Food and Nutrition for Disease Prevention

Micronutrients

• B-carotene
  • Plasma levels have sotrnger correlation with cancer prevention than dietary intake à shows that plasma markers are more reliable
  • Supplementation increased cancer incidence in asbestos workers and smokers
    • B-carotene not recommended for cancer prevention, backed up by meta-analysis
    • Doses of 20-30mg/d
    • study had to be stopped
    • no deleterious effects observed with vit A and E
• Folate
  • Double edged sword: due to methylation, folate can promote cancer growth once tumorous cells have developed
  • Higher intake not found to increase cancer risk in 5.5y RCTs yet
  • Epidemiological studies show inverse relation between intake and development of colorectal cancer

CVD epidemiology

• CH
  • CVD: increasing rates ever since population infectious diseases could be prevented/reduced --> opulations ages and becomes prone to CVD
    • Since 1980 and current trend: declining CVD mortality --> CH one of the highest ranking countries in terms of ortality because time to reach hospital after event is short and treatment excellent
    • cancer: trend remains stable
  • mortality vs.  incidence values available for CVD
    • changes in mortality are due to treatment or screening --> decrease in mortality due to improvements in treatment
    • changes in incidence reflect efficacy of preventive measures
    • CH: decreasing mortality but increase in incidence, especially for males --> treatment has improved, preventive measures seem ineffective
  • Age as an important factor for CVD: mortality increases as of 65, at 85+ becomes most common cause of death
    • individuals <65 can still suffer from CVD
  • death remain stable while hospitalization is increasing --> screening improved? (slide 8)
    • healthcare and socioeconomic burden big, despite decreasing mortality
  • Regional and societal differences
    • higher class less prone to CVD --> also less smokers
    • Romandie less affected than Deutschschweiz
• International
  • trends also declining
  • similar trends in US, DE, FR, and CH
  • Switzerland ranks amongst lowest CVD mortality countries --> treatment and screening efficacous

Diet and CVD evidence

• Bradford-Hill Criteria --> vgl Bild
  • most nutritional sciences studies do not fulfil criteria sufficiently, so causality remains weak
    • Coffeexception: fulfils many criteria, incl linearity
• Problems of evidence in nutritional sciences
  • intermediate risk factors & soft vs hard outcomes
    • do not necessarily correlate with actual CVD mortality, although increase risk factors --> use of hard facts as more reliable information
      • coffe affects risk factors negatively but has positive outcome on CVD risk
      • n-3 improves blood TAG but not CVD mortality
    • CVD deaths more convincing than increased TAGs or intermediate risk factors
  • residual confounding: confounding factors that cannot be adjusted for / controlled
    • age/smoking/gender can be adjusted for, but impossible to adjust for behavior/mindset --> fish consumers likely to behave differently than non fish consumers
  • sponsoring
    • margarine industry sponsored some studies on saturated fats to increase fear of butter
  • causality difficult/impossible to find/relate to certain food
    • relating one nutrient to certain outcome never possible because diet comprises many foods
    • diet affects hormones --> E storage and metabolism modulated
    • meal will affect thermogenic effect
    • microbiota as intermediate player
• Problems specific to RCTs --> vlg Bild
  • control of exposures difficult in long run --> yet CVD needs time to develop
  • behaviour adapted when aware of control --> not realistic behaviour
  • forcing people to artificially follow a protocol that would never been adhered to in real life
    • low salt intake --> hard to adhere to and unrealistic, additionally only marginal benefits
  • time-dependent results --> diseases only show up late, difficult to maintain RCT for so long
  • vulnerable populations (with hypertension or with case of CVD) usually used --> not translatable to general population

Foods and CVD

• food groups: all-cause mortality rarely linear --> U-shaped relations
• many prospective cohort studies with very limited causality
• Some RCTS available but still with limitations
• examples
  • meat: inconsistency and low point estimates (Waht does that mean?), but more consitent when looked at meat preservatives, many animal studies
  • dairy: weak scientific evidence with conflicting results, some beneficial except for prostate cancer
    • strong evidence for preventive effects on diabetes → impact on gut microbiome/fermetation (less sugar)
  • fish: effect overstimated and dependent on region (preparation, freshness), maybe real advantage is replacement of red meat with fish
    • protein swap (slide 33): fish, milk and poultry protein comparable impact on CVD risk, plant protein might lower while eggs and processed meats might increase CVD risk
  • SSB
    • moderate increase for CVD --> meta-analysis found no effect on stroke, but CHD and hypertension
    • effect mediated via IR, obesity, hypertension ? --> unknown
    • substantial residual confounding: food choices of aware/unaware person not adjustable
    • swaping sugar for artificial sweeteners --> may decrease weight but might increase risk of CVD
  • Coffee (& tea)
    • negative impact on risk factors but associations show decrease in mortality
      • acrylamide, increase in LDL cholesterol and blood pressure
      • maximal benefit @ 4 cups/d
• expert consens as most reliable source of information --> vgl table
  • high agreement:
    • beneficial: DASH, high potassium intake, fibre, fruits and vegetables, seeds, yoghurt
    • harmful: artificial fats (partilly hdrogenated vegetable oils), high sodium, SSB, refined sugar
  • medium agreement
    • beneficial: seafood, n-3, olive oil, phenolic compounds
    • harmful: moderate Na, high GI foods
  • low agreement
    • beneficial: cheese, low fat-milk
    • harmful: dietary cholesterol, eggs, butter, unprocessed red meats

