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Telomere Shortening and Mood Disorders: Preliminary Support for a Chronic Stress Model of Accelerated Aging
Abstract
Little is known about the biological mechanisms underlying the excess medical morbidity and mortality associated with mood disorders. Substantial evidence supports abnormalities in stress-related biological systems in depression. Accelerated telomere shortening may reflect stress-related oxidative damage to cells and accelerated aging, and severe psychosocial stress has been linked to telomere shortening. We propose that chronic stress associated with mood disorders may contribute to excess vulnerability for diseases of aging such as cardiovascular disease and possibly some cancers through accelerated organismal aging.
Telomere length was measured by Southern Analysis in 44 individuals with chronic mood disorders and 44 nonpsychiatrically ill age-matched control subjects.
Telomere length was significantly shorter in those with mood disorders, representing as much as 10 years of accelerated aging.
These results provide preliminary evidence that mood disorders are associated with accelerated aging and may suggest a novel mechanism for mood disorder-associated morbidity and mortality.
... and telomere shortening in a meta-analysis with forty-four studies (n = 3,767: BD = 1,979; HCs = 1,788) [14]. In addition, these patients more frequently present other medical conditions during the illness, such as cardiovascular and endocrine diseases and even dementia, leading some researchers to consider BD as a disorder of accelerated aging [15,16]. ...
... Only one study reported on telomere length in BD in relation to a demographically controlled reference sample, and the authors found no association between LTL and BD [44]. The first report investigating mood disorders and LTL found an association between shorter LTL and depression or BD when compared to controls [15]. More recently, Powell et al. [45] provided evidence that a shortened telomere length is associated with family BD risk. ...
... The telomeric length of control subjects and patients with BD and their respective relatives was compared and it was found that both the BD group and the BD relative group presented smaller telomeric sizes in relation to the control groups. Other subsequent studies investigating LTL and BD did not confirm an overall association between BD and shorter LTL when compared to healthy controls [15,16,42,[46][47][48]. Even so, no differences were found in telomere length between BD and healthy relatives in 22 families. ...
Bipolar Disorder (BD) has recently been related to a process of accelerated aging, with shortened leukocyte telomere length (LTL) in this population. It has also been observed that the suicide rate in BD patients is higher than in the general population, and more recently the telomere length variation has been described as shorter in suicide completers compared with control subjects. Objectives The aim of the present study was to investigate if there is an association between LTL and BD in families where two or more members have BD including clinical symptomatology variables, along with suicide behavior. Methods Telomere length and single copy gene ratio (T/S ratio) was measured using quantitative polymerase chain reaction in a sample of 143 relatives from 22 families, of which 60 had BD. The statistical analysis was performed with a polygenic mixed model. Results LTL was associated with suicidal ideation (p = 0.02) as that there is an interaction between suicidal ideation and course of the disorder (p = 0.02). The estimated heritability for LTL in these families was 0.68. In addition, covariates that relate to severity of disease, i.e. suicidal ideation and course of the disorder, showed an association with shorter LTL in BD patients. No difference in LTL between BD patients and healthy relatives was observed. Conclusion LTL are shorter in subjects with familial BD suggesting that stress related sub-phenotypes possibly accelerate the process of cellular aging and correlate with disease severity and suicidal ideation.
... Here we define OABD as individuals with BD and an age of 40 years or more, as an age of 40 years provides a more comprehensive picture of BD during later life that is more able to encompass individuals with a later onset of the illness [10]. Moreover, as this is a review of structural neuroimaging, it considers work suggesting that the brain begins to undergo age-related gray and white matter declines during the fourth decade of life [13,14], which is especially pertinent to OABD given hypotheses suggesting that it may be characterized by accelerated aging processes [15][16][17]. ...
... While differences at the group-level in GM and WM structure appear to be present in OABD, it is still unclear whether the illness is associated with differences in brain aging processes. It has been proposed that BD is characterized by accelerated biological aging [15][16][17], a hypothesis supported by findings in BD of more pronounced markers of biological aging such as shorter telomeres [92], greater markers of oxidative stress [93], and reduced mitochondrial DNA copy numbers [94]. Moreover, findings of group differences showing lower GM properties and FA in BD have been used to suggest that accelerated aging of the brain may also be a characteristic of the illness [15][16][17], given that these structural properties decline during typical aging [95][96][97][98][99]. ...
... It has been proposed that BD is characterized by accelerated biological aging [15][16][17], a hypothesis supported by findings in BD of more pronounced markers of biological aging such as shorter telomeres [92], greater markers of oxidative stress [93], and reduced mitochondrial DNA copy numbers [94]. Moreover, findings of group differences showing lower GM properties and FA in BD have been used to suggest that accelerated aging of the brain may also be a characteristic of the illness [15][16][17], given that these structural properties decline during typical aging [95][96][97][98][99]. However, as many of these differences in GM and WM have also been found in younger samples, their causes may be neurodevelopmental rather than related to aging. ...
Bipolar disorder (BD) is a common mood disorder that can have severe consequences during later life, including suffering and impairment due to mood and cognitive symptoms, elevated risk for dementia and an especially high risk for suicide. Greater understanding of the brain circuitry differences involved in older adults with BD (OABD) in later life and their relationship to aging processes is required to improve outcomes of OABD. The current literature on gray and white matter findings, from high resolution structural and diffusion-weighted magnetic resonance imaging (MRI) studies, has shown that BD in younger age groups is associated with gray matter reductions within cortical and subcortical brain regions that subserve emotion processing and regulation, as well as reduced structural integrity of white matter tracts connecting these brain regions. While fewer neuroimaging studies have focused on OABD, it does appear that many of the structural brain differences found in younger samples are present in OABD. There is also initial suggestion that there are additional brain differences, for at least a subset of OABD, that may result from more pronounced gray and white matter declines with age that may contribute to adverse outcomes. Preclinical and clinical data supporting neuro-plastic and -protective effects of mood-stabilizing medications, suggest that treatments may reverse and/or prevent the progression of brain changes thereby reducing symptoms. Future neuroimaging research implementing longitudinal designs, and large-scale, multi-site initiatives with detailed clinical and treatment data, holds promise for reducing suffering, cognitive dysfunction and suicide in OABD.
... 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 ...
... 2,12 MDD's association with shortened telomere length is thought to be bidirectionally influenced by inflammation such that inflammation exacerbates telomere attrition and telomere dysfunction induces inflammation (Fig. 14.2). 2,11,72,74 With this bidirectionality, disentangling the mechanisms by which MDD influence accelerated aging has been complicated; however, animal models have proved useful in exploring these concepts. An animal model of depression exhibited decreased telomerase activity, telomere shortening, and increased oxidative damage when placed under chronic mild stress. ...
... 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. ...
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.
... Findings from controlled and randomised controlled trials suggest changes in immune-related biomarkers may reflect one pathway by which MBIs' impact the prevention, progression, or cessation of disease (Davidson et al., 2003). Specifically, MBIs have been shown to reduce psychological and oxidative stress (Adachi, Kawamura, & Takemoto, 1993;Simon et al., 2006), suggesting they may impact somatic disorders by modulating the immunosuppressive effects of stressors on immune function. ...
... The two immune parameters demonstrated to most saliently benefit from MBIs in this meta-analysis (i.e., inflammatory regulation & cell ageing) offer a link between MBIs and disease. In that, chronic psychological stress is associated with reduced telomerase activity, shortened telomere length and an increase in inflammatory, and oxidative stress processes (Damjanovic et al., 2007;Epel et al., 2004;Hubert et al., 2010;Puterman et al., 2010;Segerstrom & Miller, 2004;Simon et al., 2006). Extant literature shows that MBIs can reduce psychological and oxidative stress (Adachi et al., 1993;Simon et al., 2006), suggesting MBIs may impact somatic disorders by modulating the immunosuppressive effects of stressors on immune function. ...
... In that, chronic psychological stress is associated with reduced telomerase activity, shortened telomere length and an increase in inflammatory, and oxidative stress processes (Damjanovic et al., 2007;Epel et al., 2004;Hubert et al., 2010;Puterman et al., 2010;Segerstrom & Miller, 2004;Simon et al., 2006). Extant literature shows that MBIs can reduce psychological and oxidative stress (Adachi et al., 1993;Simon et al., 2006), suggesting MBIs may impact somatic disorders by modulating the immunosuppressive effects of stressors on immune function. This is in line with our findings that suggest active control interventions such as relaxation and exercise (which are also related to stress reduction) may attenuate comparative gains observed from MBIs. ...
One proposed pathway mindfulness-based interventions (MBIs) may offer a salutogenic effect on somatic disorders is by enhancing immune function. As such, we conducted a meta-analysis of randomised controlled trials examining the effect of MBIs at post-intervention and follow-up for six immune-related biomarkers, including CD4+ cells, C-reactive protein, interleukin-6, nuclear factor-κB, telomere length, and telomerase activity. Potential studies were identified by searching ScienceDirect, Web of Science, Academic Search Complete, AMED, MEDLINE, PsycARTICLES, and PsycINFO. Searches returned 1476 studies, of which 46 (68 effects) were included (N = 4326). Pooled effect sizes indicate a reduction in C-reactive protein (SMCD = −0.14, 95% CI [−0.26 – -0.01]) and interleukin-6 (SMCD = −0.28, 95% CI [−0.61–0.05]), and an increase in CD4+ (SMCD = 0.09, 95% CI [−0.05–0.22]), telomere length (SMCD = 0.12, 95% CI [0.00–0.24]) and telomerase activity (SMCD = 0.81, 95% CI [0.17–1.46]) at post-intervention. At follow-up, results show a reduction in interleukin-6 (SMCD = −0.11, 95% CI [−0.31–0.09]) and C-reactive protein (SMCD = −0.39, 95% CI [−0.68 – −0.10]) and increase in CD4+ (SMCD = 0.22, 95% CI [−0.08–0.52]). Meta-regression results show that some heterogeneity in effect size can be accounted for by intervention dosage, medical status of the individual, and type of comparison group. Our findings quantify MBIs' potential for improving immune function.
... It has been shown that the shortening of TL can cause cellular senescence and DNA damage and is directly associated with age-related diseases, neurodegenerative disorders, and some psychiatric illnesses [13][14][15][16]. Interestingly, many [17][18][19][20][21][22][23] but not all [24][25][26][27] studies suggest a strong association of TL shortening with psychological stress and MDD in adults. Interestingly, higher severity and longer duration of depressive symptoms have been found to be significantly associated with TL shortening [28]. ...
... The main findings of this study were that TL was significantly reduced and mtDNAcn was significantly increased in depressed adolescents. The results are consistent with findings in most studies of adults with MDD for both TL [17][18][19][20][21][22][23] and mtDNAcn [34]. One prior study in adolescents no association between depressive symptoms and markers of cellular senescence and baseline but did find faster TL shortening and greater increases in mtDNAcn over two years [37]. ...
