The secret language of destiny: stress imprinting and transgenerational origins of disease

Epigenetic regulation modulates gene expression without altering the DNA sequence to facilitate rapid adjustments to dynamically changing environmental conditions. The formation of an epigenetic memory allows passing on this information to subsequent generations. Here we propose that epigenetic memories formed by adverse environmental conditions and stress represent a critical determinant of health and disease in the F3 generation and beyond. Transgenerational programming of epigenetic regulation may represent a key to understand adult-onset complex disease pathogenesis and cumulative effects of life span and familial disease etiology. Ultimately, the mechanisms of generating an epigenetic memory may become of potentially promising diagnostic and therapeutic relevance due to their reversible nature. Exploring the role of environmental factors, such as stress, in causing variations in epigenetic profiles may lead to new avenues of personalized, preventive medicine based on epigenetic signatures and interventions

Topographical disorientation after ischemic mini infarct in the dorsal hippocampus: whispers in silence

Open access journalSilent focal ischemic mini infarcts in the brain are thought to cause no clinically overt symptoms. Some populations of hippocampal cells are particularly sensitive to ischemic events, however, rendering hippocampal functions especially vulnerable to ischemiainduced deficits. The present study investigated whether an otherwise silent ischemic mini infarct in the hippocampus (HPC) can produce impairments in spatial performance in rats. Spatial performance was assessed in the ziggurat task (ZT) using a 10-trial spatial learning protocol for 4 days prior to undergoing hippocampal ischemic lesion or sham surgery. Hippocampal silent ischemia was induced by infusion of endothelin-1 (ET-1), a potent vasoconstrictor, into either the dorsal or the ventral hippocampus (dHPC and vHPC). When tested postoperatively in the ZT using a standard testing protocol for 8 days, rats with hippocampal lesions exhibited no spatial deficit. Although spatial learning and memory in the ZT were not affected by the ET-1-induced silent ischemia, rats with dHPC stroke showed more returns when navigating the ZT as opposed to the vHPC rats. Comparison of region-specific HPC lesions in the present study indicated that dorsal hippocampal function is critically required for topographic orientation in a complex environment. Topographic disorientation as reflected by enhanced return behaviors may represent one of the earliest predictors of cognitive decline after silent ischemic insult that may be potentially traced with sensitive clinical examination in humans.Ye

Ageing, Social Distancing, and COVID-19 Risk: Who is more Vulnerable?

Perceived social support represents an important predictor of healthy ageing. The global COVID-19 pandemic has dramatically changed the face of social relationships and exposed elderly as a particularly vulnerable population. Social distancing may represent a double-edged sword for older adults, protecting them against COVID-19 infection while also sacrificing personal interaction and attention at a critical time. Here, we consider the moderating role of social relationships as a potential influence on stress resilience, allostatic load, and vulnerability to infection and adverse health outcomes in the elderly population. Understanding the mechanisms how social support enhances resilience to stress and promotes mental and physical health into old age will enable new preventive strategies. Targeted social interventions may provide effective relief from the impact of COVID-19-related isolation and loneliness. In this regard, a pandemic may also offer a window of opportunity for raising awareness and mobilizing resources for new strategies that help build resilience for our ageing population and future generations

Synergistic Effects of Ancestral Stress and Aging on Anxiety-like Behaviours

Exposure to adverse environments such as prenatal stress early in life is associated with anxiety-like behaviours in adulthood, which is potentially further exacerbated by aging. Recent studies have indicated that ancestral prenatal stress can propagate across generations to alter emotional wellbeing of unexposed offspring. Here we investigated if exposure to prenatal stress in the great-grandmother (transgenerational stress), or exposure across four consecutive generations (multigenerational stress) can alter anxiety-like behaviours in male and female fourth (F4) generation offspring. Anxiety-like behaviours were evaluated by means of the elevated plus maze in both males and females across three different groups: transgenerational stress (SNNN), multigenerational stress (SSSS), and non-stressed controls (NNNN). Both sexes were evaluated at the age of 12 months (middle age) and 18 months (old age). Our results demonstrate that aging and ancestral stress synergistically heightened anxiety-like behaviour, especially in males. Interestingly, the highest levels of anxiety-like behaviours were observed in transgenerationally stressed offspring of both ages. Overall, these results indicate that males are more sensitive to ancestral stress and more likely to respond by developing anxiety-like behaviours. Thus, ancestral stress and aging may synergistically alter mental health outcomes particularly in males. *Indicates presente

