Role of telomere length and telomerase activity in accelerated cellular aging and major depressive disorder: a systematic review

Major depressive disorder (MDD) has contributed significantly to the global burden of mental disorders in recent years. With an estimated 3 million people being affected worldwide, these cases of MDD are projected to increase exponentially as a result of the recent COVID-19 outbreak [1]. Besides mental illness, individuals with MDD have an average life expectancy that is approximately ten years shorter than the healthy population [2]. This is a significant difference, and it is important to understand the biomedical mechanisms of this disparity. Therefore, it has been hypothesized that MDD is associated with accelerated age-related biological and functional decline [3, 4]. Recent research has seen a shift towards understanding the intricate relationship between cellular biology and mental health, particularly MDD. This change moves beyond the traditional views of telomeres and telomerase solely in cellular aging to explore their potential roles in mental health. One potential biomarker under study for a possible relationship between MDD and biological aging is leukocyte telomeres. Leukocyte telomeres are quantified by their length and the activity of telomerase.

Telomeres are repetitive DNA sequences located at the ends of eukaryotic chromosomes, playing a vital role in maintaining genomic stability and integrity by safeguarding against chromosomal aberrations. Chromosomal structures are known to be crucially involved in the process of cellular ageing. Telomerase, an enzyme responsible for elongating and maintaining telomeres, counteracts the natural attrition that occurs during cellular division, thus preserving chromosomal integrity. Traditionally, the shortening of telomeres has been associated with the aging process and age-related diseases, often attributed to prolonged exposure to inflammation, high levels of cortisol, and oxidative stress [5, 6]. Therefore, Telomerase Length (TL) and telomerase activity (TA) are used as biomarkers of both aging and aging-associated pathological conditions. In 2006, Simon et al. assessed leukocyte telomere lengths (LTLs) in MDD individuals, finding them significantly shorter compared to controls, indicating an accelerated aging process. Since then, studies have shown a complex relationship between telomere shortening and MDD, with limited research on LTLs and its potential restorative response to antidepressants [5, 7, 8]. While various animal models have investigated the effects of antidepressants on telomere biology, limited research exists on the connection between LTLs, TA and antidepressant response in MDD patients [7 –10].

There are a limited number of references that investigate neuronal aging in the brain of patients with MDD. However, TL and TA in the limbic area, especially the hippocampus, has been studied and linked with accelerated aging in patients with MDD. TL shortening and alteration of TA could represent a mechanism that moderates the proliferative capacity of human hippocampal progenitors, which may subsequently impact human cognitive function and mental health pathophysiology. Some studies investigate potential correlations between peripheral markers of cellular aging and their implications for brain cell function in MDD, including examining cellular senescence reversibility and its role in hippocampal neurogenesis and antidepressant treatments [11]. The significance of decreased TL in the hippocampus of individuals with MDD is highlighted by its association with depressive disorder pathophysiology [11], hippocampal volume reductions in MDD compared to controls, and neurogenesis [12]. Studies show an association between shorter leukocyte telomeres and reduced hippocampal volume [13].

Previous reviews (2006–2015) noted decreased LTLs in full syndrome MDD, especially in chronic or severe depression, though with a small effect size. Building upon this foundation, this review aims to update this analysis from 2015 onwards, exploring emerging changes and research gaps. Fundamentally, we aim to illuminate the complex interplay between molecular mechanisms and psychiatric pathology, providing insight into telomeres and telomerase roles in mental health disorders. Additionally, the review discusses other biomarkers like human telomerase reverse transcriptase (hTERT) mRNA expression and cell-free mitochondrial DNA (cf-mtDNA) in MDD neurobiology and their relevance in telomere dynamics and cellular aging [9, 14 –19].

We selected studies from 2009 onwards and focused on studies involving human subjects aged 19–65 diagnosed with unipolar MDD, emphasising clinical investigations on the relationship between MDD and changes in TL and TA, and other relevant biomarkers of cellular senescence. The main body of the review is divided into several sections, beginning with the results and discussion, presenting the main findings regarding the relationship between MDD and cellular aging, specifically focusing on TL and TA. Subsequent sections cover additional subtopics that have emerged over the past decade, including the association of MDD and cellular aging in the brain, other biomarkers of cellular aging in MDD, and the reversibility of cellular aging.

