1

Research Director Early Life Development, Early Life Nutrition, Nutricia Research

Prof. Nutritional Programming, Dept Pediatrics, UMCG, Groningen

Brain health throughout life:

the relevance of early life

environmental and nutritional factorsEline M. van der Beek

EARLY LIFE: AN OPPORTUNITY FOR PREVENTION OF NON-COMMUNICABLE DISEASES

Gluckman PD J DOHaD 2010:1(01) pp 6-18. adapted with permission 2

Life course

Fixed genetic

contribution

is small

Role of

nutrition

Timely intervention

may produce

substantial risk

reduction

Impact of late

prevention or

treatment is small

primary

tertiary

secondary

Healthy aging

primordial

Chro

nic

Dis

ease R

isk

3

Dietary intakes change dramatically over

the first two years of life

Gidding S S et al. Circulation. 2005;112:2061-2075

MATERNAL

NUTRITION

PLACENTA

BREAST

MILK

GI TRACT

0-9

NUTRITIONAL REALITY IN INFANTS & TODDLERS:

Switz.

China

Indonesia

Egypt Saudi Arabia

Vietnam

Kenya

Cameroon

Morocco

Ivory

Coast

Portugal

Lebanon

Nigeria

7

Burkina

Faso

Algeria

India

France

Brazil

MalaysiaSingapore

Thailand

Hong

Kong

Russia

Mexico

Canada

South Africa

Japan

UK

Austria

Germany

Bangladesh

USA Italy

NL

Spain

Tunesia

Senegal

Overseasterritories

Greece

HungaryBelgium

Ireland

Argentina

Myanmar

Uruguay

Iran

SwitzPoland

Turkey

Congo

Colombia

Azebaidjan

Cambodge

Chili

Bolivia

Scope nutritional reality in 3

steps:

1. Literature search and

expert interviews (40)

2. Dietary surveys (14)

3. Nutrient status studies (4)

17

28

8

Babies & Mothers*, Children, Adults

Babies & Mothers*

Children, Adults

Seniors

TARGET POPULATIONS

BRAIN DEVELOPMENT CONTINUES THROUGHOUT CHILDHOOD

AND ADOLESCENCE

Morgane et al, Neurosci Biobehav Rev, 2002; Lauritzen et al, Prog Lipid Res, 2001 %

Siz

e o

fad

ult

0

20

40

60

80

100

120

140

160

0 1 2 4 6 8 10 14 18

Thymus

Brain

Testes

Body weight

Liver

Heart

Age (years)Brain growth:1- Waves of intense branching, building connections 2- Selective reduction of neurons and connections shapes functionality:

a- between 3 and 6 yearsb- during puberty (12-14 yrs)

3- The brain is only fully functionally mature in early adult hood (23 yrs)

neuron – dendrite

increaseconnections

selective

neuron loss

HUMAN BRAIN GROWTH & MATURATION:

Brain weight peaks at birth and represents 27% of adult brain weight

Brain maturation consists of sequences of specificevents like gliosis, myelinization and enruogenesis

60% of the adult brain weight is composed of lipids

Lipids, in particular essential fatty acids, are the main brain building blocks and essential for brain growth, brain maturation as well as maintenance……

Rapid brain growth as well as DHA accumulation takes place between conception and 2 yrs of age

Morgane et al, Neurosci Biobehav Rev, 2002; Lauritzen et al, Prog Lipid Res, 2001

7

THE IMPORTANCE OF FAT IN HUMAN MILK

Lactose

53-61 g/L

Fat

30-50 g/L

Protein

9-10 g/L2’FL

1.1 g/LHMOS

10-12 g/L

MCT medium chain triglycerides, Lauric acid C12:0, Palmitic acid C16:0, Stearic acid C18:0, Oleic acid C18:1n9,

LA linoleic acid C18:2n6, ALA alpha-linolenic acid C18:3n3, DHA docosahexaenoic acid C22:6n3, ARA arachidonic acid C20:4n6

• Lipids provide 45-60% of the energy in

human milk

• The lipid contribution is stable over the

course of lactation

• The majority of lipids is composed of

fatty acids (FA)

• Milk FA composition is influenced by the

diet

CompositionQuantity

WHAT HAS CHANGED IN OUR DIET?

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omega 3

(n-3 PUFA)

Ailhaud et al, 2006; Gibson et al, 2010; McInnes et al, 2011, Muhlhausler et al, 2009, 2013

Lassek &Gaulin, 2014; Bernard et al, 2015

• Increased intake of n-6 PUFA + similar (or decreased) intake of n-3 PUFA

• Altered human milk FA composition & n6/n3 ratio

➢ Directly affects adipose tissue development

➢ Influences the development of the immune system

➢ LC-PUFAs are building blocks for all membranes

➢ DHA (ARA) support rapid brain growth & functional development

➢ Diets that differ in n6/n3 ratio affect neuronal development and adequate pruning

➢ High breast milk LA (N6) is negatively correlated to infant cognitive outcomes

Fat quality:

same quantity, different composition

omega 6

(n-6 PUFA)

