Introduction: Emerging studies highlight the telomere system as an aging mechanism underlying the association between exposure to psychological trauma and the development of a wide range of physical and mental disorders, including major depressive disorder (MDD). Here, we investigated associations of circulating levels of the steroid hormone dehydroepiandrosterone (DHEA) with immune cell telomere length (TL) in the context of lifetime trauma exposure and MDD. Methods: Lifetime traumatic events (trauma load) were assessed using the Essener Trauma Inventory in n = 22 postmenopausal female inpatients with MDD and n = 22 non-depressed controls. All women completed the Beck’s Depression Inventory II to assess the severity of current depressive symptoms. DHEA concentration in serum was measured by immunoassay, and TL was quantified in kilobase units using quantitative fluorescent in situ hybridization in total peripheral blood mononuclear cells (PBMC) and in selected T-cell subpopulations isolated by FACS separation. Results: Higher trauma load was significantly associated with lower DHEA concentration, which in turn was linked to more depression-related fatigue. Furthermore, DHEA concentration was positively and significantly associated with TL in memory CD4+ T cells as well as in naïve and memory CD8+ T cells, but not in naïve CD4+ T cells and total PBMC. Mediational analysis suggested that DHEA concentration is a mediator in the relationship between trauma load and memory CD8+ T-cell TL. Conclusion: The current findings suggest a potential role of DHEA as a biological resilience factor that may exert beneficial effects on telomere integrity, especially in conditions related to distress.

Exposure to traumatic life stressors is a potent risk factor for the onset, manifestation, and progression of a wide range of psychiatric and somatic disorders across the lifespan [1]. A growing body of evidence suggests that mechanisms related to accelerated aging of the immune system could – at least partly – underly this risk [2‒6]. Telomeres have a key role in the aging process by adjusting the cellular response to stress based on previous cell divisions and DNA damage caused by oxidative stress [7].

Telomeres are noncoding double-stranded repeats of guanine-rich tandem DNA hexamers (TTAGGG)n and shelterin protein structures that cap the ends of linear chromosomes. Due to the inability of the enzyme DNA polymerase to completely replicate the ends of nuclear DNA (“end-replication problem”), telomeres shorten with each cycle of cell division [8]. In immune cells, critical short telomere length can induce immunosenescence, a process that is characterized by the inability to mount an appropriate and effective immune response [9]. In addition, it is associated with a low-grade chronic pro-inflammatory state and elevated levels of reactive oxygen species (ROS) production [10]. Many of the immunological changes associated with aging resemble those observed following psychological trauma and/or chronic stress exposure [11], reflected by a convergent body of human research that has linked exposure to early life and adult psychosocial stressors to shortened telomeres and a steeper telomere attrition rate [12, 13]. As a result, shorter telomeres and accelerated telomere shortening have been associated with a broad range of stress- and aging-related somatic [14, 15] and psychiatric disorders, including depression [16, 17]. We have replicated and extended these findings by showing accelerated telomere shortening in cytotoxic T cells of female patients with major depressive disorder (MDD) who experienced childhood sexual abuse [2].

An area of high interest and intensified investigation is the identification of biological resilience factors that target the telomere biology system and thereby counteract the negative consequences of exposure to chronic or traumatic psychological stress on accelerated immunocellular aging. One potential biological age-related resilience factor is the steroid hormone dehydroepiandrosterone (DHEA), which together with its sulfated form, dehydroepiandrosterone sulfate (DHEA-S), is the most abundant circulating steroid hormone in humans [18]. The production of DHEA/DHEA-S steadily declines with age, with peak concentrations observed at young adult age drop to 10–20% at the age of 70–80 years. Based on this characteristic age-related pattern, DHEA is also considered the hormone of youth [18]. As a biochemical precursor, DHEA is the main prohormone for the biosynthesis of the sex steroids testosterone and estrogen. However, it is believed that DHEA is not only just a prohormone but also a hormone that directly modulates several biological processes by exerting antioxidant and anti-inflammatory activities in the periphery [19] and in the brain, where it holds neuromodulatory and neuroprotective properties [20]. In addition, DHEA plays a critical role in balancing the activity of the neuroendocrine stress response produced by the hypothalamus-pituitary-adrenal axis by counteracting the actions of glucocorticoids [20].