Fats

• trans-fats
  • most problematic of fats in regards to CVD mortality and total
  • industrial trans fats consistently show to increase CHD risk & mortality
  • ruminant trans-fats less conclusive data --> some even beneficial on T2DM (perhaps reason for protective effects of dairy on T2DM)
• saturated fats
  • saturated fats less conclusive data than trans-fats
  • some studies sponsored by margarine industry
  • replacement of kcal from SFA by other E sources affects CVD risk --> vlg Bild
    • AHA concludes that MUFA and especially PUFA should replace SFA for CVD risk reduction

Carbohydrate

• low-carb diets: not protective in the long run --> U-shaped relation with CVD risk
  • CHO source not taken into account
• all cause mortality U-shaped with optimal intake at 50-60 %En
• Whole grain: curve flattens out --> benefit up to ~60g/d

Supplements

• High dose of D3, A, b-carotene all shown to increase mortality (in specific populations)
• primary or secondary prevention with supplements is not evidence-based
• Ca supplements can even increase risk of CVD at higher doses
• main message: not suitable for primary prevention because of lack of evidence
  • drugs may not be adequate either in primary prevention, e.g. statins

Ethanol

• improves intermediate risk factors
  • fibrinogen: prevent clotting
  • increases HDL levels
  • adiponectin: promotes b-ox & increases insulin sensitivity --> lowered in metabolic syndrome
• worsen other intermediate risk factors
  • combined with beneficial influences, Lausanne study showed that despite increase in HDL, the increase in syst BP outweighs the benefit and leads to increased CAD risk
  • study in heavy drinkers
  • wine increases HDL, beer increase TAG
• Protective effect of alcohol likely to be biased finding
  • many studies suggesting beneficial effects of moderate alcohol consumption may be biased due to overestimation + residual confounding of moderate drinkers vs abstainers
    • moderate drinkers vs abstainers have different behaviors and the beneficial effect of mderate drinking might be overestimated
  • Selection biases in observational studies:
    • moderate drinkers not only adopt drinking but also particular lifestyle and have survived until study recruitment + are congintively fit enough to be enrolled --> selection bias
  • Risk thresholds for alcohol consumption:
    • Shows dose-dependent risk for different CVD-related disease depending on alcohol intake. Recent data, suggests no benefit of moderate alcohol intake on overall CVD mortality

Sodium an CVD risk

• fact: higher Na intake increases blood pressure in hyper- and normotensive individuals --> intermediary risk factor, so not necessarily increased CVD risk
  • question to ask: does reduction in salt intake result in lowered disease risk? (it does undeniably lower BP)
  • BP can be reduced without lowering Na intake --> normal salt DASH diet ==> further improvement with low Na DASH diet
  • target population who may benefit from salt reduction
    • very high salt intake population: >12g/d
    • hypertensive population
    • elderly
• Normotensive and hypertensive individual's risk for CVD depending on salt intake is different
  • U-shaped for hypertensive
  • flattened out for high intake
• TOHP (trials of hypertension prevention): Na reduction with mortality assessed --> minimal risk but big effort --> not worth it
  • Evidence on Na intake mostly from obeservations studies --> questionable
• Sodium intake vs potassium intake on different CVD-related risks
  • stroke: <5g safe zone --> increased risk with higher intake
  • myocardial infarction: not associated with Na intake
  • potassium intake:
    • linear, negative association with all CVD related risks
• K/Na excretion
  • greater K excretion generally associated with lower CVD risk
  • risk will depend on ratio, not absolute Na intake --> low Na intake with low K intake worse than higher Na intake with higher K intake --> high fruit and vegetable intake
• RAAS system
  • could explain small reduction (if any) in CVD risk of Ny intake --> hormonal counter regulation of Bp increasing hormones
  • lowered Na intake result in increase of, amongst other, stress hormones --> damages other tissues

Mediterranean Diet

• characteristics
  • no salt limits
  • low red (processed) meat
  • high unprocessed fruits and vegetable intake
  • protein mostly from plants or fish/poultry
  • High-quality olive oil as main source of fat
• much greater effect than low-fat diets (WHI study vs PREDIMED)
• overall, moderate risk reduction observed in prospective and RCT studies

