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

In the paper

“Schizophrenia, like MDD and BD, may also be associated with premature biological aging (Anthes, 2014; Jeste et al., 2011; Kirkpatrick et al., 2008; Kochunov et al., 2013; Koutsouleris et al., 2014; Okusaga, 2014; Shivakumar et al., 2014).”

What the sources say

• Partly supported

  The “Live faster, die younger” section says people with schizophrenia show signs of accelerated ageing, supporting the hedged claim about schizophrenia. It mentions major depression in connection with ageing-related disorders, but does not establish premature biological ageing in MDD, and our copy does not address BD (searched: bipolar). (LLM, conf=0.84)

  cites Anthes, 2014 sourceExperimental — accuracy not yet measured
• Not checked yetcites Jeste et al., 2011 source
• Supported

  In “Is Schizophrenia a Syndrome of Accelerated Aging?” (page not specified), the authors propose that schizophrenia may be a syndrome of accelerated aging and describe evidence consistent with that hypothesis. This supports the hedged claim about schizophrenia; the comparison with MDD and BD is context, not a finding attributed specifically to this source. (LLM, conf=0.93)

  cites Kirkpatrick et al., 2008 source

In the paper

“In total, 11 studies have investigated LTL in MDD (Table 1).”

In the paper

“Of studies having greater than 40 depressed subjects, all except two (Needham et al., 2014; Schaakxs et al., 2015) found significantly shorter LTL in MDD (Hartmann et al., 2010; Hoen et al., 2011; Lung et al., 2007; Simon et al., 2006; Verhoeven et al., 2014a; Wikgren et al., 2012b).”

What the sources say

• Not checked yetcites Needham et al., 2014
• Not checked yetcites Schaakxs et al., 2015 source

In the paper

“The studies on LTL in MDD are summarized in Table 1, where it is seen that the effect sizes for group differences in LTL ranged from 0.04–0.98 (mean Cohen’s d= 0.41; weighted mean Cohen’s d= 0.23).”

In the paper

“Six studies have examined LTL in BD subjects (type I, type II or rapid cycling) (Table 2).”

In the paper

“The three remaining studies failed to detect short LTL in schizophrenia.”

In the paper

“Seven studies have assessed LTL in schizophrenia or other psychotic disorders (Fernandez-Egea et al., 2009; Kao et al., 2008; Kota et al., In press; Malaspina et al., 2014 Mansour et al., 2011; Nieratschker et al., 2013; Yu et al., 2008) (Table 2).”

What the sources say

• Not checked yetcites Fernandez-Egea et al., 2009 source
• Not checked yetcites Kao et al., 2008 source
• Not checked yetcites Kota et al., In press

In the paper

“This explanation is similar to the finding with lithium treatment reviewed above (Martinsson et al., 2013), although no clinical studies have yet directly assessed the effect of psychotropic medications on LTL.”

What the sources say

• Not checked yetcites Martinsson et al., 2013 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

“For example, the tumor suppressor protein, p53, may be activated, which inhibits oxidative defense mechanisms (such as peroxisome proliferator-activated receptor-gamma coactivator [PGC] 1-α and β, promoting mitochondrial damage and senescence or apoptosis (Sahin et al., 2011) (Fig. 2).”

What the sources say

• Not checked yetcites Sahin et al., 2011 source

In the paper

“The particular medical illnesses that are more frequent in these psychiatric conditions are those that are more commonly seen with advanced age, e.g., cardiovascular disease (CVD), stroke, dementia, cancer, obesity, type II diabetes mellitus, osteoporosis (Evans et al., 2005).”

What the sources say

• Not checked yetcites Evans et al., 2005 source

In the paper

“Because this large meta-analysis showed that the risk of cardiovascular disease is influenced by common variations in a defined set of genes known molecularly to act specifically in telomere maintenance and protection (Codd et al., 2013), this finding supports a causal role for impaired telomere maintenance in partially contributing to cardiovascular disease.”

