Early Lifestyle Factors Research Articles

Dissociable brain structural asymmetry patterns reveal unique phenome-wide profiles.

Broca reported ~150 years ago that particular lesions of the left hemisphere impair speech. Since then, other brain regions have been reported to show lateralized structure and function. Yet, studies of brain asymmetry have limited their focus to pairwise comparisons between homologous regions. Here, we characterized separable whole-brain asymmetry patterns in grey and white matter structure from n = 37,441 UK Biobank participants. By pooling information on left-right shifts underlying whole-brain structure, we deconvolved signatures of brain asymmetry that are spatially distributed rather than locally constrained. Classically asymmetric regions turned out to belong to more than one asymmetry pattern. Instead of a single dominant signature, we discovered complementary asymmetry patterns that contributed similarly to whole-brain asymmetry at the population level. These asymmetry patterns were associated with unique collections of phenotypes, ranging from early lifestyle factors to demographic status to mental health indicators.

Social and leisure activity are associated with attenuated cortical loss in behavioral variant frontotemporal degeneration

Behavioral variant frontotemporal degeneration (bvFTD) is clinically characterized by progressive decline in social and executive domains. Previous work suggests that early lifestyle factors such as education and occupational attainment may relate to structural integrity and moderate the rate of cognitive decline in bvFTD, but the role of other cognitively stimulating activities is understudied. We sought to investigate the effect of such activities on cortical thickness (CT) in bvFTD. bvFTD patients (n = 31) completed a baseline MRI scan, and informants for the patients completed the Lifetime of Experiences Questionnaire (LEQ), which measures specific activities considered to be undertaken primarily within one particular life phase, such as education (young-life), occupation (mid-life), and social/leisure activity (late-life). At baseline, linear models assessed the effect of LEQ scores from each life phase on regional CT. A subset (n = 19) of patients completed longitudinal MRI, and to evaluate the association of LEQ with longitudinal rates of CT decline, we derived individualized slopes of decline using linear mixed effects models and these were related to LEQ scores from each life phase. At baseline, a higher late-life LEQ score was associated with less atrophy in left superior and inferior anterior temporal regions as well as right middle temporal gyrus. Longitudinally, we observed that higher late-life LEQ scores were associated with an attenuated rate of CT loss in insular cortex. Late-life LEQ score was positively associated with both relatively preserved CT early in bvFTD and a slower rate of cortical loss in regions important for social functioning. These findings suggest that social and leisure activities may contribute to a form of resilience against pathologic effects of disease.

Abstract C029: Consumption of dietary AGEs during puberty and increased breast cancer risk: A link between lifestyle and cancer disparity

Abstract Introduction. The focus of this study is on early lifestyle factors and their effect on mammary development during puberty and how they relate to increased breast cancer risk and disparities. At this time we do not understand what biological changes occur during pubertal mammary development which leads to a greater risk of developing cancer in later life. Identifying the molecular mechanisms that cause aberrant pubertal mammary development may lead to defined strategies to reduce breast cancer burden in later life. As our bodies use the sugars that we consume for energy they generate waste chemicals known as advanced glycation end products or AGEs for short. Significantly, low income, obesity and a sedentary lifestyle are established factors driving health disparity that also contribute to increased AGE accumulation levels in our bodies. In particular, AGE content in the Western Diet has consistently increased over the last 50 years due to increased consumption of sugar-laden and cheap processed/manufactured foods which are high in reactive AGE metabolites and can promote obesity. Methods. We use a dietary mouse model to assess impact of AGE on normal mammary development. Wild type FVB/n and RAGE null (RAGE-/-) mice are fed the respective diets from weaning until 7 (pubertal) or 12 (adult) weeks of age. Mammary glands are extracted for whole mounting and paraffin embedded for histology. Fibroblasts were isolated from mammary glands and cultured ex vivo. Transwell migration assays were performed with isolated fibroblasts and HC11 mouse mammary epithelial cells. qPCR was performed on the isolated fibroblasts to assess their activation status. Results. Early life exposures during mammary development influence the breast microenvironment to increase breast cancer risk. We show that due to an innate ability to influence the cellular matrix, dietary AGEs disrupt developmental programs during puberty and promote breast tumor growth. Through receptor for AGE (RAGE) dependent and independent mechanisms, chronic AGE consumption delayed ductal extension, increased ductal branching and caused aberrant terminal end bud (TEB) morphology. Dietary AGE activation of RAGE mediated a program of activated stroma leading to hyperplastic growth and the formation of pre-neoplastic lesions which persisted into adulthood. Importantly, AGE mediated effects remained even after diet intervention after puberty. In dietary-AGE breast tumor models, AGE mediated changes in tissue architecture and cell function were recapitulated and resulted in 3-fold increase in neoplastic growth. Through the perpetual activation of a reactive stroma, AGEs derived from diet represent a common early life exposure which can influence tumor behavior. Conclusions. A greater mechanistic understanding of the link between AGE intake during puberty and increased breast cancer risk may define novel potential strategies for lifestyle and pharmacological intervention aimed at reducing breast cancer risk and cancer disparities. Citation Format: Callan C Frye, Bradley A Krisanits, Reid Schuster, Jaime Randise, Lourdes M Nogueira, Kristi Helke, Amanda C LaRue, David P Turner, Victoria J Findlay. Consumption of dietary AGEs during puberty and increased breast cancer risk: A link between lifestyle and cancer disparity [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C029.