Studies investigating the effect of exposure to psychological trauma on DHEA concentrations in blood, saliva, and hair reported mixed results. For example, female adolescents who experienced sexual abuse and victims of rape diagnosed with PTSD showed reduced circulating and salivary DHEA-S levels, respectively, compared to age-matched controls [21, 22]. Contrary, a history of childhood maltreatment was associated with elevated plasma DHEA(-S) concentrations in adult patients with PTSD [23], while another study investigating a sample of adults with and without PTSD did not find a significant effect of childhood trauma on DHEA(-S) in blood serum [24]. In hair samples, positive associations between exposure to childhood maltreatment and DHEA levels were observed in women who recently gave birth [25] and in adolescent females [26].

Research investigating the link between DHEA levels and depression is more consistent. Several studies observed lower endogenous concentrations of DHEA(-S) measured in blood [27‒31] and hair [32] in relation to depression and the severity of depressive symptoms. In the past years, several clinical trials have been conducted to characterize the usefulness of exogenous DHEA supplementation in the treatment of depression [18, 33]. A recent meta-analysis including 14 randomized controlled clinical trials concluded that DHEA supplementation (25–400 mg), in contrast to placebo, significantly improved the burden of depressive symptoms [33].

To date, human studies investigating biological mechanisms underlying the effects of DHEA on cellular aging mechanisms are scarce. Higher endogenous serum levels of DHEA and DHEA-S have been associated with lower circulating levels of interleukin-6 [19], a proinflammatory cytokine related to the process of immunosenescence [34]. Furthermore, only a few studies investigated (endogenous) DHEA levels in the context of telomere biology. A prospective investigation observed a significant positive association between cord blood DHEA-S concentration and leukocyte telomere length in newborns [35]. Another study in children found that a flatter salivary DHEA diurnal slope was associated with longer telomeres in buccal cells [36]. However, in men diagnosed with idiopathic pulmonary fibrosis [37] and in the elderly [38], no relationship between DHEA(-S) levels and leukocyte TL was observed.

Based on the proposed anti-aging effects of DHEA and our previous work showing accelerated TL shortening in T-cell subsets of traumatized women with MDD [2], the present study aimed to examine associations of serum DHEA concentration with immune cell TL in the context of psychological trauma and depression. We hypothesized that (1) higher trauma load is associated with lower DHEA concentration, (2) DHEA concentration is lower in patients with MDD compared to non-depressed controls, (3) higher DHEA concentration is associated with longer immune cell TL, and (4) DHEA concentration is a mediator in the relationship between psychological trauma exposure and TL.

Recruitment and Study Design

A detailed description of the study cohort has been described elsewhere [2, 39]. In short, N = 44 women aged 50–69 participated in the study. Twenty-two participants had a current diagnosis of MDD according to DSM-IV [40] and n = 22 women served as age-matched controls. Female patients with MDD were recruited during inpatient treatment at the AMEOS Clinic for Psychiatry and Psychotherapy in Hildesheim, Germany. Females without any history of MDD or any other mental disorder were recruited via public advertisements (e.g., newspaper announcements and posters). The study fulfilled the guidelines of the Declaration of Helsinki [41] and was approved by the Ethics Committee of the Hannover Medical School. All participants provided written informed consent before participation.

Clinical Assessments

All participants were screened for MDD by trained psychiatrists using the Structural Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and completed the Beck’s Depression Inventory-II (BDI-II, self-report) to assess current depressive symptoms [42]. The number of traumatic personal and witnessed events across the lifetime (trauma load) was assessed using the Essener Trauma Inventory (self-report) [43]. Exclusion criteria for both groups contained the presence of acute infections, general medical conditions, including diabetes, neuropsychiatric conditions/comorbidities including Parkinson’s and Alzheimer’s disease, schizophrenia, eating disorders, and other clinically relevant neuropsychiatric conditions, and the current use of NSAIDs or corticosteroids. The sociodemographic and clinical characteristics of the participants are summarized in Table 1.

Table 1.

