Human Epidemiological Studies Research Articles

Air pollution-derived particulate matter dysregulates hepatic Krebs cycle, glucose and lipid metabolism in mice

Exposure to ambient air particulate matter (PM2.5) is well established as a risk factor for cardiovascular and pulmonary disease. Both epidemiologic and controlled exposure studies in humans and animals have demonstrated an association between air pollution exposure and metabolic disorders such as diabetes. Given the central role of the liver in peripheral glucose homeostasis, we exposed mice to filtered air or PM2.5 for 16 weeks and examined its effect on hepatic metabolic pathways using stable isotope resolved metabolomics (SIRM) following a bolus of 13C6-glucose. Livers were analyzed for the incorporation of 13C into different metabolic pools by IC-FTMS or GC-MS. The relative abundance of 13C-glycolytic intermediates was reduced, suggesting attenuated glycolysis, a feature found in diabetes. Decreased 13C-Krebs cycle intermediates suggested that PM2.5 exposure led to a reduction in the Krebs cycle capacity. In contrast to decreased glycolysis, we observed an increase in the oxidative branch of the pentose phosphate pathway and 13C incorporations suggestive of enhanced capacity for the de novo synthesis of fatty acids. To our knowledge, this is one of the first studies to examine 13C6-glucose utilization in the liver following PM2.5 exposure, prior to the onset of insulin resistance (IR).

Application of the comet assay for the evaluation of DNA damage from frozen human whole blood samples: Implications for human biomonitoring

This study proposes the application of the comet assay for the evaluation of DNA damage from frozen human whole blood samples that could be readily used in human biomonitoring and epidemiological studies. It was done on simply frozen whole blood samples collected from male volunteers (N = 60) aliquoted in small volumes and stored at −80 °C without the addition of cryopreservatives for a period of 5 years. To test the applicability of the alkaline comet assay for the evaluation of DNA damage in frozen whole blood, samples were quickly thawed at 37 °C and immediately embedded in an agarose matrix followed by an alkaline comet assay procedure. We concluded that the whole blood freezing and prolonged storage do not severely affect comet assay values, although background values were higher compared to our historical control data from the fresh whole blood. Even the influence of the variables tested, such as age, body mass index, smoking habit and alcohol consumption were in agreement with our previous data using fresh blood. The obtained results suggest that the comet assay could be applied to frozen blood samples, if properly stored, even for decades, which would certainly facilitate large-scale human biomonitoring and long-term epidemiological studies.

Maternal obesity accelerates rat offspring metabolic ageing in a sex-dependent manner.

Maternal obesity predisposes to metabolic dysfunction in male and female offspring Maternal high-fat diet consumption prior to and throughout pregnancy and lactation accelerates offspring metabolic ageing in a sex-dependent manner This study provides evidence for programming-ageing interactions ABSTRACT: Human epidemiological studies show that maternal obesity (MO) shortens offspring life and health span. Life course cellular mechanisms involved in this developmental programming-ageing interaction are poorly understood. In a well-established rat MO model, female Wistar rats ate chow (controls (C)) or high energy, obesogenic diet to induce MO from weaning through pregnancy and lactation. Females were bred at postnatal day (PND) 120. Offspring (F1 ) of mothers on control diet (CF1 ) and MO diet (MOF1 ) delivered spontaneously at terms. Both CF1 and MOF1 ate C diet from weaning throughout the study. Offspring were killed at PND 36, 110, 450 and 650. We determined body and liver weights, liver and serum metabolite concentrations, hormones and oxidative stress biomarkers. Male and female CF1 body weight, total fat, adiposity index, serum leptin, insulin, insulin resistance, and liver weight, fat, triglycerides, malondialdehyde, reactive oxygen species and nitrotyrosine all rose with differing ageing trajectories. Female CF1 triglycerides were unchanged with age. Age-related increases were greater in MOF1 than CF1 in both sexes for all variables except glucose in males and females and cholesterol in males. Cholesterol fell in CF1 females but not MOF1 . Serum corticosterone levels were higher in male and female MOF1 than CF1 and declined with age. DHEA serum levels were lower in male and female MOF1 than CF1 . Liver antioxidant enzymes decreased with age (CF1 and MOF1 ). exposure to the developmental challenge of MO accelerates progeny ageing metabolic and endocrine profiles in a sex specific manner, providing evidence for programming-ageing interactions.

