recognised that measures

of infant anthropometry at birth or placental size are only

crude proxies for nutritional exposure during pregnancy.

However, there are very few studies that have the capacity

to offer more meaningful measures in the context of

long-term health. Where such information is available,

the effects are often small or difficult to interpret. In the

winter of 1944–1945, western Holland was subject to a famine of approximately 6 months in duration [at the

height of the famine, the adult ration was 2.09– 2.51 MJ day

–1 (500–600 kcal day–1)] because of the

blockade of food supplies by Nazi forces (Roseboom

et al., 2001, 2011). As a result of the duration of the fam-

ine, some pregnant women were affected over the final

stages of pregnancy, whereas others were undernourished

in early pregnancy. Birth weights among babies affected

by famine in late gestation were approximately 250 g

lower than those of babies born before or conceived after

the famine (Lumey, 1992; Roseboom et al., 2001).

For mothers who experienced the famine in the first

trimester of gestation, the babies were heavier at birth

than the norm for the population. Over a number of fol-

low-ups considering health outcomes for the famine

babies compared to contemporaries born before or after

the famine, it was shown that exposure to famine in early

gestation was associated with a greater prevalence of cor-

onary heart disease and raised circulating lipids, as well as

with raised concentrations of blood clotting factors and

more obesity compared to those not exposed to the fam-

ine (Ravelli et al., 1976, 1999, 2000; Roseboom et al.,

2001). Individuals who had suffered exposure to the fam-

ine during mid-gestation were more likely to exhibit

impaired renal function as adults (Painter et al., 2005)

and exposure to famine during late gestation was associ-

ated with glucose intolerance and type-2 diabetes (de

Rooij et al., 2006a; de Rooij et al., 2007).

A study conducted in a small number of children dem-

onstrated a relationship between maternal iron status and

adiposity and offspring blood pressure (Godfrey et al.,

1994). Blood pressure was also an outcome reported by

Project Viva, a US prospective cohort study following the

children of women whose nutritional status had been

measured in detail in the period before and during preg-

nancy. Gillman et al. (2003) reported that maternal cal-

cium supplementation during pregnancy reduced blood

pressure in 6-month-old infants. Project Viva also identi-

fied an association between higher maternal vitamin D

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S. C. Langley-Evans Early life – later disease

intake and lower risk of childhood asthma among 3-year-

old children (Camargo et al., 2007). The same cohort

showed that babies born to women who gained excessive

weight in pregnancy were more likely to be obese in

childhood (Oken et al., 2009). Normia et al. (2013)

reported that, in a small cohort of mother–child (4-year- old) pairs, higher maternal carbohydrate intake was asso-

ciated with higher childhood systolic blood pressure and

higher childhood systolic blood pressure was noted in off-

spring exposed to lowest or highest tertiles of maternal

fat intake during pregnancy. A longer-term follow up of

Scots aged in their 40s for whom maternal food intake

data were available also provided evidence that maternal

intake could be a driver of intrauterine programming

(Campbell et al., 1996). Adult blood pressure was associ-

ated with maternal intakes of animal protein and sugars,

although the relationship was complex and nonlinear.

The epidemiological approaches to investigating the

relationships between events in foetal life and outcomes

60–70 years later are inevitably subject to criticism. Clearly, there is no scope for a randomised controlled

trial in this area and, although there are a number of

ongoing prospective cohort studies, it is inevitable that

the literature relies upon retrospective cohorts and case– control studies. These are prone to unadjusted confound-

ing and generally are reliant on poor proxy markers of

nutrition in pregnancy. A single measure of weight at

birth reveals little about the experience of the foetus in

utero and cannot provide any indication of whether

growth was constrained, or what factors were limiting. As

demonstrated by the Dutch Hunger Winter studies,

undernutrition at different stages of gestation may have

varying effects upon final birthweight, including an

increased size at birth (Lumey, 1992; Roseboom et al.,

2001). Moreover, among populations in developed coun-

tries, the correlation between maternal intake and birth

weight is poor (Godfrey et al., 1996; Langley-Evans &

Langley-Evans, 2003). The actual nutritional environment

encountered by the foetus is far more complex, reflecting

maternal intake, stores, maternal activity, placental func-

tion and rate of foetal growth. A meta-analysis by Huxley

et al. (2002) identified a high influence of measurement

and publication bias in the literature linking foetal growth

to cardiovascular disease but, importantly, other robust

systematic reviews and meta-analyses have confirmed

relationships between birth anthropometry and the risk of

type-2 diabetes and chronic kidney disease (Whincup

et al., 2008; White et al., 2009).