Sociodemographic and clinical characteristics and serum DHEA concentration of women in the control and MDD group

VariablesGroupstχ2p value
controlMDD
(n = 22)(n = 22)
Age, years, mean (SD) 57.64 (5.57) 58.73 (6.17) −0.62  0.54 
BMI, kg/m2, mean (SD) 24.39 (2.99) 28.52 (7.22) −2.48  0.02 
Current smoker, yes, n (%) 4 (18.18) 12 (54.54)  6.29 0.012 
Physical activity, yes, n (%) 19 (86.36) 14 (63.64)  3.03 0.08 
BDI sum score, mean (SD) 2.27 (2.27) 23.95 (10.43) −9.53  <0.001 
 Sadness 0.05 (0.21) 0.77 (0.53) −5.99  <0.001 
 Loss of energy 0.23 (0.43) 1.36 (0.58) −7.38  <0.001 
 Disrupted sleep 0.41 (0.50) 1.64 (0.90) −5.57  <0.001 
 Disrupted appetite 0.05 (0.21) 0.90 (0.92) −4.28  <0.001 
 Difficulties concentrating 0.27 (0.46) 1.32 (0.72) −5.78  <0.001 
 Fatigue 0.23 (0.43) 1.1 (0.61) −5.43  <0.001 
 Loss of interest 0.0 (0.0) 1 (0.93) −5.07  <0.001 
 Irritability 0.05 (0.21) 0.81 (0.93) −3.76  0.001 
ETI trauma load, mean (SD)a 1.82 (1.82) 3.75 (2.88) −2.57  0.012 
Documented medication, yes, n (%) 
 Antidepressants 17 (77.27)  27.70 <0.001 
 Antipsychotics 8 (36.36)  9.78 0.002 
DHEA concentration, µg/L, mean (SD)b 2.66 (1.90) 2.02 (1.11) 1.35  0.19 
VariablesGroupstχ2p value
controlMDD
(n = 22)(n = 22)
Age, years, mean (SD) 57.64 (5.57) 58.73 (6.17) −0.62  0.54 
BMI, kg/m2, mean (SD) 24.39 (2.99) 28.52 (7.22) −2.48  0.02 
Current smoker, yes, n (%) 4 (18.18) 12 (54.54)  6.29 0.012 
Physical activity, yes, n (%) 19 (86.36) 14 (63.64)  3.03 0.08 
BDI sum score, mean (SD) 2.27 (2.27) 23.95 (10.43) −9.53  <0.001 
 Sadness 0.05 (0.21) 0.77 (0.53) −5.99  <0.001 
 Loss of energy 0.23 (0.43) 1.36 (0.58) −7.38  <0.001 
 Disrupted sleep 0.41 (0.50) 1.64 (0.90) −5.57  <0.001 
 Disrupted appetite 0.05 (0.21) 0.90 (0.92) −4.28  <0.001 
 Difficulties concentrating 0.27 (0.46) 1.32 (0.72) −5.78  <0.001 
 Fatigue 0.23 (0.43) 1.1 (0.61) −5.43  <0.001 
 Loss of interest 0.0 (0.0) 1 (0.93) −5.07  <0.001 
 Irritability 0.05 (0.21) 0.81 (0.93) −3.76  0.001 
ETI trauma load, mean (SD)a 1.82 (1.82) 3.75 (2.88) −2.57  0.012 
Documented medication, yes, n (%) 
 Antidepressants 17 (77.27)  27.70 <0.001 
 Antipsychotics 8 (36.36)  9.78 0.002 
DHEA concentration, µg/L, mean (SD)b 2.66 (1.90) 2.02 (1.11) 1.35  0.19 

SD, standard deviation; BDI, Beck’s Depression Inventory-II; BMI, body mass index; MADRS, Montgomery-Åsberg Depression Rating Scale; Physical activity, self-report rating of regular physical activities (yes/no); ETI score, trauma load (number of personal and witnessed events); bold p values indicate significance on an alpha level of 0.05.

an = 42.

bn = 43.

Assessment of Serum DHEA Levels

Blood serum was prepared from a non-fasting whole blood sample collected in the morning into Serum S monovettes (Sarstedt Nürnbrecht, Germany). Blood was centrifuged at 1,000 g for 10 min at 4°C, and serum aliquots of 250 μL were stored at −80°C until analysis. Serum DHEA concentration was assessed by immunoassay analysis in the laboratories of MVZ laboratory diagnostics in Lehrte, Germany, according to the laboratory standards in clinical chemistry.

Peripheral Blood Mononuclear Cell Isolation

Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood collected in EDTA-buffered collection tubes (Sarstedt, Nümbrecht, Germany) by Ficoll-Hypaque gradient centrifugation according to the manufacturer’s protocol (GE Healthcare, Chalfon St Giles, UK). Isolated PBMCs were frozen in a cryoprotective freezing medium consisting of dimethyl sulfoxide (Sigma-Aldrich, St. Louis, MO, USA) and fetal calf serum (Sigma-Aldrich) in a 1:10 dilution and immediately stored at −80°C.