Major depressive disorder (MDD) is highly prevalent in adolescents and is a major risk factor for suicidality. Recent evidence shows that accelerated cellular senescence/aging is associated with psychiatric illness, including depression, in adults. The present study examined if the relationships of telomere length (TL) and mitochondrial DNA copy number (mtDNAcn), two critical indicators of cellular senescence/aging, are altered in depressed adolescents and whether these alterations are associated with suicidality, early-life adversities, and other co-occuring factors. In genomic DNA isolated from 53 adolescents (ages 16–19, 19 MDD with suicide attempt/suicidal ideation [MDD + SI/SA], 14 MDD without SA/SI [MDD-SI/SA], and 20 healthy controls [HC]), TL and mtDNAcn were measured as the ratio between the number of telomere repeats and that of a single-copy nuclear-hemoglobin [HBG] gene or the amount of mtDNA (NADH dehydrogenase, subunit 1) relative to HBG. Our data show that TL was significantly lower, and mtDNAcn was significantly higher in the total MDD group than HC. TL was significantly lower and mtDNAcn was significantly higher in the MDD + SA/SI group than in the HC, whereas there were no differences in the MDD-SI/SA group. TL was positively correlated with mtDNAcn in both HC and MDD-SA/SI groups; however, TL was negatively correlated with mtDNAcn in MDD + SA/SI. Furthermore, TL was negatively correlated with the severity of both depression and anxiety, while mtDNAcn was positively correlated with the severity of prior emotional abuse. Our study indicates that cellular senescence is more advanced in depressed adolescents with suicidal ideation and that childhood emotional abuse may participate in such a process.
... Based on the evidence for aberrant stress response in depression, for the first time, Simon et al. (2006) have tested accelerated ageing in mood disorders by measuring TL in chronic mood disorder patients (n=44) and age-matched control groups (n=44). They have reported significant telomere shortening in mood disorders, suggesting approximately 10 years of accelerated ageing. ...
... However, one of the most important limitations of this study is that confounding factors (e.g. current/past medication use) were not taken into account, which may affect TL (41). Wolkovitz et al. ...
Introduction:
Telomeres are specialized DNA-protein complexes located at the ends of all chromosomes and act as a "molecular clock" to determine the replicative lifespan of the cells. Recent studies indicate that life-long exposure to stress, starting from the prenatal period, causes many diseases to emerge at an early age, and telomeres may be possible mediators in this process. This article aims to review the relationship between the stress-telomere-disease triad and the potential role of telomere dysfunction in psychopathologies in the light of current literature.
Methods:
A literature search was conducted along the lines of a narrative review. PubMed and Web of Science databases were used to identify all types of articles published from inception to January 2022. After the title/abstract search, articles available in full text and English were selected based on key findings, the applicability of the method used to test the hypothesis, limitations, interpretation of the results, and impact of the results in the field. A total of 73 records were included in this narrative review.
Results:
The fact that some age-related chronic diseases, such as cardiovascular diseases and type 2 diabetes, are seen more frequently and at an earlier age in certain psychopathologies including depression, bipolar disorder, and schizophrenia suggests that these disorders are premature ageing syndromes. Although there are some conflicting results in the literature, in line with this hypothesis, the presence of shortened telomeres reported in these psychopathologies and the impact of lifelong exposure to stress on this process are remarkable.
Conclusion:
Many of the studies point to an association and do not tell much about the causality. Hence, the elucidation of the biological processes underlying the relationship between psychological stress, dysfunctional telomeres and complex, common age-related diseases, as well as psychiatric disorders is important and further studies are needed at the cellular level.
... Shorter TL is associated with stress exposure during prenatal development [6][7][8] and early childhood [9][10][11], as well as with adults' recent stress [12] and chronic stress across the lifespan [4,13,14]. Thus, there is support for the notion that TL is a marker of stress exposure across diverse developmental stages. Furthermore, recent work indicates that TL marks risk for negative health outcomes. ...
... Specifically, shorter TL is associated with poor physical health in adulthood, including metabolic risk factors [15], cardiovascular disease [16], and increased mortality [17,18]. Shorter TL has also been associated with increased psychopathology in adulthood [14,19,20], notably current and remitted depression [21] and anxiety disorders [22,23], an unsurprising pattern of findings given the significant role of stress in internalizing problems. Whether TL-symptom associations are present early in development is unclear, although the limited research available is supportive; for example, Gotlib et al. [24] found shorter TL in children at elevated risk for depression based on maternal history. ...
Shorter telomeres mark cellular aging and are linked to chronic stress exposure as well as negative physical and psychological outcomes. However, it is unclear whether telomere length mediates associations between early stress exposure and later externalizing problems, or whether boys and girls differ in pathways to these concerns. We therefore examined associations between telomere length, early stress via negative caregiving, and children’s externalizing symptom development over time in 409 three-year-old children and their parents. Telomere length mediated the association between early parental intrusiveness and later rule-breaking behavior; however, this association was moderated by children’s biological sex such that parent intrusiveness was related only to boys’ rule-breaking. Findings support the notion that children’s telomere length may mark individual differences in responses to negative early caregiving, and highlight a potential mechanism contributing to the development of rule-breaking problems in boys.
... Several studies investigated TL in patients with MDD and different results have been found, some of which showed that TL is shorter in patients than in non-psychiatric controls [66][67][68][69][70]. Similar findings have been reported in BD [67,[71][72][73][74], and different studies showed that treatment with the mood stabilizer lithium correlated with longer LTL [75][76][77]. ...
... Several studies investigated TL in patients with MDD and different results have been found, some of which showed that TL is shorter in patients than in non-psychiatric controls [66][67][68][69][70]. Similar findings have been reported in BD [67,[71][72][73][74], and different studies showed that treatment with the mood stabilizer lithium correlated with longer LTL [75][76][77]. Fewer studies investigated differences in TL between responders and non-responders to antidepressant treatment. ...
Psychiatric disorders seem to be characterized by premature cell senescence. However, controversial results have also been reported. In addition, the relationship between accelerated aging and treatment-resistance has scarcely been investigated. In the current study, we measured leukocyte telomere length (LTL) in 148 patients with treatment-resistant depression (TRD, 125 with major depressive disorder, MDD, and 23 with bipolar disorder, BD) treated with electroconvulsive therapy (ECT) and analyzed whether LTL was associated with different response profiles. We also compared LTL between patients with TRD and 335 non-psychiatric controls. For 107 patients for which genome-wide association data were available, we evaluated whether a significant overlap among genetic variants or genes associated with LTL and with response to ECT could be observed. LTL was negatively correlated with age (Spearman’s correlation coefficient = −0.25, p < 0.0001) and significantly shorter in patients with treatment-resistant MDD (Quade’s F = 35.18, p < 0.0001) or BD (Quade’s F = 20.84, p < 0.0001) compared to controls. Conversely, baseline LTL was not associated with response to ECT or remission. We did not detect any significant overlap between genetic variants or genes associated with LTL and response to ECT. Our results support previous findings suggesting premature cell senescence in patients with severe psychiatric disorders and suggest that LTL could not be a predictive biomarker of response to ECT.
... However, observational studies regarding the association between depression and TL have presented contradictory results. Some studies have shown an association between depression and TL [51][52][53][54], while others have found no association [55][56][57]. These differing results may be attributed to bias in observational studies. ...
Background
The causal relationship and the direction of the effect between depression and aging remain controversial.
Methods
We used a bidirectional two-sample Mendelian randomization analysis to examine the relationship between depression and age proxy indicators. We obtained pooled statistics from genome-wide association studies (GWAS) on depression and the age proxy indicators. We employed five MR analysis methods to address potential biases and ensure robustness of our results, with the inverse variance weighted (IVW) method being the primary outcome. We also conducted outlier exclusion using Radial MR, MRPRESSO, and MR Steiger filters. Additionally, sensitivity analyses were performed to assess heterogeneity and pleiotropy.
Results
Our MR analysis revealed that depression causally leads to shortened telomere length (β = − 0.014; P = 0.038), increased frailty index (β = 0.076; P = 0.000), and accelerated GrimAge (β = 0.249; P = 0.024). Furthermore, our findings showed that the frailty index (OR = 1.679; P = 0.001) was causally associated with an increased risk of depression. Additionally, we found that appendicular lean mass (OR = 0.929; P = 0.000) and left-hand grip strength (OR = 0.836; P = 0.014) were causally associated with a reduced risk of depression. Sensitivity analyses demonstrated the robustness of our findings.
Conclusions
Our study provides evidence that depression contributes to the accelerated aging process, resulting in decreased telomere length, increased frailty index, and accelerated GrimAge. Additionally, we found that the frailty index increases the risk of depression, while appendicular lean mass and left-handed grip strength reduce the risk of depression.
... Telomere length (TL) has gained popularity as a biomarker; apparently accelerated telomere shortening has been associated with conditions including obesity, diabetes, and cardiovascular disease [17,18]. Additionally, shorter telomere length has been used as a biomarker for exposure to lifetime stress [19][20][21][22]. Several methods have been developed to measure TL [23][24][25]. ...
In quantitative polymerase chain reaction (qPCR) experiments, primers containing mismatches with respect to the template are widely used in measuring repetitive DNA elements. Primer-template mismatches may lead to underestimation of the input sample quantity due to inefficient annealing and amplification. But how primer-template mismatches affect quantification accuracy has not been rigorously investigated. In this study, we performed a series of qPCR experiments in which we tested three pairs of mismatched telomere primers (tel1/tel2, tel1b/tel2b and telg/telc) and two pairs of perfect-match reference gene primers (36B4-F/-R and IFNB1-F/-R) at three different primer concentrations under four cycling conditions. Templates used were genomic DNA from two human cell lines and oligo duplexes which contained telomere sequences, reference gene sequences, or both. We demonstrated that the underestimation of input sample quantity from reactions containing mismatched primers was not due to lower amplification efficiency ( E ), but due to ineffective usage of the input sample. We defined a novel concept of amplification efficacy (f) which quantifies the effectiveness of input sample amplification by primers. We have modified the conventional qPCR kinetic formula to include f , which corrects the effects of primer mismatches. We demonstrated that reactions containing mismatched telomere primer pairs had similar efficiency ( E ), but varying degrees of reduced efficacy ( f ) in comparison to those with the perfect-match gene primer pairs. Using the quantitative parameter f , underestimation of initial target by telomere primers can be adjusted to provide a more accurate measurement. Additionally, we found that the tel1b/tel2b primer set at concentration of 500 nM and 900 nM exhibited the best amplification efficacy f . This study provides a novel way to incorporate an evaluation of amplification efficacy into qPCR analysis. In turn, it improves mismatched primer selection and quantification accuracy in amplifying DNA repeats using qPCR methods.
... Patients with chronic MDD presented with significantly shorter leukocyte telomere lengths (LTL) than healthy controls 38 . The number of depressive episodes has been reported to be associated with a shorter LTL 39 . Furthermore, patients with untreated MDD have significantly shorter telomeres compared to those of controls 40 . ...
