Dairying, diseases and the evolution of lactase persistence in Europe.

In European and many African, Middle Eastern and southern Asian populations, lactase persistence (LP) is the most strongly selected monogenic trait to have evolved over the past 10,000 years1. Although the selection of LP and the consumption of prehistoric milk must be linked, considerable uncertainty remains concerning their spatiotemporal configuration and specific interactions2,3. Here we provide detailed distributions of milk exploitation across Europe over the past 9,000 years using around 7,000 pottery fat residues from more than 550 archaeological sites. European milk use was widespread from the Neolithic period onwards but varied spatially and temporally in intensity. Notably, LP selection varying with levels of prehistoric milk exploitation is no better at explaining LP allele frequency trajectories than uniform selection since the Neolithic period. In the UK Biobank4,5 cohort of 500,000 contemporary Europeans, LP genotype was only weakly associated with milk consumption and did not show consistent associations with improved fitness or health indicators. This suggests that other reasons for the beneficial effects of LP should be considered for its rapid frequency increase. We propose that lactase non-persistent individuals consumed milk when it became available but, under conditions of famine and/or increased pathogen exposure, this was disadvantageous, driving LP selection in prehistoric Europe. Comparison of model likelihoods indicates that population fluctuations, settlement density and wild animal exploitation-proxies for these drivers-provide better explanations of LP selection than the extent of milk exploitation. These findings offer new perspectives on prehistoric milk exploitation and LP evolution.

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.

Early-life exposure to hardship increased risk tolerance and entrepreneurship in adulthood with gender differences.

Many entrepreneurs credit their success to early hardship. Here, we exploit geographical differences in the intensity of China's Great Famine to investigate the effect of hardship during formative years on individual personality and engagement in business entrepreneurship. To exclude factors that might confound the relation between famine intensity and entrepreneurship, we model famine intensity by random weather shocks. We find robust evidence that individuals who experienced more hardship were subsequently more likely to become entrepreneurs (defined broadly as self-employed or business owners). Importantly, the increase in entrepreneurship was at least partly due to conditioning rather than selection. Regarding the behavioral mechanism, hardship was associated with greater risk tolerance among men and women but increased business ownership only among men. The gender differences were possibly due to the intricate relationship between a Chinese social norm­men focus more on market work, while women focus more on domestic work­and interspousal risk pooling associated with occupational choices. Scientifically, these findings contribute to a long-standing debate on whether entrepreneurship is due to nature or nurture, particularly how hardship conditions people to be entrepreneurial. The findings also highlight the importance of gender differences in shaping the effect of early-life experience on life cycle outcomes.

Adults prenatally exposed to the Dutch Famine exhibit a metabolic signature associated with a broad spectrum of common diseases.

BACKGROUND: Exposure to famine in the prenatal period is associated with an increased risk of metabolic disease, including obesity and type 2 diabetes. We employed nuclear magnetic resonance (NMR) metabolomic profiling to identify the metabolic changes that are associated with survival of prenatal famine exposure during the Dutch Famine at the end of World War II and subsequently assess their link to disease. METHODS: NMR metabolomics data were generated from serum in 480 individuals prenatally exposed to famine (mean 58.8 years, 0.5 SD) and 464 controls (mean 57.9 years, 5.4 SD). We tested associations of prenatal famine exposure with levels of 168 individual metabolic biomarkers and compared the metabolic biomarker signature of famine exposure with those of 154 common diseases. RESULTS: Prenatal famine exposure was associated with higher concentrations of branched-chain amino acids ((iso)-leucine), aromatic amino acid (tyrosine), and glucose in later life (0.2-0.3 SD, p < 3 × 10-3). The metabolic biomarker signature of prenatal famine exposure was positively correlated to that of incident type 2 diabetes from the UK Biobank (r = 0.77, p = 3 × 10-27), also when re-estimating the signature of prenatal famine exposure among individuals without diabetes (r = 0.67, p = 1 × 10-18). Remarkably, this association extended to 115 common diseases for which signatures were available (0.3 ≤ r ≤ 0.9, p < 3.2 × 10-4). Correlations among metabolic signatures of famine exposure and disease outcomes were attenuated when the famine signature was adjusted for body mass index. CONCLUSIONS: Prenatal famine exposure is associated with a metabolic biomarker signature that strongly resembles signatures of a diverse set of diseases, an observation that can in part be attributed to a shared involvement of obesity.

Pestilence and famine: Continuing down the vicious cycle with COVID-19.