What the sources say

• Not checked yetcites Codd et al., 2013 source

In the paper

“(c) different results may derive from different DNA extraction and assay methods and different laboratories (Aubert et al., 2012; Aviv et al., 2011; Cunningham et al., 2013; Montpetit et al., 2014; Nieratschker et al., 2013);”

What the sources say

• Not checked yetcites Aubert et al., 2012 source
• Not checked yetcites Aviv et al., 2011 source
• Not checked yetcites Cunningham et al., 2013 source

In the paper

“CAD risk increased 21% for every standard deviation decrease in LTL, supporting a direct relationship between TL variation and certain age-related diseases like CAD (Codd et al., 2010).”

What the sources say

• Not checked yetcites Codd et al., 2010 source

In the paper

“Short LTL in humans has been associated with serious medical illnesses with some consistency according to metaanalyses, including cardiovascular disease, diabetes, and cancer (D'Mello et al., 2014; Weischer et al., 2012 Willeit et al, 2014; Wentzensen et al, 2011).”

What the sources say

• Not checked yetcites D'Mello et al., 2014
• Not checked yetcites Weischer et al., 2012 source
• Not checked yetcites Willeit et al, 2014 source

In the paper

“Since accelerated cell death due to telomere shortening can deplete populations of dividing stem cells and progenitor cells (e.g., hematopoietic stem cells, endothelial progenitor cells and neural stem cells/ neural progenitor cells) (Nalapareddy et al., 2008), cellular replacement and repair processes can become limited.”

What the sources say

• Not checked yetcites Nalapareddy et al., 2008 source

In the paper

“Important caveats must be considered in interpreting LTL (Aviv et al., 2006; Epel, 2012), e.g., (a) distinguishing between telomere shortening in the individual leukocyte vs. “apparent” telomere shortening when examining average LTL, due to a re-distribution of leukocyte cell types having different telomere lengths, such as naïve vs. memory T cells;”

What the sources say

• Not checked yetcites Aviv et al., 2006 source
• Not checked yetcites Epel, 2012 source

In the paper

“The mean LTL of the entire mood disorder group was 660 base pairs (bp) shorter than in healthy controls.”

What the sources say

• Not checked yetcites Simon et al., 2006 source

In the paper

“In the MDD group alone, mean LTL was 770 bp shorter than in healthy controls.”

What the sources say

• Not checked yetcites Simon et al., 2006 source

In the paper

“To the extent leukocyte telomeres are relatively short in psychiatric illnesses, shortening of LTL may help explain the excess medical morbidity associated with serious psychiatric illnesses.”

In the paper

“The difference in LTL between the depressed groups and the control group persisted after co-varying for age, sex, education, alcohol use, BMI, symptom duration, depression severity, co-morbid anxiety and alcohol dependence disorders, somatic diseases, and exercise.”

What the sources say

• Not checked yetcites Verhoeven et al., 2014a

In the paper

“Further, MDD has been associated with neuroanatomic/neurodevelopmental as well as brain transcriptome evidence of accelerated brain aging (Douillard-Guilloux et al., 2013; Koutsouleris et al., 2014).”

What the sources say

• Not checked yetcites Douillard-Guilloux et al., 2013 source
• Not checked yetcites Koutsouleris et al., 2014 source

In the paper

“Similarly, a number of medications, both psychiatric (discussed below) and non-psychiatric, may have significant effects on LTL, especially if these medications are not matched across groups or statistically controlled for.”

In the paper

“In addition to psychiatric and substance-related comorbidities, many serious comorbid medical illnesses may also be associated with decreased LTL (D'Mello et al., 2014; Weischer et al., 2012 Willeit et al, 2014; Wentzensen et al, 2011), and presumably this is independent of the effect of the psychiatric diagnosis.”