Methylmercury Epigenetics.

Methylmercury (MeHg) has conventionally been investigated for effects on nervous system development. As such, epigenetic modifications have become an attractive mechanistic target, and research on MeHg and epigenetics has rapidly expanded in the past decade. Although, these inquiries are a recent advance in the field, much has been learned in regards to MeHg-induced epigenetic modifications, particularly in the brain. In vitro and in vivo controlled exposure studies illustrate that MeHg effects microRNA (miRNA) expression, histone modifications, and DNA methylation both globally and at individual genes. Moreover, some effects are transgenerationally inherited, as organisms not directly exposed to MeHg exhibited biological and behavioral alterations. miRNA expression generally appears to be downregulated consequent to exposure. Further, global histone acetylation also seems to be reduced, persist at distinct gene promoters, and is contemporaneous with enhanced histone methylation. Moreover, global DNA methylation appears to decrease in brain-derived tissues, but not in the liver; however, selected individual genes in the brain are hypermethylated. Human epidemiological studies have also identified hypo- or hypermethylated individual genes, which correlated with MeHg exposure in distinct populations. Intriguingly, several observed epigenetic modifications can be correlated with known mechanisms of MeHg toxicity. Despite this knowledge, however, the functional consequences of these modifications are not entirely evident. Additional research will be necessary to fully comprehend MeHg-induced epigenetic modifications and the impact on the toxic response.

Heterologous Immunity: Role in Natural and Vaccine-Induced Resistance to Infections.

The central paradigm of vaccination is to generate resistance to infection by a specific pathogen when the vacinee is re-exposed to that pathogen. This paradigm is based on two fundamental characteristics of the adaptive immune system, specificity and memory. These characteristics come from the clonal specificity of T and B cells and the long-term survival of previously-encountered memory cells which can rapidly and specifically expand upon re-exposure to the same specific antigen. However, there is an increasing awareness of the concept, as well as experimental documentation of, heterologous immunity and cross-reactivity of adaptive immune lymphocytes in protection from infection. This awareness is supported by a number of human epidemiological studies in vaccine recipients and/or individuals naturally-resistant to certain infections, as well as studies in mouse models of infections, and indeed theoretical considerations regarding the disproportional repertoire of available T and B cell clonotypes compared to antigenic epitopes found on pathogens. Heterologous immunity can broaden the protective outcomes of vaccinations, and natural resistance to infections. Besides exogenous microbes/pathogens and/or vaccines, endogenous microbiota can also impact the outcomes of an infection and/or vaccination through heterologous immunity. Moreover, utilization of viral and/or bacterial vaccine vectors, capable of inducing heterologous immunity may also influence the natural course of many infections/diseases. This review article will briefly discuss these implications and redress the central dogma of specificity in the immune system.

Phthalate-Induced Fetal Leydig Cell Dysfunction Mediates Male Reproductive Tract Anomalies.

Male fetal Leydig cells in the testis secrete androgen and insulin-like 3, determining the sexual differentiation. The abnormal development of fetal Leydig cells could lead to the reduction of androgen and insulin-like 3, thus causing the male reproductive tract anomalies in male neonates, including cryptorchidism and hypospadias. Environmental pollutants, such as phthalic acid esters (phthalates), can perturb the development and differentiated function of Leydig cells, thereby contributing to the reproductive toxicity in the male. Here, we review the epidemiological studies in humans and experimental investigations in rodents of various phthalates. Most of phthalates disturb the expression of various genes encoded for steroidogenesis-related proteins and insulin-like 3 in fetal Leydig cells and the dose-additive effects are exerted after exposure in a mixture.