Given the unavoidable issues with epidemiology in this

area, much of the research designed to investigate the

mechanistic basis of programming, and to confirm the

association between physiological and metabolic function

in adulthood and nutrition during foetal life, has been

reliant on experimental animal studies. It is most striking

that, across a diverse range of species, including rodents,

sheep and nonhuman primates, there are solid relation-

ships between maternal nutritional status and blood pres-

sure, feeding behaviour, adiposity and glucose

homeostasis (Langley-Evans, 2013). The animal evidence

suggests that apparently very different nutritional insults

during pregnancy (e.g. iron deficiency and maternal over-

feeding) can elicit essentially the same outcomes in the

resulting adult offspring (Langley-Evans et al., 1996;

Gambling et al., 2003; Samuelsson et al., 2008). Not only

does this confirm the biological plausibility of the pro-

gramming hypothesis, but it also suggests that a limited

number of common mechanisms may link nutritional

‘stressors’ to development changes that result in later

disease.

Nutritional programming during infancy

The early studies of nutritional programming identified

growth over the first year of life as an indicator of disease

in adulthood. For example, Hales et al. (1991) reported

that, in addition to birthweight, weight at 1 year was sig-

nificantly related to glucose intolerance and beta-cell dys-

function in 64-year-old men. Such studies have not been

longitudinal in nature and so, in that study, it was not

clear whether the smaller 1-year-olds were also the small

newborns, or whether they represented a group who had

failed to thrive after birth. However, data of this nature

have been regarded as generally supportive of nutritional

programming occurring during early infancy. Other stud-

ies argue that the key driver of programmed disease is the

combination of poor early growth with rapid catch-up

growth in infancy and childhood (Eriksson et al., 1999,

2001; Forsen et al., 1999).

Nutrition in the earliest stage of infancy is provided

solely as milk, which may be human milk delivered by

breastfeeding or formula milk from bottle feeding. There

is a large amount of literature available describing the

longer-term health benefits of breastfeeding, providing

evidence suggesting that disease risk is programmed dur-

ing this period (if we accept that human milk is optimal

for growth and development and formula milk is not). A

positive effect of breast-feeding on cognitive function is

widely reported (Evenhouse & Reilly, 2005) and breast-

feeding appears likely to protect against some immune-

related diseases later in life, such as type-1 diabetes

(EURODIAB, 2002) and inflammatory bowel disease (Kle-

ment et al., 2004). There is significant literature detailing

the benefits of breastfeeding in preventing atopic disease

in children with a family history (Gdalevich et al., 2001).

However, the literature on breastfeeding and later health

is plagued by methodological difficulties, being heavily

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Early life – later disease S. C. Langley-Evans

dependent upon observational studies with self-report of

breastfeeding behaviour, and subject to the effects of con-

founding factors (Schack-Nielsen & Michaelsen, 2007).

There is limited convincing evidence that the window

for nutritional programming extends any further into

infancy. The World Health Organization recommends

exclusive breastfeeding until 6 months of age and contin-

ued breastfeeding until 2 years of age or beyond. After

6 months, appropriate complementary foods should be

introduced, although some argue that this is too late for

infants in developed countries where the risk of water- or

food-borne infection is low (Fewtrell, 2011). In develop-

ing countries, early or inappropriate complementary feed-

ing may lead to malnutrition and poor growth but, in

countries where obesity is a greater public health concern

than malnutrition, the relationship between mode of

feeding, growth and longer-term health is unclear.

A systematic review of the literature (Pearce et al.,

2013) investigating the relationship between the timing of

the introduction of complementary feeding and obesity

or being overweight during childhood found that intro-

ducing complementary foods at ≤4 months was associated with a higher body mass index (BMI) in childhood.

However, this was largely reflected in lean mass and there

was no strong evidence of earlier weaning being associ-

ated with greater adiposity. It is possible that effects of

complementary food may interact with earlier nutritional

experience. The responses of formula-fed infants to early

weaning may differ from those of breastfed babies (Przyr-

embel, 2012). There is evidence that the mode of feeding

before weaning influences flavour preferences in infants.