Major depressive disorder (MDD) is known to cause significant disability. Genome-wide DNA methylation (DNAm) profiles can be used to estimate biological aging and as epigenetic clocks. However, information on epigenetic clocks reported in MDD patients is inconsistent. Since antidepressants are likely confounders, we evaluated biological aging using various DNAm-based predictors in patients with MDD who had never received depression medication. A publicly available dataset consisting of whole blood samples from untreated MDD patients ( n = 40) and controls ( n = 40) was used. We analyzed five epigenetic clocks (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge), DNAm-based telomere length (DNAmTL), and DNAm-based age-related plasma proteins (GrimAge components), as well as DNAm-based white blood cell composition. The results indicate that patients with untreated MDD were significantly associated with epigenetic aging acceleration in HannumAge and GrimAge. Furthermore, a decrease in natural killer cells, based on DNAm, was observed in patients with untreated MDD.
... İnsanların doğayla etkileşim halinde oldukları sürece kimlik duyguları, fiziksel ve duygusal gelişimleri, bilişsel kapasiteleri, estetik ve ruhsal deneyimleri üzerinde olumlu etkilere sahip olduğu temel bir gerçektir. Yapılı çevreler bu temel gerçeği göz ardı ederek, tasarlanıp inşa edildiğinde, yalnızca doğal dünyaya zarar vermekle kalmayıp, insan deneyiminin kalitesini de azaltmakta ve insan sağlığını da olumsuz etkilemektedir(Pollack, 2006). İnsanoğlu fiziksel, ruhsal hatta kalıtımsal açıdan doğaya bağlıdır. ...
... In contrast, negative psychological conditions are associated with telomere attrition 5 . Accumulating evidence indicate that clinical depression accelerates aging, with quanti able impacts on telomere length 6-8 ; chronic stress, anxiety, and depression are associated with shorter telomeres 5,6,[9][10][11] . Accordingly, the "psilocybin-telomere hypothesis" asserts that psilocybin interventions exert quanti able positive impacts on telomere length 4 . ...
Psilocybin is the psychoactive substance contained in the psilocybe (hallucinogenic) mushroom, which has received considerable attention among the scientific community in recent years. Human studies have demonstrated that even a single-dose of psilocybin can improve debilitating physical and psychological symptoms with durable long-term effects. >136 clinical studies with psilocybin have been completed or are ongoing for various indications, including psychiatric, neurodegenerative, chronic pain, and more. However, despite considerable clinical evidence for the therapeutic effects, the underlying molecular mechanisms responsible for its beneficial actions remain enigmatic. Studies with psilocybin have overwhelmingly focused on neurological impacts and/or behavioral outcomes; however, few studies have evaluated other mechanisms by which it exerts beneficial effects. It has recently been hypothesized that psilocybin may exert beneficial effects on aging; however, no studies have experimentally investigated the impact of psilocybin on senescence/aging. Using a previously validated human cell model of replicative senescence in vitro , cells were treated with psilocybin continuously throughout their replicative cellular lifecycle. Psilocybin treatment led to a dose-dependent decrease in cell-cycle arrest markers, increased markers of DNA replication and proliferation, reduced senescence-associated secretory phenotype (SASP), and reduced oxidative stress levels. Further, psilocybin did not demonstrate senolytic activity. Overall, these data are the first experimental evidence suggesting that psilocybin may decelerate the process of cellular senescence. Given that senescence and inflammation contribute to the pathogenesis of numerous age-related diseases, these studies could lay the foundation for the use of psilocybin as a therapeutic strategy for many age-related disease indications and/or as a geroprotective agent.
... Cognitive impairment accompanied by NPS versus without NPS may also relate to higher risk for worse cognitive outcomes [14]. While clinical-level behavioral symptoms or disorders have been significantly related to other aging biomarkers, such as telomeres [16,17], less is known about the association between epige-netic aging and NPS among persons across the ADRD spectrum. Additionally, data on genome-wide differences in DNAm at specific CpG sites (i.e., leading to differences in gene expression) that may underlie variations in MCI with versus without NPS or in MCI versus CN could yield novel mechanistic insights into the development of cognitive and neuropsychiatric phenotypes. ...
Background:
Associations between epigenetic aging with cognitive aging and neuropsychiatric measures are not well-understood.
Objective:
1) To assess cross-sectional correlations between second-generation DNA methylation (DNAm)-based clocks of healthspan and lifespan (i.e., GrimAge, PhenoAge, and DNAm-based estimator of telomere length [DNAmTL]) and cognitive and neuropsychiatric measures; 2) To examine longitudinal associations between change in DNAm markers and change in cognition over 2 years.
Methods:
Participants were members of VITAL-DEP (VITamin D and OmegA-3 TriaL- Depression Endpoint Prevention) study. From previously ascertained cognitive groups (i.e., cognitively normal and mild cognitive impairment), we randomly selected 45 participants, aged≥60 years, who completed in-person neuropsychiatric assessments at baseline and 2 years. The primary outcome was global cognitive score (averaging z-scores of 9 tests). Neuropsychiatric Inventory severity scores were mapped from neuropsychiatric symptoms (NPS) from psychological scales and structured diagnostic interviews. DNAm was assayed using Illumina MethylationEPIC 850K BeadChip at baseline and 2 years. We calculated baseline partial Spearman\hfilneg correlations between DNAm markers and cognitive and NPS measures. We constructed multivariable linear regression models to examine longitudinal relations between DNAm markers and cognition.
Results:
At baseline, we observed a suggestive negative correlation between GrimAge clock markers and global cognition but no signal between DNAm markers and NPS measures. Over 2 years: each 1-year increase in DNAmGrimAge was significantly associated with faster declines in global cognition; each 100-base pair increase in DNAmTL was significantly associated with better global cognition.
Conclusion:
We found preliminary evidence of cross-sectional and longitudinal associations between DNAm markers and global cognition.
... Various mental disorders, e.g., depression and schizophrenia, are characterized by excessive telomere shortening and decreased telomerase activity [22]. The study conducted in a large cohort of patients with affective disorders revealed accelerated telomere shortening, thus supporting a hypothesis on the accelerated cell aging in depression [22,23]. The extent of telomere shortening was found to correlate with the oxidative stress level, suggesting a significant impact of oxidative stress on the telomere damage, a hallmark of cell aging, in patients with depression [24]. ...
The review describes the syndrome of endogenous intoxication in patients with mental disorders. Oxidative stress, middle-mass endotoxic molecules, impaired functional properties of serum albumin and albumin thiol groups, neurotrophic factors, and enzymes, including monoamine oxidase and semicarbazide-sensitive amine oxidase contribute to the development of endogenous intoxication. Possible pathogenetic mechanisms of the endogenous intoxication development in mental disorders and approaches to its treatment are discussed.
... Telomere shortening is a natural part of the aging process, and inflammation can exacerbate telomere dysfunction by increasing the rate of telomere attrition, leading to telomere dysfunction-mediated cellular senescence, and accelerating the aging process. Chen and Shu, 2007;Epel et al., 2010;Simon et al., 2006;Schutte and Malouff, 2016;Oliveira et al., 2016;Pepper et al., 2018;Zalli et al., 2014;de Punder et al., 2018;N. Cai et al., 2015;Martens and Nawrot, 2018;Kiefer et al., 2008). ...
Inflammation is believed to play a role in the progression of numerous human diseases. Research has shown that inflammation and telomeres are involved in a feedback regulatory loop: inflammation increases the rate of telomere attrition, leading to telomere dysfunction, while telomere components also participate in regulating the inflammatory response. However, the specific mechanism behind this feedback loop between inflammatory signaling and telomere/telomerase complex dysfunction has yet to be fully understood. This review presents the latest findings on this topic, with a particular focus on the detailed regulation and molecular mechanisms involved in the progression of aging, various chronic inflammatory diseases, cancers, and different stressors. Several feedback loops between inflammatory signaling and telomere/telomerase complex dysfunction, including NF-κB-TERT feedback, NF-κB-RAP1 feedback, NF-κB-TERC feedback, STAT3-TERT feedback, and p38 MAPK-shelterin complex-related gene feedback, are summarized. Understanding the latest discoveries of this feedback regulatory loop can help identify novel potential drug targets for the suppression of various inflammation-associated diseases.
... MET are common comorbidities in neuropsychiatric illnesses and are hypothesized to contribute to accelerated brain aging in patients (Lung et al., 2007;Simon et al., 2006;Wolkowitz et al., 2011). We plotted the regional effect size for MET calculated in non-psychiatric sample against the patient-control SSD , MDD (van Velzen et al., 2020), BD (Favre et al., 2019), and AD . ...
Metabolic illnesses (MET) are detrimental to brain integrity and are common comorbidities in patients with mental illnesses, including major depressive disorder (MDD). We quantified effects of MET on standard regional brain morphometric measures from 3D brain MRI as well as diffusion MRI in a large sample of UK BioBank participants. The pattern of regional effect sizes of MET in non-psychiatric UKBB subjects was significantly correlated with the spatial profile of regional effects reported by the largest meta-analyses in MDD but not in bipolar disorder, schizophrenia or Alzheimer's disease. We used a regional vulnerability index (RVI) for MET (RVI-MET) to measure individual's brain similarity to the expected patterns in MET in the UK Biobank sample. Subjects with MET showed a higher effect size for RVI-MET than for any of the individual brain measures. We replicated elevation of RVI-MET in a sample of MDD participants with MET versus non-MET. RVI-MET scores were significantly correlated with the volume of white matter hyperintensities, a neurological consequence of MET and age, in both groups. Higher RVI-MET in both samples was associated with obesity, tobacco smoking and frequent alcohol use but was unrelated to antidepressant use. In summary, MET effects on the brain were regionally specific and individual similarity to the pattern was more strongly associated with MET than any regional brain structural metric. Effects of MET overlapped with the reported brain differences in MDD, likely due to higher incidence of MET, smoking and alcohol use in subjects with MDD.
... In each cell division, the telomere diminishes and when arriving at a critical point of proliferation it is arrested and apoptosis tendency increases [14]. Telomere shortening and decrease in telomerase activity, which were shown in previous studies in chronic stress patients [15], were also shown in patients with mental illness [16] and patients with schizophrenia [17]. Otherwise, smoking [18], aging, stress [15] have been associated with telomere shortening. ...
Objective:
Schizophrenia is a serious mental disorder. Mutations in mitochondrial genes can change energy metabolism. Telomere is a tandem sequence at the end of chromosomes. Shorter telomere length has been shown in schizophrenia. The aim of this study was to determine the relationship between ATPase6 gene mutations and telomere length in schizophrenia patients.
Methods:
Blood samples of 34 patients and 34 healthy controls were used. In this study conventional PCR, Sanger sequencing technic and real-time PCR were utilized.
