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

May combine two claims.

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.

“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.”

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Of the 11 MDD studies, seven found significantly shorter LTL in currently depressed individuals (or in individuals with mixed mood disorders including MDD) compared to controls, while four did not.

“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”

• cites Garcia-Rizo et al., 2013 sourceNot checked yet

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• cites Hartmann et al., 2010 sourceNot checked yet

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• cites Hoen et al., 2011 sourceNot checked yet

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Shorter LTL correlates with poorer health and predicts mortality.

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

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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.

“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.”

May combine two claims.

Telomeres shorten with repeated cell divisions in somatic cells due to incomplete replication of telomere ends, replication- and nuclease-associated telomeric DNA damage, and/or chronic exposure to oxidation, certain cytotoxins or inflammation and possibly chronic exposure to stress hormones, cortisol and catecholamines.

“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).”

• cites Wolkowitz et al., 2011bNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Rare Mendelian human mutations compromising telomere maintenance or protection genes cause early death and diseases involving a wide variety of tissues and organ systems.

“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).”

• cites Armanios and Blackburn, 2012 sourceNot checked yet

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Certain psychiatric illnesses may be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), which could underlie the association with early mortality and physical disease.

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

May combine two claims.

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 and premature mortality from natural causes.

“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).”

• cites O'Donovan et al., 2011aNot checked yet

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• cites Penninx et al., 2013 sourceNot checked yet

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• cites Viron and Stern, 2010Not checked yet

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Classified as probably not a substantial claim. May combine two claims.

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

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

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

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.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

LTL is in part genetically programmed, with heritability estimates ranging from 0.36-0.84.

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

• cites Aviv, 2012 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

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.

“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).”

• cites Maser and DePinho, 2002 sourceNot checked yet

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The psychiatric condition itself may be an independent risk factor for medical illness, although lifestyle and socioeconomic factors play a role.

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

• cites Viron and Stern, 2010Not checked yet

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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.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

In a recent meta-analysis, TL heritability was estimated to be 0.7.

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

• cites Broer et al., 2013 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Relatively long telomeres tend to shorten over time, and relatively short telomeres tend to lengthen over time, possibly due to preferential recruitment of reparative mechanisms such as telomerase activity.

“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).”

• cites Epel, 2012 sourceNot checked yet

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In several studies, baseline LTL predicted the subsequent development of cancers, cardiovascular disease, diabetes or mortality.

“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).”

• cites Cawthon et al., 2003 sourceNot checked yet

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• cites Willeit et al 2010 sourceNot checked yet

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• cites Zhao et al., 2014 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Some individuals maintain and may even lengthen average LTL for some periods.

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

• cites Epel, 2012 sourceNot checked yet

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• cites Muezzinler et al., 2013 sourceNot checked yet

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Immune cells that have become senescent due to critical telomere shortening hyper-secrete pro-inflammatory cytokines such as IL-6 and TNF-α, which can lead to a vicious cycle of further inflammation, oxidative stress and telomere shortening.

“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.”

• cites Effros, 2009 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Prospective shortening of LTL over 2.5 years predicted long-term (12 year) cardiovascular mortality in men in one study, although not all studies have found this.

“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).”

• cites Epel et al., 2009aNot checked yet

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• cites Weischer et al., 2014 sourceNot checked yet

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The relationship of LTL to TL in other tissues has not been well established, and TL varies by tissue.

“(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”

• cites Daniali et al., 2013 sourceNot checked yet

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• cites Dlouha et al., 2014 sourceNot checked yet

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• cites Friedrich et al., 2000 sourceNot checked yet

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Shorter LTL is linked with premature mortality and a reduction in years of healthy living.

“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).”

• cites Cawthon et al., 2003 sourceNot checked yet

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• cites Fitzpatrick et al., 2011 sourceNot checked yet

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• cites Weischer et al., 2012 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Leukocyte telomere length generally decreases progressively over the lifespan, with average attrition rates of 14-103 bp/year in cross-sectional studies (weighted mean 21.9 bp/year) and 32.2-45.5 bp/year in longitudinal studies (weighted mean 40.7 bp/year).

“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).”

• cites Muezzinler et al., 2013 sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

LTL is an index and predictor of physical health and of processes associated with biological aging.

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

May combine two claims.

In currently depressed subjects in NESDA, LTL was inversely associated with severity of depression and with duration of depression over the preceding four years, suggesting a dose-response relationship.

“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).”

