ArticleLiterature Review

Depression gets old fast: Do stress and depression accelerate cell aging?

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Abstract

Depression has been likened to a state of “accelerated aging,” and depressed individuals have a higher incidence of various diseases of aging, such as cardiovascular and cerebrovascular diseases, metabolic syndrome, and dementia. Chronic exposure to certain interlinked biochemical pathways that mediate stress-related depression may contribute to “accelerated aging,” cell damage, and certain comorbid medical illnesses. Biochemical mediators explored in this theoretical review include the hypothalamic–pituitary–adrenal axis (e.g., hyper- or hypoactivation of glucocorticoid receptors), neurosteroids, such as dehydroepiandrosterone and allopregnanolone, brain-derived neurotrophic factor, excitotoxicity, oxidative and inflammatory stress, and disturbances of the telomere/telomerase maintenance system. A better appreciation of the role of these mediators in depressive illness could lead to refined models of depression, to a re-conceptualization of depression as a whole body disease rather than just a “mental illness,” and to the rational development of new classes of medications to treat depression and its related medical comorbidities. Depression and Anxiety, 2010. © 2010 Wiley-Liss, Inc.

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... There is a link between shorter TLs and age-related physiological disturbances, including arthritis, hypertension, diabetes mellitus, and cardiovascular illness, as well as between shorter TLs and early mortality [16][17][18]. In addition to physical stress, mental stress including that found in post-traumatic stress disorder (PTSD), anxiety disorders, depression, and schizophrenia [19][20][21][22][23][24][25] may also lead to TL shortening. This is because TL shortening has been suggested to serve as a marker of cumulative exposure to stress, which may be considered a risk factor of depressive and anxiety disorders [19]. ...
... In addition, patients with AN may experience considerable mental stress and elevated rates of comorbid psychiatric disorders such as depressive disorders, anxiety disorders, and PTSD [40][41][42][43][44][45]; this can add to the increased risk of TL shortening in these patients [19][20][21][22]25]. ...
... An important finding of this study relates to the significantly greater TL shortening in patients with AN-B/P vs. AN-R, thus confirming Hypothesis 2. Prior research suggests that the mental stress characterizing PTSD, anxiety disorders, and depressionall appearing more frequently in the AN-B/P type [40][41][42][43][44][45]-can potentially lead to TL shortening [19][20][21][22]25]. Nonetheless, our study cannot confirm these suggestions as we have not compared the two AN subtypes on any psychometric scale and have not assessed psychiatric comorbidity. ...
Article
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Physiological and psychological distress may accelerate cellular aging, manifested by shortening of telomere length (TL). The present study focused on TL shortening in anorexia nervosa (AN), an illness combining physiological and psychological distress. For that purpose, we measured TL in 44 female adolescents with AN at admission to inpatient treatment, in a subset of 18 patients also at discharge, and in 22 controls. No differences in TL were found between patients with AN and controls. At admission, patients with AN-binge/purge type (AN-B/P; n = 18) showed shorter TL compared with patients with AN-restricting type (AN-R; n = 26). No change in TL was found from admission to discharge, despite an improvement in body mass index standard deviation score (BMI-SDS) following inpatient treatment. Older age was the only parameter assessed to be correlated with greater TL shortening. Several methodological changes have to be undertaken to better understand the putative association of shorter TL with B/P behaviors, including increasing the sample size and the assessment of the relevant pathological eating disorder (ED) and non-ED psychological correlates in the two AN subtypes.
... Individuals with LLD usually experience cognitive impairment, more significant functional disability, more medical comorbidity burden, and have a higher risk for frailty compared with young adults with MDD (Diniz, 2018;Sibille, 2013;Verhoeven et al., 2014;. The increase in aging-related somatic conditions has been hypothesized to be a consequence of accelerated biological aging in the depressed population Wolkowitz et al., 2010). ...
... Our results extend recent evidence suggesting that LLD is associated with more intense age-related biological changes (Brown et al., 2018;Diniz et al., 2017). Telomere shortening has been associated with adverse health outcomes across the lifespan, including more significant medical comorbidity and higher mortality risk (Aubert, 2014;Vakonaki et al., 2018;Vance et al., 2018;Wang et al., 2018;Wolkowitz et al., 2010). Our results showed a significant association between TL, depressive symptoms severity, and medical burden consistent with the previous findings (Darrow et al., 2016;Ghimire et al., 2019;Lindqvist et al., 2015;Price et al., 2013), and corroborates the hypothesis that telomere shortening can be a potential mechanism linking LLD an increased risk for mortality in this population (Diniz et al., 2014;. ...
... Increased psychological and chronic stress can culminate in cellular aging by DNA damage (Lindqvist et al., 2015;Wolkowitz et al., 2010). Substantial evidence supports the association of depressive disorder with abnormalities in stress-related biological systems, such as the hypothalamic-pituitary-adrenal (HPA) axis (Tomiyama et al., 2012) and inflammatory responses (Glaser & Kiecolt-Glaser, 2005). ...
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Objectives Telomeres are structures at the extremity of chromosomes that prevents genomic instability, and its shortening seems to be a hallmark of cellular aging. Past studies have shown contradictory results of telomere length (TL) in major depression, and are a few studies in late-life depression (LLD). This explores the association between TL as a molecular marker of aging and diagnosis of LLD, the severity of depressive symptoms, and cognitive performance in older adults. Methods/design We included 78 older adults (45 with LLD and 33 nondepressed controls, according to DSM-V criteria), aged 60–90 years. TL was measured in leukocytes by a quantitative polymerase chain reaction, determining the relative ratio (T/S) between the telomere region copy number (T) and a single copy gene (S), using a relative standard curve. Results TL was significantly shorter in the LLD compared with control participants (p = .039). Comparing groups through the severity of depressive symptoms, we found a negative correlation with the severity of depressive symptoms (Hamilton Depression Rating Scale-21, r = −0.325, p = .004) and medical burden (r = −0.271, p = .038). There was no significant correlation between TL and cognitive performance (Mattis Dementia Rating Scale, r = 0.152, p = .21). Conclusions We found that older adults with LLD have shorter telomere than healthy controls, especially those with a more severe depressive episode. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age-associated adverse outcomes linked to depression.
... (Dhikav and Anand, 2007;Bast, 2011;Anand and Dhikav, 2012;Li et al., 2012) Chronic exposure to oxidative stress, inflammatory cytokines, or glucocorticoids can both speed up the process of shortening telomere and contribute to hippocampal atrophy. (Wolkowitz et al., 2010;Shammas, 2011b;Jacobs et al., 2014) Reactive oxygen species (ROS) are the mechanical driving cause for oxidative stress, and they are produced during ATP synthesis in mitochondria as well as from exogenous sources like UV radiation and pollution. ROS cause oxidative damage to a variety of biomolecules, especially telomeres -a high concentration of guanine make them especially sensitive to oxidative damage. ...
... (Cherbuin et al., 2019) It may suggest common pathways for telomere maintenance and hippocampal integrity. (Wolkowitz et al., 2010;Jacobs et al., 2014) However, it is unknown if inflammatory markers are simple biomarkers for shortened telomeres or a common underlying mechanism. ...
Article
Background and aim: This study looked at the genetic aspects that influence telomere length and their link to healthy brain and cerebrovascular ageing. Methods: Using sample data from UK Biobank, we looked into the association between 29 SNPs regulating telomere length and neuroimaging biomarkers of ageing and cerebrovascular disease (hippocampus, white matter hyperintensities [WMH]). The analysis was corrected for technical variables as well as clinical, demographic and lifestyle factors to correct for nuisance variables, including ApoE status due to the well-known association with cardiovascular disease and hippocampal atrophy. We used descriptive statistics and correlation analysis for the baseline assessment. Furthermore, we used variance inflation factor to select variables lacking significant co-linearity and performed linear regression for three dependent imaging-derived phenotypes (log WMHs, right hippocampus, left hippocampus). We used Bonferroni correction on the final models for interpretation. Results: The final regression models included technical confounders, genetic data and clinical, and demographic and lifestyle factors. They explained 34.6% of the variation in right hippocampal volume, 40.6% of the left total hippocampal volume, and 36.1% of the variation in log WMHs volume. As an interim step to correct for known associations, we identified the following factors contributing to WMHs load: smoking status, physical activity, diabetes diagnosed by a doctor, number of medications including medications for hypertension, HbA1c, waist to hip, pulse rate, and blood pressure (systolic and diastolic). We have also identified the following contributory factors for hippocampal volume on both sides: smoking status, maternal longevity, waist to hip ratio. Additionally, we identified paternal age and systolic blood pressure for the left hippocampus, and arterial stiffness, diastolic blood pressure and a number of non-cancerous diseases for the right hippocampus. The overall analysis uncovered that ApoE is the only genetic contributor for all three biomarkers (WMHs, right and left hippocampus), on its own, explaining 0.01% of variability for each. Two SNPs localised on chromosome 10 (rs11191848 and rs9419958) were associated with shorter telomere length and increased WMHs, on its own explaining 0.01% of the variability and 0.03% when combined. Discussion and limitations: We refuted the hypothesis on the link between SNPs regulating telomere length and hippocampal volume, which is consistent with the negative meta-analysis by Nielsen et al. looking at the association of direct leucocyte telomere length and hippocampal volume. We identified two SNPs influencing WMHs, out of which rs11191848 was previously reported to be associated with cardiovascular disorders. Limitations of this study were lack of direct telomere length, lack of longitudinal data, and analysis restricted to the Caucasian population between 40 and 85 years. Conclusions: ApoE were the only consistent genetic contributor to the neuroimaging biomarkers of brain ageing and cerebrovascular health. There is a link between rs11191848 and rs9419958 contributing to shorter telomere length and increased WMHs load, but no link between hippocampal volumes and SNPs regulating telomere length. Further studies are needed better to understand direct leucocyte telomere length on neuroimaging biomarkers and uncover potential mechanisms for those relationships
... p = 0.002). In addition, differences in total score, gait, kyphosis, and ledge score were detected between males, with effect of previous experience and genotype (total score, F (5, 80) = 3.449, K= 0.007, 3xTg-AD naïve 12 months vs. 3xTg-AD re-test 16 In females, differences were found in total score, kyphosis and gait with effect of previous experience and genotype (total score, F (4, 60) = 2,800, p = 0.034; R, F (1, 60) = 4.517, p = 0.038; G, F (1, 60) = 4.767, p = 0.033. Kyphosis score, F (4, 60) = 3.375, p = 0.015, 3xTg-AD naïve 12 months vs. 3xTg-AD re-test 16 months, p = 0.050; R, F (1, 60) = 7.791, p = 0.007. ...
... G×R, genotype and re-test effects, G×R** p < 0.01**, G×R* p < 0.05*. Bonferroni post hoc test: g, genotype, s, sex, r: re-test naïve 12 months vs. 16 ...
Article
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Longitudinal approaches for disease-monitoring in old animals face survival and frailty limitations, but also assessment and re-test bias on genotype and sex effects. The present work investigated these effects on 56 variables for behavior, functional profile, and biological status of male and female 3xTg-AD mice and NTg counterparts using two designs: (1) a longitudinal design: naïve 12-month-old mice re-tested four months later; and (2) a cross-sectional design: naïve 16-month-old mice compared to those re-tested. The results confirmed the impact as (1) improvement of survival (NTg rested females), variability of gait (3xTg-AD 16-month-old re-tested and naïve females), physical endurance (3xTg-AD re-tested females), motor learning (3xTg-AD and NTg 16-month-old re-tested females), and geotaxis (3xTg-AD naïve 16-month-old males); but (2) worse anxiety (3xTg-AD 16-month-old re-tested males), HPA axis (3xTg-AD 16-month-old re-tested and naïve females) and sarcopenia (3xTg-AD 16-month-old naïve females). Males showed more functional correlations than females. The functional profile, biological status, and their correlation are discussed as relevant elements for AD-pathology. Therefore, repetition of behavioral batteries could be considered training by itself, with some variables sensitive to genotype, sex, and re-test. In the AD-genotype, females achieved the best performance in physical endurance and motor learning, while males showed a deterioration in most studied variables.