DASH

• very similar to MedDiet
• version with salt reduction (50mmol/d) --> even more effective at reducing BP (does not mean CVD risk is reduced)

Other diets

• Nordic diet, Japanese diet, Harvard Diet...
• rely on similar features: high in fruits and vegetables, unprocessed,

• growth charts: increase in height and weight for boys and girls
  • different charts (WHO)
  • target height: mean between father and mother
• growth phases
  • infancy: first year of life mostly dependent on nutrition, less genetics / hormones
  • puberty: nutrition required to meet E demands of growing individual
    • Thyroid hormones involved as of 2 years of life
• Factors influencing growth
  • emotional stability --> especially eraly childhood
  • favorable socioeconomic conditions
  • absence of significant morbidity --> celiac disease
  • genetics: will define height but growth less dependent on it than nutrition

hormones

• satiety signals:
  • PYY, GLP-1 --> catabolic pathways (decrease food intake and increase E expenditure) --> dysfunctional in case of obesity
  • Ghrelin --> anabolic effect --> increases food intake and decreases energy expenditure (motivation to exercise)
• obesity signals: leptin & insulin

Obesity is defined using either BMI, BIA/DXA/Skinforld, or waist/hight ratio

• defined as BMI > 97th percentile (overweight >90)
  • WHO classification used for adults and IOTF for children: correlation between fat mass and obesity never been assessed for children, but likely to correlate, similarly to adults
  • healthy control children selected based on maother's health status: all continents, non-smoking, godd socioeconomic status
  • New Swiss BMI Reference also uses 97th percentile, but perhaps more
• definition using waist/hight ratio
  • waist circumference > 2 SD
  • waist/hight ratio > 0.5
• definition using BIA
  • >25% (20-25%) fat mass in boys
  • >30% fat mass in girls

BMI

• problems
  • fat and muscle mass not distinguished
    • !! prevalence can decrease but actually decrease in muscle mass and not fat mass, due to low PA
  • height strong impact on BMI value --> short statured children will have lower BMI despite being overweight/obese --> respect weight-for-height charts
  • weight-for-height charts
    • valid until age of about 5 years
    • preferred over BMI in short or high statured children

BIA to assess fat mass and not muscle mass

• skin folds difficult in children beacause fat very compact
• obesity >25% fat mass in boys and 30% in girls
• DXA also used

Waist circumference

• obesity defined as
  • waist/height < 0.5 --> individual is used as own reference, therefore useful
  • waist CF > 2 SD; based on reference charts that takes age into account, as well as waist/hight ratio
• measures abdominal fat which is associated with comorbidities: hypertension, IR in children, CVD
  • reflects abdominal fat, around the liver, dangerous!
  • <88cm for females; <105cm for males
• either waist or hip circumference used, reference table available for both
  •  

Pathophysiology

• Satiety
  • set-point of satiety upregulated if E intake and E expenditure are out of balance for prolonged period --> remains elevated despite fat/weight loss --> yoyo-effect
• Energy intake should be adapted to PA of child

Hormones

• CNS receives signals via blood and nerves
• obesity signals --> dysregulation of set-point between accelerating (anabolic) and decelerating (catabolic) pathways
  • leptin (&insulin) activates catabolic pathway --> stops eating, be active!
    • leptin and insulin resistance result in loss of breaking/decelerating signals --> hyperactivation of anabolic pathway
  • NPY anabolic pathway --> eat, stop moving!
• Reward system & neurological aspects of obesity
  • dopaminergic system rewards for eating
    • very active in child's brain
  • Ghrelin release from stomach also rewarding
  • addictive power of food
    • addiction: amount of food needs to increase to trigger satisfaction (example with mouse)
    • advertisement of fatty/sweet foods to children should be limited
• Adipose tissue is homronally highly active
  • cytokines --> inflammation and macrophage activation
  • induce insulin resistance
  • activates thrombogenic messengers
  • activation of sympathetic activates adipocyte proliferation (?)
  • vagus increases insulin's anabolic effect on adipocytes

Microbiome

• many effects (vgl Bild)
  • suppress b-ox in muscle tissue
  • increase in fermenting enzymes
  • monosacch absorbtion
  • increase in SCFA, which interact with recpetors --> increase in PYY --> satiety
  • inhibit lipolysis
• microbiome changes in response to Western diet --> mice become fat
  • artificial sweeteners negatively affect microbiome --> tendency to obesity
• use of antibiotics in first year of life associated with obesity

pre-natal: U-shaped risk of under/overnutrition

• maternal undernutrition prepares fetus to food scarcity --> hyperinsulinism after birth if food plentiful
• maternal, prenatal overweight also increases risk of hyperinsulinusm and obesity as adult (x2.2)
• genetics: 25-50% --> environment and lifestyle play greater role
  • environment: many factors leading to a toxic surrounding, resulting in increased food intake, lower food density as well as lower PA (vgl Bild)