Results:
Five different mutations (A8860G, A8836, G8697A, C8676T, and A8701G) in the ATPase6 gene were identified in schizophrenia patients. The most seen mutation was A8860G (94%). Telomere length analysis indicated the relation of ATPase6 gene mutations and telomere length variations (p = 0.001). Patients carrying the A8860G mutation had shorter telomere lengths than patients carrying other mutations. Comparing telomere length between schizophrenia patients and healthy controls revealed that the mean telomere length of schizophrenia patients was shorter than healthy controls (p = 0.006). The demographic analysis demonstrated a significant relationship between marital status and telomere length (p = 0.011). Besides that, the duration of the illness is another factor that impacts telomere length (p = 0.044). There is no significant relation between telomere length and other clinical and demographic characteristics including education status, age, gender, etc.
Conclusion:
In conclusion, telomere length and ATPase6 gene mutations have a significant relation. Studies with larger patient populations and investigation of other mitochondrial gene mutations will make the clearer link between telomere length and mitochondrial mutations.
... Post mortem studies using the brains of BD patients have shown reduced expression of mitochondrial electron transport chain (ETC) genes. Mitochondrial ROS production has been shown to lead to telomere shortening [74], and this phenomenon has been observed in humans with bipolar disorder [75]. Thus, Andreazza and her colleagues have suggested that the relationship among mit ETC (electron transport chain) dysfunction, OS, cell death and DNA damage is a promising area for investigating the pathophysiology of BD [76]. ...
Background: Increasing evidence suggests that the presence of oxidative stress and disorders of the antioxidant defense system are involved in a wide range of neuropsychiatric disorders, such as bipolar disorder, schizophrenia and major depression, but the exact mechanism remains unknown. This review focuses on a better appreciation of the contribution of oxidative stress to depression and bipolar disorder. Methods: This review was conducted by extracting information from other research and review studies, as well as other meta-analyses, using two search engines, PubMed and Google Scholar. Results: As far as depression is concerned, there is agreement among researchers on the association between oxidative stress and antioxidants. In bipolar disorder, however, most of them observe strong lipid peroxidation in patients, while regarding antioxidant levels, opinions are divided. Nevertheless, in recent years, it seems that on depression, there are mainly meta-analyses and reviews, rather than research studies, unlike on bipolar disorder. Conclusions: Undoubtedly, this review shows that there is an association among oxidative stress, free radicals and antioxidants in both mental disorders, but further research should be performed on the exact role of oxidative stress in the pathophysiology of these diseases.
... При психоэмоциональном стрессе и, особенно, при депрессивных состояниях, длина теломер сокращается [191,192]. При этом умеренные физические нагрузки снижают негативное воздействие психологического стресса на длину теломер [193]. Ожирение, курение, потребление алкоголя также приводят к укорочению теломер [194][195][196]. ...
In this review, we summarize data on the structural and functional characteristics of human telomeres and analyze how endo- and exogenous factors influence telomere length. We elucidate the history of telomere investigation, describe their structure and functions, methods of their study. We also characterize the mechanisms of telomere lengthening and shortening. We discuss in detail endo- and exogenous factors affecting telomere length during gametogenesis, embryogenesis and in the postnatal period of human development. We describe how oxidative stress influences telomere length through guanine oxidation, single-strand breaks in DNA, decrease of telomerase activity and suppression of recombination in telomeric sequences. We conclude that the multidirectional effect of various factors, both sporadic and determined by the developmental program, ensures the dynamic equilibrium of telomere length. A shift in this balance due to increased influence of one or several factors can lead to telomere lengthening or shortening. Understanding the mechanisms underlying the telomere length changes and the critical periods of exposure to both protective and negative factors is important to contribute to the knowledge about telomere functions and to develop approaches of telomere length correction.
... Doğru bir tasarım ile yapay çevrelerde de doğayı hissetmek mümkün olmaktadır. (Pollack, 2006). ...
Today, living spaces with higher floors and smaller field of use are the interior places where people’s time is mostly spent. With the new understanding of normal life, this situation has become a necessity rather than a choice, and beneficial contact with nature has inevitably been prevented. Biophilic design is not only a functional and visual discipline, but also a design approach that provides mental well-being. From this point of view the importance of biophilic design was emphasized based on its effects on human life and body, importance of bringing places that are limited by the standards of nature together with nature for human and society, and necessity of applying biophilic design criteria in the environment and interior spaces which the building is in was highlighted.
... Depression, in particular, has been extensively investigated. Nearly all studies on the subject matter have found shorter TL to be associated with MDE (22,(59)(60)(61)(62), with few exceptions (63). Meanwhile, PS and schizophrenia have been studied less often and have produced more heterogeneous results: finding decrease (61,64,65), increase (32,66), or no change (67,68) in TL when compared to the control group. ...
Premature biological aging, assessed by shorter telomere length (TL) and mitochondrial DNA (mtDNA) alterations, has been reported among people with major depressive disorders or psychotic disorders. However, these markers have never been assessed together among people who inject drugs (PWIDs), although mental disorders are highly prevalent in this population, which, in addition, is subject to other aggravating exposures. Diagnosis of mental disorders was performed by a psychiatrist using the Mini International Neuropsychiatric Interview test among active PWIDs in Haiphong, Vietnam. mtDNA copy number (MCN), mtDNA deletion, and TL were assessed by quantitative PCR and compared to those without any mental disorder. We next performed a multivariate analysis to identify risk factors associated with being diagnosed with a major depressive episode (MDE) or a psychotic syndrome (PS). In total, 130 and 136 PWIDs with and without psychiatric conditions were analyzed. Among PWIDs with mental disorders, 110 and 74 were diagnosed with MDE and PS, respectively. TL attrition was significantly associated with hepatitis C virus-infected PWIDs with MDE or PS (adjusted odds ratio [OR]: 0.53 [0.36; 0.80] and 0.59 [0.39; 0.88], respectively). TL attrition was even stronger when PWIDs cumulated at least two episodes of major depressive disorders. On the other hand, no difference was observed in mtDNA alterations between groups. The telomeric age difference with drug users without a diagnosis of psychiatric condition was estimated during 4.2–12.8 years according to the number of MDEs, making this group more prone to age-related diseases.
... Australian & New Zealand Journal of Psychiatry, 57 (3) et al., 2018; Squassina et al., 2019). Previous studies have suggested that, whenever the body experiences chronic stress, telomere shortening may be induced and even accelerated, resulting in apoptosis and genome instability (Muneer and Minhas, 2019;Simon et al., 2006). This process has therefore been proposed to be a potential biomarker in BD, alongside other markers such as inflammation and oxidative stress (Barbé-Tuana et al., 2016). ...
Background
Bipolar disorder may undertake a progressive course in a subset of patients, and research efforts have been made to understand the biological basis underlying this process. This systematic review examined the literature available on biological markers associated with illness progression in bipolar disorder.
Methods
Peer-reviewed articles were assessed using Embase, PsycINFO and PubMed, as well as from external sources. After initial screening, a total of 871 citations from databases and other sources were identified. Participants with a diagnosis of bipolar disorder were included in our systematic review; however, studies with participants younger than 15 or older than 65 were excluded. All studies were assessed using the Newcastle-Ottawa Scale assessment tool, and data pertaining to the results were extracted into tabular form using Google Sheets and Google Documents. The systematic review was registered on PROSPERO international prospective register of systematic reviews (ID Number: CRD42020154305).
Results
A total of 35 studies were included in the systematic review. Increased ventricular size and reduction of grey matter volume were the most common brain changes associated with illness progression in bipolar disorder. Among the several biomarkers evaluated in this systematic review, findings also indicate a role of peripheral inflammatory markers in this process.
Discussion
The studies evaluating the biological basis of the illness progression in bipolar disorder are still scarce and heterogeneous. However, current evidence supports the notion of neuroprogression, the pathophysiological process related to progressive brain changes associated with clinical progression in patients with bipolar disorder. The increase in peripheral inflammatory biomarkers and the neuroanatomical changes in bipolar disorder suggest progressive systemic and structural brain alterations, respectively.
... Due to the incomplete DNA replication at each cell division, the length of telomeres decreases with age, making it a marker of aging [6,7]. TL has been the most widely studied marker of cellular aging in BD and in most available studies, a significant reduction in TL was observed in individuals with BD as compared to controls (even after adjustment for any difference in chronological age) [8][9][10]. These results were further confirmed by a recent meta-analysis of ten studies including 579 individuals with BD and 551 controls (effect size g = −0.54, ...
The 10–15-years decrease in life expectancy observed in individuals with bipolar disorder (BD) has been linked to the concept of accelerated cellular aging. Telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) have been proposed as markers of cellular aging and comparisons between individuals with BD and healthy controls (HC) sometimes led to conflicting results. Previous studies had moderate sample sizes and studies combining these two markers into a single analysis are scarce. Using quantitative polymerase chain reaction, we measured both TL and mtDNAcn in DNA (peripheral blood) in a sample of 130 individuals with BD and 78 HC. Regression analyses, receiver operating characteristic (ROC), and clustering analyses were performed. We observed significantly lower TL and mtDNAcn in individuals with BD as compared to HC (respective decrease of 26.5 and 35.8%). ROC analyses showed that TL and mtDNAcn highly discriminated groups (AUC = 0.904 for TL and AUC = 0.931 for mtDNAcn). In the whole population, clustering analyses identified a group of young individuals (age around 36 years), with accelerated cellular aging (both shorter TL and lower mtDNAcn), which consisted mostly of individuals with BD (85.5%). The subgroup of patients with young age but accelerated aging was not characterized by specific clinical variables related to the course of BD or childhood maltreatment. However, patients in this subgroup were more frequently treated with anticonvulsants. Further characterization of this subgroup is required to better understand the molecular mechanisms and the risk factors of accelerated cellular aging in BD.
... Some patients with DC also present with neurocognitive and neuropsychiatric manifestations, like adjustment disorders, anxiety disorders, ADHD, intellectual disability, mood disorders and schizophrenia [19]. Shorter telomeres seem to be associated with certain psychiatric disorders [20][21][22], but a direct biological link is still lacking. It is still not clear whether short telomeres predispose patients to develop certain neuropsychiatric conditions, and this hypothesis requires further studies. ...
Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone marrow failure, hematological and solid tumors. It may also involve immunodeficiencies, dental, pulmonary and liver disorders, and other minor complication. Dyskeratosis congenita shows marked genetic heterogeneity, as at least 14 genes are responsible for the shortening of telomeres characteristic of this disease. This review discusses clinical characteristics, molecular genetics, disease evolution, available therapeutic options and differential diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling.
... 32 It has been reported that shortened TL is associated with a high level of psychosocial stress, which could be attributed to increased oxidative stress and reduced telomerase activity. 33 Moreover, in an observational study on rheumatoid arthritis, the levels of oxidative stress biomarkers rose as disease activity increased and thereafter led to significant telomere shortening. 34 In our MR study, we disregarded genetic instruments associated with the above traits and solely explored the relationship between TL and diseases (JIA and JIA-associated iridocyclitis) from a genetic perspective. ...
Background:
Telomere maintenance is increasingly being considered as fundamental to the progression of immune-mediated inflammatory diseases. However, the causality underlying the purported relationship has not been fully elucidated. In the present work, we applied Mendelian randomization (MR) analysis to obtain estimates of the causal effect of telomere length (TL) on the risk of juvenile idiopathic arthritis (JIA) and JIA-associated iridocyclitis.