... For instance, MDD has been associated with shortened telomere lengths in peripheral blood, such that patients with MDD were found to be biologically 10 years older than their chronological age. 72,73 In addition, telomere length ...
... 79 In addition, patients with MDD displayed increased levels of IL-6, which were correlated with decreased telomere length. 72,73 Despite the bidirectional relationship between inflammation and telomere shortening, only patients Potential bidirectional relationship between telomere attrition and inflammation found in mood disorders. ...
Chapter
Mood disorders, namely bipolar disorder (BD) and major depressive disorder (MDD), have been known to cause clinical symptoms of aging such as cognitive decline and increased susceptibility to age-related comorbidities (e.g., diabetes mellitus, hypertension, cardiovascular disorders), as well as structural changes in brain tissue similar to aging. These changes coincide with accelerated aging mechanisms occurring on a cellular level, primarily in epigenetic changes and telomere length. The accumulation of these changes, overall, demonstrates advanced biological age in comparison to chronological age within patients. This process is thought to occur by dysregulation of the hypothalamic-pituitary-adrenal axis, inflammation, and oxidative stress, among other mechanisms. Furthermore, pharmacological therapies demonstrate promising outcomes with potential reversal of these accelerated aging changes in individuals with BD and MDD.
... One possibility is that some pathological processes that predispose aged individuals to depressive disorders may exacerbate cognitive changes in the presence of other co-morbidities, such as hypertension, diabetes or vascular disorders, and may contribute to the cognitive heterogeneity associated with cerebral dysfunctions inducing impairment in higher-order cognitive domains (Geraets et al. 2022;Jellinger 2021;Kim et al. 2018;Kim and Han 2021). Accelerated aging processes in LLD may be driven by altered proteostasis control, inflammatory mechanisms, and systemic oxidative stress (Kuo et al. 2021;Wolkowitz et al. 2010), and linked to enhanced senescence processes compared with healthy individuals (Diniz et al. 2021;Seitz-Holland et al. 2023). There is a complex relationship between depression and incident CI across races as follows: previously established risk factors between depression and dementia were not found among African Americans and non-hispanic Whites, while Hispanics and Asians had a higher hazard for progression to incident CI (Babulal et al. 2022). ...
Article
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Depression is frequent in older individuals and is often associated with cognitive impairment and increasing risk of subsequent dementia. Late-life depression (LLD) has a negative impact on quality of life, yet the underlying pathobiology is still poorly understood. It is characterized by considerable heterogeneity in clinical manifestation, genetics, brain morphology, and function. Although its diagnosis is based on standard criteria, due to overlap with other age-related pathologies, the relationship between depression and dementia and the relevant structural and functional cerebral lesions are still controversial. LLD has been related to a variety of pathogenic mechanisms associated with the underlying age-related neurodegenerative and cerebrovascular processes. In addition to biochemical abnormalities, involving serotonergic and GABAergic systems, widespread disturbances of cortico-limbic, cortico-subcortical, and other essential brain networks, with disruption in the topological organization of mood- and cognition-related or other global connections are involved. Most recent lesion mapping has identified an altered network architecture with "depressive circuits" and "resilience tracts", thus confirming that depression is a brain network dysfunction disorder. Further pathogenic mechanisms including neuroinflammation, neuroimmune dysregulation, oxidative stress, neurotrophic and other pathogenic factors, such as β-amyloid (and tau) deposition are in discussion. Antidepressant therapies induce various changes in brain structure and function. Better insights into the complex pathobiology of LLD and new biomarkers will allow earlier and better diagnosis of this frequent and disabling psychopathological disorder, and further elucidation of its complex pathobiological basis is warranted in order to provide better prevention and treatment of depression in older individuals.
... Accelerated ageing processes in LLD may be driven by increased allostatic load, altered proteostasis control, pro-inflammatory mechanisms and systemic oxidative stress 7,8 . Research also suggests that accelerated ageing in LLD may occur on the cellular and subcellular level 9 and be linked to enhanced senescence processes 10 . Cellular senescence 11 has emerged as a pivotal hallmark of the biology of ageing. ...
... Accelerated ageing processes in LLD may be driven by increased allostatic load, altered proteostasis control, pro-inflammatory mechanisms and systemic oxidative stress 7,8 . Research also suggests that accelerated ageing in LLD may occur on the cellular and subcellular level 9 and be linked to enhanced senescence processes 10 . Cellular senescence 11 has emerged as a pivotal hallmark of the biology of ageing. ...
Article
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Previous studies suggested the role of cellular senescence in late-life depression (LLD). However, it is unclear how this finding relates to common features of LLD, such as medical and cognitive problems. We applied factor analyses to an extensive battery of clinical variables in 426 individuals with LLD. Here we tested the relationship between these factors, age and sex, with an index of cellular senescence based on 22 senescence-associated secretory phenotype proteins. We found four factors: ‘depression and anxiety severity’, ‘cognitive functioning’, ‘cardiovascular and cardiometabolic health’ and ‘blood pressure’. A higher senescence-associated secretory phenotype index was associated with poorer ‘cognitive functioning’ and ‘cardiovascular and cardiometabolic health’ but not with ‘depression and anxiety severity’. These findings highlight the role of cellular senescence in poorer physical and cognitive health in LLD. They are consonant with the viewpoint that co-occurring medical burdens and their associated disabilities are part of a phenotype of accelerated ageing in LLD.
... Independently of age, MDD affects around 20% of the population and correlates with short-term and working memory deficits, which exacerbate the effects of aging in some older adults 2 . Depression can resemble a state of accelerated aging as depressed individuals often exhibit a higher incidence of age-associated diseases, including Alzheimer's and other neurodegenerative diseases 3 . ...
Article
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Cognitive decline and mood disorders increase in frequency with age. Many efforts are focused on the identification of molecules and pathways to treat these conditions. Here, we demonstrate that systemic administration of growth differentiation factor 11 (GDF11) in aged mice improves memory and alleviates senescence and depression-like symptoms in a neurogenesis-independent manner. Mechanistically, GDF11 acts directly on hippocampal neurons to enhance neuronal activity via stimulation of autophagy. Transcriptomic and biochemical analyses of these neurons reveal that GDF11 reduces the activity of mammalian target of rapamycin (mTOR), a master regulator of autophagy. Using a murine model of corticosterone-induced depression-like phenotype, we also show that GDF11 attenuates the depressive-like behavior of young mice. Analysis of sera from young adults with major depressive disorder (MDD) reveals reduced GDF11 levels. These findings identify mechanistic pathways related to GDF11 action in the brain and uncover an unknown role for GDF11 as an antidepressant candidate and biomarker.
... In AA women, socioeconomic stress and discrimination are associated with accelerated aging and DNA methylation (DNAm; de Mendoza et al., 2018;McCrory et al., 2019). Depressive phenotypes demonstrate links with several aging indicators (e.g., telomeres, inflammatory pathways), but use of age acceleration as defined by DNAm is nascent (Wolkowitz et al., 2010). It is not known how age acceleration may be related to depressive phenotypes in AA women, a population at risk for developing CM conditions-which are often considered associated with aging-at significantly younger ages (Brailean et al., 2020;D'Eramo Melkus et al., 2010). ...
Article
Background: Depression is a growing global problem with significant individual and societal costs. Despite their consequences, depressive symptoms are poorly recognized and undertreated because wide variation in symptom presentation limits clinical identification-particularly among African American (AA) women-an understudied population at increased risk of health inequity. Objective: To explore depressive symptom phenotypes among AA women and examine associations with epigenetic, cardiometabolic, and psychosocial factors. Methods: This cross-sectional, retrospective analysis included self-reported Black/AA mothers from the Intergenerational Impact on Blood Pressure (InterGEN) study (data collected 2015-2020). Clinical phenotypes were identified using latent class analysis. Bivariate logistic regression examined epigenetic age, cardiometabolic traits (i.e., BMI ≥ 30, hypertension, or diabetes), and psychosocial variables as predictors of class membership. Results: All participants were Black/AA and predominantly non-Hispanic. Over half of the sample had one or more cardiometabolic traits. Two latent classes were identified (low vs. moderate depressive symptoms). Somatic and self-critical symptoms characterized the moderate symptom class. Higher stress overload scores significantly predicted moderate symptom class membership. Discussion: In this sample of AA women with increased cardiometabolic burden, increased stress was associated with depressive symptoms that standard screening tools may not capture. Research examining the effect of specific stressors and the efficacy of tools to identify at-risk AA women are urgently needed to address disparities and mental health burdens.
... This follows, in part, from evidence of advanced age-related gray matter degradation in adults (Koutsouleris et al., 2014;Dunlop et al., 2021;Han et al., 2020) and adolescents (Drobinin et al., 2021) with major depressive disorder (MDD). Chronic stress, which engages similar biological systems as depression, is also associated with advanced aging processes (Wolkowitz et al., 2011;Wolkowitz et al., 2010). Conversely, psychological characteristics that lower stress and facilitate well-being may mitigate unfavorable neurobiological trajectories (Schutte et al., 2016). ...
Article
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Background Individual variation in brain aging trajectories is linked with several physical and mental health outcomes. Greater stress levels, worry, and rumination correspond with advanced brain age, while other individual characteristics, like mindfulness, may be protective of brain health. Multiple lines of evidence point to advanced brain aging in schizophrenia (i.e., neural age estimate > chronological age). Whether psychological dimensions such as mindfulness, rumination, and perceived stress contribute to brain aging in schizophrenia is unknown. Methods: We estimated brain age from high-resolution anatomical scans in 54 healthy controls (HC) and 52 individuals with schizophrenia (SZ) and computed the brain predicted age difference (BrainAGE-diff), i.e., the delta between estimated brain age and chronological age. Emotional well-being summary scores were empirically derived to reflect individual differences in trait mindfulness, rumination, and perceived stress. Core analyses evaluated relationships between BrainAGE-diff and emotional well-being, testing for slopes differences across groups. Results: HC showed higher emotional well-being (greater mindfulness and less rumination/stress), relative to SZ. We observed a significant group difference in the relationship between BrainAge-diff and emotional well-being, explained by BrainAGE-diff negatively correlating with emotional well-being scores in SZ, and not in HC. That is, SZ with younger appearing brains (predicted age < chronological age) had emotional summary scores that were more like HC, a relationship that endured after accounting for several demographic and clinical variables. Conclusions: These data reveal clinically relevant aspects of brain age heterogeneity among SZ and point to case-control differences in the relationship between advanced brain aging and emotional well-being.
... For all analyses, a generalized Poisson model using robust error variances was applied to estimate appropriately narrow 95% confidence intervals (CI) of the raw and adjusted prevalence rates (PR). The variables included in the full model were age [29], gender [30], educational level [31], household income [32], living in couple [32], alcohol use [33], high body fat percentage [34], and diabetes [35]. Age and gender were included in model 2, and all variables were included in model 3. ...
Article
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Worldwide, depressive disorder is one of the leading determinants of disability-adjusted life years. Although there are benefits associated with a higher physical activity (PA) level, there is a lack of information related to this relationship, especially in countries such as Czechia, where modern approaches to mental health care only recently emerged. The present study aimed to evaluate the association between the level of depression and different PA levels following the World Health Organization (WHO) PA guidelines and according to specific symptoms that indicate depression. Multivariable-adjusted Poisson regression models were used to calculate the prevalence rate (PR) in a sample of 2123 participants (45.3% men, median 48 years). Compared to subjects with insufficient PA, moderate and high PA levels were inversely associated with continuous depression scores (PR = 0.85;95% CI: 0.75–0.97; and PR = 0.80; 95% CI: 0.70–0.92). Depressed mood and worthlessness were the symptoms associated with moderate and high PA. Tiredness, change in appetite, and concentration problems were related to high PA. The results suggest that reaching the minimum PA target according to the guidelines seems to be effective, and this could stimulate adherence. However, more specific improvements in symptomatology will require a subsequent gradual increase in PA levels.