Evaluation of FGF10 as a candidate gene for high myopia in a Han Chinese population

BackgroundFibroblast growth factor 10 (FGF10) is implicated in the growth and development of the eye. Four singles nucleotide polymorphisms (SNPs) in the FGF10 gene (including rs1384449, rs339501, rs12517396 and rs10462070) were found to be associated with extreme myopia (EM, refractive error ≤ − 10.0 diopters) in Japanese and Chinese Taiwan population. This case-control association study was conducted to explore the relationship between these four SNPs and high myopia in a western Chinese population.MethodsA total of 869 high myopia patients (HM, including 485 EM patients) and 899 healthy controls were recruited. These four SNPs were genotyped using the ABI SNaPshot method. Five genetic models (allelic, homozygous, heterozygous, dominant, and recessive) were applied to further evaluate the possible correlation between the SNPs and high myopia. The linkage-disequilibrium block (LD) structure was tested by Haploview Software.ResultsIn our study, no statistically significant differences were found between HM/EM patients and controls after Bonferroni multiple-correction (P > 0.05) in the allele frequencies of these four SNPs in the FGF10 gene. We further found that rs12517396AA and rs10462070GG carriers showed a decreased risk of HM/EM compared with rs12517396AC + CC and rs10462070GA + AA carriers (P = 0.045, OR = 0.366; P = 0.021, OR = 0.131; P = 0.03, OR = 0.341; P = 0.015, OR = 0.122; respectively). Additionally, rs12517396AA and rs10462070GG carriers showed the same decreased risk of HM/EM compared with rs12517396CC and rs10462070AA carriers (P = 0.048, OR = 0.370; P = 0.023, OR = 0.133; P = 0.032, OR = 0.346; P = 0.017, OR = 0.126). However, these significant associations between rs12517396/rs10462070 and HM/EM disappeared after Bonferroni multiple-correction (P > 0.05).ConclusionOur findings indicate that rs12517396 and rs10462070 had marginal association with HM and EM. The other two common polymorphisms in FGF10 unlikely have significant effects in the genetic predisposition to HM/EM in western Chinese population. Further replication studies are needed to validate our findings in both animal models and human genetic epidemiologic studies.

Cardiopulmonary Health Effects of Airborne Particulate Matter: Correlating Animal Toxicology to Human Epidemiology.

The effects of particulate matter (PM) on cardiopulmonary health have been studied extensively over the past three decades. Particulate matter is the primary criteria air pollutant most commonly associated with adverse health effects on the cardiovascular and respiratory systems. The mechanisms by which PM exerts its effects are thought to be due to a variety of factors which may include, but are not limited to, concentration, duration of exposure, and age of exposed persons. Adverse effects of PM are strongly driven by their physicochemical properties, sites of deposition, and interactions with cells of the respiratory and cardiovascular systems. The direct translocation of particles, as well as neural and local inflammatory events, are primary drivers for the observed cardiopulmonary health effects. In this review, toxicological studies in animals, and clinical and epidemiological studies in humans are examined to demonstrate the importance of using all three approaches to better define potential mechanisms driving health outcomes upon exposure to airborne PM of diverse physicochemical compositions.

Maternal valproic acid exposure leads to neurogenesis defects and autism-like behaviors in non-human primates

Despite the substantial progress made in identifying genetic defects in autism spectrum disorder (ASD), the etiology for majority of ASD individuals remains elusive. Maternal exposure to valproic acid (VPA), a commonly prescribed antiepileptic drug during pregnancy in human, has long been considered a risk factor to contribute to ASD susceptibility in offspring from epidemiological studies in humans. The similar exposures in murine models have provided tentative evidence to support the finding from human epidemiology. However, the apparent difference between rodent and human poses a significant challenge to extrapolate the findings from rodent models to humans. Here we report for the first time the neurodevelopmental and behavioral outcomes of maternal VPA exposure in non-human primates. Monkey offspring from the early maternal VPA exposure have significantly reduced NeuN-positive mature neurons in prefrontal cortex (PFC) and cerebellum and the Ki67-positive proliferating neuronal precursors in the cerebellar external granular layer, but increased GFAP-positive astrocytes in PFC. Transcriptome analyses revealed that maternal VPA exposure disrupted the expression of genes associated with neurodevelopment in embryonic brain in offspring. VPA-exposed juvenile offspring have variable presentations of impaired social interaction, pronounced stereotypies, and more attention on nonsocial stimuli by eye tracking analysis. Our findings in non-human primates provide the best evidence so far to support causal link between maternal VPA exposure and neurodevelopmental defects and ASD susceptibility in humans.