What the sources say

• Not checked yetcites D'Mello et al., 2014
• Not checked yetcites Weischer et al., 2012 source
• Not checked yetcites Willeit et al, 2014 source

In the paper

“For example, there is preliminary evidence that statins (Olivieri et al., 2012), certain hormones (Lin et al., 2011), and caffeine (Romano et al., 2013) may impact LTL.”

What the sources say

• Not checked yetcites Olivieri et al., 2012 source
• Not checked yetcites Lin et al., 2011 source
• Not checked yetcites Romano et al., 2013 source

In the paper

“For example MDD has a 50% comorbidity with anxiety disorders (Fava et al., 1997), making it difficult to ascribe telomere effects to single diagnosis.”

What the sources say

• Not checked yetcites Fava et al., 1997 source

In the paper

“Major depressive disorder (MDD) has been considered a syndrome of “premature aging” (Heuser, 2002), and this notion has been reiterated in several recent reviews (Kinser and Lyon, 2013; Luca et al., 2013; Wolkowitz et al., 2011b).”

What the sources say

• Not checked yetcites Heuser, 2002 source
• Not checked yetcites Kinser and Lyon, 2013
• Not checked yetcites Luca et al., 2013 source

In the paper

“(d) even slight DNA degradation can yield spurious TL measuements (Dlouha et al., 2014).”

What the sources say

• Not checked yetcites Dlouha et al., 2014 source

In the paper

“Moreover, several preliminary reports suggest that alcohol and certain types of substance abuse may be associated with altered LTL (Pavanello et al., 2011; Yang et al., 2013).”

What the sources say

• Not checked yetcites Pavanello et al., 2011 source
• Not checked yetcites Yang et al., 2013 source

In the paper

“Many psychiatric diagnoses has a high comorbidity with secondary psychiatric illnessess such as substance abuse, various anxiety disorders, and PTSD (Kessler et al., 1994; Lamers et al., 2011).”

What the sources say

• Not checked yetcites Kessler et al., 1994 source
• Not checked yetcites Lamers et al., 2011 source

In the paper

“Further, many subject-level variables, such as age, sex, genetic polymorphisms, “resiliency,” education, history of early life adversities, parental responsiveness, socioeconomic status, health behaviors, diet, and latent or active viral infections (e.g., cytomegalovirus or herpes virus) may affect LTL, independent of the disease process being studied (Adler et al., 2013; Asok et al., 2013;”

What the sources say

• Not checked yetcites Adler et al., 2013 source
• Not checked yetcites Asok et al., 2013 source

In the paper

“According to the authors’ calculations, this represents a very large effect, representing approximately 10 years of accelerated cellular aging in the combined mood disorder group.”

What the sources say

• Not checked yetcites Simon et al., 2006 source

In the paper

“In another report, Hoen et al. (2013), found that baseline anxiety disorders in a population-based sample, but not depressive disorders, predicted LTL two years later.”

What the sources say

• Not checked yetcites Hoen et al. (2013) source

In the paper

“The “dose-response” hypothesis is supported by the longitudinal study of Shalev et al. (2014), which found, in men, that duration of “internalizing disorders” (including MDD) between the ages of 11– 38 years old predicted LTL at age 38 years, in a dose-response manner.”

What the sources say

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

In the paper

“Martinsson et al. (2013) reported significantly increased LTL in lithium-treated BD subjects compared to controls.”

What the sources say

• Not checked yetcites Martinsson et al. (2013) source

In the paper

“Years of bipolar illness (corrected for age) were not significantly correlated with LTL.”

What the sources say

• Not checked yetcites Rizzo et al., 2013 source

In the paper

“Rizzo et al. (2013) found significantly shorter PBMC TL in euthymic women with BD type I (men were not studied).”

What the sources say

• Not checked yetcites Rizzo et al. (2013) source

In the paper

“The lack of difference in LTL between active and remitted depressed subjects suggested to the authors that MDD episodes leave a lasting “imprint” on LTL (Verhoeven et al., 2014a; Verhoeven et al., 2014b).”