... These pro-inflammatory indicators were related to depressive and anxious symptoms [97]. According to those findings, metabolic illnesses such as obesity, hypertension, and advanced age all serve as significant risk factors for depression, cognitive dysfunction, and dementia [98], and individuals suffering from severe depression have an increased risk of developing aging-related disorders affecting the cardiovascular, cerebrovascular, neuroendocrine, metabolic, and immunological systems [99][100][101]. Potential biomarkers with their features are shown in Table 1. ...
Article
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Neurodegenerative diseases (NDDs) are disorders that affect both the central and peripheral nervous systems. To name a few causes, NDDs can be caused by ischemia, oxidative and endoplasmic reticulum (ER) cell stress, inflammation, abnormal protein deposition in neural tissue, autoimmune-mediated neuron loss, and viral or prion infections. These conditions include Alzheimer's disease (AD), Lewy body dementia (LBD), and Parkinson's disease (PD). The formation of β-sheet-rich aggregates of intra- or extracellular proteins in the CNS hallmarks all neurodegenerative proteinopathies. In systemic lupus erythematosus (SLE), numerous organs, including the central nervous system (CNS), are affected. However, the inflammatory process is linked to several neurodegenerative pathways that are linked to depression because of NDDs. Pro-inflammatory signals activated by aging may increase vulnerability to neuropsychiatric disorders. Viruses may increase macrophages and CCR5+ T cells within the CNS during dementia formation and progression. Unlike medical symptoms, which are just signs of a patient's health as expressed and perceived, biomarkers are reproducible and quantitative. Therefore, this current review will highlight and summarize the neurological disorders and their biomarkers.
... Res. 10(08), 275-280 276 which than causes cardiovascular disease, atherosclerosis, anxiety premature aging, cancer, chronic diseases and neuromodulation (1)(2)(3)(4)(5)13). The Other hormones release by the adrenal gland from Zona Reticularis like DHEA,DHEA-S(5-6) arealso released in small amounts from ovaries, testis, brain tissue in males and females respectively. ...
Article
Background: Increased stress levels are associated with various health issues due to the dysregulation of HPA axis, more so when the stress is chronic in nature.As the DHEA-S is a catabolic hormone the chronic stress levels may be involved with long term diseases like early ageing, hypertension, cancer and various other diseases Objectives: The aim of this study was to see the effect of perceived chronic stress in a subset of healthy population of male and female volunteers who willingly participated in the study. The selected male and female population was than stratified into age and stress matched groups and then one time DHEA-S levels were ascertained to see for changes in the DHEA-S values. Methods: DHEA-S levels were measured within 6 hours of collection of the Blood Samples, randomly collected at different time points in the day by Chemiluminescence method which was than statistically evaluated by using Mini Tab statistical tool. Results: There was no significant correlation in both genders when age and stress matched.
... For all the analysis, a generalized Poisson model using robust error variances was applied to estimate appropriately narrow 95% Confidence Intervals (CI) of raw and adjusted Prevalence Rates (PR). The variables included in the full model were age [28], gender [29], educational level [30], household income [31], living in couple [31], alcohol use [32], high body fat percentage [33] and diabetes [34]. Age and gender were included in model 2 and all the variables in model 3. Results. ...
Preprint
Worldwide, depressive disorder is one of the leading determinants of disability-adjusted life years. Although the benefits associated with physical activity (PA), there is a lack of information related to depression, especially in countries like Czechia, where modern approaches to mental health care only recently emerged. The PA levels were associated with aspects of depression such as clinician-diagnosed history; different severities; continuous depression scores; and specific symptoms that characterize the depression. The multivariable-adjusted Poisson regression models were carried out on 2123 participants (45.3% men, median 48 years). Compared to subjects with insufficient PA, the moderate and high PA levels were inversely associated with clinician-diagnosed depression history (respectively, prevalence rate [PR]= 0.84; 95% CI 0.66-0.82 and PR=0.50; 95% CI 0.36-0.67); and with continuous depression scores (PR=0.85; 95% CI 0.75-0.97; and PR=0.79; 95%CI 0.70-0.90).; but only high PA showed association with depression categories (PR=0.75; 95%CI 0.60-0.95). Depressed mood and worthlessness were the symptoms associated with moderate and high PA. Tiredness, change in appetite, and problems with concentration only with high PA. Although only high PA was sufficient for people intending changes among depression categories, the moderate PA may be enough for slight changes in depressive symptoms, and a good strategy when starting.
... Although the prevalence of major depression does not increase with aging, the negative impact of depression on health parameters is significantly greater in the elderly [65]. One possible hypothesis is that there is an interaction between the biological changes associated with major depression and aging, negatively impacting health parameters and leading to worse health outcomes [14,49,66]. Our study provides support for this hypothesis since many of the biological processes abnormally regulated in LLD are also considered major hallmarks of biological aging, in particular, the activation of pro-inflammatory pathways, proteostasis control, nutrient sensing, and metabolic control pathways [67,68]. ...
Article
Depression is a complex and multifactorial disease, affecting about 6.5% of the elderly population in what is referred to as late-life depression (LLD). Despite its public health relevance, there is still limited information about the molecular mechanisms of LLD. We analyzed the blood plasma of 50 older adults, 19 with LLD and 31 controls, through untargeted mass spectrometry, and used systems biology tools to identify biochemical pathways and biological processes dysregulated in the disease. We found 96 differentially expressed proteins between LLD patients and control individuals. Using elastic-net regression, we generated a panel of 75 proteins that comprises a potential model for determining the molecular signature of LLD. We also showed that biological pathways related to vesicle-mediated transport and voltage-dependent calcium channels may be dysregulated in LLD. These data can help to build an understanding of the molecular basis of LLD, offering an integrated view of the biomolecular alterations that occur in this disorder. Significance Major depressive disorder in the elderly, called late-life depression (LLD), is a common and disabling disorder, with recent prevalence estimates of 6.5% in the general population. Despite the public health relevance, there is still limited information about the molecular mechanisms of LLD. The findings in this paper shed light on LLD heterogeneous biological mechanisms. We uncovered a potential novel biomolecular signature for LLD and biological pathways related to this condition which can be targets for the development of novel interventions for prevention, early diagnosis, and treatment of LLD.
... There are many factors that may contribute to immune aging in an individual including genetics, environmental factors, diet, health behaviors, and allostatic load. Here we focus on depression which has been previously proposed to be a driver of premature biological aging [98]. ...
Article
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The aging process can have detrimental effects on the immune system rendering the elderly more susceptible to infectious disease and less responsive to vaccination. Major depressive disorder (MDD) has been hypothesized to show characteristics of accelerated biological aging. This raises the possibility that depressed individuals will show some overlap with elderly populations with respect to their immune response to infection and vaccination. Here we provide an umbrella review of this literature in the context of the SARS CoV-2 pandemic. On balance, the available data do indeed suggest that depression is a risk factor for both adverse outcomes following COVID-19 infection and for reduced COVID-19 vaccine immunogenicity. We conclude that MDD (and other major psychiatric disorders) should be recognized as vulnerable populations that receive priority for vaccination along with other at-risk groups.
... Among these, the only variable showing significant associations to changes in DNA/RNA damage from oxidation was AUC full , which can be considered a marker of individual overall cortisol "exposure" during the day. This finding adds support to the body of literature suggesting an important biological connection between corticosteroids and oxidative stress [49], which in turn has been suggested to underlie the association between stress, depression, and aging [50]. However, in the present study, the preversus post-treatment change in AUC full was negatively associated with 8-oxodG and 8-oxoGuo. ...
Article
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Previous studies have indicated that antidepressants that inhibit the serotonin transporter reduces oxidative stress. DNA and RNA damage from oxidation is involved in aging and a range of age-related pathophysiological processes. Here, we studied the urinary excretion of markers of DNA and RNA damage from oxidation, 8-oxodG and 8-oxoGuo, respectively, in the NeuroPharm cohort of 100 drug-free patients with unipolar depression and in 856 non-psychiatric community controls. Patients were subsequently treated for 8 weeks with escitalopram in flexible doses of 5–20 mg; seven of these switched to duloxetine by week 4, as allowed by the protocol. At week 8, 82 patients were followed up clinically and with measurements of 8-oxodG/8-oxoGuo. Contextual data were collected in patients, including markers of cortisol excretion and low-grade inflammation. The intervention was associated with a substantial reduction in both 8-oxodG/8-oxoGuo excretion (25% and 10%, respectively). The change was not significantly correlated to measures of clinical improvement. Both markers were strongly and negatively correlated to cortisol, as measured by the area under the curve for the full-day salivary cortisol excretion. Surprisingly, patients had similar levels of 8-oxodG excretion and lower levels of 8-oxoGuo excretion at baseline compared to the controls. We conclude that intervention with serotonin reuptake inhibitors in unipolar depression is associated with a reduction in systemic DNA and RNA damage from oxidation. To our knowledge, this to date the largest intervention study to characterize this phenomenon, and the first to include a marker of RNA oxidation.
... Evidence also indicates that ischemic damages to the brain, particularly the frontostriatal brain regions, might be a common etiologic factor for depression and cognitive dysfunction [36,43]. Besides, it had been proposed that increased cortisone levels, frequently observed in depression, can lead to worsening hippocampal atrophy, which is a well-known characteristic of Alzheimer disease [36,44]. Other possible systemic etiology includes chronic in ammatory processes [45] as well as changed levels of circulating brain-derived neurotrophic factors [46,47]. ...
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Background: Dementia and depression have emerged as two of the major mental health concerns for elderly people, which are likely to substantially affect public health in the coming decades. Both dementia and geriatric depression are associated with increased morbidity, health care utilization, and mortality. Early detection and treatment initiation are some of the best strategies to minimize the ill effects of dementia and depression on the elderly people. To this end, large-scale screening may be the first step. Methods: Screening of individuals ≥65 years old was conducted in the outpatient department of a university hospital. Ascertainment of dementia 8 (AD8) and five-item Brief Symptom Rating Scale (BSRS-5) were used to screen for cognitive decline and depression, respectively. Findings: In total, 3079 elderly people completed both AD8 and BSRS-5. Patients tested positive for cognitive impairment and depression were 28.2% and 15%, respectively. However, 7% were tested positive by both AD8 and BSRS-5 and with statistical significance. Interpretation: The high ratio of suspected dementia and suspected depression suggested the needs and cost-effect of screening among the elderly outpatients. However, the statistically significant overlap implied potential bias when screening only one condition. Future screening program of geriatric mental health needs to consider this.
... Stres, kecemasan, depresi, dan kesepian, telah dikaitkan dengan hal-hal seperti penurunan kekebalan, peningkatan peradangan, dan penurunan harapan hidup. (Wolkowitz, 2010). Kebahagiaan telah dikaitkan dengan berbagai hasil termasuk peningkatan umur panjang dan peningkatan kepuasan pernikahan. ...