• cites Verhoeven et al., 2014aNot checked yet

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Needham et al. (2014) found that individuals with MDD who were receiving antidepressants had significantly shorter LTL than controls, but depressed individuals not taking antidepressants did not.

“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.”

• cites Needham et al. (2014)Not checked yet

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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.

“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).”

• cites Elvsashagen et al., 2011 sourceNot checked yet

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In Rizzo et al., IgG antibodies to cytomegalovirus were significantly elevated in the BD group and these levels were inversely correlated with LTL.

“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.”

• cites Rizzo et al., 2013 sourceNot checked yet

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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.

“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..”

May combine two claims.

Wolkowitz et al. (2011a) found no overall differences in LTL between 18 individuals with MDD and 17 controls, but in an exploratory analysis found significantly shorter LTL in the more chronically depressed individuals (above the median cumulative duration of active MDD of 9.2 years).

“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).”

• cites Wolkowitz et al., 2011aNot checked yet

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Across the MDD group in Wolkowitz et al., lifetime untreated depression duration was significantly inversely correlated with LTL, consistent with a dose-response relationship.

“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.”

• cites Wolkowitz et al., 2011aNot checked yet

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Teyssier et al. (2012) found no significant difference in LTL between subjects with MDD and controls, but did find increased expression of p16INK4a and STMN1 genes in the depressed sample.

“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).”

• cites Teyssier et al., 2012 sourceNot checked yet

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Elvsåshagen et al. (2011) found the percentage of telomeres shorter than 3,000 bp was increased in BD type II subjects (p=0.04) and a trend for shortened absolute LTL in BD type II subjects (p=0.08), although those tests were one-tailed.

“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.”

• cites Elvsashagen et al., 2011 sourceNot checked yet

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Classified as probably not a substantial claim. May combine two claims.

Martinsson et al. 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.

“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).”

• cites Martinsson et al., 2013 sourceNot checked yet

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

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

Classified as probably not a substantial claim. May combine two claims.

Since all individuals with schizophrenia in Nieratschker et al. were receiving psychotropic medication, the authors suggested a similarity with 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.

“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.”

• cites Savolainen et al. (2012) sourceNot checked yet

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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.

“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.”

• cites Yu et al. (2008)Not checked yet

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Mansour et al. (2011) found no significant LTL difference in schizophrenia vs. controls, but LTL was confounded by the extent of inbreeding in the schizophrenia population.

“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.”

• cites Mansour et al. (2011) sourceNot checked yet

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In Martinsson et al., 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.

“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.”

• cites Martinsson et al., 2013 sourceNot checked yet

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

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

• cites Lima et al. (2014)Not checked yet

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

“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.”

• cites Nieratschker et al., 2013 sourceNot checked yet

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Kao et al. (2008) found LTL was significantly shortened in individuals with schizophrenia and was unrelated to antipsychotic use or duration of illness.

“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).”

• cites Kao et al., 2008 sourceNot checked yet

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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 controls was assessed only for the preceding two years.

“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.”

• cites Malaspina et al. (2014) sourceNot checked yet

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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.

“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.”

May combine two claims.

Oxidative stress markers are inversely correlated with LTL in MDD and in healthy pre-menopausal women.

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

• cites Wolkowitz et al., 2011aNot checked yet

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• cites Epel et al., 2004 sourceNot checked yet

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Classified as probably not a substantial claim.

Kananen et al. suggested that more prolonged exposure to anxiety disorder-related stress might be needed for accelerated telomere shortening to be detected.

“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).”

• cites Kananen et al., 2010 sourceNot checked yet

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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 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.”

May combine two claims.

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 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.”

May combine two claims.

Okereke et al. (2012) found that 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.

“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).”

• cites Okereke et al., 2012 sourceNot checked yet

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Classified as probably not a substantial claim.

Verhoeven et al. suggested that LTL shortening with anxiety disorders may be more reversible than that associated with MDD.

“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.”

• cites Verhoeven et al., 2014aNot checked yet

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

“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.”

May combine two claims.

Pro-inflammatory cytokine concentrations are inversely correlated with LTL in MDD, in individuals with histories of early life stress, and in healthy individuals with high C-reactive protein levels or high cumulative inflammatory load.

“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).”

• cites Wolkowitz et al., 2011aNot checked yet

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• cites Kiecolt-Glaser et al., 2011 sourceNot checked yet

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• cites O'Donovan et al., 2011bNot checked yet

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Telomere shortening may be related to specific biological processes or endophenotypes more than to specific diagnostic categories, although this remains to be adequately tested.