These effects of exposure to either breast milk (and the

exposure to flavours in the maternal diet) or formula

may affect food choices and health in later life. (Trabulsi

& Mennella, 2012).

In addition to the timing of introduction of comple-

mentary feeding, the nature of the foods used in weaning

have been considered as potential determinants of child-

hood obesity or being overweight. The systematic review

of Pearce & Langley-Evans (2013) found some evidence

of an association between high protein intakes at

2–12 months of age and higher BMI or body fatness in childhood. Higher energy intake during complementary

feeding was also associated with a higher BMI in child-

hood. Adherence to dietary guidelines during weaning

was associated with a higher lean mass, although consum-

ing specific foods or food groups made no difference to

childhood BMI.

Although the early nutritional environment may have

some limited effects on adiposity in childhood, the

longer-term relationship to health in adulthood is

unclear. There is strong evidence indicating that a degree

of the risk of adult obesity and being overweight is

related to being overweight in childhood, a phenomenon

known as tracking (Freedman et al., 2001). It is likely that

the strongest determinant of weight and fat mass tracking

is genetics rather than diet, however, and it is also appar-

ent that childhood obesity has no strong independent

effect upon risk of either cardiovascular disease or meta-

bolic disorders (Lloyd et al., 2010, 2012). These are heav-

ily influenced only by adult adiposity.

Data from robust longitudinal cohort studies suggest

that there is no strong relationship between breastfeeding

and the risk of coronary heart disease in adulthood (Mar-

tin et al., 2004; Rich-Edwards et al., 2004). In the Caer-

philly study of more than 2500 middle-aged men, Martin

et al. (2005) reported that breastfeeding was associated

with an increased risk of coronary heart disease mortality.

This was not coinsidered to be causal because there was

no relationship between mortality and the duration of

breastfeeding. Although mortality from heart disease is

not explained by feeding in infancy, there are weak but

significant associations between breastfeeding and risk

factors for heart disease. Adults who were breastfed have

lower blood pressure and lower total cholesterol than

those who were formula fed (Owen et al., 2002, 2003).

The systematic review of Arenz et al. (2004) suggested

that breastfeeding was protective against obesity in child-

hood, with a longer duration of breastfeeding having a

greater effect. A further review by Owen et al. (2005),

however, concluded that the protective effect was likely

to be heavily confounded and did not persist into

adulthood.

Disease risk across the lifespan

The most robust research linking early-life nutrition to

disease in adulthood demonstrates associations between

diet during pregnancy and the risk of cardiovascular dis-

ease, the metabolic syndrome and type-2 diabetes. These

are conditions that develop with ageing, typically mani-

festing in the fifth decade of life. The determinants of risk

at any stage of life are not simple interactions of the indi-

vidual with his/her environment at that particular point

in time. They are in fact the products of cumulative

exposures across the whole lifespan. The environment

encountered at each stage of life, from the periconceptual

period through to senescence, modifies the individual

response to nutrients and other challenges at successive

stages.

Primarily, the risk of most noncommunicable disease is

determined by genetic factors, with numerous single nucle-

otide polymorphisms (SNPs) accounting for significant

risk of coronary heart disease, obesity, type-2 diabetes

and cancer (Norheim et al., 2012). For example, the

C677T polymorphism of methyl-tetrahydrofolate reductase

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S. C. Langley-Evans Early life – later disease

(MTHFR) is associated with the risk of cardiovascular dis-

ease (McNulty et al., 2012) and colorectal cancer (Sohn

et al., 2009) and the apo E4 variant of apolipoprotein E is

associated with atherosclerosis and Alzheimer’s disease

(Kofler et al., 2012; Hauser & Ryan, 2013). These gene

variants rarely provide a simple predisposition to disease.

This is largely because most disease states are not mono-

genic in origin, as well as there being a degree of gene– environment or gene–nutrient interactions in the aetiology of disease. Again, taking the C677T polymorphism of

MTHFR, it is clear that, with an adequate folate status, any

association of the TT variant with cardiovascular disease is

removed and that, for colorectal cancer, a positive folate

balance decreases risk with respect to the TT genotype

(Homocysteine Studies Collaboration, 2002; Kim et al.,

2012). Abarin et al. (2012) reported that, among girls car-

rying a SNP of FTO, which is normally associated with

higher BMI in adolescence, exclusive breastfeeding negated

the effect of the high-risk allele.