Methods:
Two-sample MR analysis was conducted using summary-level data from the largest genome-wide association studies concerning TL (78,592 individuals), JIA (6056 cases and 25,086 controls), and JIA-associated iridocyclitis (1430 cases and 9,2767 controls). All the participants were of European ancestry. The inverse variance weighted (IVW) method was applied to estimate the causal effects. Sensitivity analyses incorporating multiple complementary MR approaches were implemented to test the robustness of the association and examine potential bias from pleiotropy.
Results:
In our MR analysis, genetically predicted shorter TL was associated with an increased risk of JIA (IVW: odds ratio=1.68, 95% CI: 1.13-2.48, P=0.009), but not with the risk of JIA-associated iridocyclitis (IVW: odds ratio=1.75, 95% CI: 0.81-3.79, P=0.155). The other MR methods produced consistent results. Besides, a leave-one-out sensitivity analysis yielded similar findings and validated the robustness of the causal relationship. MR-Egger regression revealed no notable horizontal pleiotropy (intercept=0.046, P=0.175).
Conclusion:
This work provides evidence of a negative association between TL and JIA risk, but not for the association between TL and the risk of JIA-associated iridocyclitis, in a European population. Future studies with larger sample sizes are warranted to elucidate the underlying role of TL in these diseases.
... Major depressive disorder (MDD), one of the most common serious psychiatric disorders worldwide, is associated with increased risks of many biological and physiological pathologies such as dementia/cognitive decline (Byers and Yaffe, 2011;Holmquist et al., 2020), cardiovascular disease (Gan et al., 2014), and osteoporosis (Cizza et al., 2009) which occur in the process of normal aging. Accordingly, there are growing evidences suggesting that MDD leads to an accelerated biological aging as revealed by biochemical (Wolkowitz et al., 2011;Levada and Troyan, 2020), genetic (Simon et al., 2006;Protsenko et al., 2021), and neuroimaging (Sacchet et al., 2017;Cheng et al., 2020;Dunlop et al., 2021) characteristics. For instance, it was found that MDD patients are significantly older (with a median gap of 2 years) than their chronological age based on predictable age-related patterns of DNA methylation (Protsenko et al., 2021). ...
Major depressive disorder (MDD) is a common psychiatric disorder which is associated with an accelerated biological aging. However, little is known whether such process would be reflected by a more rapid aging of the brain function. In this study, we tested the hypothesis that MDD would be characterized by accelerated aging of the brain's default-mode network (DMN) functions. Resting-state functional magnetic resonance imaging data of 971 MDD patients and 902 healthy controls (HCs) was analyzed, which was drawn from a publicly accessible, multicenter dataset in China. Strength of functional connectivity (FC) and temporal variability of dynamic functional connectivity (dFC) within the DMN were calculated. Age-related effects on FC/dFC were estimated by linear regression models with age, diagnosis, and diagnosis-by-age interaction as variables of interest, controlling for sex, education, site, and head motion effects. The regression models revealed (1) a significant main effect of age in the predictions of both FC strength and dFC variability; and (2) a significant main effect of diagnosis and a significant diagnosis-by-age interaction in the prediction of FC strength, which was driven by stronger negative correlation between age and FC strength in MDD patients. Our results suggest that (1) both healthy participants and MDD patients experience decrease in DMN FC strength and increase in DMN dFC variability along age; and (2) age-related decrease in DMN FC strength may occur at a faster rate in MDD patients than in HCs. However, further longitudinal studies are still needed to understand the causation between MDD and accelerated aging of brain.
... İnsanların doğayla etkileşim halinde oldukları sürece kimlik duyguları, fiziksel ve duygusal gelişimleri, bilişsel kapasiteleri, estetik ve ruhsal deneyimleri üzerinde olumlu etkilere sahip olduğu temel bir gerçektir. Yapılı çevreler bu temel gerçeği göz ardı ederek, tasarlanıp inşa edildiğinde, yalnızca doğal dünyaya zarar vermekle kalmayıp, insan deneyiminin kalitesini de azaltmakta ve insan sağlığını da olumsuz etkilemektedir(Pollack, 2006). İnsanoğlu fiziksel, ruhsal hatta kalıtımsal açıdan doğaya bağlıdır. ...
Humans by nature need contact with nature for their physical and mental health, productivity, and well-being. However, the natural habitat of modern humans has become the built environment where they spend most of their time. Unfortunately, most modern buildings and cities are places that are harmful to the environment, disconnected from nature, and estranged. Therefore, the need for biological contact with nature has become increasingly important in high-rise and urbanizing societies. In this context, in this study, the concept of biophilic (healing) design is explained; its physical, social, environmental, and economic benefits are revealed; and its advantages against the most important problems of the 21st century are discussed at different scales. By examining different world examples of biophilic cities and biophilic buildings, a matrix was formed, and biophilic design principles and the benefits used were evaluated. Finally, the difficulties in implementing the biophilic design are mentioned.
... Due to the incomplete DNA replication at each cell division, the length of telomeres decreases with age, making it a marker of aging [6,7]. TL has been the most widely studied marker of cellular aging in BD and in most available studies, a significant reduction in TL was observed in individuals with BD as compared to controls (even after adjustment for any difference in chronological age) [8][9][10]. These results were further confirmed by a recent meta-analysis of ten studies including 579 individuals with BD and 551 controls (effect size g = −0.54, ...
... In that study, the average length of the peripheral leukocytes in the patients was found to be 660 bp shorter than that observed in the control group (CG). According to the authors, this difference had a large effect size, which corresponded to approximately 10 years of accelerated aging in the affected patients (Simon et al., 2006). Since then, different studies have corroborated the results of the positive association between the shortening of telomeres and MDD; however, negative association results have also been reported. ...
We analyze the leukocyte telomere length (LTL) and telomerase activity in patients with major depressive disorder (MDD) before and after treatment with selective serotonin reuptake inhibitors (SSRIs). Before treatment, there was a reduction in the LTLs and expression levels of the human telomerase reverse transcriptase (hTERT) in the patients with MDD compared with controls. However, after 24 weeks of treatment with SSRIs, there was a significant increase in the LTLs and the expression levels of hTERT, with values approaching those observed in the controls. We conclude that SSRI antidepressant therapy can directly influence the increased expression levels of hTERT in patients.
... Tennant 42 also proved that major depression is linked to an increased risk of job insecurity. In addition to these studies, studies showing that telomere length is shortened considerably with anxiety, depression, stress, mood disorders, and adjustment disorders [43][44][45][46][47][48][49][50][51] completes the cycle in a sense. However, I have not come across any study that establishes a correlation between cancer and macroeconomic phenomena such as crisis, unemployment, and poverty with a multidisciplinary approach. ...
Objective: Determining the existence of the cycle between the economic crisis-unemployment-cancer and implementing appropriate policies for this is important in the fight against cancer, which is an important public health problem. Mass unemployment caused by the practices in the COVID-19 process is worrisome in this sense. The cost of policies that may prevent the unemployment process will be much cheaper than the costs of cancer screening, diagnosis, treatment, care, organ-life losses, production and labor losses.
Materials and Methods: Augmented Dickey-Fuller (ADF) and Phillips-Perron (PP) Unit Root Tests, Engel-Granger, Johansen Cointegration Test, Granger Causality Test Over VAR Model.
Results: Unemployment and cancer incidence are not cointegrated in the long run, according to the research. A one-sided causality from unemployment to cancer incidence has been discovered in the short term. As a result, unemployment is a Granger cause of cancer.
Conclusions: The determination of unemployment as a cause of cancer incidence, implementation of emergency policies to prevent unemployment will reduce costs in fighting cancer. And it will prevent cancer cases caused by the increase in stress and anxiety caused by unemployment.
... Children who experience significant life stress have higher risk of heart disease, diabetes, cancer, chronic lung disease, skeletal fractures, liver disease, mental distress disability and overall worse health ratings [17,121]. At the tissue level, evidence of oxidative stress including cellular aging [122][123][124] and shortened telomeres [125,126] indicate systemic tissue disruption by early life stress. ...
Stress is a ubiquitous experience that can be adaptive or maladaptive. Physiological stress regulation, or allostasis, can be disrupted at any point along the regulatory pathway resulting in adverse effects for the individual. Children with cancer exhibit significant changes to these pathways in line with stress dysregulation and long-term effects similar to those observed in other early-life stress populations, which are thought to be, in part, a result of cytotoxic cancer treatments. Children with cancer may have disruption to several steps in the stress-regulatory pathway including cognitive-affective function, neurological disruption to stress regulatory brain regions, altered adrenal and endocrine function, and disrupted tissue integrity, as well as lower engagement in positive coping behaviours such as physical activity and pro-social habits. To date, there has been minimal study of stress reactivity patterns in childhood illness populations. Nor has the role of stress regulation in long-term health and function been elucidated. We conclude that consideration of stress regulation in childhood cancer may be crucial in understanding and treating the disease.
Identifying the clinical implications and modifiable and unmodifiable factors of aging requires the measurement of biological age (BA) and age gap. Leveraging the biomedical traits involved with physical measures, biochemical assays, genomic data, and cognitive functions from the healthy participants in the UK Biobank, we establish an integrative BA model consisting of multi‐dimensional indicators. Accelerated aging (age gap >3.2 years) at baseline is associated incident circulatory diseases, related chronic disorders, all‐cause, and cause‐specific mortality. We identify 35 modifiable factors for age gap ( p < 4.81 × 10 ⁻⁴ ), where pulmonary functions, body mass, hand grip strength, basal metabolic rate, estimated glomerular filtration rate, and C‐reactive protein show the most significant associations. Genetic analyses replicate the possible associations between age gap and health‐related outcomes and further identify CST3 as an essential gene for biological aging, which is highly expressed in the brain and is associated with immune and metabolic traits. Our study profiles the landscape of biological aging and provides insights into the preventive strategies and therapeutic targets for aging.
Background:
Attention Deficit Hyperactivity Disorder (ADHD) includes inattention, hyperactivity, and impulsivity as core symptoms and is associated with increased self-perceived stress.
Primary study objective:
This article evaluates the impact of acupuncture (provided in addition to regular pharmacological treatment with Atomoxetine) on self-perceived stress and ADHD core symptomatology, compared to atomoxetine (ATX) alone.
Methods/design:
In-depth single case study, involving a mixed methods approach with questionnaires and interviews was used. The participant completed two rating scales. Additionally, semi-structured interviews were held. Qualitative data were subjected to content analysis and both sets of data were triangulated.
Setting:
Data collection/intervention (treatments) took place at an Acupuncture clinic in Hamburg, Germany, EU.
Participants:
One adult, atomoxetine-taking ADHD participant.
Intervention:
Acupuncture according to Chinese medicine-diagnosis twice/week, over the course of eight weeks, following a pre-defined but flexible point protocol.
