The TOR pathway comes of age

Studies in a variety of model organisms indicate that nutrient signaling is tightly coupled to longevity. In nutrient replete conditions, organisms develop, grow, and age quickly. When nutrients become sparse as with dietary restriction, growth and development decline, stress response pathways become induced and organisms live longer. Considerable effort has been devoted to understanding the molecular events mediating lifespan extension by dietary restriction. One central focus has been on nutrient-responsive signal transduction pathways including insulin/IGF-1, AMP kinase, protein kinase A and the TOR pathway. Here we describe the increasingly prominent links between TOR signaling and aging in invertebrates. Longevity studies in mammals are not published to date. Instead, we highlight studies in mouse models, which indicate that dampening the TOR pathway leads to widespread protection from an array of age-related diseases.     

Bifidobacteria and their role in human health

Summary There is a growing consensus on the beneficial effects of bifidobacteria in human health. It is now clear that bifidobacteria that exist in the large intestine are helpful for maintenance of human health and are far more important thanLactobacillus acidophilus as beneficial intestinal bacteria throughout human life. In other words, the reduction or disappearance of bifidobacteria in the human intestine would indicate an unhealthy state. Oral administration of bifidobacteria may be effective for the improvement of intestinal flora and intestinal environment, for the therapy of enteric and hepatic disorders, for stimulation of the immune response, and possibly for the prevention of cancer and slowing the aging process. However, for consistent and positive results further well-controlled studies are urgently needed.     

Stat3 is a candidate epigenetic biomarker of perinatal Bisphenol A exposure associated with murine hepatic tumors with implications for human health

Bisphenol A (BPA) is an endocrine disrupting chemical (EDC) that has been implicated as a potential carcinogen and epigenotoxicant. We have previously reported dose-dependent incidence of hepatic tumors in 10-month-old isogenic mice perinatally exposed to BPA. Here, we evaluated DNA methylation at 3 candidate genes (Esr1, Il-6st, and Stat3) in liver tissue of BPA-exposed mice euthanized at 2 time points: post-natal day 22 (PND22; n = 147) or 10-months of age (n = 78, including n = 18 with hepatic tumors). Additionally, DNA methylation profiles were analyzed at human homologs of murine candidate genes in human fetal liver samples (n = 50) with known liver tissue BPA levels. Candidate genes were chosen based on reported expression changes in both rodent and human hepatocellular carcinoma (HCC). Regions for bisulfite sequencing were chosen by mining whole genome next generation sequencing methylation datasets of both mice and human liver samples with known perinatal BPA exposures. One of 3 candidate genes, Stat3, displayed dose-dependent DNA methylation changes in both 10-month mice with liver tumors as compared to those without liver tumors and 3-week sibling mice from the same exposure study, implicating Stat3 as a potential epigenetic biomarker of both early life BPA exposure and adult disease in mice. DNA methylation profiles within STAT3 varied with liver tissue BPA level in human fetal liver samples as well, suggesting STAT3 may be a translationally relevant candidate biomarker. These data implicate Stat3 as a potential early life biomarker of adult murine liver tumor risk following early BPA exposure with early evidence of relevance to human health.     

The role of Sirt1: At the crossroad between promotion of longevity and protection against Alzheimer's disease neuropathology

Sirt1, a mammalian member of the sirtuin gene family, holds great potential for promoting longevity, preventing against disease and increasing cell survival. For example, studies suggest that the beneficial impact of caloric restriction in promoting longevity and cellular function may be mediated, in part, by Sirt1 through mechanisms involving PGC-1α, which plays important role in the regulation of cellular metabolism and inflammatory and antioxidant responses. Sirt1 may also interfere with mechanisms implicated in pathological disorders. We will present recent evidence indicating that Sirt1 may protect against Alzheimer's disease by interfering with the generation of β-amyloid peptides. We will discuss Sirt1 as a potential novel target, in addition to the development of Sirt1 activators for the prevention and treatment of Alzheimer's disease.     

Long-term effects of birth weight and breastfeeding duration on inflammation in early adulthood

Chronic inflammation is a potentially important physiological mechanism linking early life environments and health in adulthood. Elevated concentrations of C-reactive protein (CRP)—a key biomarker of inflammation—predict increased cardiovascular and metabolic disease risk in adulthood, but the developmental factors that shape the regulation of inflammation are not known. We investigated birth weight and breastfeeding duration in infancy as predictors of CRP in young adulthood in a large representative cohort study (n = 6951). Birth weight was significantly associated with CRP in young adulthood, with a negative association for birth weights 2.8 kg and higher. Compared with individuals not breastfed, CRP concentrations were 20.1%, 26.7%, 29.6% and 29.8% lower among individuals breastfed for less than three months, three to six months, 6–12 months and greater than 12 months, respectively. In sibling comparison models, higher birth weight was associated with lower CRP for birth weights above 2.5 kg, and breastfeeding greater than or equal to three months was significantly associated with lower CRP. Efforts to promote breastfeeding and improve birth outcomes may have clinically relevant effects on reducing chronic inflammation and lowering risk for cardiovascular and metabolic diseases in adulthood.     

