All the moderators that were significant in the sub-groups and meta-regression analysis were included in the multivariable meta-regression. Table 3 showed that age, telomere measurement technique as qPCR, and depression measurement technique remained significant, but source tissue and presence of comorbidities were no longer significant. A test of the model suggests that the overall effect size is related to the included variables (Q = 25.05, p < 0.001) and that the proportion of between-study variance explained by the model was low (R2 = 0.00).
The objective of this study was to systematically review the current literature to evaluate the correlation between depression and telomere length, while also examining the influence of potential confounders such as age, gender, assessment techniques, tissue resources, and depression assessment protocols on this association. Our findings revealed a significant association between depression and telomere length shortening. Subgroup analysis unveiled significant influences of various factors on this relationship, including depression assessment tools, measurement scales, telomere measurement techniques, tissue sources, and comorbid medical conditions. Further analysis through multivariable meta-regression highlighted the significant impact of age, depression measurement technique, and telomere measurement technique on this association. Our findings emphasize the correlation between depression and telomere dynamics and highlight the importance of considering multiple factors in understanding this relationship.
Our study identified a significant relationship between depression and the reduction of telomere length, characterized by a moderate effect size (Cohen's d = -0.354, p < 0.0001). This finding is consistent with the main results of previously published meta-analyses, although there are variations in effect sizes. Specifically, our effect size was slightly larger than that reported by Ridout et al. in 2016 (Cohen's d = -0.34, p < 0.0001) and Schutte and Malouff in 2015 (r = -0.14, p < 0.0001), both of which shared similar inclusion criteria with our study. However, Yen Lin et al. in 2010 reported a higher Hedges' g value (g = -0.42, p < 0.0001), yet their analysis only included case-control studies. Despite these differences, our findings add to the growing body of evidence supporting the association between depression and TL, underscoring the relevance of this relationship across diverse study populations and methodologies.
MDD has often been described as a syndrome of "premature aging". Although the exact causality of this connection remains unclear, numerous proposed mechanisms aim to elucidate this connection some have demonstrated decreased levels of telomerase and reduced expression of telomerase reverse transcriptase (Tert) in depression models, causing telomere shortening. Others, meta-analyses, have revealed a correlation between depression and an inflammatory profile, including elevated levels of pro-inflammatory markers such as c-reactive protein and Interleukin 6. Furthermore inflammation, associated with heightened immune cell replication and increased production of free radicals and oxidative stress, presents another potential mechanism inversely correlated with telomerase activity and TL due to inefficient repair mechanisms during oxidative stress. Other potential mechanism implicated in accelerating telomere shortening involves inflammatory and stress responses induced by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and altered neuroendocrine stress response, compounded by the release of pro-inflammatory cytokines, can both elevate cortisol levels. Elevated cortisol, acting via glucocorticoid receptors, is associated with decreased telomerase activity and shortened TL. Finally, mitochondrial alterations leading to reduced ATP production, release of mitochondrial DNA and decreased activity of enzymes involved in the respiratory chain is commonly observed in psychiatric disorders in particular depression, . Although the precise mechanisms is still unknown, a significant positive association has been established between LTL and mitochondrial DNA copy number in young and middle-aged adults.
Subgroup analysis was conducted to investigate potential sources of heterogeneity within the study. Various factors were examined as potential moderators, including the measurement techniques for depression, TL measurement techniques and tissue sources, patient characteristics such as age, gender, and comorbid chronic medical conditions, as well as the study designs of the included articles.
Regarding depression measurement, both interview and self-report techniques were employed to assess depression. Our findings, supported by subgroup analyses and multivariable meta-regression, underscore the significant role of depression measurement as a moderator in the relationship between depression and telomere length. Our results indicate that both self-report and interview methodologies significantly influence the association between depression and telomere shortening. Particularly noteworthy is the amplified effect observed in studies employing self-report measures, suggesting a heightened impact compared to interview-based assessments. While previous research, exemplified by Ridout et al. (2016), has emphasized the superiority of interview-based techniques in revealing a stronger association between depression and telomere length (TL), the findings by Schutte and Malouff (2015) did not observe any significant impact of depression measurement techniques on telomere shortening. However, our study challenges this notion. The observed disparity in results can be attributed to several factors. Potential over-reporting of depression symptoms in self-report assessments may stem from individuals' reluctance to acknowledge or discuss sensitive topics due to societal stigma or denial. Moreover, state-dependent memory and memory deficits could lead to an over-expression of symptoms, further complicating self-reported measures. Additionally, individuals experiencing severe depression may struggle to accurately assess and communicate the severity of their condition, particularly when relying solely on self-report measures. It is worth noting that our results for the study employing interview technique revealed a Hedges' g of -0.33, p = 0.007, surpassing the figure reported by Yen Lin et al. (2016), highlighting the robustness of our findings. Our findings shed light on the nuances of depression assessment within the context of telomere length (TL) association. Particularly noteworthy is the significant impact observed within the interview category, where the SCID emerged as the most influential. Furthermore, our analysis comparing TL among patients diagnosed with MDD through DSM criteria-based interviews revealed a notably greater effect size. These findings underscore the importance of considering specific diagnostic criteria and assessment methodologies when evaluating the relationship between MDD and TL. Moving forward, it is imperative for future research to prioritize the use of gold standard interview-based techniques, particularly SCID, in assessing depression. By standardizing assessment methodologies and emphasizing the utilization of validated diagnostic tools such as SCID, researchers can enhance the reliability and comparability of findings across studies. This approach not only ensures consistency in depression assessment but also facilitates a deeper understanding of the association between depression and TL dynamics.
