Chronic Anxiety Speeds Aging
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"In this study of 5,243 women, high phobic anxiety was significantly associated with lower leukocyte telomere lengths......Telomeres are repetitive DNA sequences at the ends of eukaryotic chromosomes that undergo attrition each time a somatic cell divides. Factors that accelerate attrition include oxidative stress and inflammation , . Consequently, average telomere length (TL) reflects cumulative damage from these exposures, and is a potential indicator of biological aging"
"Excluding women with cardiovascular disease, diabetes or obstructive airway diseases -- "chronic diseases that may act as intermediates ... and also may be associated with telomere shortening" -- attenuated the difference for high anxiety levels to a nonsignificant trend, at a mean of -0.07 standard units (P=0.12)."
"Results were somewhat attenuated after exclusion of participants with chronic diseases that may act as intermediates and/or present with higher subjective anxiety and also may be associated with telomere shortening - suggesting that findings may be partly explained by influences of phobic anxiety on risk of development of serious chronic diseases.....because phobic anxiety is usually the temporally primary condition in comorbidity involving other mental disorders (e.g., depression, substance abuse) , early intervention not only may mitigate detrimental impacts on aging and but also could avert additional downstream consequences of accelerated telomere shortening due to secondary development of other mental disorders or serious chronic medical conditions."
By Crystal Phend, Senior Staff Writer, MedPage Today
Published: July 12, 2012
· Chronic panic, phobia, and similar anxiety disorders may contribute to premature aging by shortening telomeres.
· Point out that for women with the most severe phobia, the magnitude of the difference in telomere length was comparable to that for women 6 years apart in age.
Chronic panic, phobia, and similar anxiety disorders may contribute to premature aging by shortening telomeres, an observational study suggested.
Women with the most severe phobic anxiety had telomere length 0.09 standardized units below average (P=0.02 versus less phobic women), Olivia I. Okereke, MD, of Brigham and Women's Hospital and Harvard in Boston, and colleagues reported online in PLoS ONE.
"The magnitude of this difference was comparable to that for women 6 years apart in age," they noted.
While lesser degrees of chronic anxiety showed a trend for shorter telomeres as well, the researchers called it primarily a threshold effect.
Shortening of telomeres -- a gradual process of loss of the repetitive DNA sequences capping off chromosomes that occurs when cells divide -- isn't reversible.
Prior studies have suggested that oxidative stress and inflammation accelerates the process, leading to DNA damage linked to cancer, cardiovascular disease, cognitive decline, and dementia.
However, "phobic anxiety is treatable; thus, any potential impacts on telomere shortening may be amenable to prevention through early identification and treatment," the researchers explained.
They used phobic anxiety as a typically chronic form of anxiety to look for correlation with telomere length in peripheral blood leukocytes among 5,243 women from the Nurses' Health Study, controls in prior case-control studies of telomeres and disease, and a random group of healthy women in a cognitive function sub-study.
Higher levels of long-term general anxiety as measured on the Crown-Crisp phobic index, which focuses on 'fear' disorders like panic and agoraphobia, showed a trend for lower age-adjusted relative telomere length z-scores (P=0.09).
But the more anxious women tended to be less healthy on a wide range of characteristics. After adjustment for significant factors -- paternal age at birth, smoking, body mass index, and physical activity -- the trend was further attenuated (P=0.15).
Women with a high anxiety score of 6 points or greater (range up to 16) appeared to account for the effect.
Whereas women with scores under 6 had an adjusted mean telomere length z-score of 0.02 standard units, the mean was -0.09 for women with higher scores, yielding a significant 0.10 standard-unit difference between groups (P=0.02).
By comparison, 1 additional year of age was associated with a -0.015 lower mean relative telomere length z-score.
The impact of high chronic anxiety levels appeared to be particularly strong among nonsmokers, which the researchers called counterintuitive, although smokers had shorter telomeres to start with.
The difference in telomere length among nonsmokers with a score of 6 or more versus 5 or less was -0.25 standard units (P<0.001).
Excluding women with cardiovascular disease, diabetes or obstructive airway diseases -- "chronic diseases that may act as intermediates ... and also may be associated with telomere shortening" -- attenuated the difference for high anxiety levels to a nonsignificant trend, at a mean of -0.07 standard units (P=0.12).
This finding suggested that the "findings may be partly explained by influences of phobic anxiety on risk of development of serious chronic diseases," Okereke's group noted.
They cautioned that women in the highest phobic symptom category that was linked to telomere shortening wouldn't necessarily meet diagnostic criteria for an anxiety disorder, "although this appears plausible."
Another limitation was that the study design didn't allow for determining whether the phobic anxiety predated the telomere shortening.
Causality is possible in either direction, the group pointed out.
Lack of data on anxiety duration and treatments, depression, or other residual confounders as well as the predominantly white population studied were also limitations.
Primary source: PLoS ONE
Okereke OI, et al "High phobic anxiety is related to lower leukocyte telomere length in women" PLoS ONE 2012;7: DOI: 0.1371/journal.pone.0040516.