What the sources say

• Not checked yetcites Verhoeven et al., 2014a
• Not checked yetcites Verhoeven et al., 2014b

In the paper

“Hoen et al. (2011) found, in a large cohort of patients with coronary heart disease, that baseline MDD did not predict LTL five years later, although it is possible that the association of coronary heart disease with LTL obscured an association with MDD.”

What the sources say

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

In the paper

“Bipolar disorder (BD) may also be characterized by “accelerated aging” (Rizzo et al., 2014; Sodhi et al., 2012; Yatham et al., 2009 (but see Gildengers et al., 2013)).”

What the sources say

• Not checked yetcites Rizzo et al., 2014 source
• Not checked yetcites Sodhi et al., 2012 source
• Not checked yetcites Yatham et al., 2009 source

In the paper

“Jodczyk et al. (2014) reported that diagnoses of MDD between age 16 and 25 did not predict shorter LTL at age 28– 30.”

What the sources say

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

In the paper

“Similarly, Kota et al. (In press) reported that “unremitted,” but not “remitted,” schizophrenia was associated with short LTL compared to controls.”

What the sources say

• Not checked yetcites Kota et al. (In press)

In the paper

“A possible confounder is that an unequal number of “outlier” data points (> 3 SD from the mean) were excluded from analysis (23 data points from the schizophrenia sample and four data points from the control sample).”

What the sources say

• Not checked yetcites Nieratschker et al., 2013 source

In the paper

“The different results in the Elvsåshagen et al. (2011) and Martinsson et al. (2013) studies might, therefore, be explained by lithium treatment.”

What the sources say

• Not checked yetcites Elvsåshagen et al. (2011) source
• Not checked yetcites Martinsson et al. (2013) source

In the paper

“In another study, newly diagnosed, antipsychotic-naïve individuals with non-affective psychoses also showed shortened LTL (Fernandez-Egea et al., 2009).”

What the sources say

• Not checked yetcites Fernandez-Egea et al., 2009 source

In the paper

“Remitted anxiety disorder subjects, however, especially those in remission for 10 years or more, showed no significant difference in LTL compared to controls.”

What the sources say

• Not checked yetcites Verhoeven et al. (In press)

In the paper

“Shortened LTL has been associated with increased urinary catecholamine concentrations or increased sympathetic nervous system activity (Epel et al., 2006; Revesz et al., 2013).”

What the sources say

• Not checked yetcites Epel et al., 2006 source
• Not checked yetcites Revesz et al., 2013

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

“Studies are more, but not always, consistent in showing inverse relationships between LTL and dynamic aspects of cortisol secretion (e.g., waking-associated increases in cortisol or cortisol responses provoked by psychological stress) (Gotlib et al., 2014; Kroenke et al., 2011; Revesz et al., 2013; Tomiyama et al., 2012) as opposed to basal, resting or even circadian cortisol levels.”

What the sources say

• Not checked yetcites Gotlib et al., 2014
• Not checked yetcites Kroenke et al., 2011 source
• Not checked yetcites Revesz et al., 2013

In the paper

“Kananen et al. (2010), found no overall significant difference in LTL between a mixed group of anxiety disorder subjects (panic disorder, generalized anxiety disorder, social phobia, agoraphobia and phobia not otherwise specified, plus cases of “sub-threshold” anxiety disorders not meeting DSM-IV criteria for anxiety disorder diagnosis) and controls.”

What the sources say

• Not checked yetcites Kananen et al. (2010) source

In the paper

“Nonetheless, it is apparent that LTL shortening, when it occurs, is not confined to specific traditional diagnostic categories.”

In the paper

“Needham et al. (2014) found, in a large-scale study, that shorter LTL was significantly associated with a diagnosis of generalized anxiety disorder and panic disorder in women but not in men.”

