IDEAL - Integrated Research on Developmental Determinants of Aging and Longevity
Coordinated by P. Slagboom and B. Zwaan, Leiden and Wageningen
IDEAL, FP7 LIP F2-2011-259679 (2011-2016)
The central hypothesis in IDEAL is that healthy aging and longevity across all species is determined by mechanisms that regulate the response to early environmental exposure, that regulate homeostatic and epigenetic set-points during development, and that interfere with or regulate epigenetic and homeostatic control over the adult lifetime into old age. Our objective is to identify these biological mechanisms and especially their genetic and epigenetic components, to study their plasticity under different environmental conditions and to study how persistent developmental and aging-related changes in epigenetic control affect health and longevity. The biological effects of variations in environmental conditions (s.a.eg. nutrition, antigen exposure, IVF treatment, parental age, lifestyle and SES) will be investigated in three phases of life: a) at prenatal and postnatal development (early–life programming), b) in the adult phase, determined by the combined consequences of events during developmental stages and age-related changes contributing to a decrease in physiological capacity and c) the morbid phase in which variation between subjects leads to differences in (co)morbidity, mortality and longevity. Different study designs and subjects/animals provide unique information to reach the IDEAL objectives. Human cohorts have been selected in which phenotypic observations in early (birth weight) and later life (disease risk factors, disease, mortality) can be linked and in which the collected bio-specimens allow us to study biological mechanisms that explain such links. To establish the response to a controlled early-life exposure and the consequences for developmental set-points and long-term health in relevant tissues, we study animal model systems. The evolutionary conservation of the biological systems we will focus on allows the integration of experimental (animal models) and observational (human cohorts) designs. We will funnel results upwards from invertebrates, Xenopus and mice to humans to maximize the translation of observations to human health, and in the reverse direction to gain insights into the basic underlying processes of human longevity determination. In these studies gene functions are examined both as determinants of epigenetic regulation (responding to environmental stimuli, influencing health and longevity) and as targets of epigenetic effects following exposure (either early or later in life, influencing homeostasis). To this end we have brought together experts with a long-standing focus on developmental and evolutionary biology, epigenetic research, and research in gerontology and epidemiology.
The life trajectory is studied in six experimental work packages (WPs) each combining studies in human cohorts and animal models which will all be active from the start of the studyproject. WP1-3 focus on systems that have been implicated as crucial for lifespan regulation: growth & metabolism, immune responses, and reproduction. Different early life conditions (nutrition, infection, IVF treatment, parental lifestyle, SES age) are studied for their effect on epigenetic regulation, on growth, metabolic, immune, and stem cell features in adulthood and middle age, on reproductive schedules and pregnancies. In elderly subjects we will establish whether the history of earlier events affecting epigenetic control explains immuno-senescence and metabolic, locomotor and ovarian aging and disease. The identification of the mechanisms of early life epigenetic set-point modification is facilitated by studying phenotypic plasticity (WP4) and the transmissibility of epigenetic effects to the next generation (WP1, 3-5) within a given genetic background. All animal studies are designed such that they cover early, middle, and/or late-aged stage. The middle aged mice and humans are characterized by a suite of similar biomarkers (in serum, urine, tissue). The knowledge from WP 1-4 will be extended into WP5 to establish whether a loss of epigenetic control is occurring with increasing age in adulthood, affecting the set-points of epigenetic regulation and leading to a decrease in health condition (read by the biomarker sets, the disease risk factors, and the presence of disease). Compared to this normative aging process, the maintenance of epigenetic control is established in biomaterials of long-lived subjects and their offspring, and the relation to existing datasets of biomarkers will be studied in longevity families. In WP6 we will identify genetic determinants of human longevity in such families and highly aged subjects. Determinants of epigenetic regulation identified in WP1-5 will be studied for their associations with to human longevity and the identified human longevity loci will be studied in WP1-5 to establish whether they are major determinants or targets of epigenetic regulation.
We will apply an overlaying focus on specific biological processes (growth & metabolism, immune responses, and reproduction) and interconnected target pathways (mTOR, Insulin/IGF-1 signaling (IIS)/FoxO, steroidogenesis, thyroid signaling, NFκB) identified in aging research as central predictors of healthy aging and/or lifespan. The datasets that will be generated in IDEAL allow us to study genes from these pathways as determinants and targets of epigenetic regulation in all systems. The integration of results to establish the robustness of findings, the modeling of the results in an evolutionary context, and in the context of the well known gender differences in longevity, is the task of WP8. Monitoring and actively disseminating IDEAL results and studying potential impact is the task of WP 9. By generating genome–wide datasets in key experiments, in IDEAL we create a resource for the EU of epigenetic and phenotypic reference data in human cohorts and animal models on early life programming, aging (preceding disease), disease and longevity. This will fuel disease-related research and early-stage disease intervention strategies. Knowledge on of epigenetic and phenotypic effects of early and late-life nutrition, IVF treatment, preterm birth and parental characteristics may have major impacts on society, medical care in pediatrics and geriatrics.
Press release: 12 million euro EU contract for studies linking early development and future health: Integrated Research on Developmental Determinants of Aging and Longevity (IDEAL)
This new European consortium will study how circumstances during development and at a young age influence health at a later age. Fourteen academic centers in the EU and two companies are participating in this collaborative research program. The proposal was submitted by Leiden University Medical Centre (LUMC) in the Netherlands and will be coordinated by Professors Eline Slagboom (LUMC) and Bas Zwaan (Wageningen University & Research Centre). One of the partners in this project is the Tübingen Ageing and Tumour Immunology research group at the University of Tübingen, Germany. The TATI group, headed by Prof. Graham Pawelec, will focus on the impact of early life experiences on immune competence in later life.