NIHR SouthamptonBiomedical Research Centre

The Southampton Biomedical Research Centre is funde d by the National Institute for Health Research (NI HR) andis a partnership between University Hospital Southa mpton Foundation Trust and the University of Southa mpton

Life Course Factors, Nutrition and Body Composition

Alan A Jackson

Stockholm 18-19th April 2013

Global Health Problems

Barker Hypothesis

Catch-up growth

Conclusions

Global Health Problems

Barker Hypothesis

Catch-up growth

Conclusions

Europe: Secular Increase in Height

Plateau ~1.8 m:Denmark, Sweden, Norway, Netherlands ?genetic potential

Increasing: Belgium, Spain, Italy, Portugal

Larnkjaer et al Acta Paediatrica 2006

Europe: secular increase in height:

Stopped, 18 years following post-neonatal mortality

around 4/1000 deliveries.

Improving socio-economic conditions

better nutrition – healthier diet

decrease in infectious diseases

Brazil Costa Rica Guatemela Haiti Jamaica Nigeria India Ho ng Kong108

112

116

120

124

Martorell, 1985Martorell, 1985Martorell, 1985Martorell, 1985

- 50th- 50th- 50th- 50th

- 25 th- 25 th- 25 th- 25 th

- 10 th- 10 th- 10 th- 10 th

- 5 th- 5 th- 5 th- 5 th

NCHSNCHSNCHSNCHS

percentilepercentilepercentilepercentilehe

ight

, cm

Mean height for 7 year old boysMean height for 7 year old boysMean height for 7 year old boysMean height for 7 year old boys

high socio-economic statushigh socio-economic statushigh socio-economic statushigh socio-economic status

low socio-economic statuslow socio-economic statuslow socio-economic statuslow socio-economic status

Social Determinants of Length

STUNTING: low height for age

More common than wasting (thinness, severe acute malnutrition)

Obesity more common than wasting

↑ mortality

↑ morbidity

↓ physical work performance

↓ intellectual function

↓ Lifelong earning capability

Stunting: by 2 years of ageDeprivation: poor neurocognitive development, obesity

length

weight

weight for length

Shrimpton 2001

Global epidemic of obesity

300 million BMI>30

1.5 billion BMI>25

1.7 billion BMI>23

200 m school-age children overweight

35 m under 5yrs overweight

““““The epidemic of obesity, with its attendant comorbidities --- heart disease, hypertension, stroke, and diabetes --- is not a problem limited to industrialized countries”””” – WHO TRS 916

Prevalence of obesity among children < 5 yrs de Onis & Blossner AJCN

2005

Hillary Clinton Launches 1,000 Days MovementSeptember 2010

Double Burden of Malnutrition:

Malnutrition in All its Forms

Underweight, Overweight, Micronutrient Deficiencies

Global Action Plan for Scaling Up Nutrition (SUN)

Scaling up of evidence-based,high priority nutrition interventions

Focusing primarily on the window of opportunity conception to 24 months

Multisectoral: underlying socio-economic, intersectoral causes

Integrate: health systems, agriculture and food security and social safety nets

Body Mass Index

U-shaped relationshipall cause mortality

Preferred range 22-25 kg/m2

Global Health Problems

Barker Hypothesis

Catch-up growth

Conclusions

Barker hypothesis:Fetal Origins of Chronic Disease:

Coronary heart disease,

Stroke,

Type 2 diabetes

Hypertension

Developmental Model for Disorders

Fetal Origins Hypothesis of Chronic Disease

Disorders originate through Developmental Plasticity

Poor nutrient exposure: early life (fetus, infant, early childhood)

Permanent change in structure and function: - tissues and organs

Vulnerable period: timing, intensity, duration

Coronary heart diseaseStandardised mortality ratios (SMR) in 10141 men & 5585 women

20

40

60

80

100

120

-5.5 -6.5 -7.5 -8.5 -9.5 >9.5

Birthweight (pounds)

SMR

20

40

60

80

100

120

-5.5 -6.5 -7.5 -8.5 -9.5 >9.5

Birthweight (pounds)

SMR

MEN WOMEN

BMJ 1993;307:1519-24

Variable risk across the rangeacross the rangeacross the rangeacross the range of weight at birth & at age one year, which is not a feature of the extremes of the ranges, very low or very high.