Developmental impact of air pollution on brain function

Air pollution is an important contributor to the global burden of disease, particularly to respiratory and cardiovascular diseases. In recent years, evidence is accumulating that air pollution may adversely affect the nervous system as shown by human epidemiological studies and by animal models. Age appears to play a relevant role in air pollution-induced neurotoxicity, with growing evidence suggesting that air pollution may contribute to neurodevelopmental and neurodegenerative diseases. Traffic-related air pollution (e.g. diesel exhaust) is an important contributor to urban air pollution, and fine and ultrafine particulate matter (PM) may possibly be its more relevant component. Air pollution is associated with increased oxidative stress and inflammation both in the periphery and in the nervous system, and fine and ultrafine PM can directly access the central nervous system. This short review focuses on the adverse effects of air pollution on the developing brain; it discusses some characteristics that make the developing brain more susceptible to toxic effects, and summarizes the animal and human evidence suggesting that exposure to elevated air pollution is associated with a number of behavioral and biochemical adverse effects. It also discusses more in detail the emerging evidence of an association between perinatal exposure to air pollution and increased risk of autism spectrum disorder. Some of the common mechanisms that may underlie the neurotoxicity and developmental neurotoxicity of air pollution are also discussed. Considering the evidence presented in this review, any policy and legislative effort aimed at reducing air pollution would be protective of children's well-being.

Prenatal maternal and childhood bisphenol a exposure and brain structure and behavior of young children

BackgroundBisphenol A (BPA) is commonly used in the manufacture of plastics and epoxy resins. In North America, over 90% of the population has detectable levels of urinary BPA. Human epidemiological studies have reported adverse behavioral outcomes with BPA exposure in children, however, corresponding effects on children’s brain structure have not yet been investigated. The current study examined the association between prenatal maternal and childhood BPA exposure and white matter microstructure in children aged 2 to 5 years, and investigated whether brain structure mediated the association between BPA exposure and child behavior.MethodsParticipants were 98 mother-child pairs who were recruited between January 2009 and December 2012. Total BPA concentrations in spot urine samples obtained from mothers in the second trimester of pregnancy and from children at 3–4 years of age were analyzed. Children participated in a diffusion magnetic resonance imaging (MRI) scan at age 2–5 years (3.7 ± 0.8 years). Associations between prenatal maternal and childhood BPA and children’s fractional anisotropy and mean diffusivity of 10 isolated white matter tracts were investigated, controlling for urinary creatinine, child sex, and age at the time of MRI. Post-hoc analyses examined if alterations in white matter mediated the relationship of BPA and children’s scores on the Child Behavior Checklist (CBCL).ResultsPrenatal maternal urinary BPA was significantly associated with child mean diffusivity in the splenium and right inferior longitudinal fasciculus. Splenium diffusivity mediated the relationship between maternal prenatal BPA levels and children’s internalizing behavior (indirect effect: β = 0.213, CI [0.0167, 0.564]). No significant associations were found between childhood BPA and white matter microstructure.ConclusionsThis study provides preliminary evidence for the neural correlates of BPA exposure in humans. Our findings suggest that prenatal maternal exposure to BPA may lead to alterations in white matter microstructure in preschool aged children, and that such alterations mediate the relationship between early life exposure to BPA and internalizing problems.