Primary outcome measures:
1) The Current Symptom Scale (CSS) and the Perceived Stress Scale (PSS). 2) Semi-structured interviews.
Results:
Acupuncture treatments in addition to regular ATX intake positively affected the participant's ADHD symptoms (PSS - 31%, total score of the CSS - 47%). There was a considerable decrease in subgroup scores (attention deficit - 39%; functionality impairment - 55%; hyperactivity/impulsivity - 53%; impulsivity - 30%). Post-interventional interviews showed perceived increased self-control, (self-) awareness and centeredness. Combined treatment was perceived as more beneficial than pharmaceutical treatment alone.
Conclusion:
Acupuncture treatment appears to have a positive impact on both self-perception of stress and ADHD core symptomatology. Findings were partially congruent with the reviewed research literature but due to limitations/risks of bias (ROBs) associated with the design, no concrete conclusions regarding a potential method-related specificity can be drawn. Further research with larger samples and a more robust design is recommended.
Late-Life Depression (LLD) is one of the most prevalent psychiatric disorders in elderly, causing significant functional impairments. MicroRNAs are small molecules involved in the post-transcriptional regulation of gene expression. Elderly individuals diagnosed with LLD present down regulation of miR-184 (hsa-miR-184) expression compared to healthy patients. Therefore, this miR-184 can be used as a biomarker to diagnose LLD. Current LLD diagnosis depends primarily on clinical subjective identification, based on symptoms and variable scales. This work introduces a novel and facile approach for the LLD diagnosis based on the development of an electrochemical genosensor for miR-184 detection in plasma, using differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). DPV results presented a 2-Fold increase in current value for healthy patients, compared to individuals with LLD when monitoring ethidium bromide oxidation peak. For EIS, a 1.5-fold increase in charge transfer resistance for healthy elderly subjects was observed in comparison with depressed patients. In addition, the analytical performance of the biosensor was evaluated using DPV, obtaining a linear response ranging from 10-9 mol L-1 to 10-17 mol L-1 of miR-184 in plasma and a detection limit of 10 atomoles L-1. The biosensor presented reusability, selectivity and stability, the current response remained 72% up to 50 days of storage. Thus, the genosensor proved to be efficient in the diagnosis of LLD, as well as the accurate quantification of miR-184 in real plasma samples of healthy and depressed patients.
Inhibition of Glycogen synthase kinase 3 (GSK3) is a popular explanation for the effects of lithium ions on mood regulation in bipolar disorder and other mental illnesses, including major depression, cyclothymia, and schizophrenia. Contribution of GSK3 is supported by evidence obtained from animal and patient derived model systems. However, the two GSK3 enzymes, GSK3α and GSK3β, have more than 100 validated substrates. They are thus central hubs for major biological functions, such as dopamine-glutamate neurotransmission, synaptic plasticity (Hebbian and homeostatic), inflammation, circadian regulation, protein synthesis, metabolism, inflammation, and mitochondrial functions. The intricate contributions of GSK3 to several biological processes make it difficult to identify specific mechanisms of mood stabilization for therapeutic development. Identification of GSK3 substrates involved in lithium therapeutic action is thus critical. We provide an overview of GSK3 biological functions and substrates for which there is evidence for a contribution to lithium effects. A particular focus is given to four of these: the transcription factor cAMP response element-binding protein (CREB), the RNA-binding protein FXR1, kinesin subunits, and the cytoskeletal regulator CRMP2. An overview of how co-regulation of these substrates may result in shared outcomes is also presented. Better understanding of how inhibition of GSK3 contributes to the therapeutic effects of lithium should allow for identification of more specific targets for future drug development. It may also provide a framework for the understanding of how lithium effects overlap with those of other drugs such as ketamine and antipsychotics, which also inhibit brain GSK3.
Glycemic variability (GV) is a risk factor for depression in patients with diabetes. However, whether it is also a predictor of incident depression in people without diabetes remains unclear. We aimed to investigate the association between visit-to-visit variability in fasting serum glucose (FSG) levels and the incidence of depression among Koreans without diabetes. This retrospective cohort study included data of people without diabetes who did not have depression at baseline and had at least three FSG measurements (n = 264,480) extracted from the 2002–2007 Korean National Health Insurance Service–National Health Screening Cohort. GV was calculated as the average successive variability of FSG. Among 264,480 participants, 198,267 were observed during 2008–2013 and their hazard ratios (HR) of incident depression were calculated. Participants with the highest GV showed a higher risk of depression in fully adjusted models than those with the lowest GV (HR, 1.09; 95% CI, 1.02–1.16). The risk of incident depression heightened with increasing GV (p for trend < 0.001). Greater visit-to-visit GV may be associated with the risk of developing depression in people without diabetes. Conversely, maintaining steady FSG levels may reduce the risk of incident depression in people without diabetes.
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.
Certain life experiences can have a profound effect on human emotions. During the COVID-19 pandemic, patients are reporting mood disturbances at much higher levels. Multiple encounters with real and imagined threat, prolonged isolation, and loss of control, have adversely impacted the country’s behavioral health. However, most people will not pursue psychological care when needed and some who pursue it will be unable to access it. Nurse practitioners and other healthcare professionals are in an optimal position to help. Psychological research explains some of what is driving this phenomenon and offers suggestions of benefit to patients, families, and colleagues.
Major depressive disorder (MDD) is a common condition that affects the general population over a wide range of ages, regardless of gender and social background. Early-onset of MDD in adulthood, between ages of 18-30 years, is associated with worse outcomes and increased years of disability. Stress load and physical health have been associated with age of onset in MDD. We aim to investigate whether early onset MDD might be associated with changes in systemic inflammatory markers. We examined levels of following cytokines: IL-1β, IL-6, IL-10 and TNFα in 234 patients with MDD. Higher serum levels of TNFα and IL-1β are associated with the early onset of the disorder in patients with MDD. IL-6 levels were also higher in the early onset group and IL-10 levels were higher in the late onset group, but with no significant difference. Changes in the anti-inflammatory/pro-inflammatory balance have been described in mood disorders and may be implicated in its severity and pattern of progression. Our findings reinforce that higher serum levels of IL-1β and TNFα may be associated with the earlier onset subgroup of MDD patients. Future research that target inflammatory markers of immune modulation may be, key in the search for novel preventative therapeutics.
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.
Background
Conventional biochemical parameters may have predictive values for use in clinical identification between bipolar disorder (BD) and major depressive disorder (MDD).
Methods
This study enrolled 2470 hospitalized patients with BD (n = 1333) or MDD (n = 1137) at reproductive age from 2009 to 2018 in China. We extracted 8 parameters, uric acid (UA), direct bilirubin (DBIL), indirect bilirubin (IDBIL), lactic dehydrogenase (LDH), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), high-density lipoprotein (HDL) and prealbumin of male, patients and 12 parameters, UA, DBIL, IBIL, LDH, FT3, TSH, glutamic-pyruvic transaminase (GPT), white blood cell (WBC), alkaline phosphatase (ALP), fasting blood glucose (FBG), triglyceride and low-density lipoprotein (LDL) of female patients. Backward stepwise multivariate regression analysis and the Chi-Square Automatic Interaction Detection (CHAID) segmentation analysis via SPSS Decision Tree were implemented to define the discrimination of BD and MDD.
Results
DBIL was extracted as the first splitting variable, with LDH and IBIL as the second, TSH and prealbumin as the third in the model of male patients (p-value < .05). For the model of female patients, DBIL was also extracted as the first splitting variable, with UA, LDH, and IBIL as the second, triglyceride and FT3 as the third (p-value < .05). The predictive accuracies of the Decision Tree and multiple logistic regression models were similar (74.9% vs 76.9% in males; 74.4% vs 79.5% in females).
Conclusions
This study suggests the value of the Decision Tree models, which employ biochemical parameters as diagnostic predictors for BD and MDD. The CHAID Decision Tree identified that patients with concomitantly increased LDH, IBIL, and decreased DBIL could be in the group that showed the highest risk of being diagnosed as BD.
Background:
Williams syndrome (WS) is a rare genetic disorder caused by a microdeletion at the 7q11.23 region and is characterized by diverse symptoms encompassing physical and cognitive features. WS was reported to be associated to altered DNA methylation (DNAm) patterns. However, due to the limited information from long-term studies, it remains unclear whether WS accelerates aging. Genome-wide DNAm profiles can serve as "epigenetic clocks" to help estimate biological aging along with age-related markers, such as plasma proteins and telomere length.
Methods:
We investigated GrimAge, DNAm-based telomere length (DNAmTL), and other epigenetic clocks in blood samples of 32 patients with WS and 32 healthy controls.
Results:
We observed a significant acceleration in GrimAge, DNAmTL, and other epigenetic clocks in patients with WS as compared with those of controls. In addition, several GrimAge components, such as adrenomedullin, growth differentiation factor-15, leptin and plasminogen activator inhibitor-1, were altered in patients with WS.
Conclusions:
This study provides novel evidence supporting the hypothesis that WS may be associated to accelerated biological aging. A better understanding of the overall underlying biological effects of WS can provide new foundations for improved patient care; thus, long-term follow-up studies are still warranted.
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.
Objective
This study aims to examine the effects of methamphetamine (MA) use and dependence and MA withdrawal symptoms on the telomere length and whether shortening of the latter is associated with MA-induced psychosis (MIP).
Methods
This study included 185 MA-abuse, 118 MA-dependent, and 67 MIP patients, diagnosed using DSM-IV criteria. The Semi-structured Assessment for Drug Dependence and Alcoholism (SSADDA) questionnaire was employed to collect MA-related data. MIP was confirmed using the Methamphetamine Experience Questionnaire (MEQ). The leukocyte telomere length was measured using real-time polymerase chain reaction measuring the Telomere/Single gene ratio (T/S ratio). Data were analyzed using multivariate statistical analyses.
Results
There were no significant associations between the T/S ratio and severity of MA-use, MIP, and MA withdrawal symptoms. MIP was significantly predicted by alcohol dependence, antisocial personality disorder, and MA-use severity. There were significantly positive associations between the T/S ratio and previous traumatic and life-threatening events. The T/S ratio was not affected by alcohol and nicotine dependence. Alcohol and nicotine dependence, antisocial personality disorder, and severity of MA use increased risk of MA withdrawal symptoms.
Conclusion
MIP and MA-use severity are not associated with leukocyte telomere length, but previous traumatic and life-threatening events are associated with increased telomere length.
Objectives
Bipolar disorder (BD) may be connected with accelerated aging, the marker of this can be shorter telomere length (TL). Some data suggest that lithium may exert a protective effect against telomere shortening. The study aimed to compare the telomere length between patients with bipolar disorder and control subjects. The effect of long-term lithium treatment was also assessed.
Methods
The study group comprised 41 patients with BD, including 29 patients treated longitudinally with lithium (mean 16.5 years) and 20 healthy people. Telomere length was assessed by the quantitative polymerase chain reaction (qPCR).