T-Cell Subset TL Analysis

For a detailed description of the used protocols for assessing TL in human PBMC and subsets, see [2]. In short, cryopreserved PBMCs were thawed and separated into naïve T helper cells (CD3+CD4+CD45RA+), memory T helper cells (CD3+CD4+CD45RA−), naïve cytotoxic T cells (CD3+CD8+CD45RA+), and memory cytotoxic T cells (CD3+CD8+CD45RA−) by fluorescent-activated cell sorting on a BD FACSAria III cell sorter device (BD Biosciences, Heidelberg, Germany) using the designated antibodies (Miltenyi Biotec, Bergisch Gladbach, Germany). Then, T-cell subpopulations were fixed in a 3:1 solution (v/v) of methanol (Sigma-Aldrich) and glacial acetic acid (VWR, Radnor, PA, USA) and subjected to quantitative fluorescence in situ hybridization for TL assessment. Analysis of stained cells was performed using a digital monochromatic AxioCamMRm camera (Carl-Zeiss-Microscopy, Jena, Germany) mounted on an AxioVert200 inverted fluorescent microscope (Carl-Zeiss-Microscopy). Images were captured at a 1,000-fold magnification at standardized settings concerning gain and exposure time. The telomere fluorescence intensity (TFI), which correlates with the respective TL, was assessed in 100 cells per sample with the image acquisition software TFL-TeloV2 [44], and mean TFI was calculated as an average of all TFI values per sample. To overcome the limitation of qualitative TL analysis, an additional Southern blot analysis was conducted with six human tumor cell lines characterized by a constant TL to generate a standard curve allowing the conversion of mean TFI into the corresponding kilobase (kb) value.

Statistical Data Analysis

Statistical data analyses were performed using IBM SPSS Statistics (SPSS 26.0, Inc., Chicago, IL, USA). To account for deviances from normal distribution, DHEA concentration was natural log-transformed (Ln). Differences in sociodemographic and clinical variables between depressed and non-depressed women were tested using Student’s t tests test or χ2 tests, respectively. Group differences were observed concerning body mass index (BMI) and smoking status; depressed women showed a higher BMI (t(42) = −2.48, p = 0.02) and reported a higher percentage of smokers (χ2(1, N = 44) = 6.29, p = 0.012). According to MDD diagnosis, depressed females scored significantly higher on the clinical instrument BDI-II (t(42) = −9.53, p < 0.001) and reported higher trauma load during their lifetime (t(40) = −2.63, p = 0.012) compared to the control group (see also Table 1). No significant associations between DHEA concentration and potential confounders, such as age, smoking status, physical activity, and BMI, were observed in the total group or, separately, in the control and depression groups (all p > 0.05). However, age was included as a covariate in all statistical models given literature demonstrating its effect on both DHEA level [18] and TL attrition [7]. The mean difference in DHEA concentration between women with and without depression was assessed using ANCOVA. Because TL was influenced by group [2], and we expected DHEA to differ between groups, separate analyses within the subgroups of depressed and non-depressed subjects were performed where appropriate. The PROCESS [45] macro model 4 was used to test the mediating role of DHEA concentration in the relationships between trauma load and immune cell TL. We conducted ordinary least squares path analyses using 10,000 bootstrapping samples and a 95% confidence interval (CI). For several biological measures, data were missing (see Table 1). To avoid an artificial reduction of the available data for statistical analyses, all available biological measures were included in the analyses. Two-tailed (partial) Pearson’s correlation coefficients were calculated for correlation analyses. For all analyses, p < 0.05 was considered significant. The Benjamini-Hochberg procedure was adopted to control the effects of multi-testing on the telomere T-cell subset analyses. The false discovery rate was set at 5%.

Trauma Load and Serum DHEA Concentration

We first investigated the association of lifetime exposure to psychological trauma with serum DHEA concentration. Correlational analysis indicated that higher trauma load was significantly and inversely correlated with DHEA concentration in the total cohort (r = −0.46, p = 0.003) as well as in the subgroup of women with depression (r = −0.63, p = 0.006). No significant association between trauma exposure and DHEA concentration was observed in the control group (r = −0.22, p = 0.34); see also Figure 1.

Fig. 1.

Association between trauma load (personal and witnessed), assessed by the Essener trauma inventory (ETI), and ln-transformed values of DHEA concentration in serum (µg/L). Total cohort size: n = 41. DHEA, dehydroepiandrosterone.

