Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging

In the paper

“Emerging data suggest that LTL may be reduced in certain psychiatric illnesses, perhaps in proportion to exposure to the psychiatric illnesses, although conflicting data exist.”

In the paper

“Of these, seven found significantly shorter LTL in currently depressed individuals (or in individuals with mixed mood disorders including MDD) compared to controls (Garcia-Rizo et al., 2013; Hartmann et al., 2010; Hoen et al., 2011; Lung et al., 2007; Simon et al., 2006; Verhoeven et al., 2014a; Wikgren et al., 2012b), while four did not (Needham et al., 2014; Schaakxs et al., 2015; Teyssier et al”

What the sources say

• Not checked yetcites Garcia-Rizo et al., 2013 source
• Not checked yetcites Hartmann et al., 2010 source
• Not checked yetcites Hoen et al., 2011 source

In the paper

“Critically short telomeres can cause cells to undergo senescence, apoptosis or genomic instability, and shorter LTL correlates with poorer health and predicts mortality.”

In the paper

“Many psychiatric illnesses are associated with early mortality and with an increased risk of developing physical diseases that are more typically seen in the elderly.”

In the paper

“Telomeres shorten with repeated cell divisions in somatic cells due to incomplete replication of the telomere ends (Fig. 1), replication- and nuclease-associated telomeric DNA damage, and/or chronic exposure to oxidation, certain cytotoxins or inflammation and possibly chronic exposure to the stress hormones, cortisol and catecholamines (Wolkowitz et al., 2011b).”

What the sources say

• Not checked yetcites Wolkowitz et al., 2011b

In the paper

“Rare Mendelian human mutations compromising telomere maintenance or protection genes cause early death and diseases involving a wide variety of tissues and organ systems (Armanios and Blackburn, 2012).”

What the sources say

• Not checked yetcites Armanios and Blackburn, 2012 source

In the paper

“Moreover, certain psychiatric illnesses may be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), which could underlie this association.”

In the paper

“Many psychiatric disorders such as major depressive disorder (MDD), bipolar disorder (BD), post-traumatic stress disorder (PTSD) and schizophrenia, are associated with an increased risk of serious medical illnesses (O'Donovan et al., 2011a; Penninx et al., 2013; Viron and Stern, 2010) and premature mortality from natural causes (Viron and Stern, 2010).”

What the sources say

• Not checked yetcites O'Donovan et al., 2011a
• Not checked yetcites Penninx et al., 2013 source
• Not checked yetcites Viron and Stern, 2010

In the paper

“When telomeres reach a critically short length, cells undergo replicative senescence or can become genomically unstable.”

In the paper

“Shortened LTL reflects a cell’s mitotic history and cumulative exposure to inflammation and oxidation as well as the availability of telomerase, a telomere-lengthening enzyme.”

In the paper

“Telomeres are dynamic structures, and LTL is in part genetically programmed, with heritability estimates ranging from 0.36–0.84 (Aviv, 2012).”

What the sources say

• Not checked yetcites Aviv, 2012 source

In the paper

“In addition, failure of checkpoints in pre-cancerous cells with critically short telomeres can lead to genomic instability through DNA end-to-end fusions and can promote cancer progression (Maser and DePinho, 2002).”

What the sources say

• Not checked yetcites Maser and DePinho, 2002 source

In the paper

“Although lifestyle and socioeconomic factors play a role, the psychiatric condition itself may be an independent risk factor (Viron and Stern, 2010).”

What the sources say

• Not checked yetcites Viron and Stern, 2010

In the paper

“Telomerase has been less well characterized in psychiatric illnesses, but a role in depression and in antidepressant and neurotrophic effects has been suggested by preclinical and clinical studies.”

In the paper

“In a recent meta-analysis, TL heritability was estimated to be 0.7 (Broer et al., 2013).”

What the sources say

• Not checked yetcites Broer et al., 2013 source

In the paper

“The reasons for this are unknown, but relatively long telomeres tend to shorten over time, and relatively short telomeres tend to lengthen over time, possibly due to the preferential recruitment of reparative mechanisms such as telomerase activity (TA) (Epel, 2012).”

What the sources say

• Not checked yetcites Epel, 2012 source

In the paper

“In several studies, not only did baseline LTL correlate with medical illnesses cross-sectionally but predicted the subsequent development of cancers, CVD, diabetes or mortality (Cawthon et al., 2003; Willeit et al 2010; Zhao et al., 2014).”