Identifying the intergenerational effects of the 1959–1961 Chinese Great Leap Forward Famine on infant mortality

Using the 1959–1961 Chinese Great Leap Forward Famine as a natural experiment, this study examines the relationship between mothers’ prenatal exposure to acute malnutrition and their children's infant mortality risk. According to the results, the effect of mothers’ prenatal famine exposure status on children's infant mortality risk depends on the level of famine severity. In regions of low famine severity, mothers’ prenatal famine exposure significantly reduces children's infant mortality, whereas in regions of high famine severity, such prenatal exposure increases children's infant mortality although the effect is not statistically significant. Such a curvilinear relationship between mothers’ prenatal malnutrition status and their children's infant mortality risk is more complicated than the linear relationship predicted by the original fetal origins hypothesis but is consistent with the more recent developmental origins of health and disease theory.     

Sirt基因家族及其对细胞寿命的调节

在酵母、线虫和果蝇中,Sir2基因家族是寿命调节的关键因子。哺乳动物的Sirt基因家族在进化上与Sir2基因高度同源,共有7个成员。Sir2基因调节酵母寿命的机理已比较清楚。而哺乳动物Sirt基因,特别是Sirt1基因与细胞衰老的关系正在成为新的研究热点。最近的研究表明,在热量限制或氧化逆境条件下,SIRT1蛋白主要是通过以下3个途径影响细胞寿命:一是SIRT1蛋白抑制PPAR-γ减少细胞的脂质过氧化的损伤;二是SIRT1蛋白通过调控p53的活性影响细胞寿命;三是SIRT1蛋白通过调控FOXO的信号通路,启动细胞的抗氧化途径。进一步研究Sirt基因家族对揭示哺乳动物寿命之谜具有重要的科学意义。     

A paternal environmental legacy: Evidence for epigenetic inheritance through the male germ line

Literature on maternal exposures and the risk of epigenetic changes or diseases in the offspring is growing. Paternal contributions are often not considered. However, some animal and epidemiologic studies on various contaminants, nutrition, and lifestyle‐related conditions suggest a paternal influence on the offspring's future health. The phenotypic outcomes may have been attributed to DNA damage or mutations, but increasing evidence shows that the inheritance of environmentally induced functional changes of the genome, and related disorders, are (also) driven by epigenetic components. In this essay we suggest the existence of epigenetic windows of susceptibility to environmental insults during sperm development. Changes in DNA methylation, histone modification, and non‐coding RNAs are viable mechanistic candidates for a non‐genetic transfer of paternal environmental information, from maturing germ cell to zygote. Inclusion of paternal factors in future research will ultimately improve the understanding of transgenerational epigenetic plasticity and health‐related effects in future generations.     

Associations between duration of first trimester intrauterine exposure to genocide against the Tutsi and health outcomes in adulthood

Objectives

Hundreds of thousands of Rwandans were conceived during the 1994 genocide against the Tutsi, including thousands conceived by genocidal rape. We explore whether the duration of first trimester exposure to the genocide is associated with variation in adult mental health outcomes in individuals exposed to varying degrees of genocide-related stress in utero.

Materials and Methods

We recruited 30 Rwandans conceived via genocidal rape, 31 Rwandans conceived by genocide survivors not raped, and 30 individuals of Rwandan-descent who were conceived outside of Rwanda at the time of the genocide (control group). Individuals were age- and sex-matched across groups. Adult mental health was assessed through standardized questionnaires for vitality, anxiety, and depression.

Results

Among the genocide only group, a longer duration of first trimester prenatal exposure was associated with higher anxiety scores and lower vitality (both p < 0.010), and higher depression scores (p = 0.051). Duration of first trimester exposure was not associated with any measures of mental health among the genocidal rape or control group.

Discussion

Duration of exposure to genocide in the first trimester of gestation was associated with variation in adult mental health among the genocide only group. The lack of association between duration of first trimester exposure to genocide and adult mental health in the genocidal rape group may reflect the fact that stress associated with conception through rape persisted beyond the genocide period itself, encompassing all of gestation and likely beyond. Geopolitical and community interventions are needed in the context of extreme events during pregnancy to mitigate adverse intergenerational outcomes.     

