The Power of Programming - International Conference on Developmental Origins of Health and Disease Berthold Koletzko

Differences in nutritional experience during sensitive periods in early life, both before and after birth, can programme a person’s future
development, metabolism and health. Better scientific understanding of Early Nutrition Programming holds enormous potential
for implementing preventive strategies to enhance the long-term health, well-being and performance of people. This could not only
reduce costs of health care and social services, but could as well enhance wealth of societies. The Early Nutrition Programming
Project brings together a multi-disciplinary team of international scientists and leaders in key areas of the early nutrition programming
field from 40 major research centres across 16 European countries. The project with a total budget of 16.5 million Euros is
funded by the EC under the Sixth Framework Programme for Research and Technical Development and is co-ordinated by the
Children’s Hospital at Ludwig-Maximilians-University of Munich. The integrated programme of work combines experimental studies
in humans, prospective observational studies and mechanistic animal work including physiological studies and cell culture models,
with molecular biology techniques. The project started in 2005 and will run to October 2010. After the end of the project, the Early
Nutrition Academy (www.early-nutrition.org) will continue to serve as a platform for exchange of information,
scientific collaboration and training activities in the area of programming. This presentation will highlight some of the scientific
results and achievements and the efforts of the Early Nutrition Programming Project in respect to training and dissemination.

It is over twenty years since epidemiological studies that revealed that there was a relationship between patterns of early growth and subsequent risk of diseases such as type 2 diabetes, cardiovascular disease and the metabolic syndrome. Studies of identi- cal twins, individuals who were in utero during periods of famine and animal models have provided strong evidence that the early environment, including early nutrition, plays an important role in mediating these relationships. The concept of early life program- ming is therefore widely accepted. However the mechanisms by which a phenomenon that occurs in early life can have long-term effects on the function of a cell and therefore metabolism of an organism many years later are only starting to emerge. These include: (1) Permanent structural changes in an organ resulting from suboptimal levels of an important factor during a critical period of development. Such an example is the requirement of the neurotrophic action of leptin during a restricted period of development during neonatal life. (2) Persistent alterations in epigenetic modifications (e.g. DNA methylation and histone modifications) leading to changes in gene expression. Several transcription factors are susceptible to programmed changes in gene expression through such mechanisms. (3) Permanent effects on regulation of cellular ageing. Increases in oxidative stress leading to macromolecular damage, including that to DNA and specifically telomeres can contribute to such effects. Further understanding of such processes will enable the development of preventive and intervention strategies to combat the burden of common diseases such as type 2 diabetes and cardiovascular disease.

Nutrition throughout the life course has great significance not only for women and children but also for the health and wellbeing of society. The role of pre-and pregnancy nutritional status can no longer be ignored since it impacts not only conception, gestation, growth and development of the fetus and infant but it also has short and long term consequences on health and disease patterns and economic productivity at later stages of life. Nutrition marks structurally and/or functionally the development of the fetus with lifelong impacts. The magnitude, timing and duration of the nutritional insults define the final impacts; patterns of gene expression and epigenetic changes affect transcription factors controlling multiple target genes thus explaining the consequences on human and economic development. Optimization of environmental conditions affecting early growth should lead to effective approaches to optimize fetal growth to achieve not only an adequate birth-weight but also maximize lifelong health preventing adult disease and disability. Malnourished populations are also more vulnerable to infections and poor length growth affecting brain development and cognitive performance. Labor productivity and income will be lower than that observed in well nourished peers. Poverty will only
be broken by actions to improve early nutrition and linear growth. Malnutrition in early life is no longer a health or an ethical-social dilemma but the cause of self perpetuating constraints on economic development. Thus, the impact of early programming has major human-socio-economic implications for all countries, especially societies undergoing a rapid nutrition transition.

Convincing evidence has accumulated to show that both pre- and post-natal nutrition pre-programme long-term health, well-being and performance until adulthood and old age. This is supported by three separate lines of evidence, including lifetime experimental studies in animals, historical and prospective observational studies in humans, and experimental, hypothesis-testing trials in humans with long-term follow-up. There is enormous potential in applying this knowledge for preventive approaches with regard to improving the health and well-being of the population, to reducing costs for health care and social services, and for enhancing productivity and wealth of societies. To achieve such benefits, solid science based knowledge is required to assess the effect sizes of early life programming in contemporary European populations with regard to specific outcomes related to long term health and burden of adult disease, to characterize underlying mechanisms, to establish sensitive time periods during which these exposures act, and to understand potential effect differences in different subgroups of the populations characterized e.g. by genetic predis- position or gender. The results of this research should lead to conclusions on best nutritional practice in pregnancy, lactation and infancy. In this presentation, we shall review the state of the knowledge, identify some key issues that need to be resolved, and describe opportunities for future research.

Convincing evidence has accumulated to show that both pre- and post-natal nutrition pre-programme long-term health, well-being and performance until adulthood and old age. This is supported by three separate lines of evidence, including lifetime experimental studies in animals, historical and prospective observational studies in humans, and experimental, hypothesis-testing trials in humans with long-term follow-up. There is enormous potential in applying this knowledge for preventive approaches with regard to improving the health and well-being of the population, to reducing costs for health care and social services, and for enhancing productivity and wealth of societies. To achieve such benefits, solid science based knowledge is required to assess the effect sizes of early life programming in contemporary European populations with regard to specific outcomes related to long term health and burden of adult disease, to characterize underlying mechanisms, to establish sensitive time periods during which these exposures act, and to understand potential effect differences in different subgroups of the populations characterized e.g. by genetic predis- position or gender. The results of this research should lead to conclusions on best nutritional practice in pregnancy, lactation and infancy. In this presentation, we shall review the state of the knowledge, identify some key issues that need to be resolved, and describe opportunities for future research.

The ways in which epigenetic modifications fix the effects of early environmental events, ensuring sustained responses to transient stimuli, which result into modified gene expression patterns and phenotypes later in life, is a topic of considerable interest. Increasing numbers of genome-wide studies based on high-throughput technologies and focusing on humans and mice have revealed additional complexity in epigenetic processes, highlighting the importance of stage-, sex-, and cell-specific epigenetic landscapes,
and of crosstalk between the different epigenetic marks. This paper focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics, positions and functions of relevant epigenetic marks. Animal models, including mice, rats, sheep, pigs and rabbits, remain a vital tool for studying the influence of early nutritional events on adult health and disease. In recent months, a number of studies focusing on the Developmental Origin of Health and Disease (DOHaD) and metabolic programming have identified links between early nutrition, epigenetic processes, and long-term illness. They have demonstrated the existence
of an on-going self-propagating epigenetic cycle, of metabolic memories and ageing processes. However most epigenetic studies have only addressed the long-term effects on a small number of epigenetic marks, at the global or individual gene level, of environmental stressors in humans and animal models. Despite recent progress, we are still far from understanding how, when and where environmental stressors disturb key epigenetic mechanisms. Thus identifying the original key marks and their changes throughout development, during an individual’s lifetime or over several generations, remains a challenging issue.