High Phobic Anxiety Is Related to Lower Leukocyte Telomere Length in Women
Telomeres are repetitive DNA sequences at the ends of eukaryotic chromosomes that undergo attrition each time a somatic cell divides. Factors that accelerate attrition include oxidative stress and inflammation , . Consequently, average telomere length (TL) reflects cumulative damage from these exposures, and is a potential indicator of biological aging . Furthermore, by protecting chromosomal ends, telomeres maintain genomic stability , , ; critically short telomeres lead to DNA damage (e.g., end-to-end fusion, atypical recombination or rearrangement) implicated in development of several age-related diseases . For example, epidemiological studies have reported associations between shorter TLs and increased risks of cancers ,  and cancer mortality , cardiovascular disease , cognitive decline and dementia , . Because telomere shortening may underlie many adverse health outcomes in aging, it is important to identify addressable risk factors.
An emerging literature implicates psychological distress and mood disorders, both highly prevalent in women, as potential paths toward accelerated aging , , , . Prior work has indentified relations of depression to higher levels of inflammatory mediators and oxidative stress . Although less is known about its relations to these mechanistic paths, anxiety could also be a risk factor for morbidity or mortality in aging. In a previous investigation in the Nurses' Health Study (NHS), phobic anxiety was significantly related to higher levels of inflammatory markers  and a elevated risk of sudden cardiac death and fatal coronary disease . Importantly, phobic anxiety is treatable; thus, any potential impacts on telomere shortening may be amenable to prevention through early identification and treatment. However, there have been few prior investigations of anxiety and telomere shortening.
Thus, we conducted an examination of the relation of phobic anxiety to peripheral blood leukocyte TLs (LTLs) in 5,243 participants of the Nurses' Health Study, who ranged from age 42-69 years (mean = 59) when they provided self-reports of phobic symptoms and blood samples. As phobic anxiety tends to be chronic - median age at onset is 11 years , and course tends to be highly persistent without treatment , ,  - we hypothesized strong inverse associations between phobic anxiety and LTLs measured at mid- and later-life.
In this study of 5,243 women, high phobic anxiety was significantly associated with lower leukocyte telomere lengths. To aid interpretation of findings , we can compare the mean difference in RTL z-scores associated with high phobic anxiety to the estimate for women aged one year apart: compared to those with <6 points on the Crown-Crisp, women with ≥6 points had adjusted RTL z-scores equivalent to 6 years of age. In addition, effect modification was identified: associations were stronger among women who were born to older fathers, were heavier or never smoked. Results were somewhat attenuated after exclusion of participants with chronic diseases that may act as intermediates and/or present with higher subjective anxiety and also may be associated with telomere shortening - suggesting that findings may be partly explained by influences of phobic anxiety on risk of development of serious chronic diseases . Finally, exploratory work indicated that endorsements of higher phobic symptom levels on individual CCI items were generally related to lower RTLs; estimates appeared strongest for items reflecting panic and agoraphobia. Overall, this study provides a key addition - phobic anxiety - to an emerging literature that posits mental distress and disorders as risk factors for accelerated aging , , , .
This report is consistent with earlier studies involving well-characterized samples of patients with diagnosed psychiatric disorders and controls , , . However, there have been few larger-scale (n>500) population-based studies that specifically addressed anxiety and telomeres. Kananen et al.  measured RTLs in a sample (aged 30-87 years) of 321 participants with anxiety diagnosed via structured clinical interviews and 653 controls. Cases included both those with diagnostic manual criteria-level symptoms and those with core features of anxiety who did not meet full criteria; the majority of cases, however, met full criteria for generalized anxiety disorder (GAD), panic disorder, agoraphobia, and social and other phobia. Although RTLs were similar among cases and controls overall, cases had significantly shorter RTLs than controls in the older half of the sample (48-87 years). In contrast, Surtees et al.  did not observe significant differences in RTLs among 4,441 women (aged 41-80 years) with vs. without either 12-month or lifetime GAD, as diagnosed by participant self-assessment forms. Discrepant findings may have resulted from differences in ascertainment methods of diagnoses (self-assessment forms vs. structured interviews by clinical raters) or in the samples (e.g., age, gender, clinical features). For example, the symptoms of disorders under study by Kananen et al.  (specifically, panic and phobic disorders) have high overlap with the symptoms captured by the CCI; Surtees and co-workers  considered only GAD. Overall, our finding that lower RTLs were observed among those with the highest phobic symptoms - i.e., potentially a “caseness” level - compared to those below that threshold, is consistent with work in clinical samples. Nevertheless, it is not known whether women in the highest phobic symptom category would necessarily meet criteria  for diagnosis of an anxiety disorder (particularly, panic or agoraphobia), although this appears plausible.