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Along with the times, the human population and the demands of the times continue to grow, so humans must adapt to survive. In life, humans face many obstacles that affect their mental condition and performance. When humans are in a happy mood, the degree of quality of human life increases, and vice versa. However, life in this fast-paced and dense urban area makes it difficult for them to release their stressful feelings due to the problems they face every day, the space as a stress-relief place in urban areas is not enough to handle stress in this crowded city. The design of a space as an activator for human mood is designed to reach points in urban areas, in order to help release their stress. A place that helps people's activities and helps release the stress they face. Dense cities, make people have to be able to make good use of space. Therefore, this activator chamber is designed to have a small-scale area. This project starts from determining the main program and objectives, the main program will be proposed at each point of project development, but this program will still be reviewed for suitability with the site to be taken. Then a sample location was taken, namely Pasar Baru Village as a research location before this project was spread to various points in urban areas. Three locations were found in Pasar Baru Village, due to differences in the function and compatibility of the main program with the function of the program to be referred to at that site. The results of this sample will then be used as a reference for project development at different location points in the future. Keywords: Activator; Mood; Room; Stress.AbstrakSeiring perkembangan zaman, populasi manusia dan tuntutan zaman pun terus berkembang sehingga manusia harus menyesuaikan diri untuk dapat bertahan hidup. Dalam kehidupannya manusia menghadapi banyak rintangan yang mempengaruhi kondisi dari mental dan kinerja mereka. Ketika manusia berada dalam suasana hati yang senang, maka derajat kualitas hidup manusia pun meningkat, begitu pun sebaliknya. Namun, kehidupan di perkotaan yang serba cepat dan padat ini, membuat mereka sulit untuk melepaskan perasaan stres mereka akibat masalah yang dihadapi setiap harinya, ruangan sebagai tempat pelepas stres yang ada di perkotaan tidak cukup untuk menangani stres di perkotaan yang padat ini. Perancangan sebuah ruang sebagai aktivator bagi suasana hati manusia ini dirancang untuk menjangkau titik - titik yang ada di perkotaan, supaya dapat membantu melepaskan stres mereka. Tempat yang membantu aktivitas masyarakat dan membantu melepaskan stres yang mereka hadapi. Perkotaan yang padat, membuat manusia harus dapat memanfaatkan ruangan dengan baik. Oleh karena itu ruang aktivator ini dirancang agar memiliki luasan berskala kecil. Proyek ini dimulai dari menentukan program dan tujuan utama, program utama akan diajukan pada setiap titik pengembangan proyek, namun program ini akan tetap dikaji kembali kecocokannya dengan tapak yang akan diambil. Lalu diambil sampel lokasi, yaitu Kelurahan Pasar Baru sebagai lokasi penelitian sebelum proyek ini disebar ke berbagai titik di perkotaan. Ditemukan 3 titik lokasi pada Kelurahan Pasar Baru, karena perbedaan fungsi dan kecocokan program utama dengan fungsi program yang akan dirujuk pada tapak tersebut. Hasil sampel ini kemudian akan menjadi acuan bagi pengembangan proyek di titik lokasi yang berbeda kedepannya.
... It has been hypothesized that psychosocial stress can act on the brain during the stages when it undergoes changes, such as in early life development and older age [11]. Other research suggested that the alterations in the amygdala and the hippocampus and the decrease in the volume are dependent on the age at which the traumatic psychosocial event occurs [12]. ...
Article
Objective: This study aims to assess the effects of stressful events in senior patients who later developed ischemic stroke, Alzheimer's or Parkinson's disease. Background: Psychological stress may be a risk factor for dementias, but the association between exposure to stressful life events and the development of cognitive dysfunction has not been conclusively demonstrated. We hypothesize that if a stressful event has an impact on the subjects, its effects would be different in the three diseases. Material and methods: Together with demographic variables (age, sex, race, socioeconomic and cultural levels), five types of past stressful events were recorded in 1024 patients with Alzheimer's, Parkinson's diseases and Ischemic Stroke: death or serious illness of close relatives, job dismissal, change of financial status, retirement, and change of residence. Time-to-diagnosis (months from the event to the first symptoms: retrospective study) and evolution time (years of follow-up of each patient: prospective study) were recorded. Analysis of variance and non-parametric methods were applied to the variables time-to-diagnosis and evolution time to analyze differences between these diseases. Results: The demographic variables age, sex, race, economic and cultural levels were found to be statistically non-significant; differences in the economic level were significant (P<0.05). Significant differences (P<0.001) were found in the mean time-to-diagnosis between diseases (Alzheimer>Parkinson's>Stroke), and minor differences (P<0.05) in evolution time. Conclusion: Differences in time-to-diagnosis between the diseases indicate that the stressful effect of having experienced the death or serious illness of a close relative has an impact on their emergence. The measurement of time-to-diagnosis and evolution time proves useful in detecting differences between diseases.
... MDD has been associated with poor health outcomes including increased risk of mortality, reduced life expectancy (Chesney, Goodwin and Fazel, 2014;Cuijpers et al., 2014), increased risk of cognitive decline and Alzheimer's disease (Speck et al., 1995;Chodosh et al., 2007;John et al., 2019), advanced physical ageing (such as handgrip strength and walking speed) (Lever-van Milligen et al., 2017), and increased risk of poor cardiovascular and somatic health (Penninx et al., 2013;Hare et al., 2014). It has been proposed that the link between depression and poor physical and cognitive health may be explained by accelerated ageing trajectories in those with MDD (Wolkowitz et al., 2010). Biological evidence supporting this includes accelerated epigenetic ageing in MDD (Whalley et al., 2017;Han et al., 2018), increased immunosenescence (Diniz et al., 2019) and telomere shortening (Darrow et al., 2016;Lin, Huang and Hung, 2016). ...
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Background: Major Depressive Disorder (MDD) is associated with accelerated ageing trajectories including functional markers of ageing, cellular ageing and markers of poor brain health. The biological mechanisms underlying these associations remain poorly understood. Chronic inflammation is also associated with advanced ageing; however, the degree to which long-term inflammation plays a role in ageing in MDD remains unclear, partly due to difficulties differentiating long-term inflammation from acute cross-sectional measures. Methods: Here, we use a longer-term measure of inflammation: a DNA methylation-based marker of C-reactive protein (DNAm CRP), in a large cohort of individuals deeply phenotyped for MDD (Generation Scotland, GS, N=804). We investigate associations between DNAm CRP and serum CRP using linear modelling with two brain ageing neuroimaging-derived phenotypes: (i) a machine learning based measure of brain-predicted age difference (brain-PAD) and (ii) white matter hyperintensities (WMH). We then examine inflammation by depression interaction effects for these brain ageing phenotypes. We sought to replicate findings in an independent sample of older community-dwelling adults (Lothian Birth Cohort 1936, LBC1936; N=615). Results: DNAm CRP was significantly associated with increased brain-PAD (β=0.111, p=0.015), which was replicated in the independent sample with a similar significant effect size (β=0.114, p=0.012). There were no associations between the inflammation markers and WMH phenotypes in the GS-imaging sample, however in the LBC1936 sample, DNAm CRP was significantly associated with both Wahlund infratentorial (β=0.15, PFDR= 0.006) and Fazekas deep white matter hyperintensity scores (β= 0.116, PFDR=0.033). There were no interaction effects between inflammation and MDD in either cohort. Conclusions: This study found robust associations between a longer-term marker of inflammation and brain ageing as measured by brain-PAD, consistent across two large independent samples. However, we found no evidence for interaction effects between inflammation and MDD on any brain ageing phenotype in these community-based cohorts. These findings provide evidence that chronic inflammation is associated with increased brain ageing, which is not specific to MDD. Future work should investigate these relationships in clinical samples including with other inflammatory biomarkers and should furthermore aim to determine causal directionality.
... Major depressive disorder has been linked to increased accelerated biological aging at the cellular level (O'Donovan et al., 2012;Verhoeven et al., 2014;Wolkowitz et al., 2010) via epigenetic age measured by DNA methylation (Han et al., 2018). Both major depressive disorder and higher depressive symptoms have been linked to increased physiological dysregulation measured by allostatic load (McEwen, 2003) and inflammatory markers often used in measures of physiological dysregulation such as C-reactive protein (Copeland et al., 2012). ...
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Objectives Black persons in the US are more likely to suffer from social inequality. Chronic stress caused by social inequality and racial discrimination results in weathering of the body that causes physiological dysregulation and biological age being higher than chronological age (accelerated aging). Depression has been linked to both racial discrimination and accelerated aging and accelerated aging has been demonstrated to be higher in Black than White persons, on average. However, we know little about accelerated aging across the life course in Black Americans. Methods We used mixed effects growth models to measure biological age acceleration, measured with cardiometabolic markers, over a 20-year period in Black participants of the Coronary Artery Risk Development in Young Adults Study (CARDIA) who were aged 27 - 42 years at analytic baseline. We included an interaction between depressive symptoms and time to determine whether risk of depression was associated with a faster rate of biological aging. Results We found that the rate of biological aging increased over a 20-year span and that those at risk for depression had a faster rate of biological aging than those not at risk. We also found that various social factors were associated with biological age acceleration over time. Discussion Given the known association between perceived racial discrimination and depressive symptoms, we provide a novel instance of the long-term effects of social inequality. Specifically, biological age acceleration, a marker of physiological dysregulation, is associated with time among Black persons and more strongly associated among those with depressive symptoms.
... Major Depressive Disorder (MDD) is a prevalent debilitating condition, but its overall pathophysiology remains unknown. Further, the extent to which it is purely a "mental illness" or a "brain disease," as opposed to a disorder with peripheral somatic pathologies is uncertain [1]. Apart from its psychiatric and behavioral manifestations, MDD is associated with early mortality and increased risk for several somatic conditions [2], raising the possibility of systemic pathologies, perhaps even cellular disturbances, such as telomere length shortening, inflammation, oxidative stress, and mitochondrial dysregulation [3][4][5][6][7][8]. ...
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Mitochondrial dysfunction has been implicated in major depressive disorder (MDD). A measure of mitochondrial respiratory chain (RC) enzymatic activity—the Mitochondrial Health Index (MHI)—has previously been found to correlate with stress and emotional states in caregivers. We here report mitochondrial RC activities, mitochondrial DNA copy number (mtDNAcn), and the composite MHI in unmedicated and somatically healthy subjects with MDD (n = 47) and healthy controls (HC) (n = 11). We also explore, in a subset of the MDD sample (n = 33), whether these markers are associated with response to 8 weeks of SSRI treatment. Mitochondrial RC complexes I, II, IV, citrate synthase (CS), mtDNAcn, and the MHI were assayed in peripheral blood mononuclear cells. Treatment response was defined as >50% decrease on the 25-item Hamilton Depression Rating Scale (HRDS-25). There were no significant differences in MHI or any of the mitochondrial markers between MDD subjects and HCs. Compared to SSRI nonresponders, SSRI responders had significantly higher baseline mitochondrial content markers CS (p = 0.02) and mtDNAcn (p = 0.02), and higher complex I activity (p = 0.01). Complex II activity increased significantly over treatment, irrespective of clinical response (p = 0.03). Complex I activity decreased in responders (n = 9), but increased in nonresponders (n = 18) (group x time interaction, p = 0.02). Absolute treatment-associated change in HDRS-25 scores correlated significantly with change in complex I activity between baseline and week 8 (r = 0.47, p = 0.01). Although mitochondrial markers did not distinguish MDD from controls, they did distinguish SSRI responders from nonresponders. If larger studies validate these mitochondrial differences, they may become useful biomarkers and identify new drug targets.
... Stress factors and reactions to stress in life could also lead to the development of disorders such as depression and anxiety (Akerstedt, Kecklund & Axelsson, 2007;Wolkowitz, Epel, Reus, & Mellon, 2010). In the metacognitive framework, literature included studies which reported that metacognitive features affected the development of psychopathology such as depression, anxiety and stress (Normann, Emmerik, & Morina, 2014;Roussis & Wells, 2006;Spada et al., 2008;Yılmaz, Gençöz & Wells, 2014). ...
