1. NIHR Southampton
Biomedical Research Centre
The Southampton Biomedical Research Centre is funded by the National Institute for Health Research (NIHR) and
is a partnership between University Hospital Southampton Foundation Trust and the University of Southampton
Overview of Life Course Factors and
Nutrition and Cancer
Alan A Jackson
NIHR Southampton Biomedical Research Centre
Obesity, Physical Activity and Cancer
IAOS WCRF, 16-17th
April 2013
3. Greater birth weight
Adult attained height
Body fatness
Abdominal fatness
Adult weight gain
Physical inactivity
Sugary, alcoholic drinks
4. Michels et al, Lancet, 1996, 348, 1542-1546.
Odds ratio for breast cancer by birthweight in
USA nurses study
- 2500 - 2999 - 3499 - 3999 > 4000
0.5
0.6
0.7
0.8
0.9
1.0
birth weight
oddsratioforbreastcancer
5. Coronary heart disease
Standardised 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 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
6. 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
7. Standardised mortality by average height,
Counties of England and Wales, age 37-74, 1968-78
Barker, 1992
0 1 2 3 4 5
80
100
120
men IHD
men stroke
men prostate
women IHD
women stroke
women breast
fifths of height
standardisedmortality
11. Chronic NCD, Cancer risk
Plasticity:
Setting up phenotype
Life course
No intervention
Mother
& infant
Earlier intervention
improves functional
capacity & responses
to new challenges
Vulnerability:
Inadequate response to new challenges
Childhood
Adulthood
Early intervention
Late intervention
Late intervention
impactful for
vulnerable groups
Lifecourse strategy
13. 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
14. 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
15. Growth:
impact of insult: timing, intensity, duration
sensitive periods: greater vulnerability, enduring effect
Barker:
variation within normal range
associated with risk of chronic non-communicable disease
pathways to cancer associated with pelvic dimensions
(hormonal milieu around early embryonic development)
Uauy:
normal weight: stunting and adiposity
maturational processes and timing: maturational age
First 1,000 days:
stunting most common nutritional problem
aim to improve/correct as next major global initiative after MDG
16. Shape and size at birth relate to adult health:
- how are they achieved?
- how do they relate to function?
Objective:
Enhance the likelihood of achieving health by
understanding the factors which enable growth and
body composition
17. Low birth wt High birth wt
20
22
24
26
28
30
32
34
%bodyfat% 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
Hertfordshire men aged ~ 70 years
18. 23 24 25 26 27 28 29 30 31 32
20
22
24
26
28
30
32
Low birth wt
High birth wt
Body mass index (kg/m2
)
%fat
4. 85%
(p <0.004)
ANCOVA BMI v % fat (r = 0.67; p <0.001)
Kensara et al, 2005
Hertfordshire men aged ~ 70 years
19. 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
22. Calorie restriction
- extends lifespan
- decreased incidence age related disease
AMP-activated protein kinase – AMPK
Sensor of cellular energy status
Activated by constrained energy status.
Inhibits cellular proliferation
Protects against ROS
Activated by liver kinase B (LKB1) – tumour suppressor
Activate AMPK: inhibit cell proliferation, anti-inflammatory effects
Activation with drugs: anti-inflammatory (salicylate), methotrexate, pemetrexed
Activation: dietary restriction, exercise, ischaemia extension of life span reduced cancer
Activate: ghrelin adiponectin (under-fed)
Decreased with diet high in either, protein, carbohydrate, fat
Inhibit: insulin, leptin (over-fed)
23. Serine Glycine interchange.
Snell et al, Biochem J 1987: modulated serine metabolism in hepatoma.
Locasale et al, Nature Genetics, 2011: phosphoglycerate dehydrogenase diverts
glycolytic flux and contributes to oncogenesis.
Possemato et al, Nature 2011. Functional genomics reveal serine synthesis pathway
essential in breast cancer.
Zhang et al, Cell 2012. Glycine decaoboxylase activity drives non-small cell
lung cancer tumour-initiating cells and tumorigenesis.
Jain et al, Science, 2012. Key role for glycine in rapid cancer cell proliferation.
