PHENOTYPIC FLEXIBILITY AS A NEW WAY TO QUANTIFY EFFECTS OF FOOD AND NUTRITION ON HEALTH Suzan Wopereis Our mission TNO connects people and knowledge to create innovations that boost the sustainable competitive strength of industry and well-being of society. ‘INNOVATION FOR LIFE’ The power of TNO From idea to innovation TNO = Netherlands Organisation for Applied Scientific Research www.tno.nl TNO Netherlands Organisation for Applied Scientific Research Founded in 1932 Non-for-profit research institute ~3300 employees 10 sites in Netherlands + 25 sites/countries globally Funding: • Government (NL) • Contract research (world) • Public-private partnerships (world) Why is it so difficult to show an health effect in nutrition intervention trials? Subtle and longterm effects Target population is healthy Interactions between ingredients/nutrients Multiple mechanisms Multiple target tissues Interindividual variation Choice of reference Health = ? Huber et al., BMJ 2011: Two research-projects related to flexibility 1. PhenFlex Innovative and ground-breaking research to phenotypic flexibility as a new way to quantify effects of food and nutrition on health 2. Whole grain resilience Application of phenotypic flexibility to deliver proof of concept that phenotypic flexibility can substantiate health benefits of whole wheat products PhenFlex Innovative scientific approach that aims to develop methods and tools to substantiate subtle effects of food and nutrition on health (in healthy subjects!) An approach that measures health instead of disease Based on: 1. New definition of health 2. System biology based biomarkers 3. Challenge test to determine resilience The ‘challenge concept’ Healthy situation: Too high Too low The ‘challenge concept’ Unhealthy PhenFlex challenge Healthy PhenFlex challenge ‘PhenFlex challenge’: 75g glucose, 60g fat, 20g protein OPGTT Extensive analyses Time course studies: Blood sampling at multiple time points after challenge, up to 10 hours metabolome proteome clinical chemistry transcriptome Aim: to monitor response of multiple biological processes Biomarkers of health: • Challenge response • Difference “healthy” vs “T2D”  Reduced adaptability study Healthy subjects hrs PhenFlex challenge Subjects with type-2 diabetes hrs PhenFlex challenge Summary Only baseline effect PhenFlex challenge effect Blunted lipolysis Blunted energy metabolism ↑ liver damage hypertriglyceridemia Biomarkers of health: • Variation in response within 100 healthy subjects with different phenotypic flexibility  Healthy ranges study hrs PhenFlex challenge 20-29 L-N 30-59 30-59 30-59 Low Normal High 60-70 N-H hrs PhenFlex challenge Variation in phenotypic flexibility in healthy subjects 60-70 N-H stress lipids 20-29 L-N Based on ~160 markers Variation in phenotypic flexibility in healthy subjects Age 30-59 LOW FAT% stress lipids Based on ~160 markers Variation in phenotypic flexibility in healthy subjects Age 30-59 LOW FAT% NORMAL FAT% stress lipids Based on ~160 markers Variation in phenotypic flexibility in healthy subjects Age 30-59 LOW FAT% NORMAL FAT% HIGH FAT% stress lipids Based on ~160 markers Low education shows higher score on Flex-index hrs Flex-index hrs Education level Higher hours of sleep shows higher score on Flex-index hrs Flex-index hrs hours of sleep Especially in persons that report on sleeping problems… hrs Flex-index hrs hours of sleep The phenotypic flexibility health space Age 30-59 LOW FAT% NORMAL FAT% HIGH FAT% stress lipids Subject S052 Age: 59 Fat: 21.4% (=Low) Metabolic age > 80! Diagnosis: • Induced liver stress: ALAT, GGT, Fisher • Reduced lipid handling: TG, NEFA, cholesterol • Insulin resistant: ↓Matsuda, ↑HOMA, ↑glucose, ↑insulin, ↑C-peptide • Induced muscle stress: Creatinin, prot deficiency, 3-methylhistidine From Phase 1…. Biomarkers of health: • Challenge response • Difference healthy vs T2D Biomarkers of health: • Variation in response within 100 healthy subjects with different phenotypic flexibility Reduced adaptability study Healthy ranges study ….into Phase 2 INTERVENTION STUDY Proof of concept that new biomarkers of health are useful to substantiate beneficial health effects in a dietary intervention study New partners welcome to join ! Whole grain resilience: towards health claim substantiation for whole wheat products Human study Randomised, double blind, placebo controlled, including challenge test Group A: whole grain wheat 12 weeks Group B: No whole grain wheat Use of self-measuring devices Take home message For substantiation of health benefits of nutrition we need biomarkers of health rather than biomarkers of disease These are “multi-biomarker” panels representing defined and accepted health-related processes In combination with the new PhenFlex challenge test most defined health related processes are modulated In this way we believe to be able to measure health effects of nutrition In 2020: New book releases with scientific health facts? Acknowledgements Ben van Ommen Sabina Bijlsma Gertruud Bakker Tim van den Broek Annette Stafleu Wilrike Pasman Annelies Dijk-Stroeve Andre Boorsma Herman van Wietmarschen Marjan van Erk Nard Clabbers Jan Willem van der Kamp Carina de Jong and many others… THANK YOU FOR YOUR ATTENTION