Results
In the control group, the TL was significantly longer in males than in females. Male bipolar patients had significantly shorter TL compared with the control male group. In bipolar patients, there was no correlation between TL and duration of treatment. The TL was negatively correlated with age in male bipolar patients.
Conclusion
The study did not confirm the lithium effect on TL in bipolar patients. TL showed gender differences, being shorter in BD males, compared to control males, and longer in healthy males, compared to control females.
Normal human cells undergo a finite number of cell divisions and ultimately enter a nondividing state called replicative senescence.
It has been proposed that telomere shortening is the molecular clock that triggers senescence. To test this hypothesis, two
telomerase-negative normal human cell types, retinal pigment epithelial cells and foreskin fibroblasts, were transfected with
vectors encoding the human telomerase catalytic subunit. In contrast to telomerase-negative control clones, which exhibited
telomere shortening and senescence, telomerase-expressing clones had elongated telomeres, divided vigorously, and showed reduced
staining for β-galactosidase, a biomarker for senescence. Notably, the telomerase-expressing clones have a normal karyotype
and have already exceeded their normal life-span by at least 20 doublings, thus establishing a causal relationship between
telomere shortening and in vitro cellular senescence. The ability to maintain normal human cells in a phenotypically youthful
state could have important applications in research and medicine.
To study telomere length dynamics in hematopoietic cells with age, we analyzed the average length of telomere repeat sequences in diverse populations of nucleated blood cells. More than 500 individuals ranging in age from 0 to 90 yr, including 36 pairs of monozygous and dizygotic twins, were analyzed using quantitative fluorescence in situ hybridization and flow cytometry. Granulocytes and naive T cells showed a parallel biphasic decline in telomere length with age that most likely reflected accumulated cell divisions in the common precursors of both cell types: hematopoietic stem cells. Telomere loss was very rapid in the first year, and continued for more than eight decades at a 30-fold lower rate. Memory T cells also showed an initial rapid decline in telomere length with age. However, in contrast to naive T cells, this decline continued for several years, and in older individuals lymphocytes typically had shorter telomeres than did granulocytes. Our findings point to a dramatic decline in stem cell turnover in early childhood and support the notion that cell divisions in hematopoietic stem cells and T cells result in loss of telomeric DNA.
The study examined the role of parental death and chronic depression with severe episodes in affecting risk of breast cancer. This avenue of research is in accord with oncology findings, which suggests that causative factors of breast cancer occur and develop over a period of 20 years or longer.
Participants consisted of 1213 women in the Baltimore Epidemiologic Catchment Area study surveyed in 1980 and followed through 1994-1995. They were assessed for depressive and anxious disorders, paternal death in childhood and relatively recent adverse life events prior to cancer hospitalization.
In the course of the study, 29 women were hospitalized for breast cancer and 10 died of breast cancer. The psychosocial variables that predicted increased risk of breast cancer were maternal death in childhood (OR = 2.56, P < 0.001) and chronic depression with severe episodes (OR = 14.0, P < 0.001). Neither relatively recent life events nor other depressive and anxiety disorders were associated with increased risk. Maternal death and chronic depression with severe episodes were reported to have occurred at least 20 years prior to breast cancer hospitalization.
Maternal death and chronic and severe depression occurred at least 20 years prior to breast cancer hospitalization and could have been involved in the causation or facilitation of cancer development. The authors suggest that meta-analysis of other prospective studies are needed to create larger groups of individuals with these stresses to confidently establish these variables as risk factors.
Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH).
The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed.
Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychiatric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling.
Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways.
It has been established that telomere-dependent replicative senescence of human fibroblasts is stress-dependent. First, it was shown that telomere shortening, which is a major contributor to telomere uncapping, is stress-dependent to a significant degree. Second, the signalling pathway connecting telomere uncapping and replicative senescence appears to be the same as the one that is activated by DNA damage: uncapped telomeres activate signalling cascades involving the protein kinases ATM, ATR and, possibly, DNA-PK. Furthermore, phosphorylation of histone H2A.X facilitates the formation of DNA damage foci around uncapped telomeres, and this in turn activates downstream kinases Chk1 and Chk2 and, eventually, p53. It appears that this signalling pathway has to be maintained in order to keep cells in a senescent state. Thus, cellular senescence can be regarded as a permanently maintained DNA damage response state. This suggests that antibodies against DNA damage foci components might be useful markers for senescent cells in vivo.
The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research.
Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors.
Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed.
A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.
Obesity and smoking are important risk factors for many age-related diseases. Both are states of heightened oxidative stress, which increases the rate of telomere erosion per replication, and inflammation, which enhances white blood cell turnover. Together, these processes might accelerate telomere erosion with age. We therefore tested the hypothesis that increased body mass and smoking are associated with shortened telomere length in white blood cells. We investigated 1122 white women aged 18-76 years and found that telomere length decreased steadily with age at a mean rate of 27 bp per year. Telomeres of obese women were 240 bp shorter than those of lean women (p=0.026). A dose-dependent relation with smoking was recorded (p=0.017), and each pack-year smoked was equivalent to an additional 5 bp of telomere length lost (18%) compared with the rate in the overall cohort. Our results emphasise the pro-ageing effects of obesity and cigarette smoking.
The telomerase activity and length of telomeres of peripheral blood mononuclear cells obtained from 124 healthy individuals
aged 4–95years was measured. Telomerase activity level was semiquantitatively assessed by a fluorescent-telomeric repeat amplification
protocol (fluorescent-TRAP) using an internal telomerase assay standard, fluorescent primers and an automated laser fluorescent
DNA sequencer. Telomeric length, measured by assay of terminal restriction fragments (TRFs), was determined in HinfI-digested DNA by Southern blot analysis using a (TTAGGG)4 probe. TRF length was determined in 80 individuals and age-related progressive reduction of size was observed. TRF length
in peripheral blood mononuclear cells obtained from normal individuals (aged 4–39years) decreased by approximately 84bp per
year, while in individuals aged ≥40years it decreased by 41bp per year. In contrast, telomerase activity showed an apparent biphasic pattern with aging. Individuals
aged 4–39years showed a progressive decrease in telomerase activity, whereas 65% of those aged ≥40years showed relatively stable but very low telomerase activity, and the remaining individuals aged ≥40years had no detectable telomerase activity. These data obtained from normal individuals might in the future be of value
to help risk stratify and manage the care of patients with leukemia.
During major depression, dysfunction of limbic structures resulting in hypersecretion of corticotropin-releasing factor (CRF) is believed to cause the well-known hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in this disorder. Nonsuppression of the HPA axis by dexamethasone in depressed patients suggest that this increased CRF secretion may be due, at least in part, to altered feedback inhibition by glucocorticoids. Because glucocorticoid-induced feedback inhibition of the HPA axis is mediated by glucocorticoid receptors (GRs) in the brain and pituitary, the possibility that depression is associated with a primary alteration in GRs number and/or function has been an important consideration regarding the pathophysiology of the depressive disorders. Nevertheless, studies investigating GRs kinetics in depressed patients have been inconsistent. In some studies, decreased GRs number in depressed patients has been observed; others have obtained discordant results. The inconsistency of results may be due to a number of factors, including patient heterogeneity, the cell populations sampled, and the methods used to determine receptors number. Fewer studies have investigated the functional sensitivity of cells to the inhibitory effects of glucocorticoids, but they have been more consistent, showing increased resistance of cells from depressed patients to the inhibitory effects of glucocorticoids on immune function. In view of intriguing data indicating monoamine regulation of GR number and function in a hormone independent fashion along with the well-known effects of glucocorticoids on behavior, further scrutiny of the role of GR in depression and its treatment is warranted.
Depression has been proposed as a predisposing factor for cancer, but prospective studies have been inconclusive. We examined whether a high level of depressive symptoms, present for a long time, is associated with increased risk of cancer in the elderly.
Data were obtained and analyzed from persons who lived in three communities (Massachusetts, Iowa, and Connecticut) of the Established Populations for Epidemiologic Studies of the Elderly, a prospective cohort study with a mean follow-up of 3.8 years that included 4825 persons (1708 men and 3117 women) aged 71 years and older. Chronically depressed mood was defined as present when the number of depressive symptoms exceeded specific cut points on the Center for Epidemiologic Studies-Depression scale at baseline (1988) and 3 and 6 years before baseline. New cases of cancer were identified from Medicare hospitalization records and death certificates.
Of the 4825 persons studied, 146 (3.0%) were chronically depressed. The incidence rate of cancer was 30.5 per 1000 person-years for the 146 persons with chronic depression and 21.9 per 1000 person-years for the 4679 nonchronically depressed persons. After adjustment for age, sex, race, disability, hospital admissions, alcohol intake, and smoking, the hazard ratio for cancer associated with chronically depressed mood was 1.88 (95% confidence interval = 1.13-3.14). The excess risk of cancer associated with chronic depression was consistent for most types of cancer and was not specific to cigarette smokers.
When present for at least 6 years, depression was associated with a generally increased risk of cancer.
Telomere length has frequently been used as a means to predict the future
life of cells. But by itself it can be a poor indicator of ageing or cell
viability. What, then, is the important property of a telomere? Here recent
findings are integrated into a new, probabilistic view of the telomere to
explain how and when it can signal not only its own fate but also that of
a cell.
Hyperactivity of the hypothalamic--pituitary--adrenal (HPA) axis has been reliably observed in patients with major depression. One of the primary features of this HPA axis hyperactivity is reduced sensitivity to the inhibitory effects of the glucocorticoid dexamethasone on the production of adrenocorticotropic hormone and cortisol during the dexamethasone suppression test and, more recently, the dexamethasone--corticotropin-releasing hormone test. Because the effects of glucocorticoids are mediated by intracellular receptors including, most notably, the glucocorticoid receptor (GR), a number of studies have considered the possibility that the number and/or function of GRs are reduced in depressed patients. Moreover, whether antidepressants act by reversing these putative GR changes has been examined. The extant literature on GR receptors in major depression was reviewed along with studies examining the impact of antidepressants on the GR. The data support the hypothesis that the function of the GR is reduced in major depression in the absence of clear evidence of decreased GR expression. The data also indicate that some antidepressants have direct effects on the GR, leading to enhanced GR function and increased GR expression. Hypotheses regarding the mechanism of these receptor changes involve relevant second messenger pathways that regulate GR function. The findings indicate that the GR is an important molecular target in major depression. Further elucidation of the biochemical and molecular mechanisms involved in GR changes in major depression is an exciting frontier that will no doubt lead to new insights into the pathophysiology and treatment of affective disorders.
This review describes the structure of telomeres, the protective DNA-protein complexes at eukaryotic chromosomal ends, and several molecular mechanisms involved in telomere functions. Also discussed are cellular responses to compromising the functions of telomeres and of telomerase, which synthesizes telomeric DNA.
