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.

Early Famine Exposure Results in Left Ventricular Remodeled, Diastolic Dysfunction and Systolic Function Preserved in Adults.

INTRODUCTION: Malnutrition during a critical window of development in a fetus or infant can result in abnormal cardiac remodeling and function. It is uncertain whether the contribution of these effects continues to impact the cardiac remodeling and function of adults over the course of several decades of growth. Our study examined the impact of early Chinese famine exposure on cardiac remodeling, left ventricular (LV) diastolic function, and LV systolic function in adults. METHODS: Participants at high risk of cardiovascular disease from the China Patient-Centered Evaluative Assessment of Cardiac Events Million Persons Project (PEACE MPP) were enrolled. The famine in China lasted from 1959 to 1962. A total of three groups were formed based on the participants' birth dates: pre-famine group, famine exposure group, and post-famine group. Logistic regression and linear mixed models were used to explore the association between famine exposure and cardiac remodeling, LV diastolic function and LV systolic function in adults. RESULTS: The study included 2,758 participants, the mean age was 57.05 years, 62.8% were female, 26.4% had LV hypertrophy (LVH), 59.6% had LV diastolic dysfunction (LVDD), and 10.5% had reduced global longitudinal strain (GLS). Compared to post-famine exposure, participants had independently increased risk of LVH in the famine exposure group (OR: 2.02, 95% CI: 1.60-2.56) and pre-famine exposure (OR: 1.36, 95% CI: 1.06-1.76). Compared to post-famine exposure, the risk of LVDD remarkably increased in the famine exposure group (OR: 3.04, 95% CI: 2.49-3.71) and pre-famine exposure group (OR: 1.87, 95% CI: 1.52-2.31). Famine exposure had no significant impact on GLS but was associated with a significant increase in LV ejection fraction (LVEF) and LV end-diastolic diameter (LVEDD). Significant interactions were observed between the effects of famine exposure and other clinical/sociodemographic variables (gender, systolic blood pressure [SBP] ≥140 mm Hg or not, high school or above or not, and annual income <50,000 RMB or not) on these outcomes. CONCLUSION: Exposure to famine, particularly during fetal and infant stages, increases the risk of LVH and LVDD in adults. However, the LV systolic function remains preserved. These impacts are more pronounced in females, individuals with SBP ≥140 mm Hg, those with low income, or those with high educational status.

Insights from social-ecological systems thinking for understanding and preventing famine.

The risk of famine is rising in many countries today. Bold changes to famine information and response systems are urgently needed to improve capacities to prevent famine. To this end, the paper identifies six insights from social-ecological systems (SES) thinking for understanding and preventing famine. It argues that a state of famine emerges from human-environment interdependencies, complex causality, and non-linear system dynamics, shaped by history and context. The likelihood of famine can be reduced by strengthening resilience to the diverse stresses and shocks that drive destitution, food insecurity, undernutrition, morbidity, and mortality. SES thinking offers new opportunities to understand the dynamics of famine, diagnose lesser-known drivers, pinpoint new metrics, ascertain leverage points for intervention, and develop conceptual frameworks to inform policy. SES concepts and methods could also support the development of practical analytical tools to guide decisionmakers on how, where, and when to intervene most effectively and efficiently to strengthen resilience to the drivers of famine.

Early-life exposure to the Great Chinese Famine and gut microbiome disruption across adulthood for type 2 diabetes: three population-based cohort studies.

BACKGROUND: The early life stage is critical for the gut microbiota establishment and development. We aimed to investigate the lifelong impact of famine exposure during early life on the adult gut microbial ecosystem and examine the association of famine-induced disturbance in gut microbiota with type 2 diabetes. METHODS: We profiled the gut microbial composition among 11,513 adults (18-97 years) from three independent cohorts and examined the association of famine exposure during early life with alterations of adult gut microbial diversity and composition. We performed co-abundance network analyses to identify keystone taxa in the three cohorts and constructed an index with the shared keystone taxa across the three cohorts. Among each cohort, we used linear regression to examine the association of famine exposure during early life with the keystone taxa index and assessed the correlation between the keystone taxa index and type 2 diabetes using logistic regression adjusted for potential confounders. We combined the effect estimates from the three cohorts using random-effects meta-analysis. RESULTS: Compared with the no-exposed control group (born during 1962-1964), participants who were exposed to the famine during the first 1000 days of life (born in 1959) had consistently lower gut microbial alpha diversity and alterations in the gut microbial community during adulthood across the three cohorts. Compared with the no-exposed control group, participants who were exposed to famine during the first 1000 days of life were associated with consistently lower levels of keystone taxa index in the three cohorts (pooled beta - 0.29, 95% CI - 0.43, - 0.15). Per 1-standard deviation increment in the keystone taxa index was associated with a 13% lower risk of type 2 diabetes (pooled odds ratio 0.87, 95% CI 0.80, 0.93), with consistent results across three individual cohorts. CONCLUSIONS: These findings reveal a potential role of the gut microbiota in the developmental origins of health and disease (DOHaD) hypothesis, deepening our understanding about the etiology of type 2 diabetes.