What the sources say

• Not checked yetcites Needham et al. (2014)

In the paper

“In the largest population-based study to date on cell aging in anxiety disorders, Verhoeven et al. (In press) reported that subjects with current anxiety disorder diagnoses (including panic with agoraphobia, social phobia and generalized anxiety disorder) had significantly shorter LTL than controls, even after accounting for health, demographics, lifestyle factors and concurrent MDD.”

What the sources say

• Not checked yetcites Verhoeven et al. (In press)

In the paper

“Two important drivers of LTL shortening, apart from that resulting from incomplete DNA end replication in cells undergoing frequent mitoses, are inflammation and oxidative stress (Wolkowitz et al., 2011a; von Zglinicki 2002)”

What the sources say

• Not checked yetcites Wolkowitz et al., 2011a
• Not checked yetcites von Zglinicki 2002 source

In the paper

“In the studies reviewed here, the evidence for a “dose-response” relationship is suggestive but mixed.”

In the paper

“Inherited telomerase deficiencies resulting in a two-fold drop in gene dosage are directly linked to malignancies and several other diseases in humans (Armanios and Blackburn, 2012).”

What the sources say

• Not checked yetcites Armanios and Blackburn, 2012 source

In the paper

“A caveat when interpreting that study, however, is that pre-test PBMC basal TA measures were not available for the meditation group, thus the analyses relied on cross-sectional post-meditation data only (Jacobs et al., 2011).”

What the sources say

• Not checked yetcites Jacobs et al., 2011 source

In the paper

“several behavioral and psychological intervention studies in non-psychiatric populations have examined the effects on PBMC basal TA or LTL of interventions ranging from intensive lifestyle modification, mindful eating, mindfulness-based stress reduction and various types of meditation (see Verhoeven et al. 2014b for an overview)”

What the sources say

• Not checked yetcites Verhoeven et al. 2014b

In the paper

“A recent metaanalysis of four studies with randomized controlled designs (Jacobs et al., 2011; Daubenmier et al., 2012; Ho et al., 2012; Lavretsky et al., 2013) found an effect size of d= 0.46 for meditation intervention increasing PBMC basal TA (Schutte and Malouff, 2014b).”

What the sources say

• Not checked yetcites Schutte and Malouff, 2014b

In the paper

“The ribonucleoprotein enzyme telomerase provides the major mechanism for telomere preservation and length replenishment (Armanios and Blackburn, 2012; Chakhparonian and Wellinger, 2003) (Fig 1).”

What the sources say

• Not checked yetcites Armanios and Blackburn, 2012 source
• Not checked yetcites Chakhparonian and Wellinger, 2003

In the paper

“Wolkowitz et al. (In press) reported a significant positive correlation between PBMC basal TA and hippocampal volume in a small group of unmedicated individuals with MDD but not in healthy controls.”

What the sources say

• Not checked yetcites Wolkowitz et al. In press

In the paper

“Nonetheless, several studies reported “dose-response” relationships, with greater improvement in mental well-being or sense of purpose in life or greater adherence to the behavioral intervention, associating with larger increases in PBMC basal TA (Epel, 2012; Jacobs et al., 2011).”

What the sources say

• Not checked yetcites Epel, 2012 source
• Not checked yetcites Jacobs et al., 2011 source

In the paper

“Mutations that increase expression of telomerase reverse transcriptase (TERT; the catalytic subunit of telomerase) by two-fold, cause large increases in risks of certain cancers (Horn et al., 2013; Huang et al., 2013).”

What the sources say

• Not checked yetcites Horn et al., 2013 source
• Not checked yetcites Huang et al., 2013 source

In the paper

“Despite these theoretical possibilities, the actual relationship between LTL and telomere length in brain cells is unknown.”

In the paper

“These studies have generally found intervention-associated increases in PBMC basal TA (Epel, 2012; Epel et al., 2009b; Epel, 2009; Jacobs et al., 2011; Lengacher et al., 2014; Ornish et al., 2008; Schutte and Malouff, 2014b; Starkweather et al., 2014).”