Fig. 1.

Association between trauma load (personal and witnessed), assessed by the Essener trauma inventory (ETI), and ln-transformed values of DHEA concentration in serum (µg/L). Total cohort size: n = 41. DHEA, dehydroepiandrosterone.

Close modal

DHEA Concentration and MDD Severity

Next, we examined DHEA concentration in the context of MDD diagnosis and the severity of depressive symptoms. Mean DHEA concentration (Ln) was not significantly different (F1, 40 = 1.24, p = 0.30) among depressed patients (M = 0.75, 95% CI: 0.47–1.03) and non-depressed controls (M = 0.56, 95% CI: 0.27–0.85). Accordingly, no significant correlation was observed between DHEA concentration and the BDI-II sum score analyzed among all participants (r = −0.23, p = 0.15) or, separately, within the group of women with depression (r = −0.24, p = 0.30) or in the control group (r = 0.06, p = 0.80). However, when examining the BDI-II subscales, we found that lower DHEA concentration was associated with more fatigue symptoms measured in the total group of participants (r = −0.38, p = 0.01), as well as among women with depression (r = −0.67, p = 0.001). We observed no significant relationship between DHEA concentration and fatigue in the control group (r = −0.006, p = 0.98).

DHEA Concentration and Immune Cell TL

Relationships between circulating DHEA concentration and immune cell TL were tested separately for total PBMCs and T-cell subpopulations. We observed no significant association between DHEA concentration and total PBMC TL (r = −0.25, p = 0.12, Fig. 2a) and naïve CD4+ T cells (r = 0.09, p = 0.59, Fig. 2b). However, DHEA concentration was positively associated with TL in memory CD4+ T cells (r = 0.37, p = 0.02, Fig. 2c), as well as in naïve CD8+ (r = 0.43, p = 0.005, Fig. 2d) and memory CD8+ T cells (r = 0.45, p = 0.003, Fig. 2e).

Fig. 2.

Association between serum DHEA concentration (µg/L) Ln and TL in total PBMC (a) (n = 43), CD4+ naïve T cells (b) (n = 43), CD4+ memory T cells (c) (n = 43), CD8+ naïve T cells (d) (n = 43), and CD8+ memory T cells (e) (n = 42). DHEA, dehydroepiandrosterone; kb, kilobase.

Fig. 2.

Association between serum DHEA concentration (µg/L) Ln and TL in total PBMC (a) (n = 43), CD4+ naïve T cells (b) (n = 43), CD4+ memory T cells (c) (n = 43), CD8+ naïve T cells (d) (n = 43), and CD8+ memory T cells (e) (n = 42). DHEA, dehydroepiandrosterone; kb, kilobase.

Close modal

In the subgroup of women with depression, almost similar results were found. Again, no significant relationships between DHEA concentration and TL in total PBMC (r = −0.22, p = 0.36) and naïve CD4+ T cells (r = 0.02, p = 0.94) were observed, while significant associations were found between DHEA concentration and naive CD8+ T cells (r = 0.60, p = 0.005) and memory CD8+ T cells (r = 0.66, p = 0.002). The relationship between DHEA and memory CD4+ T cells now showed a trend towards a significant effect (r = 0.43, p = 0.06). None of the correlations between DHEA concentration and TL in total PBMC (r = −0.24, p = 0.31) and T-cell subsets (naïve CD4+ T cells, r = 0.13, p = 0.59; memory CD4+ T cells, r = 0.27, p = 0.23; naïve CD8+ T cells, r = 0.25, p = 0.28; memory CD8+ T cells, r = 0.25, p = 0.29) were significant in the control group. The application of the Benjamini-Hochberg procedure did not change the significance of the results.

The Effect of Trauma Load on Immune Cell TL Is Mediated by DHEA

Next, we examined the role of serum DHEA concentration in the relationship between trauma load and CD8+ memory T-cell TL and observed a significant mediating effect in both the total group (indirect effect, b = −0.10, 95% CI: −0.21 to −0.006, p < 0.05) and in the subgroup of women with depression (indirect effect, b = −0.21, 95% CI: −0.44 to −0.02, p < 0.05).