What the sources say

• Not checked yetcites Cawthon et al., 2003 source
• Not checked yetcites Willeit et al 2010 source
• Not checked yetcites Zhao et al., 2014 source

In the paper

“Some individuals maintain and may even lengthen average LTL for some periods (Epel, 2012; Muezzinler et al., 2013).”

What the sources say

• Not checked yetcites Epel, 2012 source
• Not checked yetcites Muezzinler et al., 2013 source

In the paper

“In addition, immune cells that have become senescent due to critical telomere shortening (e.g., CD8+CD28− T lymphocytes) hyper-secrete pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α (Effros, 2009), which can lead to a vicious cycle of further inflammation, oxidative stress and telomere shortening.”

What the sources say

• Not checked yetcites Effros, 2009 source

In the paper

“Also, prospective shortening of LTL over relatively short periods of time (2.5 years) has predicted long-term (12 year) cardiovascular mortality in men in one study (Epel et al., 2009a), although not all studies have found this (Weischer et al., 2014).”

What the sources say

• Not checked yetcites Epel et al., 2009a
• Not checked yetcites Weischer et al., 2014 source

In the paper

“(b) the relationship of LTL to TL in other tissues has not been well established, and TL varies by tissue (although TL is generally positively correlated across certain, but not all, tissues within individuals) (Daniali et al., 2013; Dlouha et al., 2014; Friedrich et al., 2000; Gadalla et al., 2010; Lukens et al., 2009; Mitchell et al., 2014; Nakamura et al., 2002; Takubo et al., 2002; Takubo et a”

What the sources say

• Not checked yetcites Daniali et al., 2013 source
• Not checked yetcites Dlouha et al., 2014 source
• Not checked yetcites Friedrich et al., 2000 source

In the paper

“There are some studies linking shorter LTL with premature mortality (Cawthon et al., 2003; Fitzpatrick et al., 2011; Weischer et al., 2012) and a reduction in years of healthy living (Njajou et al., 2009).”

What the sources say

• Not checked yetcites Cawthon et al., 2003 source
• Not checked yetcites Fitzpatrick et al., 2011 source
• Not checked yetcites Weischer et al., 2012 source

In the paper

“Leukocyte telomere length generally decreases progressively over the lifespan, with estimates of average attrition rate ranging between 14 to 103 base pairs (bp) per year (weighted mean of 21.9 bp per year) in cross-sectional studies, and between 32.2 to 45.5 bp per year (weighted mean of 40.7 bp per year) in longitudinal studies (Muezzinler et al., 2013).”

What the sources say

• Not checked yetcites Muezzinler et al., 2013 source

In the paper

“In summary, LTL is an index and predictor of physical health and of processes associated with biological aging.”

In the paper

“In the currently depressed subjects, LTL was inversely associated with severity of depression and with the duration of depression over the preceding four years (although longer-term depressive history was not available), suggesting a “dose-response” relationship (see below in sections 2 and 3).”

What the sources say

• Not checked yetcites Verhoeven et al., 2014a

In the paper

“The negative study by Needham et al. (2014) found that individuals with MDD who were receiving antidepressants did have significantly shorter LTL than controls, but depressed individuals not taking antidepressants did not, and the authors speculated that the former group may have had more serious depressions that required medication treatment.”

What the sources say

• Not checked yetcites Needham et al. (2014)

In the paper

“Elvsåshagen et al found that the total lifetime number of depressive episodes (corrected for age), but not hypomanic episodes, was significantly correlated with the percentage of telomeres shorter than 3,000 bp (by two tailed criteria), consistent with a “dose-response” relationship with depression (Elvsashagen et al., 2011).”

What the sources say

• Not checked yetcites Elvsashagen et al., 2011 source

In the paper

“In that study, IgG antibodies to cytomegalovirus (CMV) were significantly elevated in the BD group, and these levels were inversely correlated with LTL, suggesting that exposure to this virus might have played a role in immunosenescence and telomere shortening in the BD group.”

What the sources say

• Not checked yetcites Rizzo et al., 2013 source

In the paper

“Cumulatively, the bulk of evidence suggests that LTL is decreased in individuals with full syndromal diagnoses of MDD, especially in those with more chronic or severe depression, although the effect size is small..”

In the paper

“The remaining small-scale study that did not find overall differences in LTL between 18 individuals with MDD and 17 controls, did find, in an exploratory analysis, significantly shorter LTL in the more chronically depressed individuals (above the median cumulative duration of active MDD of 9.2 years) (Wolkowitz et al., 2011a).”

