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Aging-Related Molecular Pathways in Chronic Cholestatic Conditions.

ABSTRACT: Aging is commonly defined as the time-dependent functional decline of organs and tissues. Average life expectancy has increased considerably over the past century and is estimated to increase even further, consequently also the interest in understanding the aging processes. Although aging is not a disease, it is the major risk factor for the development of many chronic diseases. Pathologies, such as Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC) are cholestatic liver diseases characterized by chronic inflammation, biliary damage and ultimately liver fibrosis, targeting specifically cholangiocytes. To date, the influence of aging in these biliary diseases is not fully understood. Currently, liver transplantation is the only solution because of lacking in efficiently therapies. Although liver cells have a high regenerative capacity, they undergo extensive molecular changes in response to aging. Following time-dependent damage induced by aging, the cells initially activate protective compensatory processes that, if hyperstimulated, can lead to the decline of regenerative ability and the development of pathologies. Recent studies have introduced novel therapeutic tools for cholangiopathies that have showed to have promising potential as novel therapies for PSC and PBC and for the development of new drugs. The recent advancements in understanding of molecular aging have undoubtedly the potential to unveil new pathways for selective drug treatments, but further studies are needed to deepen their knowledge.

SUBMITTER: Pinto C

PROVIDER: S-EPMC6985088 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Aging-Related Molecular Pathways in Chronic Cholestatic Conditions.

Pinto Claudio C Ninfole Elisabetta E Benedetti Antonio A Maroni Luca L Marzioni Marco M

Frontiers in medicine 20200121

Aging is commonly defined as the time-dependent functional decline of organs and tissues. Average life expectancy has increased considerably over the past century and is estimated to increase even further, consequently also the interest in understanding the aging processes. Although aging is not a disease, it is the major risk factor for the development of many chronic diseases. Pathologies, such as Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC) are cholestatic liver ...[more]

PMID: 32039217

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Project description:IntroductionCognitive complaints in older adults may be indicative of progressive cognitive decline including Alzheimer's disease (AD), but also occur in other age-related chronic conditions, complicating identification of early AD symptoms. To better understand cognitive complaints in aging, we systematically reviewed the evidence to determine their prevalence and characterization among older adults with the most common age-related chronic conditions.MethodsThis systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the review protocol was prospectively registered with PROSPERO (ID: CRD42020153147). Searches were conducted in PubMed, CINAHL, PsycINFO, Web of Science, and ProQuest Dissertations & Theses A&I in June 2020. Two members of the review team independently determined article eligibility for inclusion and conducted quality appraisal. A narrative synthesis of results was used to integrate findings across studies and draw conclusions regarding the strength of the evidence in each chronic condition category.ResultsThirty-seven articles met eligibility criteria and were included in the review. Conditions represented were diabetes (n = 20), heart disease (n = 13), hypertension (n = 10), chronic lung disease (n = 5), arthritis (n = 4), heart failure (n = 2), and hyperlipidemia (n = 2). In addition, 16 studies included a measure of multimorbidity. Overall, there was a higher prevalence of cognitive complaints in individuals with higher multimorbidity, including a potential dose-dependent relationship. Findings for specific conditions were inconsistent, but there is evidence to suggest that cross-sectionally, older adults with diabetes, heart disease, chronic lung disease, and arthritis have more cognitive complaints than those without these conditions.ConclusionThere is strong evidence demonstrating that cognitive complaints are more common in older adults with higher multimorbidity, but little research examining these associations over time. Improving our understanding of the longitudinal trajectory of cognitive complaints, multimorbidity, and objective cognition in older age is an important area for future research.

Project description:Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. We, therefore, investigated the molecular signaling pathways mediating the effects of cortisol on proliferation, neuronal differentiation, and astrogliogenesis, in an immortalized human hippocampal progenitor cell line. In addition, we examined the molecular signaling pathways activated in the hippocampus of prenatally stressed rats, characterized by persistently elevated glucocorticoid levels in adulthood. In human hippocampal progenitor cells, we found that low concentrations of cortisol (100 nM) increased proliferation (+16%), decreased neurogenesis into microtubule-associated protein 2 (MAP2)-positive neurons (-24%) and doublecortin (Dcx)-positive neuroblasts (-21%), and increased differentiation into S100?-positive astrocytes (+23%). These effects were dependent on the mineralocorticoid receptor (MR) as they were abolished by the MR antagonist, spironolactone, and mimicked by the MR-agonist, aldosterone. In contrast, high concentrations of cortisol (100 ?M) decreased proliferation (-17%) and neuronal differentiation into MAP2-positive neurons (-22%) and into Dcx-positive neuroblasts (-27%), without regulating astrogliogenesis. These effects were dependent on the glucocorticoid receptor (GR), blocked by the GR antagonist RU486, and mimicked by the GR-agonist, dexamethasone. Gene expression microarray and pathway analysis showed that the low concentration of cortisol enhances Notch/Hes-signaling, the high concentration inhibits TGF?-SMAD2/3-signaling, and both concentrations inhibit Hedgehog signaling. Mechanistically, we show that reduced Hedgehog signaling indeed critically contributes to the cortisol-induced reduction in neuronal differentiation. Accordingly, TGF?-SMAD2/3 and Hedgehog signaling were also inhibited in the hippocampus of adult prenatally stressed rats with high glucocorticoid levels. In conclusion, our data demonstrate novel molecular signaling pathways that are regulated by glucocorticoids in vitro, in human hippocampal progenitor cells, and by stress in vivo, in the rat hippocampus.

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Aging-Related Molecular Pathways in Chronic Cholestatic Conditions.

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Aging-Related Molecular Pathways in Chronic Cholestatic Conditions.

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