parental overweight

• overall most impactful risk factor (44% compared to ~10% for other common risk factors)
• regardless of parental status, overweight is carried over into adulthood more often if obesity develops in adolescence
• children of obese parents are more likely to become and remain obese thourghout life

physical activity & screen time

• 60min/d of PA only met by children up to 12y
• associations between number of cars and television viewing in a family more impactful on obesity than fat intake
• decrease in performance of recruits reflecting decreased PA and fitness
• differences amongst Swiss regions, genders and cultural background --> female expats the least physically active, Swiss Germans the most

nutrition

• taste-development in tuero --> sweet foods consumed during pregancy modulate taste preferences of child
• breast feeding
• nighttime feeding problematic --> important to respect "fasting period" in infants of about 10h

smoking during pregnancy

• increases likelihood of obesity by about 14%

socioeconomic factors

• education as remedy against toxic environment is difficult to obtain in low socioeconomic classes
• chlidren with migrational background more susceptible to obesity --> being fat culturally appraised

sleep duration

• less than 10.5h/night
• hypothesis: lack of a fasting period or lack of GH and its lipolytic effects, also stress reduction with sleep and relation between stress and IR

psychiatric risk factors

• ADHD and increasde impuslivity associated with overweight
• depression --> obese children suffer from emotional eating
• stress, including pre-school children
• strongly reduce QoL and self confidence --> QoL as low as cancer patients

Arthrosis

• orthopedic issues most common in obese children
• ataxia / lack of motor control and malatriculation

Atherosclerosis & CVD

• dyslipidemia
  • TG & HDL correlate with obesity in children
  • fructose intake, especially in processed form
• high blood pressure
• Impaired glucose tolerance / Diabetes / imapred fasting glucose
• metabolic syndrome
  • present if 2 artherosclerotic-related risk factors + abdominal obesity diagnosed
• Subclinical inflammation
  • correlates with total dietary fat and % En from fat
  • meat intake correlates with IL-6 and leptin

Liver cirrhosis

• generally defined as NAFLD
  • liver enzymes elevated > 1.5 normal
  • ultra-sound of steatosis hepatitis
• non-alsoholic steatohepatitis (NASH): histologic signs of fat infiltration >5%, fibrosis and inflammation
• boys more susceptible to NAFLD due to testosterone --> fat deposition in abdominal area

Sleep apnea

• neurocognitive deficit

Diabetes & insulin resistance

• total E, fat SFA, and protein intake correlate with IR
• insulin resistance diagnosis
  • fasting glucose, HOMA or QUICKI-sensitivity
  • acanthosis nigricans around neck as visual indicator of IR
  • cut-off values same as for adults
• insulin resistance blocks glc import into cells, but not parallell effect of insulin on mitogenesis --> hyperactivated gene expression might cause cancer

Strategies to adress childhood obesity

• targets
  1. reduce blood pressure
  2. reduce burden of co-morbidities
  3. reduce sedentariness
  4. limit sugar intake & improve nutrition in the entire family
     • choice of foods
     • preparation
     • portions
     • rythm
     • company
  5. increase self-esteem and conflict-management
  6. improve parenting skills
• timing & duration
  • prenatal: avoid antibiotics and ideally mother should not be obese at pregnancy
  • at age 7-10: increases in BMI best predictor of adulthood obesity
  • usually 1y therapy with 5y follow-up
  • long studies, expensive, but effective
• Approach
  • group setting: & individual setting possible
  • multidisciplinary: sports, nutrition, psyche, behavior...
    • all participants loose weight regardless of starting condition
• Education/simplification of information
  • nutritional pyramid
    • only water, not juices/soft drink
    • fruits and vegetables, daily
    • small portion of fish/meat
    • 3 dairy products/day
  • hand-size model used to easily explain portion size
  • 3-5 meals per day
  • ideally 10h fasting/d
  • PA pyramid
    • max 1h screen time
    • muscle mass and coordination improved through PA
    • depression reduced
• Age of patients defines if her/his family is included in therapy or not (vgl Bild)
• contraindications: lack of motivatino or effective treatment
  • motivation difficult to obtain --> only ~1% of Swiss children undergo therapy
• pharmacologic interventions do not really represent a solution
  • usual medicine not allowed for children
  • leptin injections do not work --> antibody development
  • cannabinoids lead to depression
• QoL and mental disease: absence of mental issues important for weight reduction
  • improved QoL correlates with lowered BMI

Obesity & related complications

• 4Ms: used to assess obesity complications
  • mental: form addition to psychosis and depression
  • mechanical: ostheoarthritis, chronic pain, sleep apnea
  • metabolic: T2D, CVD, dyslipidemia
    • obesity major risk factor for NAFLD, cancer, T2D, CVD
  • monetary: loss of job and lowered employability, disability, low income
• Obesity can be present in absence of 4Ms, which are the dangerous co-morbidities of obesity
• weight-loss as first and most important strategy to adress obesity and co-morbidities
• BMI & mortality: x3 increase of mortality as of BMI >40
  • x 1.5 as of BMI 30
• controllable vs non-controllable risk factors
  • genetics
  • lifestely, microbiome, diet