Throughout life, the pathways that lead from any given

genetic predisposition will be modified by both nutrition-

related and non-nutritional factors. The effects of multi-

ple protective or harmful SNPs are also modified by their

interactions with each other and by epigenetic factors that

ultimately control the expression of these ‘disease’ genes;

for example, silencing their expression through DNA

methylation (Jaenisch & Bird, 2003). At any given life

stage, the expression of the genotype is dependent upon

nutritional-signals that play a regulatory role. At the epi-

genetic level, this essentially comprises the B vitamins,

although nutritional status also influences gene expression

via transcription factors such as the peroxisome prolifera-

tor activated receptors (PPARs) or nuclear receptors.

Although nutritional exposures at all stages of life can

modify the disease pathway, the fact that early-life pro-

gramming can alter tissue function and responsiveness to

environmental cues means that nutritional exposures

occurring early in life are able to determine how an indi-

vidual will respond to nutritional signals that come later

in life (Fig. 1). To some extent, this is demonstrated by

some of the epidemiology that describes the association

between foetal growth and adult disease. Studies by Phil-

lips and colleagues showed that, although insulin resis-

tance was greater in 50-year-olds who had been relatively

thin at birth, the influence of this marker of early growth

was greater in individuals who were overweight or obese

in adulthood (Phillips et al., 1994). Similarly, the studies

of the Helsinki cohort showed that women who devel-

oped coronary heart disease had been born small but had

gained weight and increased BMI more rapidly in child-

hood (Forsen et al., 1999). Overall, their increased disease

risk was the product of cumulative nutritional factors at

different life stages.

Underpinning all of the interactions between nutri-

tional or non-nutritional exposures across the lifespan is

the influence of genotype upon disease risk. A body of

evidence favours the concept that nutritional program-

ming provides a layer of risk-modification between the

genotype and later lifestyle behaviours (Fig. 1). A range

of studies have reported that birthweight modulates the

normally observed relationships between specific gene

polymorphisms and disease. The PP variant of the

Pro12Ala SNP of the PPAR-gamma2 gene is associated

with an increased risk of type-2 diabetes. Eriksson et al.

(2002) reported that this association was present only in

individuals who had been of lower weight at birth, show-

ing that an interaction exists between programming influ-

ences and the genotype. This may be regarded in two

ways, with the inferences that programming only occurs

in individuals with a susceptible genotype (i.e. because

birthweight did not predict diabetes in individuals with-

out the PP variant) or that the effect of genotype is only

expressed in individuals subject to adverse programming,

with both being equally valid. de Rooij et al. (2006b) fol-

lowed up individuals from the Dutch Hunger Winter

cohort and found that the effects of the Pro12Ala SNP on

glucose homeostasis varied with the timing of exposure

to famine in utero. However, in contrast to the work of

Eriksson et al. (2002), it was the Ala variant that

increased the risk of type-2 diabetes, although only in

those exposed to famine during mid-gestation.

There are other examples of interactions between early

life factors and genotype. The K121Q SNP of plasma cell

glycoprotein 1 is implicated in development of type-2 dia-

betes, with the Q allele increasing insulin resistance. In the

study by Kubaszek et al. (2004), 121Q increased the risk of

hypertension, type-2 diabetes and insulin resistance,

although only in adults who had been of lower weight at

birth. Lips et al. (2007) followed up individuals from the

Hertfordshire cohort to examine the relationship between

early growth, genotype and bone health. Their study found

that, among women, the 11 genotype of the calcium-sens-

ing receptor CASRV3 polymorphism was associated with

higher lumbar spine bone mineral density within the low-

est birthweight tertile. The opposite was observed among

individuals in the highest birthweight tertile.

Given that the risk of developing cardiovascular disease

or the metabolic syndrome in adulthood is determined by

factors interacting across the lifespan, including powerful

effects of genotype and dietary exposures at all stages of

life, the fact that it is possible to detect any influence of

foetal growth-related factors at all is remarkable. The per-

sistence of early-life events as influences upon the

response to nutritional challenges in adulthood is a testa-

ment to the likely strength of early-life programming

effects upon the development of organs and systems.