What the sources say

• Not checked yetcites Epel, 2012 source
• Not checked yetcites Epel et al., 2009b
• Not checked yetcites Jacobs et al., 2011 source

In the paper

“Two studies in MDD (Verhoeven et al., 2014a; Wikgren et al., 2012b) and one in BD type II (Elvsåshagen et al., 2011) found no significant difference in LTL between those who were currently receiving psychoactive medication compared to those who were not”

What the sources say

• Not checked yetcites Verhoeven et al., 2014a
• Not checked yetcites Wikgren et al., 2012b
• Not checked yetcites Elvsåshagen et al., 2011 source

In the paper

“Jacobs et al., (2011) found that retreat participants, meditating for 6 hours daily for 3 months, had greater PBMC basal TA at the end of the three months than did a waitlist control group.”

What the sources say

• Not checked yetcites Jacobs et al., 2011 source

In the paper

“Lengacher et al. (2014) showed, in a sample of breast cancer patients, that mindfulness-based stress reduction for six weeks significantly increased PBMC basal TA compared to a waitlist control group.”

What the sources say

• Not checked yetcites Lengacher et al., 2014 source

In the paper

“However, the measures of stress and of health behaviors were self-reported, possibly influencing the results.”

What the sources say

• Not checked yetcites Puterman et al., 2015 source

In the paper

“In a pilot non-randomized study in low-risk prostate cancer patients, Ornish et al. (2008) showed that three-months of comprehensive lifestyle changes were associated with significant increases in PBMC basal TA accompanied by a decrease in psychological distress.”

What the sources say

• Not checked yetcites Ornish et al., 2008 source

In the paper

“One study found that aspects of “multi-system resiliency” and positive lifestyle (e.g., social support, good emotion regulation, sleep and exercise), collectively but not individually, statistically attenuated the negative relationship between MDD and LTL (Puterman et al., 2013).”

What the sources say

• Not checked yetcites Puterman et al., 2013 source

In the paper

“Moreover, the treatment program was relatively short and thus only allowed for short-term assessment of PBMC basal TA.”

What the sources say

• Not checked yetcites Lengacher et al., 2014 source

In the paper

“Short LTL is unlikely to be specific to any one categorical psychiatric illness.”

In the paper

“Since subjective stress ratings and the anticipation of threat bear closer relationships to cell aging than do objective stressors (Epel et al., 2004; O'Donovan et al., 2012), it is conceivable that psychotherapy and stress coping mechanisms might also attenuate stressassociated cell aging (Biegler et al., 2012), but this has not been well-studied.”

What the sources say

• Not checked yetcites Epel et al., 2004 source
• Not checked yetcites O'Donovan et al., 2012

In the paper

“Further, insufficient calibration of assay methods across labs and the lack of accepted “normal ranges” for LTL and PBMC basal TA make it premature for cell aging markers to enter clinical use at this time (Martin-Ruiz et al., In press).”

What the sources say

• Not checked yetcites Martin-Ruiz et al., In press

In the paper

“If it occurs, it is more likely related to underlying trans-diagnostic biological abnormalities or behavioral dimensions/ phenotypes (Wolkowitz et al., 2010).”

What the sources say

• Not checked yetcites Wolkowitz et al., 2010 source

In the paper

“For example, a recent study found that the combination of short telomere length with depression was (compared with either measure alone) a strong prospective predictor of both cancer disease progression and mortality in a cohort of bladder cancer patients (Lin et al., 2015).”

What the sources say

• Not checked yetcites Lin et al., 2015 source

In the paper

“For example, recent data suggest that “high risk” genetic polymorphisms in the serotonin and dopamine systems may interact with early life adversity to affect adult LTL (Mitchell et al., 2014).”

What the sources say

• Not checked yetcites Mitchell et al., 2014 source