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  • 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.

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  • NIHR SouthamptonBiomedical Research CentreThe Southampton Biomedical Research Centre is funded by the National Institute for Health Research (NIHR) andis a partnership between University Hospital Southampton Foundation Trust and the University of SouthamptonOverview of Life Course Factors andNutrition and CancerAlan A JacksonNIHR Southampton Biomedical Research CentreObesity, Physical Activity and CancerIAOS WCRF, 16-17thApril 2013
  • Greater birth weightAdult attained heightBody fatnessAbdominal fatnessAdult weight gainPhysical inactivitySugary, alcoholic drinks
  • Michels et al, Lancet, 1996, 348, 1542-1546.Odds ratio for breast cancer by birthweight inUSA nurses study- 2500 - 2999 - 3499 - 3999 > 40000.50.60.70.80.91.0birth weightoddsratioforbreastcancer
  • Coronary heart diseaseStandardised mortality ratios (SMR) in 10141 men & 5585 women20406080100120-5.5 -6.5 -7.5 -8.5 -9.5 >9.5Birthweight (pounds)SMR20406080100120-5.5 -6.5 -7.5 -8.5 -9.5 >9.5Birthweight (pounds)SMRMEN WOMENBMJ 1993;307:1519-24Variable 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 diseaseGrowth in childhood – to 11 yearsMean z scores for height, weightand body mass indexBarker et al Ann Hum Biol 2009;36:445-458Finnish Studies
  • Standardised mortality by average height,Counties of England and Wales, age 37-74, 1968-78Barker, 19920 1 2 3 4 580100120men IHDmen strokemen prostatewomen IHDwomen strokewomen breastfifths of heightstandardisedmortality
  • height weightCentralfatFatmassLeanmassVisceralleanMusclemassPeripheralfatWiddowson - “Harmony of Growth”pace and proportion, partitioning of nutrientsearly life structure and functioinDiet: Quantity and Quality
  • Chronic NCD, Cancer riskPlasticity:Setting up phenotypeLife courseNo interventionMother& infantEarlier interventionimproves functionalcapacity & responsesto new challengesVulnerability:Inadequate response to new challengesChildhoodAdulthoodEarly interventionLate interventionLate interventionimpactful forvulnerable groupsLifecourse strategy
  • Genetic/epigeneticEnvironmentalNutritionalGenetic/epigeneticEnvironmentalNutritionalEnergy, nutrientsMeet requirementsExcess – detoxify, excreteInadequateSlow pace of growth, minimisecancerEnergy, nutrientsMeet requirementsExcess – detoxify, excreteInadequateSlow pace of growth, minimisecancerHormonesEarly exposureHypothalamic setReceptors and ligandsHormonesEarly exposureHypothalamic setReceptors and ligands
  • Europe: Secular Increase in HeightPlateau ~1.8 m:Denmark, Sweden,Norway, Netherlands?genetic potentialIncreasing:Belgium, Spain,Italy, PortugalLarnkjaer et al Acta Paediatrica 2006
  • Europe: secular increase in height:Stopped, 18 years following post-neonatal mortalityaround 4/1000 deliveries.Improving socio-economic conditionsbetter nutrition – healthier dietdecrease in infectious diseases
  • Growth:impact of insult: timing, intensity, durationsensitive periods: greater vulnerability, enduring effectBarker:variation within normal rangeassociated with risk of chronic non-communicable diseasepathways to cancer associated with pelvic dimensions(hormonal milieu around early embryonic development)Uauy:normal weight: stunting and adipositymaturational processes and timing: maturational ageFirst 1,000 days:stunting most common nutritional problemaim 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 byunderstanding the factors which enable growth andbody composition
  • Low birth wt High birth wt2022242628303234%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, 2005Age 62-75 yearsHertfordshire men aged ~ 70 years
  • 23 24 25 26 27 28 29 30 31 3220222426283032Low birth wtHigh birth wtBody mass index (kg/m2)%fat4. 85%(p <0.004)ANCOVA BMI v % fat (r = 0.67; p <0.001)Kensara et al, 2005Hertfordshire men aged ~ 70 years
  • For the same weight or BMI at 70 years of ageLower birth weight- less muscle- more fat- more central fat- function difference- altered cellular nutrient environment
  • Social stressorsBehavioursPhysical activitysmokingDietBody compositionGenotype EpigenesisInflammationSignallingPOPULATIONINDIVIDUALCELLFood Securityquantity, qualityEnvironmentalstressorsMetabolicCompetenceIntegration
  • Warburg reaction: replicating cells- absolute requirement- changed cellular reaction- shift to glycolysis – pyruvate - lactateWarburg effect:: macromolecules: lipid, carbohydrate, amino acids: activated by glutaminolysisGlutamine – arginine, -proline: leucine, BCAAaddicted cellular replication: oncogene controlGlycine – serine/cysteine/taurine: threonine, cholineI