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Early life – later disease S. C. Langley-Evans

Transgenerational effects of nutrition in pregnancy

Current thinking in the developmental programming area

is that disease arises as a result of a mismatch between

the prenatal and postnatal environment. This is supported

by evidence demonstrating that rapid catch-up growth

following prenatal growth restriction is the strongest pre-

dictor of the metabolic syndrome. In populations under-

going economic and nutritional transition from poor to

relatively affluent status (e.g. India, China, South Africa),

an explosion of obesity, type-2 diabetes and cardiovascu-

lar disease is expected as a result of such a mismatch.

Although rapid improvements in maternal nutrition in

such countries may be expected to lessen the importance

of nutritional programming as a contributor to the over-

all disease burden, it is argued that transgenerational

effects may occur, whereby the consequences of deficits in

maternal nutrition in pregnancy are ultimately transmit-

ted to grandchildren. This means that, across the globe,

nutritional/economic transition may represent a sharp

decline in malnutrition-related disease, to be followed by

half a century of unavoidable metabolic disease.

Pembrey (1996) proposed that an transgenerational

feed-forward control loop exists, linking the growth and

health of an individual with the nutrition of their grand-

parents. This form of control would be likely to involve

some genomic imprinting of genes, which are then passed

on to subsequent generations. The outcome of such

imprinting would be very long-term health consequences

for populations that are exposed to either undernutrition

or over-nutrition at some stage in their history. The com-

plexity of the epidemiological studies that would be nec-

essary to investigate transgenerational programming in

human populations largely precludes such work.

Studies of individuals exposed to the Dutch famine

indicate that undernutrition of women during pregnancy

influenced the nutrition of their daughters and subse-

quently had an impact upon the birthweight of their

grandchildren. Veenendaal et al. (2013) reported that the

grandchildren of women who were pregnant during the

famine had greater neonatal adiposity and poor health in

later life. Women who were exposed to famine in utero

were themselves more likely to give birth to low birth

weight children (Lumey, 1992), which suggests a grand-

maternal influence upon foetal growth and development.

Health Disease

Genome

Epigenome

Nutritional environment

Non-dietary exposures

Smoking

Social class

Infection

Stress

In utero

Infancy

Childhood

Adult

Ef fe

ct s

ar e

cu m

u la

ti ve

Effects are interactive

Figure 1 Disease risk is the product of cumulative risk factors across the lifecourse. Primarily, the risk of most noncommunicable disease is

determined by genetic factors, with numerous polymorphisms accounting for significant risk of coronary heart disease, obesity, type-2 diabetes

and cancer. The effects of protective or harmful polymorphisms may be modified by their interactions with each other and epigenetic factors that

control the expression of these ‘disease’ genes. Throughout life, the pathways which lead from any given genetic predisposition will be modified

by non-nutritional factors. Nutritional exposures at all stages of life also modify the disease pathway. Exposures that occur early in life are able,

through programming, to determine how an individual will respond to nutritional signals in later life.

7ª 2014 The British Dietetic Association Ltd.

S. C. Langley-Evans Early life – later disease

Transgenerational effects are not necessarily the product

of deficits only in maternal nutrition. Bygren et al. (2001)

have reported that the grandchildren of men who were

overfed in the prepubertal growth period had a signifi-

cantly shorter lifespan. Davis et al. (2008) reported that

childhood BMI correlated strongly with grandparental

BMI, irrespective of parental BMI. This has been inter-

preted as the transgenerational transmission of obesity,

although BMI also reflects lean mass and any relation-

ships could reflect family behaviours as much as a biolog-

ical transmission.

Transgenerational programming, the physiological

response of offspring across two or more generations, has

been previously noted in studies of animals. Beach &

Hurley (1982)assessed immune function in the offspring

of mice fed a zinc deficient diet in pregnancy. Immuno-

suppression was severe and persisted into a third genera-

tion following the initial nutritional insult before

resolving. More recently, Drake et al. (2005) have

reported that the treatment of pregnant rats with dexa-

methasone in pregnancy, an intervention known to retard

foetal growth and programme hypertension and glucose

intolerance in the offspring, produces effects on glucose

homeostasis that persist for two generations. Maternal

high fat feeding elicited a sex-specific insulin resistant

phenotype in second- and third-generation mice offspring

(Zambrano et al., 2005).