Approaches to Integrating the Toxicology and Epidemiology Evidence on PFAS

S05: PFAS Research Reaches its Adolescence: What Have We Learned and Where Are We Going?, Beatrix Theater, August 26, 2019, 10:30 AM - 12:00 PM Per- and polyfluoroalkyl substances (PFASs) have gained wide attention the last two decades. At present 4,600 CAS Registry Numbers are associated with PFASs that may have been on the global market (OECD 2018), while only some very few of these have been studied extensively. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), belonging respectively to the sub groups of perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkyl sulfonic acids (PFSAs), are the best studied PFASs. Under the European REACH regulation, some PFCAs and PFSAs have been identified as substances of very high concern (SVHC), demonstrating a need for undertaking risk assessments. The risk assessment process include several steps, including hazard assessment and identification of the critical effect. The importance of integrating data from both experimental animal studies and human epidemiological studies have been highlighted, as both types of data have specific advantages and disadvantages. However, for many PFASs the amount of data is very limited, making this impossible. In the case of PFOS and PFOA data from both animal studies and human epidemiological studies are available for several endpoints. In this presentation, there will be a discussion on how these complementary types of data can be used in hazard assessments and how to utilize this knowledge for other PFASs where the data, in particular epidemiological data, are more limited or do not exist. However, for some endpoints such as changes in blood lipids, contradictory results have been observed between studies on experimental animals and humans. This, along with differences in exposure and toxicokinetics, needs to be considered when combining data from experimental animal studies and epidemiological studies. Reference OECD. 2018. Toward a New Comprehensive Global Database of Per- and Polyfluoroalkyl Substances (PFASs): Summary Report on Updating the OECD 2007 List of Per- and Polyfluoroalkyl Substances (PFASs). OECD Series on Risk Management No. 39.

Radiofrequency radiation from nearby mobile phone base stations-a case comparison of one low and one high exposure apartment.

Radiofrequency (RF) radiation in the frequency range of 30–300 GHz has, since 2011, been classified as a ‘possible’ human carcinogen by Group 2B, International Agency for Research on Cancer (IARC) at WHO. This was based on a number of human epidemiology studies on increased risk for glioma and acoustic neuroma. Based on further human epidemiology studies and animal studies, the evidence on RF radiation carcinogenesis has increased since 2011. In previous measurement studies, it has been indicated that high environmental RF radiation levels are present in certain areas of Stockholm Sweden, including in one apartment. Field spatial distribution measurements were performed in the previously measured apartment in Stockholm, which exhibited high RF radiation from nearby base stations. Based on the RF broadband analyzer spot measurements, the maximum indoor E-field topped at 3 V m−1 in the bedroom at the 7th floor. The maximum outdoor exposure level of 6 V m−1 was encountered at the 8th floor balcony, located at the same elevation and only 6.16 m away from the base station antennas. For comparison, a measurement was made in a low exposure apartment in Stockholm. Here, the maximum indoor field 0.52 V m−1 was measured at the corner window, with direct line of sight to the neighboring house with mobile phone base station antennas. The maximum outdoor field of 0.75 V m−1 was measured at the balcony facing the same next-door building with mobile phone base station antennas. The minimum field of 0.10 V m−1 was registered on the apartment area closest to the center of the building, demonstrating the shielding effects of the indoor walls. Good mobile phone reception was achieved in both apartments. Therefore, installation of base stations to risky places cannot be justified using the good reception requirement argument.

Early-life factors contributing to type 1 diabetes.

The incidence of type 1 diabetes has increased since the mid-twentieth century at a rate that is too rapid to be attributed to genetic predisposition alone. While the disease can occur at any age, mounting evidence from longitudinal cohort studies of at-risk children indicate that type 1 diabetes associated autoantibodies can be present from the first year of life, and that those who develop type 1 diabetes at a young age have a more aggressive form of the disease. This corroborates the hypothesis that environmental exposures in early life contribute to type 1 diabetes risk, whether related to maternal influences on the fetus during pregnancy, neonatal factors or later effects during infancy and early childhood. Studies to date show a range of environmental triggers acting at different time points, suggesting a multifactorial model of genetic and environmental factors in the pathogenesis of type 1 diabetes, which integrally involves a dialogue between the immune system and pancreatic beta cells. For example, breastfeeding may have a weak protective effect on type 1 diabetes risk, while use of an extensively hydrolysed formula does not. Additionally, exposure to being overweight pre-conception, both in utero and postnatally, is associated with increased risk of type 1 diabetes. Epidemiological, clinical and pathological studies in humans support a role for viral infections, particularly enteroviruses, in type 1 diabetes, but definitive proof is lacking. The role of the early microbiome and its perturbations in islet autoimmunity and type 1 diabetes is the subject of investigation in ongoing cohort studies. Understanding the interactions between environmental exposures and the human genome and metagenome, particularly across ethnically diverse populations, will be critical for the development of future strategies for primary prevention of type 1 diabetes.