E balance

• stored energy = E intake - E expenditure
  • E exp:
    • 70% BMR
    • 20% PA
    • 10% thermogenesis
  • E intake
    • 20-35 %En fat intake
    • type of ingested fats (SFA;MUFA;PUFA) defines diet's quality
• Hormonal regulation
  • increase hunger: ghrelin
  • decrease hunger: leptin, CCK/GIP, GLP-1, PYY, insulin
    • leptin replacement therapy in children capable of reversing obesity
    • liraglutide: glp-1 receptor agonist --> stimulates insulin secretion/decreases excessive glucagon release
    • adipose tissue (leptin) hormonally active as well as stomach/gut (glp-1)
  • hormonal regulation > power of will --> addiction and uncontrollable fod intake in case of dysregulation
• lipogenesis and lipolysis
  • lipogenesis for fat storage
    • fat stored in subcutaneous depots, can also accumulate in visceral fat --> spill over to ectopic in extreme case
  • lipolysis to release energy in case of fasting/starvation/food deprivation

Fatty acids

• Structure
  • hydrocarbon chain
    • most FA have hydrocarbon chain attached to different backbones (e.g. glycerol)
  • carboxyl group
    • carbon chains sterified to head groups
    • head groups can also consist of protein or sugars
  • steroids & cholesterol: have no hydrocarbon chain
• EFA
  • DHA and EPA technically not essential, but conversion rates too low and deficiency if not adequately consumed
  • ALA and LA essential according to terminology
• Lipid diversity and different functions, 3 main categories
  • transport & storage
    • TAG, DAG, cholesterol
  • cell signalling
    • FA removed from membrane and converted by PLA2
    • PIP2/PIP3 and others (vgl Bild)
  • cell memrane
    • phsophatidil-cholin/serine
    • sphinglipids
    • can be cleaved from membrane and metabolized via PLA2 (phospholpase A2) --> become cell signaling FA

Treatment strategies

• bariatric surgery
  • problems
    • rebound: tendency for weight regain after many years, still not back to baseline weight
    • some patients develop NAFLD
    • cost --> restricted to severly obese subjects
  • most effective treatment
  • severe impact on patient physiology
• medication for weight loss: 5-15% weight reduction
  • GLP-1 analogs (liraglutide)
    • also effective at reducing co-mordbidities, such as dyslipidemia
  • Leptin replacement
• lifestyle intervention
  • modest interventions based on simple recomendations ("eat less, move more") are capable of reducing body weight by <5% --> not enough to reduce risk of co-morbidities
  • intensive interventions: require adherence, program to follow, can reduce weight by up to 10%
    • IF, low calorie intake
    • prone to yoyo effect
• overall problem: effectiveness depends on patient's individual characteristics + no clear and effective treatment for obesity available
  • metabolic challenge (fasting) to assess metabolic state of patient
  • hormonal state of patient aslo assessed
  • solution: stratify patients into groups that are most responsive to certain treatment

Dieting

• Atkins, Zone Diet, Weight Watchers, and Ornish Diet tested against each other: all reduce weight by max 5%, co-morbidities are reduced but reappear after certain time
  • either reduce portion size, increase protein intake, limit calories --> different strategies
• ketogenic diet
  • not yet proven to work in obesity, perhaps in combination with surgery
  • effective in epileptic patients

Personalized medicine; example of DIOGENES Study

• Study presenten (DIOGENES) with three parts
  • 8 weeks of very low calorie intake --> responders and non-responders defined as weight loss > 5% BW
    • very well controlled: food replacement (how check for adherence and avoidance of other foods?)
• responders undergo second part of study: 26 weeks on different kinds of diet (high/low GI and high/low protein)

DIOGENES Study

• non-responders are studied to identiffy how hormones (glp-1 and insulin), glycemia, lipidemia and nutrient interact
• phenotyping: used to stratify non-responders into sub-groups who may have a chance of betterment with tailored treatment
  • hypothesis: non-responders have other lipid signature and therefore do not respond to specific nutrient
• lipidomics: specific lipids as markers for responsiveness to alternative treatments
  • uses pre-clinical data (cell and animal model) to establish relationships between lipid & glucose metabolism --> non-responders screened for these
  • non-responders' lipid, glucose and hormone moetabolism (glp1) is assessed to study relationship between nutrient & metablolic markers
• functional foods: to positively influence metabolism
• goal: design treatment for non-responders