What the sources say

• Not checked yetcites Wolkowitz et al., 2011a

In the paper

“Across the MDD group, lifetime untreated depression duration was significantly inversely correlated with LTL, consistent with a “dose-response” relationship, although the pilot sample size was too small too draw meaningful conclusions.”

What the sources say

• Not checked yetcites Wolkowitz et al., 2011a

In the paper

“Despite finding no difference in mean LTL, however, the latter study did find increased expression of p16INK4a and stathmin (STMN1) genes in the depressed sample, which are markers of cellular senescence, telomere dysfunction, microtubule dynamics and biological aging, and are regulators of cell cycle dynamics (Teyssier et al., 2012).”

What the sources say

• Not checked yetcites Teyssier et al., 2012 source

In the paper

“Elvsåshagen and colleagues (Elvsashagen et al., 2011) found the percentage of telomeres shorter than 3,000 bp (“short telomeres”) was increased in BD type II subjects (p= 0.04) and a trend for shortened absolute LTL in the BD type II subjects (p=0.08), although those statistical tests were one-tailed and would not be considered statistically significant by two-tailed criteria.”

What the sources say

• Not checked yetcites Elvsashagen et al., 2011 source

In the paper

“The authors suggested that lithium may exert a protective effect against telomere shortening, especially when therapeutically efficacious, and that lithium-induced telomerase activation might be involved, although TA was not measured (Martinsson et al., 2013).”

What the sources say

• Not checked yetcites Martinsson et al., 2013 source

In the paper

“Overall, the studies of LTL in BD are inconclusive, perhaps due to the effects of medication on LTL.”

In the paper

“Since all of the individuals with schizophrenia were receiving psychotropic medication, the authors suggested a similarity of their findings with those of Savolainen et al. (2012) in a mixed inpatient psychiatric sample, which found that telomere lengthening in certain psychiatric patients may be moderated by psychotropic medication usage.”

What the sources say

• Not checked yetcites Savolainen et al. (2012) source

In the paper

“Yu et al. (2008) found shorter LTL in individuals with schizophrenia who responded poorly to treatment but not in the schizophrenia group as a whole.”

What the sources say

• Not checked yetcites Yu et al. (2008)

In the paper

“Mansour et al. (2011), studying a relatively young, highly inbred population, found no significant LTL difference in schizophrenia vs. controls, but LTL was confounded by the extent of inbreeding in the schizophrenia population, and no data were available regarding comorbid diagnoses, medications or treatment response.”

What the sources say

• Not checked yetcites Mansour et al. (2011) source

In the paper

“The cumulative amount of time receiving lithium over the preceding 30 months was associated with increased LTL, and lithium responders had longer LTL than lithium non-responders.”

What the sources say

• Not checked yetcites Martinsson et al., 2013 source

In the paper

“Most recently, Lima et al. (2014) corroborated shorter LTL in BD, although they lacked data on duration of illness and medication treatment.”

What the sources say

• Not checked yetcites Lima et al. (2014)

In the paper

“The largest study to date (comprising 539 schizophrenia subjects and 519 controls) (Nieratschker et al., 2013) reported an unexpected increase in LTL in individuals with schizophrenia in comparison to healthy controls, especially in the younger subjects.”

What the sources say

• Not checked yetcites Nieratschker et al., 2013 source

In the paper

“In one study, LTL was significantly shortened in individuals with schizophrenia and was unrelated to antipsychotic use or duration of illness (Kao et al., 2008).”

What the sources say

• Not checked yetcites Kao et al., 2008 source

In the paper

“Most recently, Malaspina et al. (2014) reported no significant difference in LTL between medicated individuals with schizophrenia compared to controls, but the control sample size was small, and the psychiatric history of the controls was assessed only for the preceding two years.”

What the sources say

• Not checked yetcites Malaspina et al. (2014) source

In the paper

“Therefore, it is unlikely that LTL measurement, used alone, will come into clinical practice as a diagnostic biomarker, let alone a diagnostic aid in psychiatric diagnoses.”

In the paper

“Oxidative stress markers are inversely correlated with LTL in MDD (Wolkowitz et al., 2011a) and in healthy pre-menopausal women (Epel et al., 2004).”

What the sources say

• Not checked yetcites Wolkowitz et al., 2011a
• Not checked yetcites Epel et al., 2004 source

In the paper

“However, LTL was significantly shorter among the older anxiety disorder subjects (48–87 years of age) compared to controls, and the authors suggested that more prolonged exposure to anxiety disorder-related stress might be needed for accelerated telomere shortening to be detected (Kananen et al., 2010).”