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The metacognitive functions significantly affect the levels of psychological symptoms such as depression, anxiety, stress in individuals. Thus, it was considered that metacognitive traits also have a significant effect on the subjective well-being levels. In the present study, the correlations between metacognitive functions and depression, anxiety, stress and subjective well-being levels of adult individuals were analyzed. The study was conducted with 114 female and 137 male, a total of 251 adult individuals. The study data were collected with the Metacognitions Questionnaire (MCQ-30), Depression, Anxiety, Stress Inventory, Subjective Well-being Scale and a Personal Information Form. The study data were analyzed using Pearson Correlation Analysis and Hierarchical Regression method. The analysis findings revealed that metacognitive functions, uncontrollability and danger, the need to control the thoughts, cognitive confidence, positive belief, and cognitive awareness levels were positively associated with depression, anxiety, and stress variables. On the other hand, there were negative correlations between subjective well-being and positive beliefs, need to control thought, levels of uncontrollability and danger, cognitive confidence, uncontrollability of thoughts and danger. According to the hierarchical regression analysis made by creating models, sub-dimensions of metacognition predict depression, anxiety, stress and subjective well-being levels. Citation: Yazar, R., & Tolan, Ö. (2020). İnvestigation of the relationships between metacognitive functions and subjective well-being and depression, anxiety and stress levels in adult individuals. Research on Education and Psychology (REP), 4(2), 172-193. Yazar, Tolan / Investigation of the relationships between metacognitive functions and subjective well-being and depression, anxiety and stress levels in adult individuals 173 Humans perceive, make sense and actively implement the sensations they receive from the environment throughout their lives. It is possible for individuals to make sense of life through various emotions and ideas that they develop based on experiences, exhibit various behaviors, and employ their cognitive processes. Cognition is defined as a type of mechanism that combines intellectual processes and functions (Irak, Çapan, & Soylu, 2015). In addition, Neisser (1967) defines that cognition means the transformation, reduction, processing, recording, restructuring of emotional input. On the other hand, metacognition is a concept first described by Flavel (1979). According to Flavel (1979), metacognition is the knowledge about cognitive abilities and strategies that an individual possesses. Brown (1987) defined metacognition as a type of higher system that allows an individual to be aware of, control and employ the cognitive skills and strategies that the individual possesses for certain purposes. According to Wells (2008), metacognition is the knowledge of self-intellectual processes, the way individuals organize their thoughts and the way they react. While mental processes such as perception and remembrance are cognitive functions, metacognitive functions include thinking about one's acts such as perception and remembrance (Garner & Alexander, 1989). Thus, individuals could have knowledge about their intellectual functions and thinking structures due to metacognitive processes and guide their minds purposefully and functionally (Tosun & Iraq, 2008). In this context, it was reported that the concept of metacognition, which includes awareness and regulation of cognitive capacity, includes several functions and individuals develop positive or negative beliefs based on their metacognitive beliefs about daily life events (Wells et al., 2009). Flavell (1979) argued that metacognition included three dimensions: "metacognitive knowledge", "metacognitive experiences" and "metacognitive strategies". Knowledge on the development of cognitive processes and beliefs about these processes is defined as metacognitive knowledge. Metacognitive experiences include the experiences of the individual in intellectual processes such as thinking and decision making when a situation or event is encountered. These experiences could be emotional or cognitive experiences. Metacognitive strategies, on the other hand, include the reactions (avoidance, control) of the individual against the encountered events throughout life. Also, Wells (2002) reported that metacognitive knowledge, metacognitive experiences and metacognitive strategies form the metacognitive system. It is known that the metacognitive system is effective in the development of coherent response styles by the individual (Cartwright-Hatton & Wells, 1997; Gwilliam, Wells, & Cartwright-Hatton, 2004). A diversion in this system could lead to various psychopathologies (Wells & Cartwright-Hatton, 2004). According to Cartwright-Hatton and Wells (1997), positive and negative beliefs play an important role in the development of psychopathology, affecting an individual's dysfunctional thoughts and the way they analyze the events. These beliefs are combined in the metacognitive system and lead to incoherent reactions. It was reported that the inadequate coping mechanisms such as rumination and the need to control thoughts, when discussed in this context, were effective on the emergence and progression of certain psychopathologies. In summary, metacognitive beliefs are associated with individual attempts to cope with stressful events such as anxiety, rumination, avoidance, and suppression. Thus, high inadequate coping efforts could lead to an increase in negative emotions and more intense anxiety and could create a vicious anxiety, avoidance and rumination cycle. The review of the literature on metacognitive model demonstrated that metacognitive processes were studied in association with disorders such as mood disorders (Matthews & Wells,
... Stress factors and reactions to stress in life could also lead to the development of disorders such as depression and anxiety (Akerstedt, Kecklund & Axelsson, 2007;Wolkowitz, Epel, Reus, & Mellon, 2010). In the metacognitive framework, literature included studies which reported that metacognitive features affected the development of psychopathology such as depression, anxiety and stress (Normann, Emmerik, & Morina, 2014;Roussis & Wells, 2006;Spada et al., 2008;Yılmaz, Gençöz & Wells, 2014). ...
... Human studies of dopamine signaling in MDD often focus on reward processing in younger adults to the exclusion of cognitive and sensorimotor domains relevant for older adults. Normal aging and age-related pro-inflammatory processes are further associated with declines in dopaminergic molecular functioning and impairment in dopamine signaling [6][7][8], while depression itself may accelerate aging processes [9]. The confluence of age-related declines and pre-existing dopaminergic system functional alterations may increase vulnerability to depression and exacerbate the presentation of episodes in later life. ...
Article
Deficits in cognition, reward processing, and motor function are clinical features relevant to both aging and depression. Individuals with late-life depression often show impairment across these domains, all of which are moderated by the functioning of dopaminergic circuits. As dopaminergic function declines with normal aging and increased inflammatory burden, the role of dopamine may be particularly salient for late-life depression. We review the literature examining the role of dopamine in the pathogenesis of depression, as well as how dopamine function changes with aging and is influenced by inflammation. Applying a Research Domain Criteria (RDoC) Initiative perspective, we then review work examining how dopaminergic signaling affects these domains, specifically focusing on Cognitive, Positive Valence, and Sensorimotor Systems. We propose a unified model incorporating the effects of aging and low-grade inflammation on dopaminergic functioning, with a resulting negative effect on cognition, reward processing, and motor function. Interplay between these systems may influence development of a depressive phenotype, with an initial deficit in one domain reinforcing decline in others. This model extends RDoC concepts into late-life depression while also providing opportunities for novel and personalized interventions.
... Interestingly, existing research further suggests that mental disorders can be characterized by "accelerated aging", which means that certain biological correlates amplify with increasing illness duration. For instance, Wolkowitz et al. (2010) highlighted that in depression, stronger alterations of HPA axis functioning over time are accompanied by increased cell damaging processes, immune dysregulation, and oxidative stress. Similarly, Miller and Sadeh (2014) reviewed existing evidence on the "accelerated aging" hypothesis in post-traumatic stress disorder (PTSD) and reported that chronic and repeated activation of the HPA axis-for example, when re-experiencing traumatic experiences-has deleterious effects on the brain, such as hippocampal atrophy and neuronal cell death. ...
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Patients with borderline personality disorder (BPD) often display increased stress vulnerability, which may be linked to altered hypothalamus–pituitary–adrenal (HPA) axis functioning. Corresponding deviations of the cortisol awakening response (CAR) are presumed to mirror maladaptive neuroendocrine processes, which may explain why CARs are increased compared to healthy controls (HC). Prior research speculated that these alterations may be caused by early life stress and/or chronic stress related to the ongoing burden of the disorder. Yet, it remains to be investigated how BPD influences CAR in the course of development. Therefore, the current study examined CAR in female adolescents and adults with BPD compared to HC with a particular focus on associations with age. These potential associations were especially focused, as it was hypothesized that the CAR would be even more elevated (i.e., higher) in older individuals with BPD. CAR was assessed in 54 female individuals with BPD (aged 15–40 years) and 54 sex-, age-, and intelligence-matched HC (aged 15–48 years). Group differences were investigated and analyses of covariance using age as continuous predictor were performed to analyze potential developmental associations with CAR alongside BPD-specific effects. Pearson’s correlations were calculated to examine associations between CAR and age. Analyses were repeated with potential confounders as control factors. Results not only demonstrated increased CARs in female individuals with BPD compared to HC but demonstrated elevated CARs with increasing age in BPD individuals exclusively. Effects remained stable after controlling for potential confounders. Thereby, findings suggest that endocrine alterations in BPD may reinforce with increasing age and BPD chronicity.
... Altered aging effects of MDD including the number of fixations, duration of fixation, number of saccades, and fixation density are also of particular interest. Indeed, accelerated brain aging was reported in MDD patients (45). In terms of symptoms, Dunlop et al. (46) suggested that accelerated aging was associated with greater impulsivity and depression severity. ...
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Background: Despite their high lifetime prevalence, major depressive disorder (MDD) is often difficult to diagnose, and there is a need for useful biomarkers for the diagnosis of MDD. Eye movements are considered a non-invasive potential biomarker for the diagnosis of psychiatric disorders such as schizophrenia. However, eye movement deficits in MDD remain unclear. Thus, we evaluated detailed eye movement measurements to validate its usefulness as a biomarker in MDD. Methods: Eye movements were recorded from 37 patients with MDD and 400 healthy controls (HCs) using the same system at five University hospitals. We administered free-viewing, fixation stability, and smooth pursuit tests, and obtained 35 eye movement measurements. We performed analyses of covariance with group as an independent variable and age as a covariate. In 4 out of 35 measurements with significant group-by-age interactions, we evaluated aging effects. Discriminant analysis and receiver operating characteristic (ROC) analysis were conducted. Results: In the free-viewing test, scanpath length was significantly shorter in MDD ( p = 4.2 × 10 ⁻³ ). In the smooth pursuit test, duration of saccades was significantly shorter and peak saccade velocity was significantly lower in MDD ( p = 3.7 × 10 ⁻³ , p = 3.9 × 10 ⁻³ , respectively). In the fixation stability test, there were no significant group differences. There were significant group differences in the older cohort, but not in the younger cohort, for the number of fixations, duration of fixation, number of saccades, and fixation density in the free-viewing test. A discriminant analysis using scanpath length in the free-viewing test and peak saccade velocity in the smooth pursuit showed MDD could be distinguished from HCs with 72.1% accuracy. In the ROC analysis, the area under the curve was 0.76 (standard error = 0.05, p = 1.2 × 10 ⁻⁷ , 95% confidence interval = 0.67–0.85). Conclusion: These results suggest that detailed eye movement tests can assist in differentiating MDD from HCs, especially in older subjects.
... However, we did not find any associations between regional GMV and age at onset of depression. Another possible explanation is that lower GMV reduction arises from accelerated aging 50,51 . Notably, consistent with a previous study 23 , we found a negative correlation between age and GMV in our healthy cohort, which was not present in LLD i.e. the GMV differences were most pronounced between the younger www.nature.com/scientificreports/ ...
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Late-life depression (LLD) is associated with a risk of developing Alzheimer’s disease (AD). However, the role of AD-pathophysiology in LLD, and its association with clinical symptoms and cognitive function are elusive. In this study, one hundred subjects underwent amyloid positron emission tomography (PET) imaging with [ ¹⁸ F]-flutemetamol and structural MRI: 48 severely depressed elderly subjects (age 74.1 ± 7.5 years, 33 female) and 52 age-/gender-matched healthy controls (72.4 ± 6.4 years, 37 female). The Geriatric Depression Scale (GDS) and Rey Auditory Verbal Learning Test (RAVLT) were used to assess the severity of depressive symptoms and episodic memory function respectively. Amyloid deposition was quantified using the standardized uptake value ratio. Whole-brain voxel-wise comparisons of amyloid deposition and gray matter volume (GMV) between LLD and controls were performed. Multivariate analysis of covariance was conducted to investigate the association of regional differences in amyloid deposition and GMV with clinical factors, including GDS and RAVLT. As a result, there were no significant group differences in amyloid deposition. In contrast, LLD showed significant lower GMV in the left temporal and parietal region. GMV reduction in the left temporal region was associated with episodic memory dysfunction, but not with depression severity. Regional GMV reduction was not associated with amyloid deposition. LLD is associated with lower GMV in regions that overlap with AD-pathophysiology, and which are associated with episodic memory function. The lack of corresponding associations with amyloid suggests that lower GMV driven by non-amyloid pathology may play a central role in the neurobiology of LLD presenting as a psychiatric disorder. Trial registration : European Union Drug Regulating Authorities Clinical Trials identifier: EudraCT 2009-018064-95.
