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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
Jackson opac2013
Greater birth weight
Adult attained height
Body fatness
Abdominal fatness
Adult weight gain
Physical inactivity
Sugary, alcoholic drinks
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
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
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
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
Jackson opac2013
Jackson opac2013
height weight
Central
fat
Fat
mass
Lean
mass
Visceral
lean
Muscle
mass
Peripheral
fat
Widdowson - “Harmony of Growth”
pace and proportion, partitioning of nutrients
early life structure and functioin
Diet: Quantity and Quality
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
Genetic/epigenetic
Environmental
Nutritional
Genetic/epigenetic
Environmental
Nutritional
Energy, nutrients
Meet requirements
Excess – detoxify, excrete
Inadequate
Slow pace of growth, minimise
cancer
Energy, nutrients
Meet requirements
Excess – detoxify, excrete
Inadequate
Slow pace of growth, minimise
cancer
Hormones
Early exposure
Hypothalamic set
Receptors and ligands
Hormones
Early exposure
Hypothalamic set
Receptors and ligands
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
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
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
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
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
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
Social stressors
Behaviours
Physical activity
smoking
Diet
Body composition
Genotype Epigenesis
Inflammation
Signalling
POPULATION
INDIVIDUAL
CELL
Food Security
quantity, quality
Environmental
stressors
Metabolic
Competence
Integration
Warburg reaction: replicating cells
- absolute requirement
- changed cellular reaction
- shift to glycolysis – pyruvate - lactate
Warburg effect:
: macromolecules: lipid, carbohydrate, amino acids
: activated by glutaminolysis
Glutamine – arginine, -proline: leucine, BCAA
addicted cellular replication: oncogene control
Glycine – serine/cysteine/taurine: threonine, choline
I
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)
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
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.
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
GLYCINE
Pacemaker of Metabolism
Fetal accumulation of amino acids at day 270
glycine
glutamate
alanine
proline
aspartate
arginine
serine
histidine
tyrosine
leucine
lysine
valine
threonine
isoleucine
phenylalanine
methionine
0 1 2 3 4 5 6 7
Widdowson, Southgate, Hey, 1979
Metabolic demand for amino acids
Collagen 30% glycine, 25% proline
Plasma flux of individual amino acids
Leucine 100 - 150 µmol/kg/h
Lysine 100 µmol/kg/h
Phenylalanine 60 µmol/kg/h
Tyrosine 70 µmol/kg/h
Arginine 50 µmol/kg/h
Glycine 200 - 300 µmol/kg/h
Glutamine 300 - 700 µmol/kg/h
Plasma glycine flux
control, 29y control, 62y diabetes, 62y
0
100
200
300
glycineflux,µmol/kg/h
p = 0.013
Urinary 5-L-oxoproline
control, 29y control, 62y diabetes, 62y
0
25
50
75
100
5-L-oxoproline/creatinine,
µmol/mmol
p = 0.041
Plasma glycine concentration
control, 29y control, 62y diabetes, 62y
0
100
200
glycineµmol/L
p = 0.5
Glycine supplements: improve insulin sensitivity, etc
Jackson et al, unpublished
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
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)
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
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
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
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
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

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Jackson opac2013

  • 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
  • 10. height weight Central fat Fat mass Lean mass Visceral lean Muscle mass Peripheral fat Widdowson - “Harmony of Growth” pace and proportion, partitioning of nutrients early life structure and functioin Diet: Quantity and Quality
  • 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
  • 12. Genetic/epigenetic Environmental Nutritional Genetic/epigenetic Environmental Nutritional Energy, nutrients Meet requirements Excess – detoxify, excrete Inadequate Slow pace of growth, minimise cancer Energy, nutrients Meet requirements Excess – detoxify, excrete Inadequate Slow pace of growth, minimise cancer Hormones Early exposure Hypothalamic set Receptors and ligands Hormones Early exposure Hypothalamic set Receptors and ligands
  • 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
  • 20. Social stressors Behaviours Physical activity smoking Diet Body composition Genotype Epigenesis Inflammation Signalling POPULATION INDIVIDUAL CELL Food Security quantity, quality Environmental stressors Metabolic Competence Integration
  • 21. Warburg reaction: replicating cells - absolute requirement - changed cellular reaction - shift to glycolysis – pyruvate - lactate Warburg effect: : macromolecules: lipid, carbohydrate, amino acids : activated by glutaminolysis Glutamine – arginine, -proline: leucine, BCAA addicted cellular replication: oncogene control Glycine – serine/cysteine/taurine: threonine, choline I
  • 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
  • 27. Fetal accumulation of amino acids at day 270 glycine glutamate alanine proline aspartate arginine serine histidine tyrosine leucine lysine valine threonine isoleucine phenylalanine methionine 0 1 2 3 4 5 6 7 Widdowson, Southgate, Hey, 1979 Metabolic demand for amino acids Collagen 30% glycine, 25% proline
  • 28. Plasma flux of individual amino acids Leucine 100 - 150 µmol/kg/h Lysine 100 µmol/kg/h Phenylalanine 60 µmol/kg/h Tyrosine 70 µmol/kg/h Arginine 50 µmol/kg/h Glycine 200 - 300 µmol/kg/h Glutamine 300 - 700 µmol/kg/h
  • 29. Plasma glycine flux control, 29y control, 62y diabetes, 62y 0 100 200 300 glycineflux,µmol/kg/h p = 0.013 Urinary 5-L-oxoproline control, 29y control, 62y diabetes, 62y 0 25 50 75 100 5-L-oxoproline/creatinine, µmol/mmol p = 0.041 Plasma glycine concentration control, 29y control, 62y diabetes, 62y 0 100 200 glycineµmol/L p = 0.5 Glycine supplements: improve insulin sensitivity, etc Jackson et al, unpublished
  • 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

  1. Evidence for important developmental effects on later disease 1 st came from this analysis in over 15,000 men &amp; 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 &amp; 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 &amp; preterm infants are increased risk for CHD. There are 3 further facets of the epidemiological data that I would like to emphasise.