Over 60 cell lines – 140 metabolites
transformed cells – “metabolic reprogramming”
altered nutrient uptake and use
Glycine consumed by rapidly proliferating cells, released by slowly proliferating cells
Human breast cancer Increased expression enzymes: SHMT2, MTHFD2, MTHFD1L:
above median expression, greater mortality, hazard ratio 1.82
24. Serine Glycine interchange.
Markert, Levine, Vazquez, Cell Death and Disease 2012
Common patterns gene expression signatures for cancer:
proliferation
tissue remodelling
Distinct sub-types:
Proliferation: p53, PTEN inactivation with Myc activation
up-regulation glycolysis, serine glycine interchange
Tissue remodelling: RAS, HIF-1 alpha, NFkB activation.
down-regulation oxidative phosphorylation
Example Myc driven liver tumorigenesis
transition switch through 3-phosphoglycerate
SERINE BIOSYNTHESIS, GLYCINE CLEAVAGE SYSTEM :
Serine synthesis over 10 times that needed for protein synthesis,
But imperative for high proliferation rates.
Molecular crowding: aerobic glycolysis; novel pathway for ATP generation.
25. Requirement for Glutamine:
- enable amino acid uptake: AMPK, mTor
- signal transduction pathways
- divert citrate enable lipogenesis, ribose formation, membrane formation
- enable nucleotide synthesis: ribonucleotide formation
-redox homeostasis
activity: muscle mass
Requirement for glycine
- diversion glucose to
- enable nucleotide synthesis,
- enable methyl group availability and balance
- enable antioxidant capability
substantial demands for:
DNA, RNA, collagen, creatine; haem, glutathione, xenobiotics
30. Systolic Blood Pressure
Maternal Exposure to Protein Diet
6% 9% 12% 18%
100
120
140
160
180
casein content of maternal diet during pregnancy
systolicbloodpressure,mm
Hg
mother offspring
Dietary
manipulation
Effect
Offspring blood pressure
maternal pregnancy protein
18% 9% 9% glycine 9% urea 9% ala
80
100
120
140
maternal diet during pregnancy
systolicbloodpressure,mmHg
*
*
*
Langley, Jackson Clin Sci 1994; Jackson et al Clin Sci 2002
31. Glycine and folic acid supplementation prevent hypertension
Blood pressure at 4 weeks in females18%
9%
9%
+
glycine
50
70
90
110
130
*
Maternal diet
Systolicbloodpressure
(mmHg)
Jackson et al. 2002, Torrens et al. 2006
Blood pressure at 4 weeks in females
18%
9%
Folic
acid
supplem
ented
50
70
90
110
130
*
Maternal diet
Systolicbloodpressure
(mmHg)
32. Control Low protein LP with folic acid
50
75
100
dietary group
DNAmethylation
Control Low protein LP with folic acid
0
100
200
300
400
dietary group
mRNAconcentration
Hepatic Glucocorticoid Receptor:
methylation of promoter region of gene and gene expression
Lillycrop et al J Nutr 2005
33. 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
34. Cancer protection:
decreased intake: food restriction
increase demand: increased activity
Capacity for endogenous formation:
Long chain poly-unsaturated fatty acids
Non-essential amino acids (dispensable amino acids)
requirement
essential amino acids 20-25 g protein
non-essential amino acids 40-45 g protein
habitual intake 60-90 g protein
Lower intake: challenge to make enough non-essential amino acids
Higher intakes: challenge to detoxify excess essential amino acids
Activity enables the formation of non-essential amino acids:
glutamine synthesis
Developmental timing: capacity for endogenous formation
35. height
1 2 3 4
0
1
2
fourths for height
relativerisk
fat free mass
1 2 3 4
0
1
2
3
fourths for FFM
relativerisk
waist-hip circumference
1 2 3 4
0
1
2
3
fourths of WHC
relativerisk
Colon cancer and body size in men.
MacInnis et al, Cancer Epidemiol Biomarkers Prev 2004, 13, 553-559
Fat free mass and waist:hip circumference
Independent association with cancer of the colon
36. LIFE CYCLE (intergenerational) effects on phenotype:
Adiposity
current activity/diet experience
immediate social drivers
Waist circumference
programmed metabolic regulation
epigenetic effects
pregnancy, early life driven
Length/ Fat free mass
secular change
whole body intergenerational experience
dietary habits, social/sexual behaviour
changed social opportunities/ stressors
Jackson, J Nutr 2005
Editor's Notes
Evidence for important developmental effects on later disease 1 st came from this analysis in over 15,000 men & women of death rates from CHD on the vertical axis, arrayed according to the individual ’ s weight at birth. Death rates fell progressively with increasing birthweight in both men & women. Rates were not simply raised in the smallest babies; rather, there was a graded relation across the range of birthweights. A small rise at the highest birthweights could relate to the macrosomic infants of women with gestational diabetes. Further studies have suggested that both growth restricted & preterm infants are increased risk for CHD. There are 3 further facets of the epidemiological data that I would like to emphasise.