Multiple techniques are available for measuring TL, each with its strengths and limitations. In our analysis, we found that both Southern blot and qPCR demonstrated a significant association between depression and shortened TL, with Southern blot showing a higher impact with studies using this technique. This contrasts with a previous meta-analysis that suggested FISH and Southern blotting had a greater impact compared to qPCR. This discrepancy can be attributed to the widespread use of qPCR-based methods, which are cost-effective and less time-consuming in the majority of included studies. Southern blot analysis and the FISH method have specific limitations that make them less suitable for epidemiological and population studies. For instance, the FISH technique requires fresh blood and is not suitable for solid tissues or preserved samples, making it more costly and time-consuming. While the qPCR technique focuses solely on evaluating the canonical aspect of telomeres to measure TL signals (T), It is then standardized in relation to a single-copy gene signal (S) within the same sample, resulting in a T/S ratio that provides an indication of the average TL per genome. Southern blotting measures both the canonical (strictly TTAGGG repeats) and non-canonical components of telomeres to determine the length of terminal restriction fragments (TRF) and present telomere length. Previous papers have shown that both Southern blot and qPCR demonstrate good reliability and high reproducible results in measuring telomere length. However, southern blot showed less measurement error compared to qPCR. Therefore, despite being more laborious and time-consuming technically, Southern blot is recommended for future research assessing the association of depression with telomere length due to its higher measurement reliability than qPCR. Also, large-scale epidemiological studies that compare Southern blot analysis to qPCR, and potentially other methods, would greatly enhance our understanding of telomere length physiology.
Leukocyte emerged as the primary tissue source for TL assessment in the majority of the included articles, and our subgroup analysis demonstrated that they had the most robust effect on the association between depression and TL, consistent with findings from previously published meta-analyses. Immune cells, such as leukocytes, hold particular significance in telomere research for several reasons. Firstly, their accessibility and the ease of blood collection make them a convenient tissue source for studying telomere dynamics. Furthermore, immune cells are exposed to both internal and external factors circulating throughout the body, which can profoundly influence telomere physiology. Moreover, the connection between psychological processes and the neurological and immunological systems is intertwined with immune cells. This interplay underscores the importance of immune cell research in elucidating the biological mechanisms underlying the relationship between depression and TL dynamics. Given the pivotal role of immune cells in telomere research and their relevance to the biological mechanisms underlying depression, future studies should continue to prioritize the investigation of immune cell telomere dynamics. Additionally, expanding research efforts to explore the interactions between psychological factors, immune function, and telomere biology could yield further insights into the complex relationship between depression and TL. This interdisciplinary approach holds promise for advancing our understanding of depression's etiology and identifying novel therapeutic targets for intervention.
Comorbid conditions, such as diabetes, high blood pressure, and cancer, have been documented to exert a significant impact on telomere length (TL), as evidenced by previous studies. In our subgroup analysis, we observed a significant difference between patients with and without chronic medical conditions, with a larger effect size noted in the group with chronic comorbidities, aligning with the findings of Ridout et al. (2016). Particularly noteworthy was our observation that patients with cancer exhibited the strongest association compared to all other conditions. Chronic comorbidities are often associated with a persistent stress environment, triggering the release of glucocorticoids. This hormonal response can lead to increased mitochondrial activity and the production of Reactive Oxygen Species (ROS), ultimately inhibiting telomerase activity and contributing to TL shortening. Chronic systemic inflammation is a common background to various chronic diseases (diabetes, hypertension, cancer, and depression), all of which were associated with telomere erosion. Persistent inflammation leads to increased oxidative stress and immune system activation, both contribute to telomere shortening and telomerase dysregulation. In diabetes and hypertension, elevated systemic inflammation and oxidative stress accelerate telomere shortening, that also contribute for worsening disease progression and severity. Similarly, in cancers, particularly those with an inflammatory component or exposure to known carcinogens, the resulting oxidative stress promotes telomere erosion, potentially driving genomic instability and tumor development. ROS define this link between chronic inflammation and cancer. Additionally, recent studies indicate that individuals with shorter telomeres have a higher risk of developing carcinomas, suggesting a bidirectional mechanistic link between telomere length and cancer susceptibility. Moreover, exposure to smoking and inflammation-related factors, associated with cancer, accelerates telomere erosion. This effect results from the interplay between genetic predisposition and environmental factors, making individuals more prone to rapid telomere degradation. These findings underscore the complex interplay between chronic medical conditions, stress physiology, and telomere dynamics. These insights underscore the importance of holistic approaches to healthcare, emphasizing the management of comorbidities and stress reduction strategies to mitigate the impact on TL health and overall well-being.