The Mediating Role of Systemic Inflammation in the Effects of Fetal Famine Exposure on Cardiovascular Disease in Adults: A Cohort Study.

BACKGROUND: A few studies have reported the association between famine exposure during fetal development and risk of CVD, but no mechanisms have been explored. OBJECTIVES: The objective of this study was to examine risk of CVD in adulthood after exposure to famine during the fetal stage and explore the mediating role of systemic inflammation. METHODS: A total of 59,416 participants of the Kailuan Study without CVD were included. All participants were divided into 3 groups based on date of birth, including the unexposed group (1963-1974), the fetal-exposed group (1959-1962), and the childhood-exposed group (1949-1958). Systemic immune-inflammation index (SII) (neutrophils × platelets / lymphocytes) and systemic inflammatory response index (SIRI) (neutrophils × monocytes / lymphocytes) are 2 novel systemic inflammation indexes that represent the level of systemic inflammation. Time-weighted Cox regression was used to test the effect of famine exposure on risk of CVD, and a mediation model was used to calculate the role of systemic inflammation. RESULTS: During a median follow-up period of 12.36 (12.69, 13.16) y, a total of 3772 cases of CVD were documented. Compared with unexposed participants, the fetal-exposed group had an increased risk of CVD (HR: 1.19; 95% CI: 1.04, 1.38) and stroke (HR: 1.28; 95% CI: 1.09, 1.51) but not MI. No association was observed in the childhood-exposed group. In mediation analysis, SII mediated an estimated 24.43% of the association between fetal exposure and CVD (24.61% for stroke and 23.27% for MI). For SIRI, this percentage was 30.20% for CVD (29.94% for stroke and 31.25% of MI). CONCLUSIONS: Fetal exposure to famine may increase risk of CVD in adulthood. Systemic inflammation may play an intermediary role in the effect of fetal famine exposure on CVD.

Prenatal exposure to famine and the development of diabetes later in life: an age-period-cohort analysis of the China health and nutrition survey (CHNS) from 1997 to 2015.

PURPOSE: Prenatal exposure to famine has been linked to increased diabetes risk in adulthood. However, one fundamental issue to be addressed is that the reported famine-diabetes relation may be confounded by the age differences between the exposed and non-exposed groups. We aimed to determine the association between prenatal exposure to the Chinese famine of 1959-1962 and risk of diabetes by applying age well-controlled strategies. METHODS: Among 20,535 individuals born in 1955-1966 who participated in the China Health and Nutrition Survey from 1997 to 2015, we constructed age-matched exposed vs. non-exposed groups to investigate the role of prenatal exposure to the Chinese famine of 1959-1962 in relation to diabetes. We also built a hierarchical age-period-cohort (HAPC) model to specifically examine the relation of famine to diabetes risk independent of age. RESULTS: Compared to the age-balanced men in the non-exposed group, the exposed men born in 1961 had a 154% increased risk of diabetes [odds ratio (OR) 2.54 (95% CI 1.07-6.03), P = 0.04). In the HAPC analysis, the predicted probabilities of diabetes peaked in the 1961-birth cohort of men [3.4% (95% CI 2.4%-5.0%)], as compared to the average probability of diabetes (reference) of 1.8% for men overall. Neither analytical strategy revealed any strong relation between famine exposure and diabetes risk in women. CONCLUSION: Among the pre-defined Chinese famine period of 1959-1962, early-life exposure to famine was associated with increased diabetes risk in men but not in women, and these relations were independent of age.

Exposure in utero to adverse events and health late-in-life: Evidence from China.

This paper estimates the effect of in utero exposure to adverse events on late life diabetes, cardiovascular disease risks and cognition deficiency. We merge data on the regional violence during the Cultural Revolution and the excessive death rates during the Chinese Great Famine with data from the China Health and Retirement Longitudinal Study survey. Results show that female babies who were exposed in utero to the famine have higher diabetes risks, while male babies who were exposed to the Cultural Revolution are shown to have lower cognitive abilities.