Metabolomic Profiling of Biomarkers Indicative of Ancestral and Lifetime Adversity in a Two-Hit Stress Model

Introduction: Chronic prenatal maternal stress (PNMS) can have adverse effects on the developing fetus and lifetime health. The effects depend on the number of stressors individuals are exposed to. Over-activation of the mother’s stress response also potentially triggers epigenetic marks that can be transmitted to several generations of offspring. To date, very little research has focused on how exposure to ancestral PNMS affects an individual’s response to both chronic and acute stress throughout their lifetime. The purpose of this study was to investigate if exposure to ancestral PNMS puts an individual at an evolutionary advantage or disadvantage with respect to their altered stress response. This study utilized a rat model of ancestral PNMS to explore the response of the metabolome to both acute and chronic stress. Methods: Forty-eight male rats from the third filial generation were derived from three different lineages: (1) a transgenerational PNMS lineage where only the F0 mother was exposed to stress; (2) a multigenerational PNMS lineage where the mother from each generation was exposed to stress; and (3) a control lineage where there was no experimental stress exposure. Each of these groups were split in two; an acute stress group and a chronic stress group. Plasma was collected from each animal, processed to extract the water-soluble metabolites, added to NMR buffer, and pipetted into NMR tubes. NMR spectra were acquired and the data underwent a data reduction step (binning), normalization, scaling, and both univariate and multivariate statistical testing. These tests identified spectral peaks from metabolites that had been significantly altered across comparison groups. Chemometric software was utilized to determine the identity of altered metabolites and pathway topology analysis was performed. Results: Multivariate and univariate statistical tests indicated that exposure to chronic stress in ancestrally stressed rats creates significant alteration in the metabolomic profile when compared to control animals. No differences were observed in the case of acute stress. Conclusions: Our results support the hypothesis that ancestral and lifetime stress cumulatively affect the metabolome. A subset of metabolites can potentially act as biomarkers of stress during pregnancy. This procedure may aid in the development of new predictive and diagnostic strategies in precision medicine approaches. *Indicates presente

Metabolomic Analysis of Prenatal Maternal Stress Effects on Offspring as a Result of the 2011 Queensland Flood

INTRODUCTION: It is widely acknowledged that the health outcomes of offspring are directly linked to the health of their mother during pregnancy. The impacts of pre-natal maternal stress (PNMS) can cascade as development of the offspring continues, and are linked to negative health outcomes. OBJECTIVE: Our goal was to determine the metabolomic differences in offspring who were exposed in utero to the 2011 Queensland Flood in relation to the mother’s level of subjective distress and objective hardship. METHODS: Ninety urine samples were obtained from 51 male and 39 female 4-year-old offspring. Metabolomic profiles were acquired using a 700 MHz Bruker Avance III HD NMR spectrometer and subsequently binned. Partial Least Squares-Discriminant Analysis (PLS-DA) was used to identify differences in high vs. low composite subjective distress and high vs. low objective hardship in metabolic profiles, in both male and female groups. Metabolites leading to significant group separation were identified using both Variable Importance Analysis based on random Variable Combination (VIAVC) and a Mann-Whitney U test. Metabolanalyst software was used for metabolite sets enrichment analysis of altered metabolites, and to identify potential biochemical pathways and disease pathologies in the offspring. RESULTS: Group separation was observed between high and low levels of both objective hardship and composite subjective distress groups, in both males and females. Several metabolites were detected as being either up- or down-regulated, thus contributing to the observed separation, including creatinine and formate. CONCLUSIONS: The metabolites identified as significantly altered have been associated with several negative health outcomes. Creatinine down- regulation has been associated with dysfunction in Krebs cycle thus potentially disturbing energy metabolism and contributing to psychiatric illness. Formate up-regulation has been linked to oxidative stress and correlated to metabolic dysfunction in genes relating to neurodegenerative diseases. Understanding the biological pathways affected by exposure to PNMS allows for an improved approach to patient treatment. *Indicates presente