Accelerated biological aging six decades after prenatal famine exposure.

To test the hypothesis that early-life adversity accelerates the pace of biological aging, we analyzed data from the Dutch Hunger Winter Families Study (DHWFS, N = 951). DHWFS is a natural-experiment birth-cohort study of survivors of in-utero exposure to famine conditions caused by the German occupation of the Western Netherlands in Winter 1944 to 1945, matched controls, and their siblings. We conducted DNA methylation analysis of blood samples collected when the survivors were aged 58 to quantify biological aging using the DunedinPACE, GrimAge, and PhenoAge epigenetic clocks. Famine survivors had faster DunedinPACE, as compared with controls. This effect was strongest among women. Results were similar for GrimAge, although effect-sizes were smaller. We observed no differences in PhenoAge between survivors and controls. Famine effects were not accounted for by blood-cell composition and were similar for individuals exposed early and later in gestation. Findings suggest in-utero undernutrition may accelerate biological aging in later life.

Lessons learned from 25 Years of Research into Long term Consequences of Prenatal Exposure to the Dutch famine 1944-45: The Dutch famine Birth Cohort.

This paper describes the findings of a historical cohort study of men and women born around the time of the Dutch famine 1944-45. It provided the first direct evidence in humans of the lasting consequences of prenatal undernutrition. The effects of undernutrition depended on its timing during gestation, and the organs and tissues undergoing periods of rapid development at that time. Early gestation appeared to be particularly critical, with the effects of undernutrition being most apparent, even without reductions in size at birth. Undernutrition during gestation affected the structure and function of organs and tissues, altered behaviour and increased risks of chronic degenerative diseases. This demonstrates the fundamental importance of maternal nutrition during gestation as the building blocks for future health.

Premature brain aging in humans exposed to maternal nutrient restriction during early gestation.

BACKGROUND: Prenatal exposure to undernutrition is widespread in both developing and industrialized countries, causing irreversible damage to the developing brain, resulting in altered brain structure and decreased cognitive function during adulthood. The Dutch famine in 1944/45 was a humanitarian disaster, now enabling studies of the effects of prenatal undernutrition during gestation on brain aging in late adulthood. METHODS: We hypothesized that study participants prenatally exposed to maternal nutrient restriction (MNR) would demonstrate altered brain structure resembling premature brain aging in late adulthood, expecting the effect being stronger in men. Utilizing the Dutch famine birth cohort (n = 118; mean age: 67.5 ± 0.9 years), this study implements an innovative biomarker for individual brain aging, using structural neuroimaging. BrainAGE was calculated using state-of-the-art pattern recognition methods, trained on an independent healthy reference sample, then applied to the Dutch famine MRI sample, to evaluate the effects of prenatal undernutrition during early gestation on individual brain aging in late adulthood. RESULTS: Exposure to famine in early gestation was associated with BrainAGE scores indicative of an older-appearing brain in the male sample (mean difference to subjects born before famine: 4.3 years, p < 0.05). Furthermore, in explaining the observed variance in individual BrainAGE scores in the male sample, maternal age at birth, head circumference at birth, medical treatment of hypertension, history of cerebral incidences, actual heart rate, and current alcohol intake emerged to be the most influential variables (adjusted R2 = 0.63, p < 0.01). INTERPRETATION: The findings of our study on exposure to prenatal undernutrition being associated with a status of premature brain aging during late adulthood, as well as individual brain structure being shaped by birth- and late-life health characteristics, are strongly supporting the critical importance of sufficient nutrient supply during pregnancy. Interestingly, the status of premature brain aging in participants exposed to the Dutch famine during early gestation occurred in the absence of fetal growth restriction at birth as well as vascular pathology in late-life. Additionally, the neuroimaging brain aging biomarker presented in this study will further enable tracking effects of environmental influences or (preventive) treatments on individual brain maturation and aging in epidemiological and clinical studies.

The risk of stroke after prenatal exposure to famine.

Prenatal exposure to famine is associated with an increased risk of metabolic and cardiovascular diseases in the offspring at adult age. The aim of this study was to assess whether prenatal exposure to undernutrition increases the risk of stroke. This study was performed in the Dutch famine birth cohort, which consist of 2414 members who were born between 1943 and 1947 in the Netherlands. In a subsample of 1177 individuals, interviews were conducted using standardized questionnaires to obtain information about medical history (which included specific questions regarding stroke) and lifestyle. Information on stroke-related mortality was collected by linking the cohort with Statistics Netherlands. A Cox's proportional hazard analysis was performed to calculate hazard ratios (HRs) comparing the incidence of non-fatal stroke between participants who were exposed, subdivided into early, mid and late gestation, and unexposed to famine prenatally. Three cohort members died of stroke. Of the 1177 subjects who responded to the questionnaires 49 (4.2%) survived a stroke. Unadjusted and adjusted HRs for the risk of non-fatal stroke did not show a significant difference between the unexposed and exposed subjects: HR 1.23 (95% CI 0.53-2.83), HR 1.23 (95% CI 0.53-2.82), HR 1.12 (95% CI 0.46-2.71) for those exposed in late, mid and early gestation, respectively. We were unable to find evidence for a major effect of prenatal exposure to famine on the risk of stroke in later life, although one should be aware that this study was underpowered and the study population too selected and young to identify smaller risks.

Early life undernutrition and adult height: The Dutch famine of 1944-45.