DIOGENES Study

• genotyping: identification of reponder and non-responder group
• Matsuda index: glycemic outcome is improved in responders
  • improvement of this more important than sheer weight loss because it reflects a positive change in metabolism --> persists to follow-up
• BMI
  • responders lose more weight than non-responders
  • challenge of paradigm: does weight loss necessarily reflect improvement in metabolism?
    • weight loss independent of imprvoement in matsuda index possible
    • non-responder: no association between weight loss and glycemic outcome
• Identified pathways differing between responders and non responders --> can be used to deisgn treatment for non-responders
  • De novo lipogenesis
    • upregulated in non-responders
  • bile acid metabolism
    • 2nd bile acids (TCA GCA TCDCA), involved in gut microbiome
      • baseline values can be used as predictive markers because already differ before intervention
  • ARA metabolism
    • involved in inflammation --> low grade inflammation --> diseases + IR
  • fatty acid oxidation
    • responders: better than non-resp in b-ox as well as ketone body synthesis
    • stimulation of this pathway may be helpful in treatment of non-responders
• genes: key genes regulating lipogenesis in adipocytes sign. different between resp./nonresp.
  • SCD; FASN, FASN1; FASN2
• microbiome
  • fecal transplant from obese to germ free mouse
  • hypothesis: transplant must provoke change in metabolism --> can be used to study
  • outcomes: previously observed pathays change --> confirmation that microbiome contributes to different reponses between resp/nonresp.
    • ARA pathways
    • 2ndary bile acid

Factors influencing pregnancy outcomes

• genetic: maternal birth weight correlates with ponderal index of offspring
  • no correlation for paternal birth weight and PI
  • ponderal index: comparable to BMI, reflects body weight/volume ratio, m^3
• nutritional
  • intrauterine environment pre-programmes fetus to later life --> under/overnutrition negative impact
  •  
• environmental
  • epigenetics: will interfere between environment/nutrition and genotype and can lead to mismatch between phenotype and its environment (postnatal hyperinsuliemic response to food after in utero starvation)

Birth weight & adult-onset NCDs

• Barker: SGA newborns become adults and undergo developmental programming. Due to mismatches, these individuals develop a "thrifty" phenotype, i.e. that is likel to conserve as much E as possible. Consequently, they gain weight and become prone to NCDs: obesity, hypertension, diabetes, and cardiovascular disease
  • low BW correlates with greater mortality (vgl Bild)
• animal model: SGA births can catch up normo-weight births in postnatal period of adequate nutrition is provided, however, eventually resulting in obesity --> plausible that orexigenic mechanisms involved
• high birthweigt (>4000-4500g):
  • linear increase in risk for overweight as of 2300g

Intrauterine growth retardation (IUGR)

• causes
  • inadequate maternal nutrition
    • see Dutch famine
  • chronic diseases: congenital heart diseases, CKD, hyperthyroidism
  • lifestyle factors: smoking, alcohol, drugs
  • chormosomal abdonmalities --> trisomie 21
  • placental issues affecting maternal-fetal circulation
• consequences
  • growth & development
    • restricted growth and development of muscle and other organs
    • vascular development affected
  • hormonal
    • Insulin: IR as well as lowered insulin secretion in offspring possible
    • HPPA: overactivation
  • metabolic
    • glc uptake in liver reduced
• example: Dutch Famine --> time of exposure dictates how undernutrition will affect offspring
  • first half pregnancy: increased obesity, because hypothalamic centers affected
    • first trimester most vulnerable compared to other 2
  • last trimester and first motnhs of life: reduced obesity rates, because adipose tissue development affected negatively

CHO

• physiological IR to increase glc delivery to fetus
• gestational diabetes
  • definitions vgl Bild
  • consequences: likelihood of insulin-related complications/diseases increases for mother and child postpartum

PRO

• daily protein intake recommendations vg Bild
• cohort study in CH
  • 1/3 CH women, classified into socioeconomic classes --> protein intake assessed
  • average protein intake 69g/d --> deliver babies with normal weight

FAT

• PUFAs important --> 200mg DHA/d
• Fish consumption encouraged to pregnant women, alternatively supplementation
  • supplementatino only effective in case of deficiency, overdosing increases risk of preterm delivery
  • ideal range of omega-3 between 4.1 and 4.9% (of erythrocyte DHA?)
  • 11% risk reduction for preterm delivery with Omega-3 supplementation
• increased fat intake increases likelihood of vaginal infection (Gardnerella)

Micronutrients

• recommended intake of different micros changes with course of pregnancy

Folic acid

• important before conception --> spina bifida roots in first 4 weeks after conception in case of deficiency
• supplementation may reduce risk of complications by 75! --> very strong impact on birth outcomes and therefore worthwhile
• reduces risk of
  • spina bifida
  • cleft lip
  • inherited heart defects
  • possibly autism & preterm delivery

Iron

• most common deficiency worldwide, 32% in Swiss women --> more of a third-world problem
• increases risk of
  • IUGR
  • Anemia and iron deficiency in child
  • SGA birth