=

REDUCING MATERNAL DIETARY LA SUPPLY IMPROVESOFFSPRING BRAIN N3PUFA ACCUMULATION

LOWn-6 diet

P2 start diet

P0

P5 P10 P16 P21offspring

Control diet

brain Fatty Acid

composition

End expP21

birth

% o

f to

tal bra

in F

A%

of

tota

l bra

in F

A

**

* ** **

*

*

*

LOWn-6 diet

Control diet

11,0

12,0

13,0

14,0

15,0

P5 P10 P16 P21

DHAC22:6n-3

0,0

0,1

0,2

0,3

0,4

0,5

P5 P10 P16 P21

n-3DPAC22:5n-3

0,00

0,05

0,10

P5 P10 P16 P21

EPAC20:5n-3

0,0

0,5

1,0

1,5

P5 P10 P16 P21

n-6DPAC22:5n-6

0,0

1,0

2,0

3,0

4,0

P5 P10 P16 P21

AdrAC22:4n-6

5,0

7,0

9,0

11,0

13,0

15,0

P5 P10 P16 P21

ARAC20:4n-6

*

* *

*

*

*#

**

Brain n-3

PUFA

Brain n-6

PUFA

lactating mother

ctrl

Low n6

Schipper et al. PLEFA, 2016

bloodstream

perinatal high fat diet

IR -> adiposity

[leptin surge] (neurotrophic)

malformation axons

(permanent)

impaired function

Overeating / obesityNutrients

(e.g. FA)

EARLY LIFE NUTRITON AFFECTSHYPOTHALAMIC SATIETY REGULATION

Structural formation of axons is steered by the nutritional environment

Simerly, Physiol & Behav, 2008

DEVELOPMENT OF HYPOTHALAMIC CIRCUITRY IS ALTERED BY DIETARY N6/N3 PUFA

Postnatal +n3 and low LA reduce density of ARH fibers

These effects were sustained into adulthood following a WSD challenge

Schipper et al, AJCN, 2013

EARLY LIFE DIET FATTY ACID COMPOSITION & LATER ADIPOSITY RISK

Oosting et al, Pediatr Res. 2010; Oosting et al, Nutr Res. 2016

ctrl

+DHA

ctrl

Low n6

EXP diet

EARLY LIFE STRESS INDUCES METABOLIC AND COGNITIVE DEFICITS

IN LATER LIFE

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A diet with reduced omega-6 to omega-3 fatty acid ratio in the early life:

1- prevented early-life stress induced cognitive impairments in behavioral testing in adulthood

(PN180)

2- prevented ELS induced reduction in cell survival in adulthood (PN245)

PhD thesis K. Yam 2018; collaboration with Dr. A. Korosi & Prof Dr. P. Lucassen, Univ Amsterdam

Yam et al, Psychoneuroendocrinology, 2017

INFANTS AT RISK OF LATER LIFE NCDs

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Obesogenic

environment LGA SGA

Maternal

GDM

Maternal

obesity Preterm

Large

at 1 yrUnbalanced

growth 0-12 moIncreased

adiposity

TOFI

Increased NCD risk: (childhood) obesity, cardio-metabolic disease, neurological disease

Stunting, wasting

& malnutrition

BIRTH

WEIGHT

POSTNATAL

GROWTH

15

SGA

Preterm

1- Postnatal growth in preterm infants affects later health outcomes,

e.g. cardiometabolic risks and cognitive impairments

2- Postnatal growth in infants born term but small for gestational age

is associated with later adverse cognitive and metabolic outcomes

3- Dietary intervention during GDM can reduce birth weight as a

result of well controlled maternal hyperglycemia, but is still a risk

factor for higher infant growth and adiposity despite exclusive breast

feeding

Maternal

GDM

Ong et al, 2015, Acta Pediatrica, 104:974-86; Castanys-Muñoz E et al 2017, Acta Paediatrica, 106:1230-

38; Yamamoto et al, 2018, Diabetes Care, 41:1346-1361; Logan et al 2016, Diabetes Care, 39:1045-51,

ACADEMIC-INDUSTRY EXPERT CONSULTATIONILSI INSTITUTE FOR LIFE SCIENCES, EUROPE

• Reduced insulin

sensitivity

• Altered nutrient flux

to the fetus

(↑AA and FFA)

• Obesity risk

GDM DRIVES LATER DIABETES AND OBESITY RISK

Silverman et al. Diabetes Care 1998;21:B142-9; Hamilton et al 2010 Obesity (18):340-346 16

GDM

fetal hyper-

insulinemia

adipogenesis

BUT WHAT ABOUT THE BRAIN?

1. Altered leptin & insulin signaling

2. Placenta ‘trapping’: DHA suppletion

during pregnancy is not effective

3. Reduced DHA status at birth

4. Increased risk of cognitive deficits

EARLY LIFE DIETARY LIPID QUALITY: KEY MESSAGING

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▪ Dietary intakes of vegetables, EFA (n-3 fatty acids), iron, vitamin D and iodine are low; in contrast those of protein, saturated fatty acids and added sugar are high

▪ Poor maternal health and dietary gaps affecting postnatal infant growth impact not only physical growth & body composition but also (functional) brain development

▪ Dietary lipids provide the main building blocks AND affect functional development of the brain

▪ Increased supply of n3 DHA as well as reduced levels of dietary n6 LA

✓ improve brain membrane composition

✓ reduce obesity susceptibility (improve immune development)

✓ alter the neural circuit for satiety regulation

✓ prevent ELS induced cognitive impairments

▪ Challenged maternal health (obesity, GDM) impacts brain functional

development and may require a different dietary approach