At the present time, it is likely that the observed pro-

gramming of physiology, metabolism, health and disease

is in part a product of the maternal environment signal-

ling to the foetal epigenome. This is an issue of major sig-

nificance because epigenetic marks, although sensitive to

environment and ageing, may be stably inherited by any

future offspring. This allows potential for a nutritional

insult in one pregnancy to have effects over several genera-

tions. Feeding a low-protein diet to rats during pregnancy

programmed blood pressure and nephron number over

two generations. Importantly, transmission occurred via

the male as well as the female line, which is strongly sug-

gestive of an influence of the epigenome (Harrison &

Langley-Evans, 2009). This opens up the possibility that

paternal, as well as maternal, nutritional status may be an

important determinant of disease risk. This would radi-

cally change the way that we think about optimising nutri-

tional status in the peri-conceptual period.

Mechanistic considerations

The evidence to link early-life nutrition (in particular

maternal nutritional status in pregnancy) with disease in

later life is overwhelming. The challenge is to utilise this

information for the development of novel approaches to

public health, or other interventions, to prevent and treat

disease. To be able to even put in place simple measures

such as advice for optimising nutrition in the peri-con-

ceptual period requires an understanding of the mecha-

nisms that explain how nutritional programming occurs.

The animal experiments suggesting that even relatively

mild perturbations of dietary quality during can bring

about altered function in the ageing offspring are a cause

for caution. Any ill-considered intervention in humans

could have far-reaching, transgenerational consequences.

As described above, the most likely mechanism that

allows a possibly transient nutritional insult, acting during

early life, to exert a lasting effect upon physiological func-

tion, decades later, involves changes to the structure of

organs and tissues during their phases of growth, differen-

tiation and maturation (Fig. 2). This tissue remodelling is

typified by observations of the effects of undernutrition

and growth restraint upon the kidney in both animals and

humans. Nephrons are the functional units of the kidney,

being the sites of blood filtration and urine formation. In

the human kidney, nephron number is determined before

birth and is hypervariable between individuals, ranging

between 300 000 and 10 00 000 nephrons per kidney

(Mackenzie & Brenner, 1995). Nephron number is an

important marker of the likelihood of chronic kidney dis-

ease because nephrons are progressively lost with ageing.

It is argued that a lower starting number is associated with

an earlier loss of functional capacity.

Autopsy studies strongly suggest an association between

nephron number and birthweight (Hughson et al., 2003)

and investigations of Australian aboriginal populations

suggest that poverty is a driver of lower nephron number

and disease (Singh & Hoy, 2004). Animal studies confirm

that nephron number is extremely sensitive to maternal

undernutrition and can be constrained by food restric-

tion, protein restriction or iron deficiency during nephro-

genesis (Langley-Evans et al., 1999; Swali et al., 2011).

There is also evidence of remodelling being associated

with maternal nutritional insults in the brain (Plagemann

et al., 2000) and pancreas (Snoeck et al., 1990) but only

in animals.

The conditions that appear to be programmed in utero

are exclusively diseases that have their onset in middle-

age or the later years. This suggests that key features of

tissue remodelling are the depletion of functional reserve,

as illustrated in the case of the kidney above, and a sus-

ceptibility to more rapid loss of functional units. There

are numerous examples in animal studies that suggest a

greater susceptibility to oxidative injury and senescence in

the offspring of mothers that were undernourished in

pregnancy (Jennings et al., 2000; Langley-Evans & Sculley,

2005, 2006; Tarry-Adkins et al., 2013).

Remodelling of tissues is not a simple response to a

lack of substrate, or endocrine signals from mother to

8 ª 2014 The British Dietetic Association Ltd.

Early life – later disease S. C. Langley-Evans

foetus indicating a sub-optimal environment. The process

inevitably involves changes in these signals, eliciting

changes in gene expression that impact upon tissue devel-

opment. The programming literature now contains innu-

merable reports of long-term gene expression changes in

response to an early-life insult; for example, altered

expression of the genes involved in hepatic glucose han-

dling following intrauterine exposure to maternal over-

feeding in the rat (Erhuma et al., 2007; Bayol et al.,

2010). In humans, there are fewer such reports and, in

most cases, it is impossible to ascribe causal relationships

between gene expression and outcome. For example, D�ıaz

et al. (2013) reported that placental expression of pre-adi-

pocyte factor 1 was inversely correlated with infant fat

mass at age 1 year. Similarly Lewis et al. (2012) reported

that placental expression of Pleckstrin homology-like

domain family A2 was related to bone mass in 4-year-old

children. These studies provide potentially useful predic-

tive biomarkers for disease but do not cast significant

light on how maternal nutritional status elicits program-

ming responses. The state of research in humans in this

context is far less advanced and convincing than the envi-

ronment–polymorphism interactions described above. Although of interest in terms of exploring how longer-

term disease states are driven by early-life nutrition, these

reports do not provide a strong basis for determining the

initial drivers of programming. It is likely that, in the face

of intrauterine nutrient excess or deficit, a number of

changes occur in gene expression that are very short-term

but sufficient to perturb tissue development irreversibly.