The frequent comorbidity of anxiety disorders and mood disorders has been documented in previous studies. However, it remains unclear whether specific anxiety traits or disorders are more closely associated with unipolar major depression (MDD) or bipolar disorder (BPD). We sought to examine whether MDD and BPD can be distinguished by their association with specific types of anxiety comorbidity. Individuals with a primary lifetime diagnosis of either bipolar disorder (N=122) or major depressive disorder (N=114) received diagnostic assessments of anxiety disorder comorbidity, and completed questionnaires assessing anxiety sensitivity and neuroticism. The differential association of these anxiety phenotypes with MDD versus BPD was examined with multivariate modeling. Panic disorder and generalized anxiety disorder (GAD) specifically emerged amongst all the anxiety disorders as significantly more common in patients with BPD than MDD. After controlling for current mood state, anxiety sensitivity and neuroticism did not differ by mood disorder type. This study supports prior research suggesting a specific panic disorder-bipolar disorder connection, and suggests GAD may also be differentially associated with BPD. Further research is needed to clarify the etiologic basis of anxiety disorder/BPD comorbidity and to optimize treatment strategies for patients with these co-occurring disorders.
The brain controls both the physiologic and the behavioral coping responses to daily events as well as major stressors, and the nervous system is itself a target of the mediators of those responses through circulating hormones. The amygdala and hippocampus interpret what is stressful and regulate appropriate responses. The amygdala becomes hyperactive in posttraumatic stress disorder (PTSD) and depressive illness, and hypertrophy of amygdala nerve cells is reported after repeated stress in an animal model. The hippocampus expresses adrenal steroid receptors. It undergoes atrophy in several psychiatric disorders and responds to repeated stressors with decreased dendritic branching and reduction in number of neurons in the dentate gyrus. Stress promotes adaptation ("allostasis"), but a perturbed diurnal rhythm or failed shutoff of mediators after stress ("allostatic state") leads, over time, to wear and tear on the body ("allostatic load"). Neural changes mirror the pattern seen in the cardiovascular, metabolic, and immune systems, that is, short-term adaptation versus long-term damage. Allostatic load leads to impaired immunity, atherosclerosis, obesity, bone demineralization, and atrophy of nerve cells in brain. Allostatic load is seen in major depressive illness and may also be expressed in other chronic anxiety disorders such as PTSD and should be documented.
Subclinical depression, often clinically unrecognized, may pose increased risk of cardiovascular disease. Few studies have prospectively investigated cardiovascular events related to depression in older women. We describe prevalence, cardiovascular correlates, and relationship to subsequent cardiovascular events of depressive symptoms among generally healthy postmenopausal women.
The Women's Health Initiative Observational Study followed up 93 676 women for an average of 4.1 years. Depression was measured at baseline with a short form of the Center for Epidemiological Studies Depression Scale. Risks of cardiovascular disease (CVD) events were estimated from Cox proportional hazards models adjusting for multiple demographic, clinical, and risk factor covariates.
Current depressive symptoms above the screening cutoff point were reported by 15.8% of women. Depression was significantly related to CVD risk and comorbidity (odds ratios ranging from 1.12 for hypertension to 1.60 for history of stroke or angina). Among women with no history of CVD, depression was an independent predictor of CVD death (relative risk, 1.50) and all-cause mortality (relative risk, 1.32) after adjustment for age, race, education, income, diabetes, hypertension, smoking, high cholesterol level requiring medication, body mass index, and physical activity. Taking antidepressant medications did not alter the depression-associated risks associated.
A large proportion of older women report levels of depressive symptoms that are significantly related to increased risk of CVD death and all-cause mortality, even after controlling for established CVD risk factors. Whether early recognition and treatment of subclinical depression will lower CVD risk remains to be determined in clinical trials.
The role of cytokines in depression was first considered when the cytokine interferon resulted in "sickness behaviour", the symptoms of which are similar to those of major depression. The latter is associated with an increase in pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha). These cytokines are potent modulators of corticotropin-releasing hormone (CRH) which produces heightened hypothalamic-pituitary-adrenal axis (HPA) activity characterized by increases in ACTH and cortisol, both of which are reported elevated in major depression. Antidepressant treatment has immunomodulatory effects with increases in the production of IL-10, which is an anti-inflammatory cytokine. This review based on a Medline search from 1980-2003, focuses on the evidence available of cytokine changes in acute stress, chronic stress and major depression. It examines the effects of antidepressant treatment on immune parameters in both animal models and clinical trials. We suggest that future antidepressants may target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.
We examined the association between depressive symptoms and all-cause mortality in a population sample. Published findings on the relation between depressive symptoms and mortality risk point to an inconsistent association and one that is likely influenced by health status. Few studies have assessed this relation in randomly selected population samples.
Participants were 3617 noninstitutionalized adults, age 25 years or older, from the Americans' Changing Lives Study, an ongoing longitudinal study of a nationally representative sample. Depressive symptoms were measured by the 11-item version of the Center for Epidemiological Studies Depression Scale (CES-D). Cox proportional hazards models estimated the relative risk of mortality as a function of the CES-D scores at baseline.
In 7.5 years of follow-up, 542 deaths occurred. Each 1-standard unit increase on the CES-D predicted a 21% increased risk of all-cause mortality, adjusting for age, gender, and race (hazard ratio = 1.21, 95% confidence interval = 1.08 to 1.36, p = .001). This association was weakened somewhat following adjustment for education, income, body mass index, smoking and alcohol consumption (hazard ratio = 1.13, 95% confidence interval = 0.99 to 1.28, p = .06). However, control for self-reported functional limitations or chronic health conditions at baseline effectively eliminated the relationship. Analyses limited to participants with good to excellent health or no functional impairments at baseline showed no association between depressive symptoms and subsequent mortality risk. Secondary analyses showed no association between depressive symptoms and cardiovascular mortality.
These findings from a randomly selected, nationally representative sample do not support the hypothesis that depressive symptoms are independently related to mortality in the general population, after adequate adjustment for the confounding effects of physical health status.
Depression may be a risk factor for cardiovascular disease (CVD) mortality. We evaluated long-term mortality risk associated with depressive symptoms measured at middle age among men at high risk for coronary heart disease (CHD).
12,866 men without definite evidence of CHD at study entry but who had above average risk of CHD based on blood pressure, blood cholesterol levels, and/or cigarette smoking were recruited into the Multiple Risk Factor Intervention Trial (MRFIT). Survivors at the end of the trial were followed-up for mortality for an additional 18 years. Men who had completed the Center for Epidemiologic Studies Depression (CES-D) scale near the end of the trial (n=11,216) were used in a prospective analysis of post-trial all-cause and cause-specific mortality during 18-year follow-up after CES-D assessment.
Greater depressive symptoms measured at the end of the trial were associated with significantly higher risk of all-cause mortality and for cause-specific death, a higher risk of CVD, and, more specifically, stroke mortality (all P values <0.02) but not CHD mortality (P=0.48) in linear trend analyses. The significant associations were strongest for those reporting the greatest depression: hazard ratio (HR)=1.15 (95% CI, 1.03 to 1.28; P<0.01) for all-cause mortality for those in the highest depressive symptom quintile, HR=1.21 for CVD mortality (95% CI, 1.03 to 1.41; P<0.05), and HR=2.03 for stroke mortality (95% CI, 1.20 to 3.44; P<0.01) compared with those in the lowest quintile. These associations were adjusted for age, intervention group, race, educational attainment, smoking at baseline and visit 6, trial averaged systolic blood pressure, alcohol consumption, and fasting cholesterol, as well as the occurrence of nonfatal cardiovascular events during the trial.
Greater depressive symptoms are associated with an increase in the risk of all-cause and, more specifically, CVD mortality in men. Stroke but not CHD was the form of CVD with which depressive symptoms were associated.
Numerous studies demonstrate links between chronic stress and indices of poor health, including risk factors for cardiovascular disease and poorer immune function. Nevertheless, the exact mechanisms of how stress gets “under the skin” remain elusive. We investigated the hypothesis that stress impacts health by modulating the rate of cellular aging. Here we provide evidence that psychological stress— both perceived stress and chronicity of stress—is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, which are known determinants of cell senescence and longevity, in peripheral blood mononuclear cells from healthy premenopausal women. Women with the highest levels of perceived stress have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women. These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age-related diseases.
• psychological stress
• telomere length
• telomerase
• oxidative stress
Folk wisdom has long suggested that stressful events take a toll on health. The field of psychoneuroimmunology (PNI) is now providing key mechanistic evidence about the ways in which stressors--and the negative emotions that they generate--can be translated into physiological changes. PNI researchers have used animal and human models to learn how the immune system communicates bidirectionally with the central nervous and endocrine systems and how these interactions impact on health.
Rapidly accruing evidence from a diversity of disciplines supports the hypothesis that psychosocial factors are related to morbidity and mortality due to cardiovascular diseases. We review relevant literature on (a) negative emotional states, including depression, anger and hostility, and anxiety; (b) chronic and acute psychosocial stressors; and (c) social ties, social support, and social conflict. All three of these psychosocial domains have been significantly associated with increased risk of cardiovascular morbidity and mortality. We also discuss critical pathophysiological mechanisms and pathways that likely operate in a synergistic and integrative way to promote atherogenesis and related clinical manifestations. We conclude by discussing some of the important challenges and opportunities for future investigations.
Biological age may be distinct from chronological age and contribute to the pathogenesis of age-related diseases. Mean telomeres lengths provide an assessment of biological age with shorter telomeres, indicating increased biological age. We investigated whether subjects with premature myocardial infarction (MI) had shorter leukocyte telomeres.
Mean terminal restriction fragment (TRF) length, a measure of average telomere size, was compared in leukocyte DNA of 203 cases with a premature MI (<50 years) and 180 controls. Age- and sex-adjusted mean TRF length of cases was significantly shorter than that of controls (difference 299.7+/-69.3 base pairs, P<0.0001) and on average equivalent to controls 11.3 years older. The difference in mean TRF length between cases and controls was not accounted for by other coronary risk factors. Compared with subjects in the highest quartile for telomere length, the risk of myocardial infarction was increased between 2.8- and 3.2-fold (P<0.0001) in subjects with shorter than average telomeres.
The findings support the concept that biological age may play a role in the etiology of coronary heart disease and have potentially important implications for our understanding of its genetic etiology, pathogenesis, and variable age of onset.
Bipolar disorder is one of the world’s 10 most disabling conditions,
taking away years of healthy functioning from individuals who have the illness.1 With no predilection for nation, race, or socioeconomic
status, classic manic-depressive illness has a prevalence of approximately
1% across all populations.2 However, the personal
and societal costs of bipolar disorders are not limited to the more traditional
bipolar I subtype, which includes episodes of full-blown mania and major depression.3 Bipolar II disorder, involving episodes of less severe
hypomania and major depression, and bipolar spectrum subtypes, which probably
bring the prevalence of all bipolar disorders to more than 3% of US individuals,
can also be devastating conditions. All bipolar disorders are chronically
recurring illnesses associated with substantial morbidity and mortality.4- 6
Massa-chusetts General Hospital and Harvard Medical School; Department of Medical Oncology Dana Farber Cancer Institute; and Center for Human Genetic Research (JWS) Massachusetts General Hos-pital Address reprint requests to Naomi
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