  • Calorie restriction- extends lifespan- decreased incidence age related diseaseAMP-activated protein kinase – AMPKSensor of cellular energy statusActivated by constrained energy status.Inhibits cellular proliferationProtects against ROSActivated by liver kinase B (LKB1) – tumour suppressorActivate AMPK: inhibit cell proliferation, anti-inflammatory effectsActivation with drugs: anti-inflammatory (salicylate), methotrexate, pemetrexedActivation: dietary restriction, exercise, ischaemia extension of life span reduced cancerActivate: ghrelin adiponectin (under-fed)Decreased with diet high in either, protein, carbohydrate, fatInhibit: 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 divertsglycolytic flux and contributes to oncogenesis.Possemato et al, Nature 2011. Functional genomics reveal serine synthesis pathwayessential in breast cancer.Zhang et al, Cell 2012. Glycine decaoboxylase activity drives non-small celllung 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 metabolitestransformed cells – “metabolic reprogramming”altered nutrient uptake and useGlycine consumed by rapidly proliferating cells, released by slowly proliferating cellsHuman 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 2012Common patterns gene expression signatures for cancer:proliferationtissue remodellingDistinct sub-types:Proliferation: p53, PTEN inactivation with Myc activationup-regulation glycolysis, serine glycine interchangeTissue remodelling: RAS, HIF-1 alpha, NFkB activation.down-regulation oxidative phosphorylationExample Myc driven liver tumorigenesistransition switch through 3-phosphoglycerateSERINE 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 homeostasisactivity: muscle massRequirement for glycine- diversion glucose to- enable nucleotide synthesis,- enable methyl group availability and balance- enable antioxidant capabilitysubstantial demands for:DNA, RNA, collagen, creatine; haem, glutathione, xenobiotics
  • GLYCINEPacemaker of Metabolism
  • Fetal accumulation of amino acids at day 270glycineglutamatealanineprolineaspartatearginineserinehistidinetyrosineleucinelysinevalinethreonineisoleucinephenylalaninemethionine0 1 2 3 4 5 6 7Widdowson, Southgate, Hey, 1979Metabolic demand for amino acidsCollagen 30% glycine, 25% proline
  • Plasma flux of individual amino acidsLeucine 100 - 150 µmol/kg/hLysine 100 µmol/kg/hPhenylalanine 60 µmol/kg/hTyrosine 70 µmol/kg/hArginine 50 µmol/kg/hGlycine 200 - 300 µmol/kg/hGlutamine 300 - 700 µmol/kg/h
  • Plasma glycine fluxcontrol, 29y control, 62y diabetes, 62y0100200300glycineflux,µmol/kg/hp = 0.013Urinary 5-L-oxoprolinecontrol, 29y control, 62y diabetes, 62y02550751005-L-oxoproline/creatinine,µmol/mmolp = 0.041Plasma glycine concentrationcontrol, 29y control, 62y diabetes, 62y0100200glycineµmol/Lp = 0.5Glycine supplements: improve insulin sensitivity, etcJackson et al, unpublished
  • Systolic Blood PressureMaternal Exposure to Protein Diet6% 9% 12% 18%100120140160180casein content of maternal diet during pregnancysystolicbloodpressure,mmHgmother offspringDietarymanipulationEffectOffspring blood pressurematernal pregnancy protein18% 9% 9% glycine 9% urea 9% ala80100120140maternal diet during pregnancysystolicbloodpressure,mmHg***Langley, Jackson Clin Sci 1994; Jackson et al Clin Sci 2002
  • Glycine and folic acid supplementation prevent hypertensionBlood pressure at 4 weeks in females18%9%9%+glycine507090110130*Maternal dietSystolicbloodpressure(mmHg)Jackson et al. 2002, Torrens et al. 2006Blood pressure at 4 weeks in females18%9%Folicacidsupplemented507090110130*Maternal dietSystolicbloodpressure(mmHg)
  • Control Low protein LP with folic acid5075100dietary groupDNAmethylationControl Low protein LP with folic acid0100200300400dietary groupmRNAconcentrationHepatic Glucocorticoid Receptor:methylation of promoter region of gene and gene expressionLillycrop et al J Nutr 2005
  • Fetus:reset of central set-point for key hormonal axeshypothalamo - pituitary-adrenalgrowth hormone – IGF – insulinthyroid axissex steroid axis- response to diet- response to stressors
  • Cancer protection:decreased intake: food restrictionincrease demand: increased activityCapacity for endogenous formation:Long chain poly-unsaturated fatty acidsNon-essential amino acids (dispensable amino acids)requirementessential amino acids 20-25 g proteinnon-essential amino acids 40-45 g proteinhabitual intake 60-90 g proteinLower intake: challenge to make enough non-essential amino acidsHigher intakes: challenge to detoxify excess essential amino acidsActivity enables the formation of non-essential amino acids:glutamine synthesisDevelopmental timing: capacity for endogenous formation
  • height1 2 3 4012fourths for heightrelativeriskfat free mass1 2 3 40123fourths for FFMrelativeriskwaist-hip circumference1 2 3 40123fourths of WHCrelativeriskColon cancer and body size in men.MacInnis et al, Cancer Epidemiol Biomarkers Prev 2004, 13, 553-559Fat free mass and waist:hip circumferenceIndependent association with cancer of the colon
  • LIFE CYCLE (intergenerational) effects on phenotype:Adipositycurrent activity/diet experienceimmediate social driversWaist circumferenceprogrammed metabolic regulationepigenetic effectspregnancy, early life drivenLength/ Fat free masssecular changewhole body intergenerational experiencedietary habits, social/sexual behaviourchanged social opportunities/ stressorsJackson, J Nutr 2005