What the sources say

• Not checked yetcites Kananen et al., 2010 source

In the paper

“In summary, the data are mixed, but the evidence tends to support LTL shortening in anxiety disorders, especially with more severe anxiety disorders (meeting full diagnostic criteria) and with longer exposure to the anxiety disorder.”

In the paper

“In summary, although the number of studies is small, the existing evidence base is consistent with LTL shortening in PTSD, although several confounds, especially early life adversity, exist, making conclusions difficult.”

In the paper

“In a large-scale study, while phobic anxiety was not overall significantly correlated with LTL, there was evidence of a threshold or “dose-response” effect, with more severe phobia being associated with shorter LTL (Okereke et al., 2012).”

What the sources say

• Not checked yetcites Okereke et al., 2012 source

In the paper

“This differed from this group’s finding, using the same study population, that remitted MDD was still associated with shortened LTL (Verhoeven et al., 2014a), and they suggested that LTL shortening with anxiety disorders may be more reversible than that associated with MDD.”

What the sources say

• Not checked yetcites Verhoeven et al., 2014a

In the paper

“In summary, data on LTL in schizophrenia and other psychotic disorders are mixed, and it is possible that age, medication exposure, treatment response, comrbidities and confounds may explain some of the variability in findings.”

In the paper

“Pro-inflammatory cytokine concentrations are inversely correlated with LTL in MDD (Wolkowitz et al., 2011a), in individuals with histories of early life stress (Kiecolt-Glaser et al., 2011), and in healthy individuals with high C-reactive protein levels or high cumulative inflammatory load (O'Donovan et al., 2011b; Revesz et al., 2013).”

What the sources say

• Not checked yetcites Wolkowitz et al., 2011a
• Not checked yetcites Kiecolt-Glaser et al., 2011 source
• Not checked yetcites O'Donovan et al., 2011b

In the paper

“Since such biochemical abnormalities cut across traditional psychiatric diagnoses (Pandya et al., 2013; Rosenblat et al., 2014; Smyth and Lawrie, 2013), telomere shortening may be related to specific biological processes or endophenotypes more than to specific diagnostic categories, although this remains to be adequately tested.”

What the sources say

• Not checked yetcites Pandya et al., 2013 source
• Not checked yetcites Rosenblat et al., 2014
• Not checked yetcites Smyth and Lawrie, 2013

In the paper

“As seen from the above reviews, there are inconsistent reports of LTL associations with psychiatric illnesses with the strongest evidence seen in MDD.”

In the paper

“Biological abnormalities seen in certain psychiatric conditions (e.g. inflammation, oxidative stress and perhaps changes in steroids or in biogenic amine activity) are associated with, and may cause, telomere shortening (Wolkowitz et al., 2011a; Wolkowitz et al., 2011b).”

What the sources say

• Not checked yetcites Wolkowitz et al., 2011a
• Not checked yetcites Wolkowitz et al., 2011b

In the paper

“There is a modest preponderance of evidence suggesting that shorter LTL is seen across these illnesses, although methodological differences and, in many cases, small sample sizes preclude more definitive conclusions.”

In the paper

“Two post-mortem studies of TL in cerebellar gray matter and occipital cortex found no significant differences between MDD subjects and controls, although correlations with LTL were not assessed (Teyssier et al., 2010; Zhang et al., 2010).”

What the sources say

• Not checked yetcites Teyssier et al., 2010 source
• Not checked yetcites Zhang et al., 2010 source

In the paper

“In summary, there have not yet been enough studies, especially large-scale ones, in psychiatric populations to assess possible changes in PBMC basal TA, although stress seems a potent regulator of TA, even though the direction and mechanisms of these effects are unknown at this time.”

In the paper

“Further, these studies have often been non-randomized and not adequately controlled.”

In the paper

“A recent population-based study, not specifically in MDD, found that LTL was positively associated with total cerebral volume, including white and cortical matter gray volume, as well as with hippocampal volume and volumes of several other sub-regions (King et al., 2014).”

What the sources say

• Not checked yetcites King et al., 2014 source

In the paper

“Without determining their relationship to neural process that are presumably more closely related to psychiatric illnesses, their ultimate informational value will be limited.”

In the paper

“These preclinical studies suggest that hippocampal TA in mice is involved in the regulation of “depression-like” behaviors and possibly “antidepressant-like” mechanisms, perhaps by regulating adult neurogenesis in the dentate gyrus (Zhou et al., 2011).”

What the sources say

• Not checked yetcites Zhou et al., 2011 source

In the paper

“In this study, baseline PBMC basal TA was controlled for, but potential limitations were that the active group was heterogeneous in terms of treatment received and time since treatment completion.”