M73 - CAPICE: CHILDHOOD AND ADOLESCENCE PSYCHOPATHOLOGY: UNRAVELLING THE COMPLEX ETIOLOGY BY A LARGE INTERDISCIPLINARY COLLABORATION IN EUROPE

Background The CAPICE project aims to 1) identify genetic variants associated with the occurrence and course of common childhood psychopathology including depression, anxiety and Attention Deficit Hyperactivity Disorder related traits, and establish the genetic overlap within childhood psychiatric disorders and with adult psychiatric disorders, 2) unravel the mechanisms underlying the associations between early lifestyle factors and childhood psychiatric disorders, 3) identify new drug targets, and 4) build a risk prediction model that identifies groups of children that are at highest risk to have persistent symptoms. This poster provides an overview of the plan to achieve these goals. Methods CAPICE is an international training network, funded by an EU Marie Curie grant, in which 12 PhD students will be trained in psychiatric genomics. This network will elaborate on the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium. EAGLE is a well-established collaboration of many birth and adolescent population based (twin and family) cohorts, with unique longitudinal information on lifestyle, family environment, health, and emotional and behavioral problems. Phenotypic and genome-wide data are available for over 60,000 children, in addition to genome-wide data for over 20,000 mothers and epigenome-wide data for over 6,000 children. Analyses will include (but will not be limited to) twin analyses, genome-wide association meta-analyses, polygenic analyses, Mendelian randomization, and biological pathway analyses. Results We expect that the results will provide insight into the etiology of mental health symptoms in children and adolescents and shed light on possible targets for prevention and intervention (e.g. by drug target validation or by tailoring treatment based on the risk for persisting symptoms). Discussion It is well known that psychiatric symptoms in childhood be the precursor of many psychiatric disorders during adulthood. Longitudinal population based cohorts provide a good opportunity to show how genetic factors influence development over the ages. Since these disorders are the extreme end of the continuum, collaborations with case-control samples may strengthen the results.

Lifestyle Factors Affecting the Gut Microbiota's Relationship with Type 1 Diabetes.

The incidence of type 1 diabetes (T1D) is rising drastically for the past decades at a rate that cannot be explained by genetic changes alone. Environmental changes are considered to be the main drivers of this change. Recently, the gut microbiota has been suggested as a missing link between known environmental disease modulators and T1D promotion. Lifestyle factors have changed over time and have altered the gut microbiota-host interaction affecting T1D development. The purpose of this review is to discuss recent data emphasizing the modulatory potential of early lifestyle factors on gut microbiota and to elucidate their implication for T1D. Recent findings show that lifestyle factors, especially those that affect the early establishment of gut homeostasis and the education of the immune system, are crucial disease modulators. Changing lifestyle factors affecting the early establishment of gut homeostasis are suggested to be key drivers of the rising T1D incidence.

The Role of the Microbiome in the Developmental Origins of Health and Disease.

Although the prominent role of the microbiome in human health has been established, the early-life microbiome is now being recognized as a major influence on long-term human health and development. Variations in the composition and functional potential of the early-life microbiome are the result of lifestyle factors, such as mode of birth, breastfeeding, diet, and antibiotic usage. In addition, variations in the composition of the early-life microbiome have been associated with specific disease outcomes, such as asthma, obesity, and neurodevelopmental disorders. This points toward this bacterial consortium as a mediator between early lifestyle factors and health and disease. In addition, variations in the microbial intrauterine environment may predispose neonates to specific health outcomes later in life. A role of the microbiome in the Developmental Origins of Health and Disease is supported in this collective research. Highlighting the early-life critical window of susceptibility associated with microbiome development, we discuss infant microbial colonization, beginning with the maternal-to-fetal exchange of microbes in utero and up through the influence of breastfeeding in the first year of life. In addition, we review the available disease-specific evidence pointing toward the microbiome as a mechanistic mediator in the Developmental Origins of Health and Disease.

The impact of early lifestyle factors on wheezing and asthma in Austrian preschool children

This study investigated the influence of early lifestyle factors on the prevalence of asthma and wheezing in preschool children in Tyrol, Austria. A cross-sectional questionnaire survey was performed in 1761 preschool children to obtain information on wheezing and asthma in the light of early lifestyle factors. Factors independently associated with an increased risk for wheezing in the past 12 months included high parental education (OR: 1.5, 95% CI: 1.1-2.1) and parental hay fever (OR: 1.5, 95%CI: 1.1-2.2). Risk factors for doctor-diagnosed asthma (DDA) were early pet contact (OR: 2.2, 95% CI: 1.1-4.8) and parental asthma (OR: 3.0, 95%CI: 1.0-9.1), whereas breastfeeding decreased the risk (OR: 0.5, 95% CI: 0.2-1.0). Boiling the pacifier/sucker daily increased the risk for wheezing in the past 12 months (OR: 1.4, 95%CI: 1.0-2.0) and revealed a tendency towards DDA (OR: 1.9, 95% CI: 0.9-4.0). In preschool children, we established an independent association between wheezing in the past 12 months, DDA and boiling frequency of the pacifier/bottle sucker during infancy. The impact of pacifier boiling frequency on atopic diseases on the basis of the hygiene hypothesis needs further investigation.