Community Research and Development Information Service - CORDIS

Periodic Report Summary 3 - BRAINAGE (Impact of Prenatal Stress on BRAIN AGEing)

Project Context and Objectives:
In view of the worldwide ageing population, understanding the biology of healthy ageing is more relevant than ever. In Europe, the progressively ageing population has prompted concerns amongst the inhabitants and politicians that a large fraction of the populace will suffer cognitive decline and dementia with increasing age. The same situation applies to other typical age-associated brain disorders such as stroke. A major goal of the health program in FP7 was to find ways to ensure that this increase in longevity is also accompanied by an improvement in disease-free life expectancy. The question is how can therapy delay the onset of typical age-associated diseases? Based on our own studies and on work by others, the project consortium believes that prenatal stress influences health and disease in later life and an analysis of this process is the key to identification of therapeutic procedures.
Exposure of the fetus to increased stress hormone levels is mainly attributable to three factors: maternal stress, treatment with stress hormones and undernutrition. Apart from maternal stress in today´s stressful lifestyle, treatment with stress hormones is very common. Almost 10% of all pregnant women threatening preterm delivery are treated with stress hormones (glucocorticoids) to enhance fetal lung maturation. Furthermore, moderate undernutrition during pregnancy is widespread in both developing countries and in Western societies such as in the EU thanks to a lifestyle comprising of restricting dieting intake (including global food reduction) for cosmetic, a cause of fetal nutrition. A recent study showed that most women do not improve their dietary and lifestyle patterns during pregnancy. Finally, poor fetal nutrition due to relative placental insufficiency is also present in teenage and in elderly pregnancies which are on the increase.
In the present project, the focus is placed on analysing the link between prenatal stress exposure during human development and brain ageing and the most important age-related brain diseases: cognitive decline and stroke. The relationship between prenatal stress and ageing is rather complex involving several factors. Indeed, analyses in human cohorts (e.g. the Dutch famine cohort) and experimental studies have identified several pathways and mechanisms which appear to be critical for early brain ageing.
Exposure of the fetus to increased stress hormone levels leads to epigenetic reprogramming of central glucocorticoid receptor sensitivity and, thus to an increase in the activity of the hypothalamo-pituitary adrenal stress axis. The increased activity of the hypothalamo-pituitary adrenal stress axis leads in increased stress sensitivity during entire life span. A brain sensitive to stress is particularly vulnerable to an early loss of brain resilience toward challenges. Increased stress sensitivity contributes to biological ageing and cognitive decline both through excessive stress hormone secretion and glucocorticoid receptor resistance. The latter increases the production of pro-inflammatory cytokines, accentuating potential neuronal damage after stroke.
Taken together, the consortium examines the effects and mechanisms of prenatal programming and explores interventions which may be employed to support healthy brain ageing in subjects at risk. For this purpose, we compare the impact of different types of prenatal stress: maternal psychophysiological stress, undernutrition, and therapeutic glucocorticoid exposure. We analyse indicators and measures for brain ageing and compare these to the biological and numerical age. The goal is to develop therapeutic interventions for conditions that are still reversible. To translate experimental results from rodents into the human situation we use non-human primates.

Project Results:
We examined the link between prenatal stress and brain ageing. In rats, we showed that stress sensitivity of the fetus strongly depends on gestational age and leads to behaviour disturbances in later life. Phenotypic appearance shows age-dependent patterns. The adverse effects of prenatal stress (moderate maternal nutrient restriction of 30%) could be reproduced in non-human primates under standardized conditions. Similarly, prenatal exposure to maternal psychological stress produced behavioural and cognitive disturbances in the human infant associated with disturbances in structural and functional neurodevelopment. In the elderly, prenatal stress (maternal nutrient restriction) was associated to early cognitive decline based on earlier structural brain ageing. All effects show strong gender specificity.
Examining the underlying mechanisms of the link between prenatal stress and brain ageing in rats revealed that prenatal stress not only changes DNA methylation of the glucocorticoid receptor gene but also the imprinting control region of the H19/IGF2 locus and of genome-wide repetitive elements (LINES). These effects were gender-and tissue-specific. The methylation changes were accompanied by changes of the stress sensitivity which showed age-dependent patterns. Moreover, activity of the 11βHSD1 which activates inactive precursors to cortisol or corticosterone increases with age suggesting that 11βHSD1contributes to early cognitive decline by exposing neurons to increased cortisol/corticosterone levels. In non-human primates, disturbances in the negative feedback system of the hypothalamo-pituitary-adrenal (HPA) axis and activity of 11ßHSD could be reproduced. Similarly, stress sensitivity (autonomic dysfunction) was altered in the human infant.
In addition, prenatal stress worsened the outcome of age-related brain diseases such as stroke. Underlying mechanisms included an increased cerebrovascular tone and an altered glucocorticoid receptor mediated immunoresponse which exposes the brain to increased cerebral inflammation. Examination of the effects of the SSRI citalopram as preventive or interventional therapy showed a decrease of vascular tone but no improvement of stroke outcome thus far.
With regard to searching for biomarkers of brain development and ageing, we examined the potential of structural, functional, metabolic, immune and telomere-based markers.
Structural markers: we developed a unique MRI-based computational age estimation algorithm that can recognize brain atrophy earlier, even before the onset of clinical symptoms. The age estimation framework allows prediction of brain age with an error between 1.3y (for children) and 5y (for adults). Using this technique our preliminary results show an altered trajectory of structural brain development in non-human primates and earlier brain ageing in humans after nutrient restriction during pregnancy.
Functional markers: we developed a novel neurocognitive approach assessing the information processing capacity of the cerebral attention network in humans. The information processing capacity shows a strong age-dependent dependence. We adapted this approach for use in our differently aged human cohorts. Analysis of the effects of prenatal stress in our human cohorts is ongoing.
Immune markers: Our preliminary results in rodents show that major pro-inflammatory cytokines increase with ageing. Analysis of the effects of prenatal stress is ongoing.
Metabolic markers: We developed kit-based metabolome assays to determine concentrations of several metabolite classes. Preliminary results show that certain key metabolites were notably altered over the ageing process but exposure to famine had no effects.
Telomere length: In humans, shortening of leukocyte telomere length was not associated to prenatal exposure to famine.
All in all, we have made considerable progress, however, final data analysis and, consequently, integration of all data in order to receive a more detailed picture of the effects of prenatal stress on brain development, function and ageing, of the underlying mechanisms, of the effectiveness of SSRI as interventional approach and of the usefulness of biomarkers for aberrations in brain development and ageing are ongoing.