Barker Hypothesis

Early Life origins of disease:

Evidence from wide range of internationalstudies

Metabolic changes already

evident in childhood by

5 years of age

Birthweight Tertile andPrevalence of Insulin Resistance Syndrome

Valdez et al, Diabetologia 1992

1 2 3

Birthweight tertile

0

2

4

6

8

10

12

14

16

IRS

per

cent

age

Non-hispanic American

Mexican American

Birthweight Tertile, Adult BMI and Insulin Resistance Syndrome

Valdez at al, Diabetologia 1994

1 2 3

Birthweight Tertile

0

5

10

15

20

25

30

IRS

Pre

vale

nce

BMI Tertile1

23

Adults who had coronary heart disease

Growth in childhood – to 11 years

Mean z scores for height, weight and body mass index

Barker et al Ann Hum Biol 2009;36:445-458

Finnish Studies

Coronary Heart Disease: Finnish menCoronary Heart Disease: Finnish menCoronary Heart Disease: Finnish menCoronary Heart Disease: Finnish menForsen et al, BMJ 1997, 315, 837-40Forsen et al, BMJ 1997, 315, 837-40Forsen et al, BMJ 1997, 315, 837-40Forsen et al, BMJ 1997, 315, 837-40

< 25< 25< 25< 25 - 27- 27- 27- 27 - 29- 29- 29- 29 > 29> 29> 29> 290000

25252525

50505050

75757575

100100100100

125125125125

150150150150

maternal ht > 1.58mmaternal ht > 1.58mmaternal ht > 1.58mmaternal ht > 1.58m

maternal ht < 1.58mmaternal ht < 1.58mmaternal ht < 1.58mmaternal ht < 1.58m

ponderal index of baby, kg/mponderal index of baby, kg/mponderal index of baby, kg/mponderal index of baby, kg/m3333

sta

nd

ard

ise

d m

ort

ali

ty r

ate

sta

nd

ard

ise

d m

ort

ali

ty r

ate

sta

nd

ard

ise

d m

ort

ali

ty r

ate

sta

nd

ard

ise

d m

ort

ali

ty r

ate

Coronary Heart Disease: Finnish menForsen et al BMJ 1997, 315, 837-40Forsen et al BMJ 1997, 315, 837-40Forsen et al BMJ 1997, 315, 837-40Forsen et al BMJ 1997, 315, 837-40

< 24< 24< 24< 24 - 26- 26- 26- 26 - 28- 28- 28- 28 - 30- 30- 30- 30 > 30> 30> 30> 300000

50505050

100100100100

150150150150maternal ht > 1.58m

maternal ht < 1.58mmaternal ht < 1.58mmaternal ht < 1.58mmaternal ht < 1.58m

maternal BMI, kg/m 2

stna

dard

ised

mor

talit

y ra

te

Coronary heart disease: mother < 1.58 mCoronary heart disease: mother < 1.58 mCoronary heart disease: mother < 1.58 mCoronary heart disease: mother < 1.58 m

standardised mortality ratestandardised mortality ratestandardised mortality ratestandardised mortality rate

Forsen et al, BMJ 1997; 315: 837-840

Ponderal index Ponderal index Ponderal index Ponderal index of babyof babyof babyof baby

< 24< 24< 24< 24 -26-26-26-26 -28-28-28-28 -30-30-30-30 > 30> 30> 30> 30 AllAllAllAll

<25<25<25<25 55555555 106106106106 168168168168 170170170170 224224224224 131131131131

-27-27-27-27 55555555 70707070 146146146146 113113113113 134134134134 104104104104

-29-29-29-29 26262626 54545454 31313131 137137137137 149149149149 75757575

> 29> 29> 29> 29 0000 63636363 26262626 55555555 75757575 48484848

AllAllAllAll 43434343 73737373 88888888 114114114114 136136136136 90909090

BMI of motherBMI of motherBMI of motherBMI of mother

Stunting and overweight in children Countries in transition

Popkin, Public Health Nutrition 1998, 1, 5-21

High rates of lower birth weights

High rates of stunting in childhood (15-35%)

Increased prevalence of obesity

Changes in dietary habits

Reduced levels of activity associated with urbanization

Increased prevalence of heart disease and type 2 diabetes

Global trend towards increase weight and height:

generally desirable:

BUT

increase in weight achieved - before increase in height

Increase in childhood overweight and adiposity

Increased risk of shortness/stunting and obesity

The Thin-Fat Indian Baby

Pune: newborn baby

Weight 2,800g

Thin: reduced lean mass.