Creatine for the Treatment of Depression.

Depressed mood, which can occur in the context of major depressive disorder, bipolar disorder, and other conditions, represents a serious threat to public health and wellness. Conventional treatments are not effective for a significant proportion of patients and interventions that are often beneficial for treatment-refractory depression are not widely available. There is, therefore, an immense need to identify novel antidepressant strategies, particularly strategies that target physiological pathways that are distinct from those addressed by conventional treatments. There is growing evidence from human neuroimaging, genetics, epidemiology, and animal studies that disruptions in brain energy production, storage, and utilization are implicated in the development and maintenance of depression. Creatine, a widely available nutritional supplement, has the potential to improve these disruptions in some patients, and early clinical trials indicate that it may have efficacy as an antidepressant agent.

Association between urine lead levels and cardiovascular disease risk factors, carotid intima-media thickness and metabolic syndrome in adolescents and young adults

Environmental lead exposure is a known risk factor of cardiovascular disease (CVD) in animal and human epidemiological studies of adults, but limited research has been conducted in young populations. Moreover, the association between lead level and common carotid artery intima-media thickness (CIMT) has never been documented. and Participants: In this study, 738 subjects were recruited from a cohort of Taiwanese adolescents and young adults to study the relationship between lead levels in urine and CVD risk factors, metabolic syndrome (MS) and CIMT. The geometric mean of the urine lead level was 1.50 μg/g creatinine. We found a significant positive association between urine lead levels and CVD risk factors, including diastolic blood pressure (DBP), mean arterial pressure (MAP), as well as markers of glucose homeostasis, such as serum glucose, serum insulin, homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of β-cell function (HOMA-β), body mass index (BMI) z score, and CIMT. Overall, increased urine lead concentrations were positively correlated with the prevalence of MS, specifically the criteria of waist/BMI and serum HDL-C. The relationship between urine lead levels and CIMT remained unchanged in all subgroups. In this study, we found that increased urinary levels of lead were positively associated with CVD risk factors, CIMT, and MS in this cohort. Future research to explore the pathogenic basis of exposure to lead and risk of CVDs and their risk factors are warranted.

Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms.

For a long time, viruses have been shown to modify the clinical picture of several autoimmune diseases, including type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), herpetic stromal keratitis (HSK), celiac disease (CD), and multiple sclerosis (MS). Best examples of viral infections that have been proposed to modulate the induction and development of autoimmune diseases are the infections with enteric viruses such as Coxsackie B virus (CVB) and rotavirus, as well as influenza A viruses (IAV), and herpesviruses. Other viruses that have been studied in this context include, measles, mumps, and rubella. Epidemiological studies in humans and experimental studies in animal have shown that viral infections can induce or protect from autoimmunopathologies depending on several factors including genetic background, host-elicited immune responses, type of virus strain, viral load, and the onset time of infection. Still, data delineating the clear mechanistic interaction between the virus and the immune system to induce autoreactivity are scarce. Available data indicate that viral-induced autoimmunity can be activated through multiple mechanisms including molecular mimicry, epitope spreading, bystander activation, and immortalization of infected B cells. Contrarily, the protective effects can be achieved via regulatory immune responses which lead to the suppression of autoimmune phenomena. Therefore, a better understanding of the immune-related molecular processes in virus-induced autoimmunity is warranted. Here we provide an overview of the current understanding of viral-induced autoimmunity and the mechanisms that are associated with this phenomenon.