This literature review utilized PubMed and OVID databases, employing keywords such as 'telomeres,' 'telomerase,' 'major depressive disorder,' and 'depression' to identify relevant studies over the past 15 years. We selected studies from 2009 onwards and focused on studies involving human subjects aged 19–65 diagnosed with unipolar MDD, emphasising clinical investigations on the relationship between MDD and changes in TL and TA, and other relevant biomarkers of cellular senescence. The identified articles were thoroughly reviewed. This systematic review followed the PRISMA 2020 flow diagram for a set of reporting standards.

The majority of studies reviewed reported shorter TL in MDD patients compared to healthy controls, with some studies also noting increased TA in MDD following antidepressant treatment. Among the twenty-two studies in Table 1, eleven found significantly shorter leukocyte TL in individuals with MDD compared to controls [7, 9, 14, 20 –27], while four identified a significant association between shortened TL and higher depressive symptom severity [15, 21, 28, 29]. Notably, one study found no baseline TL difference between MDD cases and controls but observed greater TL shortening over a span of two years in MDD cases [30]. This suggests a consistent trend across the majority of studies, indicating an association between MDD and shorter TL. However, notable inconsistencies existed among studies, with seven reporting no significant differences in TL or TA between MDD and control [10, 31 –36]. (Tables 1 and 2) Factors such as the age, gender, duration of MDD and comorbidities including metabolic syndrome, cardiovascular and psychiatric disorders (e.g., comorbid anxiety, adverse childhood experiences) influenced TL and TA alterations across these studies [20, 22, 25, 28, 29, 31, 33, 35]. Furthermore, these studies exhibit considerable methodological diversity in terms of setting, study design, sample size, sources of human samples and measurement techniques. They were conducted across various settings, including hospitals, psychiatric clinics, and cohort studies, utilizing both cross-sectional and longitudinal designs. Sample sizes varied from small cohorts with fewer than 100 participants to large-scale longitudinal studies with several thousand participants. The data is based on various sources of telomeres and telomerase activity from human samples (e.g., blood, saliva, brain tissue, cell types, etc.). Brain telomere samples were obtained from post-mortem studies. The studies were primarily cross-sectional with a minority of longitudinal studies. Measurement techniques for TL and TA predominantly included quantitative polymerase chain reaction (qPCR) and quantitative fluorescence in situ hybridization (qFISH), with peripheral blood leukocytes being the most common tissue source.

Results section to describe various sources of telomeres and telomerase activity from human samples (e.g. blood, saliva, brain tissue and cell types, etc), different measures of TL and TA, diagnosis and occurrence of MDD gathered from all the studies for this systematic review.

Our results yield similar findings to a previous review done in 2015 by Lindqvist et al., which suggested a potential association between TL and PBMC basal TA in full syndromic MDD especially in those with longer illness duration or more severe symptoms albeit with conflicting reports and challenges in drawing definitive conclusions due to small effect sizes, methodological differences and small sample sizes across studies [16].

Since 2015, several new studies have contributed to our understanding of the relationship between TL, TA and MDD. A notable trend observed in these newer studies is the consistent finding of shortened TL in individuals with MDD compared to healthy controls observed in studies by Ochi et al., da Silva et al., Huang et al., Kuehl et al., Pisanu et al., AlAhwal et al., Vance et al., Verhoeven et al., Whisman et al., Révész et al [7, 9, 14, 15, 20, 21, 27 –30].