Barker's Hypothesis Among the Global Poor: Positive Long-Term Cardiovascular Effects of in Utero Famine Exposure.

An influential literature on the Developmental Origins of Health and Disease (DOHaD) has documented that poor conditions in utero lead to higher risk of cardiovascular disease at older ages. Evidence from low-income countries (LICs) has hitherto been missing, despite the fact that adverse in utero conditions are far more common in LICs. We find that Malawians exposed in utero to the 1949 Nyasaland famine have better cardiovascular health 70 years later. These findings highlight the potential context specificity of the DOHaD hypothesis, with in utero adversity having different health implications among aging LIC individuals who were exposed to persistent poverty.

Separate and combined effects of famine exposure and menarche age on metabolic syndrome among the elderly: a cross-sectional study in China.

BACKGROUND: Epidemiological studies have revealed multiple risk factors for metabolic syndrome. However, there are no consistent findings on the association between famine exposure, age at menarche, and the prevalence of metabolic syndrome. This cross-sectional study aimed to reveal the individual and combined effects of famine exposure and age at menarche on the prevalence of metabolic syndrome among elderly women. METHODS: Four thousand seven hundred seventy participants between 60 and 93 years of age were selected from the China Health and Retirement Longitudinal Study. Statistical differences between the baseline characteristics of famine exposure, age at menarche, and metabolic syndrome were evaluated using the t-test, F-test, and Chi-square test. Three multivariable-adjusted logistic regression models were used to test the association between famine exposure, age of menarche, and the odds ratio of metabolic syndrome. RESULTS: Two thousand one hundred ninety-eight (46.08%) participants had metabolic syndrome, while 2572 (53.92%) participants did not. Furthermore, 3068 (64.32%) women reported onset of menarche under 15 years of age, while 1702 (35.68%) women reported onset of menarche above 16 years of age. Regarding the separate association of famine exposure and age of menarche with metabolic syndrome, in model three, the adolescence/adulthood famine exposure group vs. no famine exposure group odds ratio was 2.45 (95% CI 2.02, 2.97), and the older than 16 years vs. younger than 15 years group odds ratio was 1.23 (95% CI 1.09, 1.39), which was the highest odds ratio among the three models. Regarding the combined association of famine exposure and age of menarche with metabolic syndrome, in model three, among the age of menarche ≤ 15 years group, the adolescence/adulthood famine exposure vs. no famine exposure group odds ratio was 2.45 (95% CI: 1.91, 3.14); among the menarche age ≥ 16 years group, the adolescence/adulthood famine exposure stages vs. exposed group odds ratio was 3.27 (95% CI: 2.44, 4.38), which was the highest odds ratio among the three models. CONCLUSION: These findings suggested that famine exposure and age at menarche, either separately or in combination, were positively associated with the prevalence of metabolic syndrome among older women.

Secular trend of non-communicable chronic disease prevalence throughout the life span who endured Chinese Great Famine (1959-1961).

BACKGROUND: Famine is a risk factor for non-communicable chronic diseases (NCDs), which account for over 80% of deaths in China. The effect of famine on the prevalence of NCDs in terms of various age groups, time periods and cohorts is currently poorly understood. OBJECTIVE: This study aims to explore long-term trends in the impact of China's Great Famine (1959-1961) on NCDs in China. METHODS: This study used data from the 2010-2020 China Family Panel Longitudinal Survey across 25 provinces in China. The subjects were aged 18-85 years, and the total number of subjects was 174,894. The prevalence of NCDs was derived from the China Family Panel Studies database (CFPS). An age-period-cohort (APC) model was used to estimate the age, period and cohort effects of NCDs in 2010-2020 and the effect of famine on the risk of NCDs in terms of cohort effects. RESULTS: The prevalence of NCDs increased with age. Additionally, the prevalence did not clearly decrease over the survey period. Regarding the cohort effect, people born in the years adjacent to the famine period had a higher risk of NCDs; additionally, females, those born in rural areas, and those who lived in provinces with severe famine and post-famine had a higher likelihood of NCDs. CONCLUSIONS: Experiencing famine at an early age or the experience of famine in a close relative's generation (births after the onset of famine) are associated with an increased risk of NCDs. Additionally, more severe famine is associated with a higher risk of NCDs.