... A possible source of confounding that may increase with age is the presence of chronic somatic diseases, as in population-based studies or psychiatric cohort studies the severity and chronicity of somatic conditions are usually not taken into account. As Wolkowitz and colleagues stated that the biological age of depressed adults is at least 10 years older compared to their chronological age (Wolkowitz et al., 2010), frailty might be a confounding factor. The small association between the severity of frailty and leucocyte telomere length we found should be replicated, as the NESDO study is rather small for detecting clinical correlates of telomere length shortening. ...
... Early telomere shortening can be seen in patients with MDD due to these ongoing inflammatory processes, and an increase in telomerase activity can be expected as a compensatory response to this situation. Some studies have concluded that the increase in pro-inflammatory cytokine levels in depressive patients without medication and during depressive episodes is negatively related to telomere length (Damjanovic et al., 2007;Wolkowitz et al., 2010;Wolkowitz et al., 2011). Lin, Epel, and Blackburn (2012) suggest that an excessive increase in inflammatory processes shortens cellular life and causes destruction, and this situation is regulated by a balancing system such as increased telomerase activity. ...
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The biological mechanisms responsible for depression symptoms are not yet understood. For this reason, it is important to reveal the etiopathogenetic mechanisms in this disease. This study aims to compare the levels of pro-inflammatory cytokines, Brain-Derived Neurotrophic Factor (BDNF), and telomerase activity in patients with major depressive disorder (MDD) and healthy controls. Plasma BDNF, interleukin-6 (IL-6), IL-1beta, and Tumor Necrosis Factor-alpha (TNF-alpha) levels, and telomerase activity were measured in 39 patients with major depression and 39 healthy controls matched with patients in terms of age, gender, and education year. Plasma concentration of BDNF, IL-6 levels, and telomerase activity was significantly different between patients with MDD and healthy controls. Correlation analysis showed a positive trend between plasma BDNF levels and plasma IL-6 levels in patients with MDD with melancholic features. Furthermore, the path analysis results showed that the telomerase activity was indirectly affected by gender, IL-1β, IL-6, BDNF, and BMI, via the severity of depression and anxiety and MDD status as the mediators. Further studies are needed to examine the molecular mechanism of the telomerase activity and the role of BDNF and pro-inflammatory cytokines in the telomerase activation in MDD.
... From a physiological perspective, anxiety disorders are stressful conditions, normally accompanied by deregulation of stress systems such as the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, and the immune system 8,9 . The presence of different stressful conditions has been associated with accelerated aging [10][11][12] evaluated through telomere length (TL) shortening and epigenetic age acceleration (AA) from DNA methylation (DNAm) profiles of cytosine phosphate guanines (CpGs). These measurements can be used as markers of cellular age according to different studies [12][13][14][15] . ...
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Evidence on the relationship between genetics and mental health are flourishing. However, few studies are evaluating early biomarkers that might link genes, environment, and psychopathology. We aimed to study telomere length (TL) and epigenetic age acceleration (AA) in a cohort of adolescents with and without anxiety disorders (N = 234). We evaluated a representative subsample of participants at baseline and after 5 years (n = 76) and categorized them according to their anxiety disorder diagnosis at both time points: (1) control group (no anxiety disorder, n = 18), (2) variable group (anxiety disorder in one evaluation, n = 38), and (3) persistent group (anxiety disorder at both time points, n = 20). We assessed relative mean TL by real-time quantitative PCR and DNA methylation by Infinium HumanMethylation450 BeadChip. We calculated AA using the Horvath age estimation algorithm and analyzed differences among groups using generalized linear mixed models. The persistent group of anxiety disorder did not change TL over time (p = 0.495). The variable group had higher baseline TL (p = 0.003) but no accelerated TL erosion in comparison to the non-anxiety control group (p = 0.053). Furthermore, there were no differences in AA among groups over time. Our findings suggest that adolescents with chronic anxiety did not change telomere length over time, which could be related to a delay in neuronal development in this period of life.
Article
Background: Prior research has suggested a possible link between heroin use and shortened telomere length (TL), a marker of cellular aging and genomic stability. We sought to replicate these findings by examining the relationship between TL and heroin use among individuals of African ancestry. Methods: This cross-sectional study examined TL among 57 participants [17.5 % female; mean age 48.0 (±6.80) years] of African ancestry with Opioid Use Disorder (OUD) and a mean heroin use duration of 18.2 (±10.7) years. Quantitative polymerase chain reaction (qPCR) was used to calculate TL as the ratio between telomere repeat copy number (T) and a single-copy gene, copy number (S). The primary dependent variable was TL (T/S Ratio) measured in kilobase pairs. Covariates included heroin use years and personality traits. Using a hybrid approach, multiple linear regression and Bayesian linear regression examined the association of chronological age, heroin use years and personality traits with TL. Results: The multiple linear regression model fit the data well, R2 = 0.265, F(7,49) = 2.53, p < .026. Chronological age (β = -0.36, p = .017), neuroticism (β = 0.46, p = .044), and conscientiousness (β = 0.52, p = .040) were significant predictors of TL. Bayesian linear regression provided moderate support for the alternate hypothesis that chronological age and TL are associated, BF10 = 5.77, R2 = 0.120. The posterior summary of the coefficient was M = 0.719 (SD = 0.278, 95 % credible interval [-1.28, -0.163]). Conclusions: Contrary to prior studies, these findings suggest that heroin use duration may not be significantly associated with TL among individuals of African ancestry, highlighting the need for more rigorous research to elucidate the complexity of this relationship.
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Depression, anxiety, cognitive impairment, and pain are the most common mental symptoms exhibited in a wide range of diseases. Recent progress in neuroscience has led to better understanding of those dreadful symptoms; currently, state-of-the-art brain research attempts to untangle this complex phenomenon through preclinical, clinical, and computational approaches. This E-Book complies the most recent studies published in the Special Issue “Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry 2.0”, discussing the most recent cutting-edge research and its integrative potential of interdisciplinary arena for new study design and methodology in behavioral neurology and neuropsychiatry.
Article
Background Among war veterans, research has indicated high rates of depression, anxiety, and comorbidity of these disorders, with even higher rates among prisoners-of-war. However, little is known about the longitudinal effects of comorbidity profiles on cognitive performance, particularly in the case of aging war veterans. Method This longitudinal study focuses on Israeli veterans from the 1973 Yom Kippur War, with assessments at four time-points: 1991 (T1), 2003 (T2), 2008 (T3), and 2015 (T4). Two groups were included: veterans who were held captive (ex-POWs; n = 196), and veterans who were not (war veterans; n = 159). Participants completed validated self-report measures, and their cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA). Results Three distinct profiles of comorbidity were identified: resiliency (57.5%, n = 204); delayed-onset (29.6%, n = 105), and chronic (13.00%, n = 46). The chronic profile identified mostly among ex-POW (91.3%, n = 42), veterans with lower education at T1, and with more cognitively impaired compared to the other profiles (p < .0001). No differences were found between the profiles in age and family status at T1. Conclusions The findings highlight the importance of viewing aging veterans as a high-risk population for cognitive impairments, particularly those suffering from chronic comorbidity of depression and anxiety. Therefore, the appropriate diagnosis and cognitive treatment are required to preserve cognitive abilities and prevent decline.
Article
Background Evidence suggests that depression is a risk factor for dementia in older adults, but the link between depressive symptoms and brain health earlier in life is less understood. Our aim was to investigate the association between long-term depressive symptoms in young to mid-adulthood and a measure of brain age derived from structural MRI. Methods From the Coronary Artery Risk Development in Young Adults study, we identified 649 participants (age 23–36 at baseline) with brain MRI and cognitive testing. Long-term depressive symptoms were measured with the Center for Epidemiological Studies Depression scale (CESD) six times across 25 years and analyzed as time-weighted averages (TWA). Brain age was derived using previously validated high dimensional neuroimaging pattern analysis, quantifying individual differences in age-related atrophy. Linear regression was used to test the association between TWA depressive symptoms, brain aging, and cognition. Results Each standard deviation (5-points) increment in TWA depression symptoms over 25 years was associated with one-year greater brain age (β: 1.14, 95 % confidence interval [CI]: 0.57 to 1.71). Participants with elevated TWA depressive symptoms had on average a 3-year greater brain age (β: 2.75, 95 % CI: 0.43 to 5.08). Moreover, elevated depressive symptoms were associated with higher odds of poor cognitive function in midlife (OR: 3.30, 95 % CI: 1.37 to 7.97). Limitations Brain age was assessed at one time, limiting our ability to assess the temporality of depressive symptoms and brain aging. Conclusions Elevated depressive symptoms in early adulthood may have implications for brain health as early as in midlife.
Article
Background Telomerase is a cellular enzyme that prevents telomere shortening and promoting viability. The literature has reported shortened telomere length in patients with major depressive disorder (MDD). Methods 35 patients with diagnosis of major depressive disorder (MDD) fulfilling DMS-5 criteria in the age range of 18–60 years, treatment-naïve after assessing the severity on HAM-D and HAM-A and 35 age and sex matched healthy controls were included in the study. Baseline peripheral blood monocytes (PBMC) telomerase enzyme was assessed in cases and controls and repeated in cases of MDD at 8th week after intervention with escitalopram for 8 weeks. Results Pretreatment telomerase activity (TA) was elevated in cases as compared to controls and it was also significantly correlated to the severity of depression (p = 0.00). There was a significant positive difference in telomerase activity between non-responders (higher TA) and responders at baseline (p = 0.001) and 8th week (p = 0.012). The TA did not vary significantly amidst pretreatment and post-treatment, although it was slightly lower in the post-treatment group. Limitations The study has few limitations in the form of small sample size, shorter duration of follow-up, and leucocyte telomeres length (LTL) was not assessed. Conclusion The index study concludes that TA is higher in drug naïve patients with MDD than age and sex matched healthy control. The non-responders had significantly higher TA as compared to responders at baseline and post-treatment which indicates TA as a potential biomarker in the underlying biological mechanism of MDD and in response to antidepressant pharmacotherapy.
Article
Cycloastragenol (CAG) is a sapogenin of Astragaloside IV (AG-IV), isolated from the dried roots of legumes Astragalus mongolica or Astragalus membranaceus. Cycloastragenol has a steroidal skeleton of tetracyclic triterpene and possess diverse pharmacological activities such as anti-aging, anti-inflammatory, anti-fibrosis, pro-wound healing, liver protection and endothelial protection. In addition, cycloastragenol is the only telomerase activator reported in natural products, which is closely related to MAPK and PI3K/Akt signaling pathways. This review provides a theoretical basis for the development of cycloastragenol into the candidate for the treatment of multi-factorial diseases in clinic, focusing on the extensively biological activities as well as the mechanism of action and structural modification and aiming to attract researchers to conduct in-depth studies on cycloastragenol. Meanwhile, the pharmacokinetics and toxicology studies of CAG are also described for further druggability exploration to provides valuable reference.