Detection of differential DNA methylation in repetitive DNA of mice and humans perinatally exposed to bisphenol A

Developmental exposure to bisphenol A (BPA) has been shown to induce changes in DNA methylation in both mouse and human genic regions; however, the response in repetitive elements and transposons has not been explored. Here we present novel methodology to combine genomic DNA enrichment with RepeatMasker analysis on next-generation sequencing data to determine the effect of perinatal BPA exposure on repetitive DNA at the class, family, subfamily, and individual insertion level in both mouse and human samples. Mice were treated during gestation and lactation to BPA in chow at 0, 50, or 50,000 ng/g levels and total BPA was measured in stratified human fetal liver tissue samples as low (non-detect to 0.83 ng/g), medium (3.5 to 5.79 ng/g), or high (35.44 to 96.76 ng/g). Transposon methylation changes were evident in human classes, families, and subfamilies, with the medium group exhibiting hypomethylation compared to both high and low BPA groups. Mouse repeat classes, families, and subfamilies did not respond to BPA with significantly detectable differential DNA methylation. In human samples, 1251 individual transposon loci were detected as differentially methylated by BPA exposure, but only 19 were detected in mice. Of note, this approach recapitulated the discovery of a previously known mouse environmentally labile metastable epiallele, Cabp^IAP. Thus, by querying repetitive DNA in both mouse and humans, we report the first known transposons in humans that respond to perinatal BPA exposure.     

The complex role of adiponectin in chronic kidney disease

Although adiponectin, an adipocytokine released from adipose tissue, is thought to have anti-atherogenic, anti-inflammatory, and insulin-sensitizing effects, it appears that high, rather than low, circulating levels of adiponectin predict increased mortality in chronic kidney disease (CKD) patients in whom the circulating levels may rise to about three times higher than the levels in healthy subjects. As it could be hypothesized that in the uremic milieu high adiponectin levels reflect protein-energy wasting, lower residual renal function and/or volume overload, this may explain, at least in part, the observed paradoxical link between hyperadiponectinemia and poor outcome in CKD. To determine the biological consequences of high circulating adiponectin levels on carbohydrate and insulin metabolism as well as relations with cardiovascular function and mortality in the uremic milieu, further studies need to take into account both high-, and low-molecular weight adiponectin moieties as well as the role of adiponectin receptors. This brief review summarizes some of the recent advances in our understanding of the complex and context-sensitive role of this elusive and intriguing adipokine in the uremic milieu.     

Low birth weight does not predict the ontogeny of relative leg length of infants and children: an allometric analysis of the NHANES III sample

Previous research links both low birth weight (LBW) and relative leg length (RLL) to a similar set of adult pathologies, including type II diabetes, coronary vascular disease, and some cancers. Historically, LBW has been frequently used as a broad indicator of the quality of the intrauterine environment, while RLL has been considered a sensitive measure of childhood environmental quality. While these observations have been taken to suggest that these measures reflect independent exposures at different life-stages, their mutual association with a similar set of later pathologies makes this assumption less certain than it may have previously seemed. Nationally representative data from the Third National Health and Nutrition Examination Survey (NHANES III) are used to test the hypothesis that LBW predicts reductions in the development of leg length relative to stature. After controls for important socioeconomic exposures that might confound measurement of such a relationship, we find statistical and biological evidence that variation in birth weight and variation in the development of leg length relative to stature (RLL) are independent. The results suggest that these two measures may represent independent information on prenatal and postnatal environmental quality.     

Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight

Early life experiences, including those in utero, have been linked to increased risk for adult-onset chronic disease. The underlying assumption is that there is a critical period of developmental plasticity in utero when selection of the fetal phenotype that is best adapted to the intrauterine environment occurs. The current study is the first to test the idea that extreme maternal psychosocial stressors, as observed in the Democratic Republic of Congo, may modify locus-specific epigenetic marks in the newborn resulting in altered health outcomes. Here we show a significant correlation between culturally relevant measures of maternal prenatal stress, newborn birth weight and newborn methylation in the promoter of the glucocorticoid receptor NR3C1. Increased methylation may constrain plasticity in subsequent gene expression and restrict the range of stress adaptation responses possible in affected individuals, thus increasing their risk for adult-onset diseases.     

Plasticity and constraint in response to early‐life stressors among late/final jomon period foragers from Japan: Evidence for life history trade‐offs from incremental microstructures of enamel