DHEA concentration was also a mediator in the relationship between trauma load and CD4+ memory T-cell TL in the total group (indirect effect, b = −0.07, 95% CI: −0.13 to −0.002, p < 0.05). However, the indirect effect was no longer significant in the depression subgroup (b = −0.08, 95% CI: −0.25 to 0.08, p > 0.05). No mediating effect of DHEA concentration was observed in the relationship between trauma load and CD8+ naive T-cell TL in the total group of participants (indirect effect, b = −0.09, 95% CI: −0.20 to 0.003, p > 0.05), neither among females with depression (CD8+ naive T cells: indirect effect, b = −0.13, 95% CI: −0.37 to 0.004, p > 0.05).

This study set out to examine associations between serum levels of the steroid hormone DHEA and immune cell telomere length in the context of psychological trauma and depression. In accordance with our first hypothesis, we showed that higher trauma load related to lower DHEA concentration, which in turn was associated with more fatigue symptoms. However, our study findings did not support our second hypothesis, as we observed no significant difference in DHEA concentration between women with and without depression. In line with our third hypothesis, we identified, for the first time, that higher serum DHEA concentration relates to longer telomere length in specific T-cell subsets. This association was most pronounced in CD8+ cytotoxic T cells, where DHEA concentration was determined to be a mediator in the relationship between psychological trauma exposure and TL (as per our fourth hypothesis). Taken together, our results support the assumption that DHEA may exert beneficial effects on telomere integrity, especially in conditions related to distress.

First, we observed a negative association between lifetime psychological trauma and circulating DHEA concentration. Lower circulating and salivary DHEA-S levels were also observed in female adolescents who experienced sexual abuse and victims of rape diagnosed with PTSD when compared to age-matched controls [21, 22]. Several other studies reported contradictory findings [23‒26, 46], which may be attributed to differing sample matrices (blood vs. saliva vs. hair), the application of different analytical methods (e.g., ELISA vs. radioimmunoassay vs. mass spectrometry), and differences in study design and population characteristics (e.g., depression vs. PTSD).

No significant difference in DHEA concentration between women with and without depression was found. This finding is in contrast to the majority of literature reporting lower circulating DHEA concentrations in depression [27‒31]. An explanation for this divergence might be the relatively small sample size of our study or the fact that only postmenopausal women of higher age were included. However, we did see an association between DHEA concentration and symptoms of fatigue, a finding that has been reported by several other studies [47, 48]. Further, DHEA administration improved fatigue and well-being in elderly subjects and in a variety of disease states [49‒52], although other studies do not support these findings [53, 54]. There are several potential pathways and mechanisms through which DHEA protects against fatigue. For example, fatigue may be caused, in part, by increased levels of inflammation [55]. DHEA has been shown to inhibit PBMC pro-inflammatory cytokine production in vitro [19], probably by the inhibition of nuclear factor-kappa B (NF-kappa B)-dependent transcription through its antioxidant effects [56]. Another possible explanation of how DHEA reduces fatigue is via the stimulation of testosterone production [57]. Additionally, energy homeostasis and fatigue may also be improved by DHEA-stimulated increases in mitochondrial function [58‒60].

One of the most significant findings to emerge from this study is that DHEA concentration was positively related to TL in specific T-cell subpopulations, including memory CD4+ T cells, naïve CD8+, and memory CD8+ T cells. A positive relationship between DHEA-S and immune cell TL was also observed in a large prospective study including 821 newborns. In this investigation, higher DHEA-S concentration was associated with longer leukocyte TL and inversely related to ROS levels measured in cord blood [35]. Telomeres are vulnerable to ROS-induced chemical damage, and oxidative stress impairs the function of telomerase, the enzyme that maintains telomeres [61]. Since DHEA(-S) has antioxidant effects, it may exert a protective effect on leukocyte TL [35]. In contrast to this prospective study, we did not observe a significant association of DHEA with TL in the total PBMC population, but only in T-cell subsets. Telomere length and telomerase activity vary among blood cell types [62]; therefore, this discrepancy might be explained by differences in immune cell subsets present in newborn cord blood and isolated PBMC retrieved from our study participants (postmenopausal women). Similar to our findings in total PBMCs, no significant relationship between DHEA(-S) concentration and leukocyte TL was observed in men with idiopathic pulmonary fibrosis [37] and in elderly participants [38]. However, because in these studies no T-cell subsets were analyzed, further comparisons cannot be made.