There is emerging evidence to suggest that genes control-

ling the cell cycle and DNA replication (hence the prolif-

eration phases of organ development) may be particularly

susceptible to influences of maternal undernutrition

(Fig. 2) (Swali et al., 2011, 2012).

Although other potential mechanisms cannot be ignored,

influences of epigenetic factors (e.g. DNA methylation and

histone modifications) are considered to play an important

role in developmental programming of disease (Burdge

et al., 2007). DNA methylation provides an important

mechanism for gene silencing, whereas modifications of

histone proteins can either allow gene transcription or

silence expression (Jaenisch & Bird, 2003). Environmental

challenges in early life, including under- or over-nutrition,

are likely to affect DNA methylation significantly because,

during the very early phases of embryo development, DNA

methylation is extensively reprogrammed. Differences in

methylation were found at the IGF2 locus between individ-

uals exposed to the Dutch famine and their unexposed sib-

lings (Heijmans et al., 2008). A rapidly increasing body of

evidence from both animal and human studies show that

the epigenome is sensitive to nutrition during foetal and

adult life (Sharif et al., 2007; Sinclair et al., 2007; Lillycrop

et al., 2008; Bogdarina et al., 2010).

Effects of early nutrition upon the epigenome are likely

to have a number of significant effects upon later health

and wellbeing. First, epigenetic marks control gene

expression and this means that even transient nutritional

Mature tissue with functional units Mature tissue with fewer functional units

Smaller mature tissue with fewer functional units

P ro

lif er

at io

n D

if fe

re n

ti at

io n

Insult during cell proliferation limits tissue growth and functional capacity

Insult during cell differentiation limits functional capacity of the mature tissue

Figure 2 The basis of tissue remodelling. The development of tissues depends on an ordered pattern of cell proliferation from early progenitor

cells, with later differentiation of the tissue precursors to form the specialised cell types and functional units responsible for tissue function. Tissue

development is therefore associated with waves of cell division, apoptosis and differentiation to achieve the mature structure. Remodelling of

tissues will occur if environmental factors, including signals of less than optimal nutrition, impact upon the proliferation and differentiation

phases, resulting in tissues that are smaller (or of normal size) but with fewer functional structures and hence limited capacity to withstand age-

related degeneration.

9ª 2014 The British Dietetic Association Ltd.

S. C. Langley-Evans Early life – later disease

exposures could leave an epigenetic memory within cells,

which will then govern how genes are expressed in

response to further environmental cues. Second, the state

of the epigenome is not entirely stable throughout life. As

epigenetic drift occurs, patterns of gene expression within

tissues can change and this has been linked to certain

cancers and Alzheimer’s disease (Fraga & Esteller, 2007;

Wang et al., 2008). The nature of age-related drift may be

partly mediated by early-life events and the state of the

epigenome in infancy. Finally, it is assumed that changes

to the epigenome may be heritable and this could explain

why programming effects of nutrition can persist over

several generations and be passed down the male line.

Conclusions

Although heavily reliant on findings from retrospective

cohort studies and experiments with animals, there is an

overwhelming body of evidence to demonstrate that

nutritional influences encountered during early life have a

lasting impact upon health and well-being. The potential

impact of these findings for public health is huge because

pregnancy and early infancy represent windows of oppor-

tunity during which parents are most willing to adopt

lifestyle changes that could have health implications

across multiple generations. There is a need for greater

understanding of the processes involved in early-life pro-

gramming to refine advice given to women who are preg-

nant or planning a pregnancy and mothers with young

children. The recognition that lifestyle factors impacting

upon health are operant from the moment of conception

has profound implications for the way in which we

regard the aetiology of disease and should be a factor

incorporated into any future use of genomic or epige-

nomic information as a basis for personalised nutritional

advice.

Conflict of interests, source of funding and authorship

The author declares he has no conflicts of interest.

No funding is declared.

The author critically reviewed the manuscript and

approved the final version submitted for publication.

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