Despite the fact that we produce enough food to feed everyone on Earth, world hunger is on the rise. On the other side of the table, the obesity crisis also weighs heavily. Malnutrition is less about food than about socioeconomic factors such as conflict, poverty, and global disasters such as climate change and the novel Coronavirus Disease 2019 (COVID-19) pandemic. Nutrition and infectious disease exist in an intricate dance. Adequate and balanced nutrition is critical for appropriate response to infection and any changes in the balance can serve as a tipping point for the next pandemic. On the other hand, pandemics, such as COVID-19, lead to greater malnutrition. Both over- and undernutrition increase severity of disease, alter vaccine effectiveness, and potentially create conditions for viral mutation and adaptation-further driving the disease and famine vicious cycle. These long-term health and socioeconomic repercussions have direct effects at individual and global levels and lead to long-term consequences. Therefore, investing in and strengthening public health, pandemic prevention, and nutrition programs become vital at a much more complex systems level.

Brain activity during Stroop task performance at age 74 after exposure to the Dutch famine during early gestation.

OBJECTIVE: Poorer performance on the Stroop task has been reported after prenatal famine exposure at age 58, potentially indicating cognitive decline. We investigated whether brain activation during Stroop task performance at age 74 differed between individuals exposed to famine prenatally, individuals born before and individuals conceived after the famine. METHOD: In the Dutch famine birth cohort, we performed a Stroop task fMRI study of individuals exposed (n = 22) or unexposed (born before (n = 18) or conceived after (n = 25)) to famine in early gestation. We studied group differences in task-related mean activation of the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC) and posterior parietal cortex (PPC). Additionally, we explored potential disconnectivity of the DLPFC using psychophysiological interaction analysis. RESULTS: We observed similar activation patterns in the DLPFC, ACC and PPC in individuals born before and individuals exposed to famine, while individuals conceived after famine had generally higher activation patterns. However, activation patterns were not significantly different between groups. Task-related decreases in connectivity were observed between left DLPFC-left PPC and right DLPFC-right PPC, but were not significantly different between groups. CONCLUSIONS: Although not statistically significant, the observed patterns of activation may reflect a combined effect of general brain aging and prenatal famine exposure.

Long-term mental health cost of the Great Chinese Famine.

The Great Chinese Famine (1959-1961) claimed tens of millions of lives. This study aims to causally examine the long-term mental health cost it imposed on those who survived. To estimate the nationwide total mental health cost, we use a novel dataset to measure the famine intensity of every prefecture-level region, match it to a nationally representative survey, and then identify the long-term effects of the famine on the depression of rural residents then in the early years of their lives. Difference-in-differences estimates reveal that a one-standard-deviation rise in the experienced famine intensity increased a standard measure of depression by about 0.039 and 0.064 if the individual experienced the famine at ages 0-2 and 3-5, respectively. This translates into roughly 7.99 million cases of severe depressive symptoms caused by the famine, which is likely an undercount. Examining the mechanisms behind the large effects, we find that important roles were played by starvation experience and childhood maltreatment, as well as the primary mediators including other health outcomes, economic status, and social relationship. Our findings shed light on how large-scale food security failures impact the mental well-being of the survivors.

Association between famine exposure during infancy and childhood and the risk of chronic kidney disease in adulthood.

BACKGROUND: Famine exposure in childhood is proven to be associated with multiple chornic disease in adult but has not been studied with chronic kidney disease (CKD). AIMS: This study was conducted to identify the relationship between famine exposure during infancy and childhood - specifically, the Chinese famine of 1959-1961 - and the risk of adult-onset chronic kidney disease (CKD) among Chinese individuals. METHODS: This study included 2937 individuals from the Qingdao Diabetes Prevention Program. They were stratified by birth year into infancy-exposed (1956-1958), childhood-exposed (1950-1955) and unexposed (1963-1971) groups. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. CKD was defined as an eGFR of <90 mL/min/1.73 m2. RESULTS: The mean eGFR values for the infancy-exposed and childhood-exposed groups were 107.23 ± 12.53 and 103.23 ± 12.44 mL/min/1.73 m2, respectively, both of which were lower than that of the unexposed group (114.82 ± 13.39 mL/min/1.73 m2; P < 0.05). In the crude model, the odds ratio (OR) for CKD was 2.00 (95% confidence interval (CI): 1.39-2.88) in the infancy-exposed group and 2.92 (95% CI: 2.17-3.93) in the childhood-exposed group. Further adjustments for urban/rural residence, body mass index, age, current smoking, type 2 diabetes, systolic blood pressure, diastolic blood pressure and total cholesterol did not significantly alter the association between famine exposure and CKD. The corresponding ORs were 1.71 (95% CI: 1.17-2.50) and 2.48 (95% CI: 1.81-3.40) for the infancy-exposed and childhood-exposed groups respectively. CONCLUSIONS: Famine exposure during infancy and childhood is associated with a long-term decline in eGFR and an increased adult-onset CKD risk. Early intervention for high-risk individuals may mitigate the risk of adult-onset CKD.