Relatively adipose: central fat

Small Baby: shortness and fatnessIncreased risk type 2 diabetes

Standard: how children should grow

All children grow similarly

Low birth wt High birth wt20

22

24

26

28

30

32

34

% b

ody

fat

% fat in low and high birth weight groups (mean + sem), adjusted for BMI (27.9 kg/m2)

4.85%(P<0.004)

Kensara et al, 2005

Age 62-75 years

23 24 25 26 27 28 29 30 31 3220

22

24

26

28

30

32Low birth wt

High birth wt

Body mass index (kg/m 2)

% f

at

4. 85%(p <0.004)

ANCOVA BMI v % fat (r = 0.67; p <0.001)

Kensara et al, 2005

For the same weight or BMI at 70 years of age

Lower birth weight

- less muscle- more fat- more central fat

- function difference

- altered cellular nutrient environment

Systolic Blood PressureMaternal Exposure to Protein Diet

6% 9% 12% 18%100

120

140

160

180

casein content of maternal diet during pregnancy

syst

olic

blo

od p

ress

ure,

mm

Hg

Fetus:

reset of central set-point for key hormonal axes

hypothalamo - pituitary-adrenal

growth hormone – IGF – insulin

thyroid axis

sex steroid axis

- response to diet- response to stressors

Glycine and folic acid supplementation prevent hypertension

Blood pressure at 4 weeks in females

18% 9%

9% +

glyc

ine

50

70

90

110

130*

Maternal diet

Sys

tolic

blo

od p

ress

ure

(mm

Hg)

Jackson et al. 2002, Torrens et al. 2006

Blood pressure at 4 weeks in females

18% 9%

Folic a

cid su

pplem

ente

d

50

70

90

110

130

*

Maternal dietS

ysto

lic b

lood

pre

ssur

e(m

m H

g)

Control Low protein LP with folic acid50

75

100

dietary group

DN

A m

ethy

latio

n

Control Low protein LP with folic acid0

100

200

300

400

dietary group

mR

NA

con

cent

ratio

n

Hepatic Glucocorticoid Receptor: methylation of promoter region of gene and gene expression

Epigenetics

Stable change in DNA structure

Modifies expression

Carried between generations

Variable methylation (protein and folate)

Selective methylation of promoter region

Values are means + SEM

10.0

15.0

20.0

25.0

-40% -60% -80% >80%

Godfrey, et al. Diabetes 2011

Umbilical cord RXRASH amp1 CpG13 methylation

Methylation promoter RETINOIC ACID RECEPTOR gene umbilical cord

Association adiposity 9 years of age: ‘explains’ >25 % of later adiposity;

Global Health Problems

Barker Hypothesis

Catch-up growth

Conclusions

Catch-up growth

- rapid growth, rate greater than normal

- altered efficiency of growthgreater tissue gain per unit energy

- Altered pattern of tissue deposition

Cost of Growth in relation to Change in Body Compos itionduring recovery from severe malnutrition

Jackson, 1977

0 10 20 30 40 50 60 70 80 90 1000.0

2.5

5.0

7.5

10.0

(change in muscle mass) x 100/(change in body mass) , %

cost

of w

eigh

t gai

n, k

cal/g plus

Zinc

minusPotassiumMagnesiumPhosphate

Effect of removing potassium from parenteral

nutrition on nitrogen balanceRudman et al, 1975

-150

-100

-50

0

50

100

150

200 Full Regimen

Full Regimen, 2.4 mmol K+/kg

Plasma K+ 4.6 mmol/L

No potassium

Plasma K+, 2.5 mmol/L

Nitro

gen

Balanc

e, m

g/kg

/d

Pattern of nutrients retainedNutrient requirements for net deposition:

- bone- lean tissue- adipose (by default)

Nutrient availability – altered pattern tissue deposition:

- energy- macronutrients

dietarily essential, conditionally essential- micronutrients

Non-essential or conditionally essential Nutrients:- do not have to be provided preformed in diet.

Required for metabolism - formed from precursors usually readily available in diet.

Amino acids

Longer chain polyunsaturated Fatty acids

High rates of formation

Regulated rates of formation

Diet:

Quantity:energy[macronutrients, carbohydrate, lipid (fat), protein]

Quality:Nutrients[CHO, lipid (essential fatty acids), amino acids, minerals, vitamins, trace elementswater, oxygen]

FOOD/NUTRIENT INSECURITY

Activity: Inflammation

Global Health Problems

Barker Hypothesis

Catch-up growth

Conclusions

Life course

CHRONIC

DISEASEMother’’’’s diet &

body composition

Fetal growth &

development

Infant feeding,

growth, adiposity

Childhood diet,

activity, adiposity

Adult diet, activity

other risk factors

What happens in the short term matters in the long term Life course approach to chronic disease

Standing Committee on Nutrition, United Nations System:

Chronic disease: impending global burden of ill-health

Window of vulnerability: preconception to 2 years of age

Molecular:genetic, epigentic

Cellular:membrane structure and functionreceptor functionsignalling, replication, differentiation

Tissue, organHead circumference: brain Renal size:nephron numberAbdominal circumference: hepatic architecture

Body shape:height, lean, adipose

Structure/function

Structure and function inextricably linked

height weight

Central fat

Fat mass

Lean mass

Visceral lean

Muscle mass

Peripheral fat

Widdowson - “Harmony of Growth”

pace and proportion, partitioning of nutrients

Quantity and Quality