The primary findings align with existing literature, indicating a consistent trend of shortened TL and elevated TA in MDD patients compared to controls, and support our initial hypothesis. Findings such as greater TL shortening over 2 years in MDD patients, shorter TL in those with longer symptoms duration and the inverse association of TL with severity of depression suggest a "dose-response" causal relationship of MDD on TL [15, 21, 22, 28 –30]. The absence of significant differences in TL between those with active MDD and those in remission led the researchers to propose that MDD episodes have a lasting impact on LTL. However, they also acknowledged the possibility that TL could be inherently short even before the onset of the first depressive episode, potentially representing a predisposing risk factor for depression [22]. Furthermore, one study has established a connection between hTERT genetic variation and shortened salivary TL in MDD patients, proposing a potential causal role it could play in predisposing individuals to depression [41].

To the extent that TL reflects the effect of cumulative inflammation and oxidative stress exposure, it is possible that longer or more severe depressive symptoms could result in accelerated TL shortening, suggesting a "dose-response" relationship [31]. However, there is also the possibility that TL shortening predates the onset of psychiatric illness or even serves as a risk factor for it, indicating a fixed degree of premature TL shortening regardless of illness severity [16]. Individuals susceptible to MDD, for instance due to family history or adverse childhood experiences, might already have shortened telomeres prior to illness onset and experience further acceleration in telomere shortening with greater exposure to the illness. Although there remains mixed evidences regarding MDD and TL shortening, a relatively consistent finding across studies remains, that both MDD and even anxiety are linked to oxidative stress and inflammation explained by the intense physiological stress experienced [33]. One study showed that anxiety particularly due to its fear and extreme physiological hyperarousal showed more significantly predicted telomere length over time compared to MDD which did not. Further research is needed to uncover the specific mechanisms underlying this bidirectional connection and potentially shed light on the impact of pathophysiologic changes on telomere damage [33].

This underlying mechanism is supported by the fact that effective regulation of emotions can impact a biological marker of stress in individuals with MDD. Higher levels of multisystem resilience, characterized by lower emotion suppression, stronger social connections, increased physical activity, and better sleep quality, were associated with longer telomeres. [42]. Multisystem resilience acted as a moderator between MDD and TL, revealing that individuals with current MDD had significantly shorter telomeres if they had lower resilience, but not if their resilience was higher. This demonstrates how a comprehensive approach to resilience can mitigate the negative effects of depression on cellular aging by disrupting various pathways associated with physiological stress.

However, the evidence for a "dose-response" relationship is suggestive and not entirely consistent. While some studies, such as those by Verhoeven et al. and Wolkowitz et al., found inverse correlations between depression severity or duration and LTL, others, like Hartmann et al., did not observe such relationships [24]. Additionally, findings from Garcia-Rizo et al., who observed decreased telomere content even in first-episode, never-medicated individuals with MDD, raise questions about the timing and progression of telomere shortening in relation to illness onset [26]. The relationship between depression severity and TL is still subjected to much conflicting findings in the literature. Da Silva et al. demonstrated that TL increased following an improvement in depression severity as measured by the BDI score [9]. But, Pisanu et al. found no association between TL and various indicators of depression severity, including illness duration and response to treatment [7]. Two additional studies observed a significant correlation between depression severity and duration, comorbid anxiety, suicidality, and TL [14, 22]. However, seven studies failed to establish a direct link between TL and depression severity [10, 15, 21, 24, 25, 27, 30]. In a similar vein, Karabatsiakis et al. observed no within-person association but hinted at the potential for TL lengthening during remission, thereby suggesting a reversible aspect to telomere dynamics in MDD patients [23].

This review also discovered that MDD subjects with relatively low pre-treatment TA, coupled with greater increases in TA post-treatment, exhibited better responses to antidepressants [37]. This finding suggests that telomerase activation may play a beneficial role in the treatment of depression. This elevated TA in depressed patients may represent an effort to counteract telomere shortening and thereby potentially play a role in mitigating cellular aging processes [38, 39]. However, studies have shown mixed results on the induction of telomerase reverse transcriptase, the catalytic component of telomerase [9, 17]. Considering these findings, telomerase activation is beneficial in depression, and future research on interventions promoting TA may have therapeutic implications for depression and potentially mitigate the adverse effects of telomere shortening.