Article
Major depressive disorder (MDD) and suicide have been associated with elevated indices of oxidative damage in the brain, as well as white matter pathology including reduced myelination by oligodendrocytes. Oligodendrocytes highly populate white matter and are inherently susceptible to oxidative damage. Pathology of white matter oligodendrocytes has been reported to occur in brain regions that process behaviors that are disrupted in MDD and that may contribute to suicidal behavior. The present study was designed to determine whether oligodendrocyte pathology related to oxidative damage extends to brain areas outside of those that are traditionally considered to contribute to the psychopathology of MDD and suicide. Relative telomere lengths and the gene expression of five antioxidant-related genes, SOD1, SOD2, GPX1, CAT, and AGPS were measured in oligodendrocytes laser captured from two non-limbic brain areas: occipital cortical white matter and the brainstem locus coeruleus. Postmortem brain tissues were obtained from brain donors that died by suicide and had an active MDD at the time of death, and from psychiatrically normal control donors. Relative telomere lengths were significantly reduced in oligodendrocytes of both brain regions in MDD donors as compared to control donors. Three antioxidant-related genes (SOD1, SOD2, GPX1) were significantly reduced and one was significantly elevated (AGPS) in oligodendrocytes from both brain regions in MDD as compared to control donors. These findings suggest that oligodendrocyte pathology in MDD and suicide is widespread in the brain and not restricted to brain areas commonly associated with depression psychopathology.
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Psychotherapy is one of the evidence-based clinical interventions for the treatment of depression in older adults with dementia. Randomised controlled trials are often the first methodological choice to gain evidence, yet they are not applicable to a wide range of humanistic psychotherapies. Amongst all, the efficacy of the Gestalt therapy (GT) is under-investigated. The purpose of this paper is to present a research protocol, aiming to assess the effects of a GT-based intervention on people with dementia (PWD) and indirect influence on their family carers. The study implements the single-case experimental design with time series analysis that will be carried out in Italy and Mexico. Six people in each country, who received a diagnosis of dementia and present depressive symptoms, will be recruited. Eight or more GT sessions will be provided, whose fidelity will be assessed by the GT fidelity scale. Quantitative outcome measures are foreseen for monitoring participants’ depression, anxiety, quality of life, loneliness, carers’ burden, and the caregiving dyad mutuality at baseline and follow-up. The advantages and limitations of the research design are considered. If GT will effectively result in the treatment of depression in PWD, it could enrich the range of evidence-based interventions provided by healthcare services.
Chapter
Biomarkers of PTSD are greatly needed because of the challenges to diagnose and treat due to stigma, biases in self-reporting, and limitations of identifying those at risk and the scarcity of tools to predict treatment outcome. PTSD is influenced by both genetic and environmental factors as well as its interplay. Because of the dynamic and context-dependent nature of epigenetic modifications, these offer great promise as biomarkers of PTSD for the prevention, prognosis, and prediction of treatment outcome. In this chapter, genomic and epigenomic studies of PTSD are discussed. Epigenomic studies of PTSD conducted to date include DNA methylation (including DNA methylation age), histone modifications, and noncoding RNAs. Further, we discuss recent work using integrative multiomics approach as well as related gaps, challenges, and future directions aimed at identifying biomarkers of PTSD.
Article
Impaired mitochondrial function and abnormalities in the tryptophan (Trp)-kynurenine (Kyn) pathway are linked to age-related mood disorders. This study investigated the effect of intracerebroventricular (ICV) injection of the mitochondria isolated from young rat brain on depression-like behaviors of aged rats subjected to chronic mild stress (CMS). Aged (22 months old) male rats were randomly assigned into four groups: Aged, Aged + Mit, Aged + CMS, and Aged + CMS + Mit. Anxiety- and depression-like behaviors were assessed using elevated plus maze (EPM), open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT). Mitochondrial membrane potential (MMP), ATP levels, indoleamine 2, 3-dioxygenase (IDO) levels, and Kyn metabolites were measured in the prefrontal cortex (PFC). Golgi Cox staining was used to investigate the neuronal morphology. Mitotherapy decreased immobility time and anhedonia in the FST; increased open arm time and entries in the EPM; decreased grooming and increased rearing, center time, and the entrance in the OFT. Mitotherapy also reduced IDO and Kyn metabolites, restored MMP and ATP production, and enhanced dendritic length and spine density in the PFC. Overall, mitotherapy improved anxiety-and depression-like behaviors in aged rats and it could be considered as a new therapeutic strategy for age-related depressive disorders.
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Objective: Brain's aerobic energy metabolism, abundance of the fatty acids and unsaturated lipids, generation of Reactive Oxygen Species (ROS) by hormones, physiological roles of transition metals (i.e., iron and copper), and free radicals in the nervous system may cause inclination to oxidative stress in psychiatric disorders. Electroconvulsive therapy (ECT) may cause oxidative stress by the electrical field or by the induced seizure. It was aimed to review the literature in terms of the influence of ECT on levels of oxidant and antioxidant compounds. Methods: The literature search was performed with the keywords that were oxidative stress or "DNA damage" or "RNA damage" or "lipid peroxidase" or "superoxide dismutase" or "catalase" or "glutathione" or "nitrite" or "nitric oxide" and "electroconvulsive therapy" or "electroconvulsive shock" or "electroconvulsive seizure". Twenty of 1480 records were included. Results: Eleven studies were performed in human subjects, whereas 9 studies were performed in rats. Human studies are conducted with serum, plasma, or urine samples; rat studies include brain tissues from various sites. In rats, four independent studies showed increased levels of lipid oxidation markers, and four independent studies reported increased levels of oxidative stress markers in brain samples. In human studies, studies were performed with circulating blood samples and the results were more inconsistent. Conclusion: Although some markers like superoxide dismutase or thioredoxin imply that ECT may increase the balance for oxidative stress, this notion is not supported by other markers of ECT. The current literature does not clearly suggest that the ECT is associated with oxidative stress in psychiatric disorders. Further studies with similar methods should be performed in big samples.
Article
Background/Objectives – Frailty is highly prevalent with increasing age. Based on the concept of depression as a disorder of accelerated ageing and its association with inflammation and metabolic dysregulation, we examined whether frailty measures at baseline and over time differed between immuno-metabolic subtypes of late-life depression. Methods – Clinical cohort study in primary and secondary mental health care with two-year follow-up. In total 359 depressed older patients (≥ 60 years) classified in four immuno-metabolic subgroups by latent profile analysis. We compared frailty measures at baseline and two-year follow-up adjusted for confounders between immuno-metabolic based depressed subgroups. Frailty measures included the frailty index, physical frailty phenotype, and two proxies (handgrip strength, gait speed). Results – At baseline, the relatively healthy depressed subgroup (n=181) performed best on all frailty markers. While frailty markers worsened over time, the two-year course did not differ between the subgroups for any of these markers. Conclusion – The more severe immuno-metabolic dysregulation present in late-life depression, the more frail. Nonetheless, as trajectories over time did not differ between subgroups, the difference probably emerged at midlife. Future studies should examine whether geriatric assessment might become relevant at earlier ages in specialized mental health care.
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Background Dementia and depression have emerged as two of the major mental health concerns for elderly people, which are likely to substantially affect public health in the coming decades. Both dementia and geriatric depression are associated with increased morbidity, health care utilization, and mortality. Early detection and treatment initiation are some of the best strategies to minimize the ill effects of dementia and depression on the elderly people. To this end, large-scale screening may be the first step. Methods Screening of individuals ≥65 years old was conducted in the outpatient department of a university hospital. Ascertainment of dementia 8 (AD8) and five-item Brief Symptom Rating Scale (BSRS-5) were used to screen for cognitive decline and depression, respectively. Findings In total, 3079 elderly people completed both AD8 and BSRS-5. Patients tested positive for cognitive impairment and depression were 28.2% and 15%, respectively. However, 7% were tested positive by both AD8 and BSRS-5 and with statistical significance. Interpretation The high ratio of suspected dementia and suspected depression suggested the needs and cost-effect of screening among the elderly outpatients. However, the statistically significant overlap implied potential bias when screening only one condition. Future screening program of geriatric mental health needs to consider this.
Article
Objectives This study examined whether childhood chronic physical illness burden was associated with major depression in later life (>50 years) and whether this relationship was mediated by childhood mental health status. Method Data came from the 2016 United States Health and Retirement Study (n = 18,483). Logistic regression tested associations of childhood chronic physical illness burden with childhood mental health status and major depression in later life. Path analysis quantified mediation of the association between chronic physical illness burden and major depression by childhood mental health status. Results One standard deviation increase in childhood chronic physical illness burden was associated with 1.34 (95% CI = 1.25, 1.43) times higher odds of major depression in later life. Childhood mental health status explained 53.4% (95% CI: 37.3%, 69.6%) of this association. In follow-up analyses of categorical diagnoses, having difficulty seeing, ear problems or infections, a respiratory disorder, asthma, an allergic condition, epilepsy or seizures, migraines or severe headaches, heart trouble, stomach problems, or a disability lasting ≥6 months was associated with major depression in later life with mediation by childhood mental health status. Conclusion Findings of this study indicate that children with a higher chronic physical illness burden are more likely to have major depression in later life and poor mental health during childhood mediates this relationship. Further research is needed to determine whether increased screening and treatment of psychiatric symptoms in pediatrics can decrease the burden of major depression across the life course.
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Frailty is a condition in which there is a reduced reserve capacity of the physiological systems that can lead to serious health problems when exposed to physical and psychosocial stressors. Although the clinical relevance of frailty is increasingly recognized within somatic health care, this concept is hardly applied in mental health care. Possibly the complex relationship and interaction between frailty and psychopathology underlies this. After all, many forms of psychopathology seem to be associated with accelerated biological aging and can actually be seen as a frailty model. In addition, geriatric studies often exclude patients with a psychiatric disorder. Our research shows that frailty, defined according to the biomedical frailty model, can be validly measured in elderly people with a depressive disorder. First, frailty was associated with various biomarkers of aging, such as increased inflammation parameters, shortened telomere length and decreased vitamin D levels. Second, frailty also predicted premature death within a group of depressed elderly. Frailty also appears to be clinically relevant as a predictor for a worse course of depression and may provide an explanation for medically unexplained symptoms in the elderly. Our findings indicate the existence of a so-called "depression-frailty subtype", a group of depressed elderly people with a poor mental and physical prognosis. Integrated somatic and mental health care seems appropriate for this group. Future treatment studies will have to show which interventions can improve the prognosis of these vulnerable groups. This could include a reduction in polypharmacy, more physical activity, nutritional interventions and psychotherapeutic interventions.
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The enduring effects of abuse and related adverse experiences in childhood. A convergence of evidence from neurobiology and epidemiology . Anda R.F., Felitti V.J., Bremner J.D., Walker J.D., Whitfield C., Perry B.D., Dube S.R. & Giles W.H. ( 2005 ) European Archives of Psychiatry and Clinical Neuroscience , ePub, posted online 29 November 2005 . Background Childhood maltreatment has been linked to a variety of changes in brain structure and function and stress–responsive neurobiological systems. Epidemiological studies have documented the impact of childhood maltreatment on health and emotional well-being. Methods After a brief review of the neurobiology of childhood trauma, we use the Adverse Childhood Experiences (ACE) Study as an epidemiological ‘case example’ of the convergence between epidemiological and neurobiological evidence of the effects of childhood trauma. The ACE Study included 17 337 adult HMO (Health Maintenance Organization) members and assessed eight adverse childhood experiences (ACEs) including abuse, witnessing domestic violence, and serious household dysfunction. We used the number of ACEs (ACE score) as a measure of cumulative childhood stress and hypothesized a ‘dose–response’ relationship of the ACE score to 18 selected outcomes and to the total number of these outcomes (comorbidity). Results Based upon logistic regression analysis, the risk of every outcome in the affective, somatic, substance abuse, memory, sexual, and aggression-related domains increased in a graded fashion as the ACE score increased (P < 0.001). The mean number of comorbid outcomes tripled across the range of the ACE score. Conclusions The graded relationship of the ACE score to 18 different outcomes in multiple domains theoretically parallels the cumulative exposure of the developing brain to the stress response with resulting impairment in multiple brain structures and functions.