Artificial Intelligence Based Approaches to Identify Molecular Determinants of Exceptional Health and Life Span-An Interdisciplinary Workshop at the National Institute on Aging.

Artificial intelligence (AI) has emerged as a powerful approach for integrated analysis of the rapidly growing volume of multi-omics data, including many research and clinical tasks such as prediction of disease risk and identification of potential therapeutic targets. However, the potential for AI to facilitate the identification of factors contributing to human exceptional health and life span and their translation into novel interventions for enhancing health and life span has not yet been realized. As researchers on aging acquire large scale data both in human cohorts and model organisms, emerging opportunities exist for the application of AI approaches to untangle the complex physiologic process(es) that modulate health and life span. It is expected that efficient and novel data mining tools that could unravel molecular mechanisms and causal pathways associated with exceptional health and life span could accelerate the discovery of novel therapeutics for healthy aging. Keeping this in mind, the National Institute on Aging (NIA) convened an interdisciplinary workshop titled “Contributions of Artificial Intelligence to Research on Determinants and Modulation of Health Span and Life Span” in August 2018. The workshop involved experts in the fields of aging, comparative biology, cardiology, cancer, and computational science/AI who brainstormed ideas on how AI can be leveraged for the analyses of large-scale data sets from human epidemiological studies and animal/model organisms to close the current knowledge gaps in processes that drive exceptional life and health span. This report summarizes the discussions and recommendations from the workshop on future application of AI approaches to advance our understanding of human health and life span.

Assessing children's exposure to manganese in drinking water using a PBPK model

A previously published human PBPK model for manganese (Mn) in infants and children has been updated with Mn in drinking water as an additional exposure source. Built upon the ability to capture differences in Mn source-specific regulation of intestinal uptake in nursing infants who are breast-fed and formula-fed, the updated model now describes the bioavailability of Mn from drinking water in children of ages 0–18. The age-related features, including the recommended age-specific Mn dietary intake, age-specific water consumption rates, and age-specific homeostasis of Mn, are based on the available human data and knowledge of the biology of essential-metal homeostasis. Model simulations suggest that the impact of adding drinking-water exposure to daily Mn exposure via dietary intake and ambient air inhalation in children is not greater than the impacts in adults, even at a drinking-water concentration that is 2 times higher than the USEPA's lifetime health advisory value. This conclusion was also valid for formula-fed infants who are considered at the highest potential exposure to Mn from drinking water compared to all other age groups. Our multi-route, multi-source Mn PBPK model for infants and children provides insights about the potential for Mn-related health effects on growing children and will thereby improve the level of confidence in properly interpreting Mn exposure-health effects relationships in children in human epidemiological studies.

Lack of an effective drug therapy for abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) rupture is a common cause of death in adults. Current AAA treatment is by open surgical or endovascular aneurysm repair. Rodent model and human epidemiology, and genetic and observational studies over the last few decades have highlighted the potential of a number of drug therapies, including medications that lower blood pressure, correct dyslipidaemia, or inhibit thrombosis, inflammation or matrix remodelling, as approaches to managing small AAA. This review summarizes prior AAA pathogenesis data from animal and human studies aimed at identifying targets for the development of drug therapies. The review also systematically assesses past randomized placebo-controlled drug trials in patients with small AAAs. Eleven previously published randomized-controlled clinical trials testing different drug therapies aimed at slowing AAA progression were identified. Five of the trials tested antibiotics and three trials assessed medications that lower blood pressure. Meta-analyses of these trials suggested that neither of these approaches limit AAA growth. Allocation to blood pressure-lowering medication was associated with a small reduction in AAA rupture or repair, compared to placebo (relative risk 0.94, 95% confidence intervals 0.89, 1.00, P=0.047). Three further trials assessed the effect of a mast cell inhibitor, fibrate or platelet aggregationinhibition and reported no effect on AAA growth or clinical events. Past trials were noted to have a number of design issues, particularly small sample sizes and limited follow-up. Much larger trials are needed to properly test potential therapeutic approaches if a convincingly effective medical therapy for AAA is to be identified.