This study evaluates two hypotheses that address how Late/Final Jomon period people responded to early‐life stress using linear enamel hypoplasia (LEH) and incremental microstructures of enamel. The first hypothesis predicts that Jomon people who experienced early‐life stressors had greater physiological competence in responding to future stress events (predictive adaptive response). The second hypothesis predicts that Jomon people traded‐off in future growth and maintenance when early investment in growth and survival was required (plasticity/constraint). High resolution tooth impressions were collected from intact, anterior teeth and studied under an engineer's measuring microscope. LEH were identified based on accentuated perikymata and depressions in the enamel surface profile. Age of formation for each LEH was estimated by summing counts of perikymata and constants associated with crown initiation and cuspal enamel formation times. The relationship between age‐at‐first‐defect formation, number of LEH, periodicity between LEH, and mortality was evaluated using multiple regression and hazards analysis. A significant, positive relationship was found between age‐at‐death relative to age‐at‐first‐defect formation and a significant, negative relationship was found between number of LEH relative to age‐at‐first‐defect formation. Individuals with earlier forming defects were at a significantly greater risk of forming defects at later stages of development and dying at younger ages. These results suggest that Late/Final Jomon period foragers responded to early‐life stressors in a manner consistent with the plasticity/constraint hypothesis of human life history. Late/Final Jomon period individuals were able to survive early‐life stressors, but this investment weakened responses to future stress events and exacerbated mortality schedules. Am J Phys Anthropol 155:537–545, 2014. © 2014 Wiley Periodicals, Inc.     

Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight

Early life experiences, including those in utero, have been linked to increased risk for adult-onset chronic disease. The underlying assumption is that there is a critical period of developmental plasticity in utero when selection of the fetal phenotype that is best adapted to the intrauterine environment occurs. The current study is the first to test the idea that extreme maternal psychosocial stressors, as observed in the Democratic Republic of Congo, may modify locus-specific epigenetic marks in the newborn resulting in altered health outcomes. Here we show a significant correlation between culturally relevant measures of maternal prenatal stress, newborn birth weight and newborn methylation in the promoter of the glucocorticoid receptor NR3C1. Increased methylation may constrain plasticity in subsequent gene expression and restrict the range of stress adaptation responses possible in affected individuals, thus increasing their risk for adult-onset diseases.     

Expression of imprinted genes in placenta is associated with infant neurobehavioral development

Genomic imprinting disorders often exhibit delayed neurobehavioral development, suggesting this unique mechanism of epigenetic regulation plays a role in mental and neurological health. While major errors in imprinting have been linked to adverse health outcomes, there has been little research conducted on how moderate variability in imprinted gene expression within a population contributes to differences in neurobehavioral outcomes, particularly at birth. Here, we profiled the expression of 108 known and putative imprinted genes in human placenta samples from 615 infants assessed by the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). Data reduction identified 10 genes (DLX5, DHCR24, VTRNA2-1, PHLDA2, NPAP1, FAM50B, GNAS-AS1, PAX8-AS1, SHANK2, and COPG2IT1) whose expression could distinguish between newborn neurobehavioral profiles derived from the NNNS. Clustering infants based on the expression pattern of these genes identified 2 groups of infants characterized by reduced quality of movement, increased signs of asymmetrical and non-optimal reflexes, and increased odds of demonstrating increased signs of physiologic stress and abstinence. Overall, these results suggest that common variation in placental imprinted gene expression is linked to suboptimal performance on scales of neurological functioning as well as with increased signs of physiologic stress, highlighting the central importance of the control of expression of these genes in the placenta for neurobehavioral development.     

Intrauterine growth retarded piglet as a model for humans – Studies on the perinatal development of the gut structure and function

The overall acceptance of pig models for human biomedical studies is steadily growing. Results of rodent studies are usually confirmed in pigs before extrapolating them to humans. This applies particularly to gastrointestinal and metabolism research due to similarities between pig and human physiology. In this context, intrauterine growth retarded (IUGR) pig neonate can be regarded as a good model for the better understanding of the IUGR syndrome in humans. In pigs, the induction of IUGR syndrome may include maternal diet intervention, dexamethasone treatment or temporary reduction of blood supply. However, in pigs, like in humans, circa 8% of neonates develop IUGR syndrome spontaneously. Studies on the pig model have shown changes in gut structure, namely a reduced thickness of mucosa and muscle layers, and delayed kinetic of disappearance of vacuolated enterocytes were found in IUGR individuals in comparison with healthy ones. Functional changes include reduced dynamic of gut mucosa rebuilding, decreased activities of main brush border enzymes, and changes in the expression of proteins important for carbohydrate, amino acids, lipid, mineral and vitamin metabolism. Moreover, profiles of intestinal hormones are different in IUGR and non-IUGR piglets. It is suggested that supplementation of the mothers during the gestation and/or the IUGR offspring after birth can help in restoring the development of the gastrointestinal tract. The pig provides presumably the optimal animal model for humans to study gastrointestinal tract structure and function development in IUGR syndrome.     

土壤植物营养与农产品品质及人畜健康关系

综述了土壤中Ca,Mg,S,Zn,Fe等中微量营养元素及Se,I等有益元素的丰缺情况,概述了矿质营养元素和有机物质对农产品品质的影响与人畜健康的关系,展望了今后应预以加强的研究方向,为进一步开展土壤植物营养与产品品质的研究提供参考。