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Studies of the association between depressive symptoms and mortality in elderly populations have yielded contradictory findings. To address these discrepancies, we test this association using the most extensive array of sociodemographic and physical health control variables ever studied, to our knowledge, in a large population-based sample of elderly individuals. To examine the relation between baseline depressive symptoms and 6-year all-cause mortality in older persons, systematically controlling for sociodemographic factors, clinical disease, subclinical disease, and health risk factors. A total of 5201 men and women aged 65 years and older from 4 US communities participated in the study. Depressive symptoms and 4 categories of covariates were assessed at baseline. The primary outcome measure was 6-year mortality. Of the 5201 participants, 984 (18.9%) died within 6 years. High baseline depressive symptoms were associated with a higher mortality rate (23.9%) than low baseline depression scores (17.7%) (unadjusted relative risk [RR], 1.41; 95% confidence interval [CI], 1.22-1.63). Depression was also an independent predictor of mortality when controlling for sociodemographic factors (RR, 1.43; 95% CI, 1.23-1.66), prevalent clinical disease (RR, 1.25; 95% CI, 1.07-1.45), subclinical disease indicators (RR, 1.35; 95% CI, 1.15-1.58), or biological or behavioral risk factors (RR, 1.42; 95% CI, 1.22-1.65). When the best predictors from all 4 classes of variables were included as covariates, high depressive symptoms remained an independent predictor of mortality (RR, 1.24; 95% CI, 1.06-1.46). High levels of depressive symptoms are an independent risk factor for mortality in community-residing older adults. Motivational depletion may be a key underlying mechanism for the depression-mortality effect.
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Venlafaxine is an approved antidepressant that is an inhibitor of both serotonin and norepinephrine transporters. Medical treatment with oral venlafaxine can be beneficial to depression due to reducing free radical production in the brain and medulla of depression- induced rats because oxidative stress may a play role in some depression. We investigated the effect of venlafaxine administration and experimental depression on lipid peroxidation and antioxidant levels in cortex brain, medulla and erythrocytes of rats. Thirty male wistar rats were used and were randomly divided into three groups. Venlafaxine (20mg/kg) was orally supplemented to depression-induced rats constituting the first group for four week. Second group was depression-induced group although third group was used as control. Depressions in the first and second groups were induced on day zero of the study by chronic mild stress. Brain, medulla and erythrocytes samples were taken from all animals on day 28. Depression resulted in significant decrease in the glutathione peroxidase (GSH-Px) activity and vitamin C concentrations of cortex brain, glutathione (GSH) value of medulla although their levels were increased by venlafaxine administration to the animals of depression group. The lipid peroxidation levels in the three tissues and nitric oxide value in cortex brain elevated although their levels were decreased by venlafaxine administration. There were no significant changes in cortex brain vitamin A, erythrocytes vitamin C, GSH-Px and GSH, medulla vitamin A, GSH and GSH-Px values. In conclusion, cortex brain within the three tissues was most affected by oxidative stress although there was the beneficial effect of venlafaxine in the brain of depression-induced rats on investigated antioxidant defenses in the rat model. The treatment of depression by venlafaxine may also play a role in preventing oxidative stress.
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We investigated the effects of lamotrigine, aripiprazole and escitalopram administration and experimental depression on lipid peroxidation (LP) and antioxidant levels in cortex of the brain in rats. Forty male wistar rats were randomly divided into five groups. First group was used as control although second group was depression-induced group. Aripiprazole, lamotrigine and escitalopram per day were orally supplemented to chronic mild stress (CMS) depression-induced rats constituting the third, fourth and fifth groups for 28 days, respectively. Depression resulted in significant decrease in the glutathione peroxidase (GSH-Px) activity, reduced glutathione and vitamin C of cortex of the brain although their levels and beta-carotene concentrations were increased by the three drugs administrations to the animals of CMS induced depression group. The LP levels in the cortex of the brain and plasma of depression group were elevated although their levels were decreased by the administrations. The increases of antioxidant values in lamotrigine group were higher according to aripiprazole and escitalopram supplemented groups. Vitamin A level did not change in the five groups. In conclusion, the experimental depression is associated with elevated oxidative stress although treatment with lamotrigine has most protective effects on the oxidative stress within three medicines.
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Several studies have found reduced hippocampal volume in patients with unipolar depression, but discrepancies exist. The authors performed a systematic review and meta-analysis of volumetric studies of the hippocampus in patients with mood disorders. Studies of hippocampal volume in unipolar and bipolar patients were identified. A meta-analysis of the 12 studies of unipolar depression fulfilling specific criteria was performed. The sample comprised 351 patients and 279 healthy subjects. The studies were highly heterogeneous regarding age and gender distribution, age at onset of the disorder, average number of episodes, and responsiveness to treatment, but the pooled effect size of depression was significant in both hemispheres for the unipolar patients. The weighted average showed a reduction of hippocampal volume of 8% on the left side and 10% on the right side. The causes of the heterogeneity were analyzed, and a meta-regression showed that the total number of depressive episodes was significantly correlated to right but not left hippocampal volume reduction. Hippocampal volume is reduced in patients with unipolar depression, maybe as a consequence of repeated periods of major depressive disorder. Bipolar patients did not seem to show a reduction in hippocampal volume, but this has been much less investigated.
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We recently reported that fluoxetine or paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats, increase the brain content of the neurosteroid 3alpha-hydroxy-5alpha-pregnane-20-one (3alpha5alpha-ALLO) without altering the brain content of other neurosteroids. ALLO (3alpha5alpha and 3alpha5beta isomers) binds with high affinity to various gamma-aminobutyric acid (GABA) receptor A subtypes and facilitates the action of GABA at these receptors. We hypothesized that the increase of ALLO brain content induced by treatment with SSRIs could contribute to alleviating the anxiety and dysphoria associated with the symptomatology of major unipolar depression. We measured ALLO content in four cisternal-lumbar fractions of cerebrospinal fluid (CSF) before and 8-10 weeks after treatment with fluoxetine or fluvoxamine in 15 patients with unipolar major depression. The concentration of ALLO ( approximately 40 fmol/ml in each CSF fraction of three control subjects) was about 60% lower in patients with major unipolar depression. However, in the same patients, fluoxetine or fluvoxamine treatment normalized the CSF ALLO content. Moreover, a statistically significant correlation (r = 0.58; P < 0.023; n = 15) existed between symptomatology improvement (Hamilton Rating Scale for Depression scores) and the increase in CSF ALLO after fluoxetine or fluvoxamine treatment. The CSF content of PREG and PROG remained unaltered after treatment and failed to correlate with the SSRI-induced increase of CSF ALLO. The normalization of CSF ALLO content in depressed patients appears to be sufficient to mediate the anxiolytic and antidysphoric actions of fluoxetine or fluvoxamine via its positive allosteric modulation of GABA type A receptors.
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Telomere length (TL) has been proposed as a marker of mitotic cell age and as a general index of human organismic aging. Short absolute leukocyte telomere length has been linked to cardiovascular-related morbidity and mortality. Our aim was to test whether the rate of change in leukocyte TL is related to mortality in a healthy elderly cohort. We examined a subsample of 236 randomly selected Caucasian participants from the MacArthur Health Aging Study (aged 70 to 79 years). DNA samples from baseline and 2.5 years later were assayed for mean TL of leukocytes. Percent change in TL was calculated as a measure of TL change (TLC). Associations between TL and TLC with 12-year overall and cardiovascular mortality were assessed. Over the 2.5 year period, 46% of the study participants showed maintenance of mean bulk TL, whereas 30% showed telomere shortening, and, unexpectedly, 24% showed telomere lengthening. For women, short baseline TL was related to greater mortality from cardiovascular disease (OR = 2.3; 95% CI: 1.0 - 5.3). For men, TLC (specifically shortening), but not baseline TL, was related to greater cardiovascular mortality, OR = 3.0 (95% CI: 1.1 - 8.2). This is the first demonstration that rate of telomere length change (TLC) predicts mortality and thus may be a useful prognostic factor for longevity.
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Major depression occurs in 4.4% to 20% of the general population. Studies suggest that major depression is accompanied by immune dysregulation and activation of the inflammatory response system (IRS). Our objective was to quantitatively summarize the data on concentrations of specific cytokines in patients diagnosed with a major depressive episode and controls. We performed a meta-analysis of studies measuring cytokine concentration in patients with major depression, with a database search of the English literature (to August 2009) and a manual search of references. Twenty-four studies involving unstimulated measurements of cytokines in patients meeting DSM criteria for major depression were included in the meta-analysis; 13 for tumor necrosis factor (TNF)-alpha, 9 for interleukin (IL)-1beta, 16 for IL-6, 5 for IL-4, 5 for IL-2, 4 for IL-8, 6 for IL-10, and 4 for interferon (IFN)-gamma. There were significantly higher concentrations of TNF-alpha (p < .00001), weighted mean difference (WMD) (95% confidence interval) 3.97 pg/mL (2.24 to 5.71), in depressed subjects compared with control subjects (438 depressed/350 nondepressed). Also, IL-6 concentrations were significantly higher (p < .00001) in depressed subjects compared with control subjects (492 depressed/400 nondepressed) with an overall WMD of 1.78 pg/mL (1.23 to 2.33). There were no significant differences among depressed and nondepressed subjects for the other cytokines studied. This meta-analysis reports significantly higher concentrations of the proinflammatory cytokines TNF-alpha and IL-6 in depressed subjects compared with control subjects. While both positive and negative results have been reported in individual studies, this meta-analytic result strengthens evidence that depression is accompanied by activation of the IRS.
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Elevated circulating levels of glucocorticoids are associated with psychiatric symptoms across several different conditions. It remains unknown if this hormonal abnormality is a cause or an effect of the psychiatric conditions. For example, the hypercortisolemia observed in a subset of patients with depression may have a direct impact on the symptoms of depression, but it is also possible that the hypercortisolemia merely reflects the stress associated with depression. Further, rather than causing depression, hypercortisolemia could represent a homeostatic attempt to overcome glucocorticoid resistance. Each of these possibilities will be considered, and correlational and causal evidence will be reviewed. This article will focus on the relationships between glucocorticoids and psychiatric symptoms in Cushing's syndrome, major depression, and steroid psychosis/steroid dementia, as well as the effects of exogenously administered glucocorticoids in normal volunteers. Similarities and differences in the relationship of glucocorticoid hormones to psychiatric symptoms in these conditions will be reviewed. Possible mediators of glucocorticoid effects on the brain and behavior, as well as possible "pro-aging" effects of glucocorticoids in certain cells of the body, will be reviewed. The article concludes with a conceptual model of glucocorticoid actions in the brain that may lead to novel therapeutic opportunities.
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Nervous and immune system interact through many different messenger substances such as neurotransmitters, cytokines or neuropeptides. For instance, neuropeptides are capable of affecting the metabolism of cells belonging to the immune system. Conversely, cytokines such as tumor necrosis factor (TNF)-alpha, interferon (IFN)-alpha and IFN-gamma, contribute to the receptor resistance of neuropeptides, reduce the availability of amino acids which are needed for the synthesis of neurotransmitters or show neurotoxic effects. Other cytokines like granulocyte-colony stimulating factor (G-CSF) may be highly attractive candidates for the treatment of neurodegenerative conditions. Cytokines are decisively involved in the pathophysiology of psychiatric disorders such as depression, schizophrenia or anorexia nervosa as well as in neurological, respectively neurodegenerative diseases like Parkinson's or Alzheimer's. This connection between the immune system and the pathogenesis of psychiatric disorders leads to the concept that immunomodulatory drugs which are already in use for various diseases related to the immune system may also be efficient in the treatment of psychiatric disorders. This article is supposed to give an overview over the current concepts and possibilities since hopefully these hypotheses lead to new therapeutical strategies for psychiatric patients in the future.
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