The findings regarding effect modification of anxiety-telomere relations are novel and require confirmation/replication. Obesity may worsen oxidative stress and inflammation , , and relations of high phobic anxiety and telomere length may be influenced by body mass or adiposity stores. The findings for smoking were counter-intuitive. CCI scores were higher among ever- vs. never-smokers (Wilcoxon rank sum p = 0.001), smoking may trigger oxidative stress/damage , and RTLs were lower overall among smokers in our sample; one might have expected stronger phobic-telomere associations among smokers. Explanations for this finding include chance as well as putative influences of nicotine on key inflammatory mediators ,  - possibly providing protection against telomere shortening for highly phobic smokers that would be absent for equally phobic non-smokers; however, the latter possibility is purely speculative. Finally, findings regarding advanced paternal age were intriguing. APA is associated with longer telomeres , but this also allows for more DNA abnormalities to accumulate and greater DNA fragmentation . Intriguingly, APA has recently been related to psychiatric disorders ,  and greater externalizing (vs. internalizing) behaviors in offspring ; in our cohort, paternal age ≥40 y vs. <40 y was associated with lower prevalence of high phobic anxiety (12% vs. 9%, χ2(df = 1) = 3.84, p = 0.05). Thus, while explanations remain unclear, one speculative possibility is that high phobic anxiety might exert an exaggerated impact on vulnerable DNA, with resulting faster telomere shortening, among women born to older fathers; alternatively, greater overall variability in TLs among offspring of older fathers may enhance ability to detect phobic anxiety-TL relations.
Although the literature is at an early stage, there is biologic plausibility to support relations of anxiety to shorter telomeres, particularly via oxidative stress and inflammation. For example, in a study  of 362 healthy adults, higher tension-anxiety symptom level was correlated with an oxidative DNA damage marker, 8-hydroxydeoxyguanosine. In a previous NHS investigation , elevated inflammatory markers (tumor necrosis factor-α receptor II, soluble E-selectin and soluble intercellular adhesion molecule) were observed among diabetic women with the highest phobic anxiety (those with CCI≥6 were grouped in the same category with those with CCI = 4 or 5) . Similarly, higher scores on the Spielberger State-Trait Anxiety Inventory were significantly correlated with elevated C-reactive protein, interleukin-6 and fibrinogen levels in 853 middle-aged adults . Nevertheless, despite high prevalence of anxiety , few studies have focused on its relations to oxidative stress and inflammatory biomarkers. Thus, additional investigation is necessary to delineate potential impacts of anxiety on aging via these mechanisms.
Strengths of the current study include: use of a validated phobic anxiety scale; a large, well-characterized sample; and consideration of numerous potential health, lifestyle and socio-demographic confounders. Also, high phobic symptoms may have been present among these participants for decades  - highlighting the particular value of relating this exposure to RTLs, which are markers of cumulative aging. Indeed, a connection between early-life exposure to adverse mental health environments and consequences of accelerated aging is an intriguing possibility only recently examined in the literature , , .
Potential limitations should be considered. First, the cross-sectional design precludes establishment of a temporal association between phobic anxiety and telomere length. For example, the possibility of bi-directional links has been raised by recent animal work implicating oxidative stress in development of anxiety . Also, individuals with shorter telomeres may have chronic diseases that contribute to persistence, or even worsening, of phobic symptom levels; however, this possibility appears unlikely to explain results entirely because key findings remained, albeit attenuated, after excluding individuals diagnosed with major comorbidities prior to blood collection. Second, RTL was a single measure, preventing estimation of associations between phobic anxiety and telomere attrition rate. Third, we lacked specific data on anxiety onset, duration and/or treatments and, thus, were unable to incorporate such factors into analyses. Also, we did not concurrently measure depression (such assessments began in NHS in 1992); thus, we cannot exclude confounding by depression (e.g., comorbidity of depressive disorder among persons with anxiety disorders has been estimated at 45% ). However, a potentially more likely possibility is that current depression among persons with high phobic anxiety would represent an intermediate variable: phobic conditions typically have early-life onset - decades before median onset of depression ; indeed, the “temporal primacy” of anxiety disorders was previously summarized by Kessler , . Nevertheless, although it seems unlikely that true confounding by depression would completely explain results, we cannot make conclusions regarding on the role of depression in this analysis. Fourth, as in any observational study, residual confounding is possible. Finally, generalizability is a potential concern; the Nurses were predominantly (95%) of white and European race/ethnicity. Because telomere dynamics may differ among African-Americans and Hispanics , , the magnitude of associations may not apply to women of other ethnicities or to men. Nevertheless, basic biologic relations between anxiety and telomere lengths are likely to hold in all humans.
In summary, high phobic anxiety may be associated with shorter leukocyte relative telomere lengths in middle-aged and older women. Identification of these novel associations invites further investigation in large-scale prospective studies, with detailed ascertainment of anxiety and other mental health variables and repeated measures of telomere length. Furthermore, because phobic anxiety is usually the temporally primary condition in comorbidity involving other mental disorders (e.g., depression, substance abuse) , early intervention not only may mitigate detrimental impacts on aging and but also could avert additional downstream consequences of accelerated telomere shortening due to secondary development of other mental disorders or serious chronic medical conditions.