Our results revealed a positive impact of increasing age on the association between depression and telomere attrition, a finding that diverges from the conclusions of three previous meta-analyses which failed to detect a significant effect of age. This result may be attributed to the inherent cellular process of natural telomere shortening that accompanies advancing age, with an estimated rate of 24.8-27.7 base pairs annually.
Our study did not find a significant effect of gender on the correlation between MDD and TL, consistent with previous meta-analyses that also did not support the presence of this effect. This lack of significance could be attributed to the heterogeneity of our sample, which included both pre- and post-menopausal women, as well as the variability in TL measurement techniques utilized. While some prior investigations have suggested a connection between gender and TL, with females typically exhibiting longer TL than males possibly due to the potential activation of telomerase by estrogen via the promoter region, our findings did not align with this hypothesis. It's worth noting that women beyond their reproductive years may be more susceptible to TL shortening than men, as the protective effect from estrogen diminishes. Moreover, previous meta-analyses have noted variations in the gender effect depending on the measurement methods employed, with Southern blot showing a significant impact while neither real-time PCR nor Flow-FISH did. This underscores the importance of considering the nuances of TL measurement techniques when investigating the gender effect on TL. Therefore, future prospective studies are essential to comprehensively investigate the pathophysiology of the gender effect on TL among patients with depression. Employing various measurement techniques will be crucial in achieving a more nuanced understanding of the relationship between gender, depression, and TL dynamics.
Our subgroups didn't show a difference related to the use of antidepressants, a factor that has not been thoroughly investigated in previous meta-analyses. However, research on the impact of antidepressants suggests that telomerase activity may be influenced by psychotropic medications, though the precise direction of induced changes and their correlation with clinical efficacy remain subjects requiring further investigation. Additionally, our analysis did not uncover a significant association between the duration of illness and telomere shortening, consistent with the findings of Yen Lin et al. (2016). The concept of a "dose-response" relationship, where longer exposure to illness leads to accelerated TL shortening, remains suggestive but mixed in the literature. For instance, Shalev et al. (2014) demonstrated a potential dose-response trend, indicating that the duration of "internalizing disorders," such as MDD, could predict LTL at age 38. However, other studies have failed to substantiate this "dose-response" hypothesis.Our subgroup analysis revealed that the effect of depression on TL was particularly robust in studies utilizing a case-control design. This observation may be interpreted in the context of the study design itself, as case-control studies often yield computed mean differences in TL between groups, rather than the associations typically observed in cohort and cross-sectional study designs. Furthermore, the matching process inherent in case-control designs contributes to less heterogeneity and imposes stricter inclusion criteria, potentially resulting in clearer and more pronounced effects. However, it's essential to acknowledge that previous literature has indicated that the inclusion of case-control studies may lead to inflated estimates of the association. Therefore, while case-control studies offer valuable insights into the association between depression and TL, caution should be exercised when interpreting their results and their findings should be corroborated by other study designs for a comprehensive understanding of the relationship.
Our research significantly contributes to the existing body of evidence by incorporating a broader array of articles, resulting in a substantially larger sample size compared to three previously conducted meta-analyses. Furthermore, our study explores uncharted territories by investigating the influence of antidepressant usage, various comorbidities, depression assessment methodologies, and diverse study designs on the relationship between depression and telomere length (TL). These aspects represent novel avenues of exploration that were overlooked in previous analyses, as detailed in eTable 1 of the supplementary materials. However, despite these strengths, our meta-analysis is not without limitations. Firstly, the inclusion of studies with varied research designs, such as cross-sectional, case-control, and prospective studies, restricts our ability to investigate a potential bidirectional relationship between depression and TL comprehensively. Secondly, despite conducting meticulous meta-regression and sensitivity analyses, substantial heterogeneity persisted in several outcomes. Additionally, the limited number of studies within certain moderator categories restricted our ability to effectively detect differences based on these factors. Thirdly, publication bias may be present due to the selective reporting of significant results, potentially skewing the overall findings. Finally, many publications included in our analysis originated from secondary analyses of studies initially designed for different purposes. These studies often utilized stored blood samples to measure TL, introducing variability due to differences in storage conditions or extraction methods. Therefore, it is essential to interpret the outcomes of our meta-analysis with consideration given to these potential sources of variability and bias.
Despite these limitations, our study represents a significant contribution to the field of depression and TL biology, offering novel insights and implications for both research and clinical practice. By incorporating a diverse range of articles and examining various moderators, we deepen our understanding of the complex interplay between depression and TL. Our findings highlight the need to consider individual characteristics, such as age, comorbidities, and depression assessment methodologies, when assessing TL in depressed individuals. This knowledge can inform personalized treatment strategies and aid in the identification of potential biomarkers for psychiatric disorders. Furthermore, our study identifies gaps in previous research and underscores the importance of standardized methodologies in future investigations. Ultimately, by elucidating the biological mechanisms underlying depression and its association with TL, our research contributes to improving outcomes and advancing public health initiatives aimed at addressing depression and its related health consequences.