Iodine

• Iodine supplementation (200mcg(d) does not seem to affect IQ in children at age 5-6
  • WHO rec: 250 mcg/d
  • supplementation unlikely to harm but potentially without benefit
• severe iodine deficiency rather uncommon, but mild one common!
• Evidence
  • neurodevelopment improved in cases of severe iodine deficiency --> controversy from observational studies regarding IQ of children born to iodine sufficient/insufficient mothers
  • mother may adapt to low iodine availability and maintain euthyroidism in child

Calcium

• correlation with preeclampsia (<140/90 mmHg) --> higher Ca intake, lower hypertension
  • observational data: indigenous people consuming greater amounts of Ca have lower preeclamsia prevalence (Ethiopians, Maya)
• pathophysiology
  • hypertension leads to preterm delivery and neonatal death
  • preeclampsia not treatable during pregnancy! prevention as only strategy
• in CH: recommendation of 1g/d for pregnant women as well as general population
  • most women (non-pregnant) do not reach these recommendations
  • can be covered via ~2L of mineral water (vgl Bild)
• WHO rec: 1.5-2g/d for women with low Ca intake
• evidence: cochrane reviews
  • 2014: reduced risk or preeclampsia
  • 2018: high Ca supplementation >1g/d may reduce risk in case of low-Ca diets
    • supplementation not feasibl in third world due to expensiveness and bulkyness (1kg for 20 weeks supply)

Vitamin A

• only vitamin with risk of overdosing during pregnancy. hypervitaminosis A leads to:
  • malformation of lungs, skull, eyes and heart
• liver not recommended to pregnant women

Vitamin D

• deficiencies associated with
  • mother
    • gestational diabetes & hypertension
    • preterm delivery & cesarean
  • child
    • cardiac issues: cardiomyopathy, hypocalcemic tetany --> wekaness/tetany, dysphagia
    • respiratory tract: asthma, obstructive lung diseases
• screening: in CH first pregnancy visit checks for 25OH-D levels via questionnaire and serum levels
  • 55% of white and 83% of black Swiss women have D deficiency

B12

• supplementation and monitoring necessar for vegans
• B12 deficiency has (severe) consequences --> vgl Bild

Recommendations

• Foods to avoid:
  • raw eggs, meat, and milk
  • certain cheeses
  • liver
• Vegans & veggies
  • supplement iron, B12
  • possibly supplement Ca, n-3
  • monitor closely

Life course model & fetal origins of adults disease

• risk for NCDs accumulates throughout life, inluding fetal life
• periconceptional and intrauterine period most susceptible to genetic changes due to environment --> prevention must start here and girls and women health improved
  • more cost-effective to intervene in fetal than later life
  • intrauterine environment prepares child to food scarcity --> clashes with urban overnutrition
• common associations
  • meternal micronutrient deficiences and/or undernutrition and/or overweight/diabetes --> IGUR --> thrifty phenotype
  • low brth weight --> IR
• offspring (when girls become adult, pregnant women) becomes macrosomic: exaggerated adiposity, pancreatic islet dysfunction with tendancy to develop diabetes and similar NCDs at young age --> population's nutritional past has lare impact on population's health

Pregnancy on maternal health

• weight retention
• gestational diabetes persiting after birth --> T2D
• Osteoporosis

DHA & EPA

• important for resolution of inflammation, counteract chronic inflammation
  • traditional understanding: EPA counterbalances ARA by production os less inflammatory eicosanoids
  • newer evidence: EPA-derived resolvins avoid overshoot of inflammation, DHA responsible for resolution of inflammation à both important to balance inflammatory reactions
  • n-3 FA also involved in methylation
• DHA in neurons, EPA blood vessels
• Intake of EPA and DHA associated with
  • vascular and neuronal markers of Alzheimer’s
  • not associated with cognitive impairment
  • trend for microbleeds
• Supplementation studies
  • Beneficial effect on DNA methylation à may counteract inflammation
  • 2.2 g/d:
    • increase in cortical integrity and grey matter volume in certain parts of the brain
    • no improvement in cognitive function but executive function and verbal fluency
• Interaction with B-vitamins (Oulhaj, 2016)
  • Higher intake of DHA improves effect of B-vitamin son cognitive function, EPA much less effective
  • B vitamins have no effect of n-3 are low, only in upper normal range

B-Vitamins

• involved in DNA methylation, Phospholipid & myelin synthesis, and NT synthesis
  • depending on B vitamin, parts or all pathways are blocked (transsulfuration, remethylation via SAM, etc)
• impaired one-carbon metabolism affects cognitive function in different ways
  • high homocysteine associated with vascular complications
  • low SAM levels associated with neurodegeneration
  • important to assess entire one-carbon metabloism --> screening only for homocysteine may overlook other parts of the pathway running too high/low
• Supplementation with B12, Folate, B6slightly above RDA slows brain atrophy by 53% in elderly with mild cognitive imparment and baseline high homocysteine values
  • attenuation of atrophy = attenuation of further decline in cognitive function