“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.”

• cites Pandya et al., 2013 sourceNot checked yet

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• cites Rosenblat et al., 2014Not checked yet

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• cites Smyth and Lawrie, 2013Not checked yet

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There are inconsistent reports of LTL associations with psychiatric illnesses, with the strongest evidence seen in MDD.

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

May combine two claims.

Biological abnormalities seen in certain psychiatric conditions are associated with, and may cause, telomere shortening.

“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).”

• cites Wolkowitz et al., 2011aNot checked yet

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• cites Wolkowitz et al., 2011bNot checked yet

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There is a modest preponderance of evidence suggesting that shorter LTL is seen across psychiatric illnesses, although methodological differences and small sample sizes preclude more definitive conclusions.

“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.”

May combine two claims.

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.

“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).”

• cites Teyssier et al., 2010 sourceNot checked yet

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• cites Zhang et al., 2010 sourceNot checked yet

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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 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.”

May combine two claims.

These behavioral and psychological intervention studies have often been non-randomized and not adequately controlled.

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

May combine two claims.

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.

“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).”

• cites King et al., 2014 sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable).

Without determining the relationship of peripheral markers of cell aging to neural processes more closely related to psychiatric illnesses, their ultimate informational value will be limited.

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

• AssumptionRests on an assumption: Peripheral markers of cell aging are the only markers that are practical to obtain in living humans.

May combine two claims.

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.

“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).”

• cites Zhou et al., 2011 sourceNot checked yet

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In Lengacher et al. (2014), baseline PBMC basal TA was controlled for, but the active group was heterogeneous in terms of treatment received and time since treatment completion.

“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.”

• cites Lengacher et al., 2014 sourceNot checked yet

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

“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.”

• AssumptionRests on an assumption: It is difficult to double-blind behavioral and psychological interventions.

May combine two claims.

A five-year follow-up of ten of the original Ornish et al. (2008) participants showed that their LTL significantly increased from baseline relative to control men whose prostate cancer was followed by active surveillance, although their PBMC basal TA had decreased somewhat compared to baseline.

“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).”

• cites Ornish et al., 2013 sourceNot checked yet

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May combine two claims.

Ornish et al. (2008) had a lack of a control group, only 30 of 126 eligible patients agreed to participate, and all participants were male, which may affect generalizability.

“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.”

• cites Ornish et al., 2008 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In Puterman et al. (2013), analyses were cross-sectional, so causality cannot be inferred, and data on diet were not available.

“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.”

• cites Puterman et al., 2013 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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

“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).”

• cites Biegler et al., 2012 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Ornish et al. (2013) was limited by small sample size (10 intervention subjects and 25 controls) and non-randomized design, which may introduce unknown sources of bias.

“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.”

• cites Ornish et al., 2013 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.

“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).”

• cites Ludlow et al., 2013 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Puterman et al. (2010) found in 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.

“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).”

• cites Puterman et al., 2010 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

In Puterman et al. (2015), health behaviors may have been spuriously associated with LTL if physical diseases bore the primary relationship with LTL.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

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, although the biochemical intermediaries remain to be determined.

“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.”

• cites Epel et al., 2009bNot checked yet

  Not checked in the free run.

May combine two claims.

Puterman et al. (2010) was cross-sectional, so causal interpretations are difficult, especially since the more highly stressed women were less likely to be physically active.

“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.”

• cites Puterman et al., 2010 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Biegler et al. (2012) had no control group, and four months may be too short to discern significant changes in LTL.

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

• cites Biegler et al., 2012 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Findings that certain positive lifestyle changes are correlated with lowered degrees of cell aging (as indexed by LTL and/or PBMC basal TA) provide some encouragement, although many of the studies were small-scale, open-label or inadequately controlled.

“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.”

• cites Epel, 2009Not checked yet

  Not checked in the free run.

• cites Epel, 2012 sourceNot checked yet

  Not checked in the free run.

• cites Hoge et al., 2013 sourceNot checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: Shorter LTL has been linked to current and future medical illnesses and to premature mortality.

Classified as probably not a substantial claim.

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, argue against the use of such markers as diagnostic tools, in isolation from other measures, at this time.

“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.”

May combine two claims.

A modest preponderance of the evidence reviewed suggests that several psychiatric illnesses (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.

“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.”

May combine two claims.

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

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