What the sources say

• Not checked yetcites Lengacher et al., 2014 source

In the paper

“The behavioral/ psychological/ lifestyle intervention literature relating these interventions to PBMC basal TA and LTL is intriguing and points in the hypothesized direction, but it is limited by the small-scale, non-randomized, non-blinded design of the studies, as well as, in most cases, the short duration of the interventions.”

In the paper

“A five-year follow-up of ten of the original participants from that study showed that their LTL significantly increased from baseline relative to control men whose prostate cancer was simply followed by active surveillance, although their PBMC basal TA had decreased somewhat compared to the baseline measurement (Ornish et al., 2013).”

What the sources say

• Not checked yetcites Ornish et al., 2013 source

In the paper

“A potential limitation of this study was the lack of a control group and the fact that only 30 of 126 eligible patients agreed to participate in the study after learning the details and the fact that all participants were male, which may affect generalizability of the findings.”

What the sources say

• Not checked yetcites Ornish et al., 2008 source

In the paper

“Analyses in this study were cross-sectional, thus causality cannot be inferred, and data on diet, another lifestyle factor that can influence LTL, were not available.”

What the sources say

• Not checked yetcites Puterman et al., 2013 source

In the paper

“One additional small-scale study involving telephone-based psychological stress-reduction counseling in 22 women with cervical cancer (Biegler et al., 2012), found no significant overall change in LTL following four months of counseling, but did find that changes in distress ratings over that time period were inversely correlated with changes in LTL (Biegler et al., 2012).”

What the sources say

• Not checked yetcites Biegler et al., 2012 source

In the paper

“This study was limited by the small sample size (10 subjects in the intervention group and 25 controls) and by the non-randomized study design, which may introduce unknown sources of bias.”

What the sources say

• Not checked yetcites Ornish et al., 2013 source

In the paper

“The literature on exercise and telomere length is inconsistent but generally suggests that exercise is associated with a telomere-protective phenotype in leukocytes and skeletal muscles (Ludlow et al., 2013).”

What the sources say

• Not checked yetcites Ludlow et al., 2013 source

In the paper

“The same group of investigators previously found, in a group of caregiving and non-caregiving post-menopausal women, that highly stressed women have shorter telomeres, but only if they are inactive, suggesting a protective effect of exercise (Puterman et al., 2010).”

What the sources say

• Not checked yetcites Puterman et al., 2010 source

In the paper

“Further, health behaviors may have been spuriously associated with LTL if physical diseases (that could, themselves, lessen healthful health behaviors) bore the primary relationship with LTL.”

In the paper

“The putative effects of certain of these interventions on cellular aging may be mediated by improvements in stress arousal and lessening of threat cognitions and ruminative thought (Epel et al., 2009b), although the biochemical intermediaries remain to be determined.”

What the sources say

• Not checked yetcites Epel et al., 2009b

In the paper

“Since that study was cross-sectional, though, it is difficult to draw causal interpretations, especially since the more highly stressed women were less likely to be physically active.”

What the sources say

• Not checked yetcites Puterman et al., 2010 source

In the paper

“This study, however, had no control group, and four months may be too short to discern significant changes in LTL.”

What the sources say

• Not checked yetcites Biegler et al., 2012 source

In the paper

“In an otherwise concerning picture, findings that certain positive lifestyle changes are correlated with lowered degrees of cell aging (as indexed by LTL and/or PBMC basal TA) (Epel, 2009; Epel, 2012; Hoge et al., 2013; Puterman et al., 2010; Puterman et al., 2015) provide some encouragement, although many of the studies were small-scale, open-label or inadequately controlled.”

What the sources say

• Not checked yetcites Epel, 2009
• Not checked yetcites Epel, 2012 source
• Not checked yetcites Hoge et al., 2013 source

In the paper

“The relatively small effect sizes reported in reviewed positive studies, as well as the lack of diagnostic specificity of LTL and PBMC basal TA changes, also argue against the use of such markers as diagnostic tools, in isolation from other measures, at this time.”

In the paper

“A modest preponderance of the evidence reviewed here suggests that several psychiatric illnesses (viz., MDD, anxiety disorders and PTSD) may be associated with accelerated cellular aging, as indexed by short LTL and possibly by altered PBMC basal TA, although conflicting reports exist, and no conclusions can yet be made.”

In the paper

“Methodological differences between studies, as well as many studies with small sample sizes, make conclusions difficult to draw.”