Our findings also suggest that telomere dysfunction is not an intrinsic factor and does not increase the risk of depression, in line with previous studies by Wolkowitz et al. [31]. However, in our review, somatic comorbidities such as being underweight, overweight or obese, smoking, heavy drinkers, metabolic syndrome, heart disease, diabetes, osteoarthritis, stroke, cancer, etc, were found to be more prevalent in current MDD participants [20, 22, 29]. Prior meta-analysis has suggested an unfavourable impact of somatic comorbidity in MDD on TL and might be a potential mediator of enhanced TL shortening amongst the subset of MDD patients with significant somatic comorbidities [43].

Literature search on TA yielded fewer results compared to TL, indicating that TA in psychiatric illness remains poorly studied. The studies reviewed propose several potential mechanisms underlying the relationship between TA and depression. These include the possibility that TA reflects a compensatory response to cellular damage or to telomere endangerment. Across all TA studies, there's a consistent positive correlation observed between TA and depression severity [9, 37 –39]. Additionally, the findings suggest that telomerase activation could be beneficial in the treatment of depression, although the exact implications of high baseline TA levels are not fully understood. The studies collectively suggest that baseline TA levels can predict the response to antidepressant treatment. Specifically, individuals with lower baseline TA tend to exhibit a better response to antidepressants, while those with higher baseline TA may respond less effectively or even poorly to treatment [37, 38]. Additionally, greater increases in TA during antidepressant treatment are associated with better treatment response [9, 38].

Regardless, the underlying mechanisms for the observed associations between TA and depression still remain uncertain as it may indicate compensatory mechanisms in response to shorter telomeres or that higher baseline TA could indicate more underlying depression-related pathology, potentially induced by greater telomerase activation [37, 38]. The limited number of studies, inconsistent findings, and variations in approach (e.g. duration and type of antidepressants) make it challenging to arrive at a definitive conclusion. Nevertheless, it's plausible that TA and TERT are influenced by stress and play a role in the progression of MDD and response to antidepressants.

Despite evidence supporting the connection between depression and telomere attrition, there exist conflicting findings and gaps in our current understanding. Notably, while some studies report shorter TL in MDD patients, others fail to find significant differences compared to healthy controls as a whole [10, 27, 30 –36, 39]. Such inconsistencies may stem from variations in sample characteristics (e.g. sample size, gender, age, existing comorbidities), measurement techniques, and the influence of confounding factors, warranting further exploration. For instance, AlAhwal et al. found that higher education levels were associated with shorter telomeres, possibly due to increased stress from greater responsibilities and knowledge of disease consequences [21]. Conversely, Karabatsiakis et al. did not assess various factors such as body mass index, lifestyle habits, or cardiovascular health, potentially impacting TL [23]. Hartmann et al. did not control for factors like gender, race, smoking, or socio-economic status, with all participants being Caucasian inpatients, limiting generalizability [24]. Hoen et al. suggested that TL differences between depression groups might be confounded by cardiac disease severity, while Garcia-Rizo et al. had a small MDD sample size with limited information on participant characteristics [25, 26]. Whisman et al. observed that their study's age restriction might affect TL variability, and their measures of traumatic life events and neuroticism were brief [28].

As shown in the tables above, many studies had a slightly higher percentage of female participants. Although majority of studies supporting our hypothesis had already controlled for age and sex, there are still mixed results with some showing a potential age- or sex-moderated association between TL and MDD. For example, in the study by Whisman et al., after adjusting for demographic variables, sex moderated the association between depressive symptoms and salivary TL, such that it was statistically significant for men but not for women [28]. Additionally, Verhoeven et al. saw an age- and sex-moderated association with LTL [15].

Overall, these studies collectively suggest a nuanced relationship between depression and telomere/telomerase dynamics, with potential implications for both the aetiology and treatment of depression. Further investigation into the mechanisms underlying these associations may offer novel insights into the development of targeted interventions aimed at mitigating cellular ageing processes. It's possible that cellular aging processes in depression involve complex interactions between various cell types and systems throughout the body, both peripheral and central.