Vitamin D

• deficiency and inadequacy defined differently --> vgl Bild
• deficiency even in sunny countries (burka)
  • observational data: low levels associated with Alzeiherms (ES = 1.32)
  • cochrane-review: no effect of Vit D on Alzheimers
• pleiotropic effects, inclusing in neurons
  • reulation of many neuronal processes (cell differentiation, cognition, ox damage prevention, etc)
  • reduce inflammation
  • clear amyloid plaque
• Supplementation
  • 800 IU/d, 1 year: serum 25OH-D increases, markers for amyloid-b plaques reduced, cogintive function improved in intervention group --> requires confirmation in larger trials, but promising

Vitamin E

• particularly beneficial effects as antioxidant, however
  • must come from foods
  • genetic non-responders: carriers of APOEɛ4 --> non-deterministic (can cause Alzheimer but will not necessarily)
• high dose: 2000 IU (RDA x10) for 2 years delays progression of Alzheimers by ~19%
  • caregiver time reduced --> important factor because decreases burden to relatives as well as costs for institutionalized patients
  • no safety issues
  • clashes with ESPEN guidelines --> very conservative (similar to cochrane reviews), builds on amount of studies, so innovative aproaches gain less attention

Dementia

• Alzheimer (AH) most common form of dementia
• age most important risk factor for developing dementia
• pathophysiology laregly related to chronic/systemic inflammation
  • progressive diseases (NCD)
  • BBB permeability decreases --> cytokines enter neural tissue --> hyperactivaiton of microglial cells and astrocytes --> neuroinflammation --> irreversible neuronal damage
  • lifestyle modulates inflammatory state (vgl Bild)

Preventive approach

• most promising because
  • no actual treatment available
  • dementia develops over time and manifests at irreversible stage
• role of nutritional intervention
  • treats body as a whole --> can tackle oxidative stress, inflammation, and micronutrient deficiences
• involves nutrition & lifestyle factors
  • due to progressiveness of disease, intervention requires flexible nutritional management

Nutrition

• Mediterranean Diet
  • antioxidants: brain areas affected by AH usually antioxidant depleted --> attenuate neuro-oxidative stress
  • fibre: supports healthy microbiome à often dysfunctional in AH patients due to polymedication
• supplementation of antioxidants (A, E, C, Se and/or Zn at no defined level --> people either choose supplement freely or tka eno supplements, prospective) --> ~30% reduction in cognitive impairment & decline
• healthy diet in general protective (RR ca 0.5)

Lifestyle

• exercise allows to maintain muscle mass
  • myokines beneficial effect on metabolism + anti-inflammatory
  • protein pool
• small weight loss beneficial at age 50-75
• cognitive activity most protective stategy: at older age as well as schooling as teenager

Risk factors (vgl Bild)

• cerebral microbleeds
• sleep disturbances
• depression
• diabetes
• hypertension: most preventable risk factor
• obesity
• stress

Direct impact on brain and neural development

• time-frame: 1000 days from concenption onwards are most important period of brain development
  • neural plasticity: brain's capacity to adapt to stimulus (good/bad) --> also capability to overcome insults and its longterm consequences
  • neural plasticity related to vulnerability: allows to overcome insults but can also take irreversible damage --> vulnerability usually outweighs plasticity
  • aged brain is less plastic and therefore more robust towards insults, but also less able to recover
• Brain development
  • neural tube = kick-off of brain development --> 4 weeks postconception
  • brain size 25% at birth and 75% at age 2 (1000d mark; 100% = adult brain)
  • Growth curve with two phases: steepest from conception to ~1.5y, then less steep up to age 4 and after 6 least steep
    • neural connectivity: functional complexity also increases --> synaptogenesis
      • redundand connections: synaptogenesis runs off backwards after age of 8 --> important & existing connections strengthened, unnecessary ones removed
    • different brains functions develop at different time points: basic survival functions have priority, executive functions (PFC) last --> development depends on area and processes (maybe ones that depend on environment come after ones independent thereof)
  • lifetime supply of neurons available at birth --> need to be connected via synaptogenesis
    • neurogenesis still possible throughout life
  • Myelination: crucial for brain maturation because allows rapid signal transmission through complex circuitry
    • oligodendrocytes myelinate axons, process only starts postnatal
  • 3 TM
    • corticl areas
    • myelination --> iron deficiency common and dangerous (vgl Kärtchen iron
    • hippocampus

Indirect effect

• physical activity and possibility to explore the surroundings --> input to the brain
• relationship to parents and caregivers
  • caregiver's status also affected by nutrition and if bad, liekly to affect child's brain development