Potential Impact:
The increased incidence of brain diseases with longevity poses not only a health problem, but also a social one. There is considerable concern that costs related to the dealing with the health and social problems of an increasingly ageing society could lead to a collapse of the European social and health insurance systems in the coming years. This situation calls for pioneering scientific advances which can quickly be translated into preventive strategies and therapy of early brain ageing and brain age related disorders. In this respect, we have chosen a strong translational approach to investigate the impact of early environmental stimuli on brain ageing.
The prenatal period is increasingly recognized as a target for the primary prevention of diseases in later life. The study of the prenatal environment in BrainAGE has very substantial public health implications in terms of improvement of outcome for children because maternal life style and stress are modifiable. Public knowledge on vulnerable periods and adverse environmental stimuli during pregnancy raises public awareness.
BrainAGE discovers mechanisms linking human development and ageing using molecular biological and genetic approaches, translates experimental results (e.g. by using non-human primates) into the human situation. In addition, it provides innovative strategies to detect early brain ageing and develops early implementable interventional approaches for periods when the condition is still reversible. Noticeably, BrainAGE strongly emphasizes gender specific examinations of processes which link human development and ageing.
The results achieved in the project will reveal to what extent (I) the different types of prenatal stress program early brain ageing,(II) prenatal stress programs early cognitive decline and incidence and outcome of stroke in aged subjects in a human cohort as well as in experiments on rodents, glucocorticoid resistance, increased sympathetic activity, or increased cerebrovascular tone are key mediators connecting developmental modifications to early brain ageing and increased susceptibility to age-associated brain disorders in experimental studies. Finally, the project will (IV) identify pharmacological interventions that may reverse altered stress sensitivity and vasoreactivity in rodents as a base for preventive or therapeutic human studies.
Overall, we expect to obtain a better understanding of the impact of various prenatal stressors, and achieve enhanced detection of changes in brain development and ageing induced by prenatal stress. This enables us to make recommendations to science policy makers, public health policy makers, and health professionals to avoid adverse effects of prenatal stress hormone exposure. BrainAGE also achieves a preventive effect by means of public education and via the development of approaches/methods for stress reduction during pregnancy. Our findings will enable policy makers to develop better public health policies, increase public awareness with regard to ameliorating the ageing process and thus, enabling a better integration of an ageing community into society.
Thus, BrainAGE will provide both recommendations relating to which early environmental stimuli should be avoided at what time of human development, and interventional regimes for early implementation during adulthood, if cases where individuals exposed to such prenatal stimuli. This dual approach considerably boosts the value of BrainAGE; it has the notable potential to considerably improve the health of future generations in addition to bringing immediate benefit in terms of supporting healthy brain ageing in the current population.
BrainAGE does not only contribute to a higher quality of life during ageing but in the long-term reduces the financial burden on health care providers and systems. Preventing early brain ageing also has an impact on reducing brain-related diseases, such as stroke. Stroke is one of the most common causes for disability and invalidism in Europe. Costs for prevention, treatment, rehabilitation and care consume much of the health budget in Europe. These costs rise with increasing life expectancy as stroke is closely associated to age. Thus, having indicators for early brain ageing offers the opportunity for targeted interventions. BrainAGE provides both, indicators for the diagnosis of early brain age and therapy strategies for intervention not only to the benefit for the individual but also for the advantage of the European health budget.

List of Websites:

Reported by

Universitätsklinikum Jena


Life Sciences
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