Current research shows strong associations between adult height and several positive outcomes such as higher cognitive skills, better earning capacity, increased chance of marriage and better health. It is therefore relevant to investigate the determinants of adult height. There is mixed evidence on the effects of undernutrition during early life on adult height. Therefore, our study aims at assessing the impact of undernutrition during gestation and at ages younger than 15 on adult height. We used data from the Longitudinal Aging Study Amsterdam. Exposure to undernutrition was determined by place of residence during the Dutch famine during World War II. Included respondents were born between 15 May 1930 and 1 November 1945 and lived in the northern part of the Netherlands during the famine period (n=1008). Exposure data was collected using interviews and questionnaires and adult height was measured. Exposed and non-exposed respondents were classified in the age categories pregnancy- age 1 (n=85), age 1-5 (n=323), age 6-10 (n=326) or puberty (age 11-15, n=274). Linear regression analyses were used to test the associations of adult height with exposure. The robustness of the regression results was tested with sensitivity analyses. In the models adjusted for covariates (i.e., number of siblings, education level of parents, and year of birth) and stratified by gender, adult height was significantly shorter for females exposed at ages younger than 1 (-4.45cm [-7.44--1.47]) or at ages younger than 2 (-4.08cm [-7.20--0.94]). The results for males were only borderline significant for exposure under age 1 (-3.16 [-6.82-0.49]) and significant for exposure under age 2 (-4.09cm [-7.20--0.96]). Exposure to the Dutch famine at other ages was not consistently significantly associated with adult height. In terms of public health relevance, the study's results further underpin the importance of supporting pregnant women and young parents exposed to undernutrition.

Famine food of vegetal origin consumed in the Netherlands during World War II.

BACKGROUND: Periods of extreme food shortages during war force people to eat food that they normally do not consider edible. The last time that countries in Western Europe experienced severe scarcities was during World War II. The so-called Dutch famine or Hunger Winter (1944-1945) made at least 25,000 victims. The Dutch government took action by opening soup kitchens and providing information on wild plants and other famine food sources in "wartime cookbooks." The Dutch wartime diet has never been examined from an ethnobotanical perspective. METHODS: We interviewed 78 elderly Dutch citizens to verify what they remembered of the consumption of vegetal and fungal famine food during World War II by them and their close surroundings. We asked whether they experienced any adverse effects from consuming famine food plants and how they knew they were edible. We identified plant species mentioned during interviews by their local Dutch names and illustrated field guides and floras. We hypothesized that people living in rural areas consumed more wild species than urban people. A Welch t test was performed to verify whether the number of wild and cultivated species differed between urban and rural citizens. RESULTS: A total number of 38 emergency food species (14 cultivated and 21 wild plants, three wild fungi) were mentioned during interviews. Sugar beets, tulip bulbs, and potato peels were most frequently consumed. Regularly eaten wild species were common nettle, blackberry, and beechnuts. Almost one third of our interviewees explicitly described to have experienced extreme hunger during the war. People from rural areas listed significantly more wild species than urban people. The number of cultivated species consumed by both groups was similar. Negative effects were limited to sore throats and stomachache from the consumption of sugar beets and tulip bulbs. Knowledge on the edibility of famine food was obtained largely by oral transmission; few people remembered the written recipes in wartime cookbooks. CONCLUSION: This research shows that 71 years after the Second World War, knowledge on famine food species, once crucial for people's survival, is still present in the Dutch society. The information on famine food sources supplied by several institutions was not distributed widely. For the necessary revival of famine food knowledge during the 1940s, people needed to consult a small group of elders. Presumed toxicity was a major reason given by our participants to explain why they did not collect wild plants or mushrooms during the war.

Early gestation as the critical time-window for changes in the prenatal environment to affect the adult human blood methylome.

BACKGROUND: The manipulation of pregnancy diets in animals can lead to changes in DNA methylation with phenotypic consequences in the offspring. Human studies have concentrated on the effects of nutrition during early gestation. Lacking in humans is an epigenome-wide association study of DNA methylation in relation to perturbations in nutrition across all gestation periods. METHODS: We used the quasi-experimental setting of the Dutch famine of 1944-45 to evaluate the impact of famine exposure during specific 10-week gestation periods, or during any time in gestation, on genome-wide DNA methylation levels at age ∼ 59 years. In addition, we evaluated the impact of exposure during a shorter pre- and post-conception period. DNA methylation was assessed using the Illumina 450k array in whole blood among 422 individuals with prenatal famine exposure and 463 time- or sibling-controls without prenatal famine exposure. RESULTS: Famine exposure during gestation weeks 1-10, but not weeks 11-20, 21-30 or 31-delivery, was associated with an increase in DNA methylation of CpG dinucleotides cg20823026 (FAM150B), cg10354880 (SLC38A2) and cg27370573 (PPAP2C) and a decrease of cg11496778 (OSBPL5/MRGPRG) (P < 5.9 × 10(-7), PFDR < 0.031). There was an increase in methylation of TACC1 and ZNF385A after exposure during any time in gestation (P < 2.0 × 10(-7), PFDR = 0.034) and a decrease of cg23989336 (TMEM105) after exposure around conception. These changes represent a shift of 0.3-0.6 standard deviations and are linked to genes involved in growth, development and metabolism. CONCLUSION: Early gestation, and not mid or late gestation, is identified as a critical time-period for adult DNA methylation changes in whole blood after prenatal exposure to famine.