A key strength of our study was the quantification of TL in both total PBMC and specific T-cell subpopulations. Memory T cells are characterized as long-lived circulating cells, which are most exposed to and therefore potentially most affected by circulating biological stress mediators, like ROS. Our previous findings already suggested that the overall cell population of cytotoxic (CD8+) T cells is more vulnerable to telomere shortening than T helper cells and B cells [63]. Analyses of the association between DHEA concentration and TL in cytotoxic T cells in the control and MDD subgroups further revealed that this association was more pronounced in the group of women with depression. This observation could indicate that the protective effect of DHEA on T-cell TL only becomes evident when telomeres reach a certain shortness, e.g., due to excess stress and or lifetime trauma exposure, such as observed in individuals with MDD [2, 63].

In the present study, DHEA concentration mediated, at least in part, the relationship between trauma exposure and TL in CD4+ and CD8+ memory T cells in the total group of participants and in CD8+ memory T cells among women with depression. Based on these results, it may be suggested that interventions that increase circulating DHEA levels protect against the adverse consequences of trauma exposure on telomere shortening. DHEA supplementation has already been proven to be successful in reducing the severity of depressive symptoms as well as in improving fatigue and well-being [33, 51]. Although DHEA administration exerts various beneficial effects, including a broad-spectrum cancer chemopreventive activity in various in vitro and rodent models [64], there is also the possibility of adverse effects as indicated by high dosage-induced hepatoxicity and neurotoxicity in rats [65]. The application of higher doses that are the human equivalent of therapeutically effective doses in preclinical studies is compromised by DHEA’s androgenicity, potentially increasing the risk of hormone-sensitive cancers, including prostate, breast, and ovarian cancers. The use of non-androgenic DHEA analogs that are currently being tested in clinical trials may overcome these problems [64]. Alternatively, exercise and sitting isometric yoga have been shown to increase circulating DHEA-S levels [66, 67]. Also, a functional medicine approach, including DHEA supplementation, improved general well-being [68]. In addition, interventions targeting psychological resilience may slow down telomere loss and ameliorate symptoms of fatigue by stimulating DHEA production. This idea is further supported by findings showing that psychological resilience factors, such as a sense of coherence and self-care, were positively related to hair DHEA concentration in professional caregivers [69].

A number of caveats need to be noted regarding the present study. First, the exclusive recruitment of postmenopausal women limits the general validity of our findings to both sexes and younger populations. Second, the limited sample size of our study might have increased the likelihood of a type II error resulting in nonsignificant results. Third, a substantial part of the participants in the depression group took antidepressant and/or antipsychotic medication and, to date, the effects of such pharmacological treatment on DHEA levels and telomere biology have not yet been clarified. Finally, the cross-sectional design limits the establishment of a true cause-and-effect relationship in our study.

Based on our results in support of a positive link between DHEA and TL in specific T-cell subpopulations, one future research direction will be to determine this association in the context of other (psycho)pathologies and in different stress-related states and traits, preferably using a longitudinal design including clinical intervention to test the reactivity of the biological systems. Also, further mechanistic studies, including measurements of oxidative stress and other biological stress mediators, are warranted to improve our understanding of the exact pathways by which DHEA inhibits telomere shortening and improves energy metabolism. By applying an untargeted biomarker identification approach, mass spectrometry-based metabolite fingerprinting of blood serum and other specimens could be one key technology for the biological blueprinting of DHEA alterations on a systemic scale.

To conclude, our findings suggest a potential role of DHEA as a biological resilience factor that may promote telomere integrity, particularly in the context of psychological trauma and depression. However, future studies have to replicate our observation to further support these first results.

We would like to thank Prof. Iris-Tatjana Kolassa from Ulm University for her valuable feedback on the manuscript.

The study protocol was reviewed and approved by the Medical Ethics Committee of the Hanover Medical School (MHH) in Lower Saxony, Germany, approval number 5747. All aspects of the study were conducted in accordance with the Declaration of Helsinki. All subjects provided their written informed consent before participation.

The authors have no relevant financial or non-financial interests to disclose.

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

K.d.P. participated in the data analyses and drafted the manuscript. J.S. conducted the clinical assessments and coordinated biological sampling of whole blood and serum. D.E.D. conceived of and designed the study together with A.K. who also coordinated the study, performed the data collection, participated in the analysis and interpretation of the study findings, drafted portions of the manuscript, and provided final editorial oversight. All authors revised and approved the final manuscript.

The data that support the findings of this study are not publicly available due to local data policy regulations but are available from the corresponding author, K.d.P., upon reasonable request.

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