The Effect of the Integrated Stress Response Reduction Intervention on Cellular Aging in Middle-aged Nurses: A Pilot Study

The Effect of the Integrated Stress Response Reduction Intervention on Cellular Aging in Middle-aged Nurses: A Pilot Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Effect of the Integrated Stress Response Reduction Intervention on Cellular Aging in Middle-aged Nurses: A Pilot Study Hwasook Cho, Hyunwook Kang, MeiLing Song, Nahyun Kim This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9303641/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 16 You are reading this latest preprint version Abstract Background. Nurses experience persistently high levels of occupational stress, which negatively affects their physical and psychological health and compromises the quality of patient care. Chronic psychological stress is closely linked to physiological dysregulation and cellular aging processes through stress-response pathways. However, limited evidence exists regarding whether stress management interventions targeting these mechanisms can influence cellular aging biomarkers in nurses. This study examined the effects of an integrated stress response reduction intervention ( i SRI) on cellular aging among middle-aged nurses. Methods. A non-randomized controlled pilot study was conducted with 60 nurses aged 45–60 years recruited from two tertiary hospitals. Participants were allocated to either an intervention group (n = 31) or a control group (n = 29). The 12-week ISRI comprised biofeedback training, group-based cognitive–behavioral education, mindfulness and relaxation practices, and structured physical exercise. Outcomes included perceived psychological stress, biochemical markers associated with the mechanisms through which psychological stress contributes to cellular aging (serum cortisol, interleukin-6, and superoxide dismutase), and cellular aging indicators (leukocyte telomere length and mitochondrial DNA copy number). Assessments were performed at baseline and post-intervention. Results. Perceived stress levels significantly decreased in the intervention group following the i SRI, while remaining unchanged in the control group. Although no significant between-group differences were observed in serum cortisol or interleukin-6 levels, superoxide dismutase levels increased significantly in the intervention group compared with the control group. With respect to cellular aging markers, leukocyte telomere length increased slightly in the intervention group but significantly decreased in the control group, resulting in a significant between-group difference. No significant changes were observed in mitochondrial DNA copy number. Conclusions . The i SRI was effective in reducing perceived stress and improving antioxidant activity while attenuating telomere shortening among middle-aged nurses. These findings suggest that stress management interventions grounded in physiological stress-response mechanisms may exert beneficial effects extending to cellular aging processes. Incorporating mechanism-based, multicomponent stress reduction programs into occupational health strategies may enhance nurse well-being and long-term health outcomes. Given the demonstrated effectiveness of the i SRI, administrators should consider integrating regular, evidence-based stress management programs into organizational support systems to promote nurse well-being and sustainable workforce health. biofeedback cellular senescence mitochondria nurses psychological stress telomere non-randomized controlled trial Figures Figure 1 Figure 2 Figure 3 Background Nurses constitute a major workforce in healthcare systems worldwide. Although they deliver essential care across diverse clinical settings, nursing work environments are widely recognized as highly stressful and are associated with adverse health outcomes among nurses, ultimately threatening the quality of patient care [ 1 , 2 ]. International reports consistently identify nursing as one of the most stressful occupations, characterized by high emotional demands and sustained workload pressure [ 3 ]. Primary sources of occupational stress for nurses include caring responsibilities for patients and their families, interpersonal conflicts with colleagues, and excessive workload demands [ 3 , 4 ]. Additionally, organizational and environmental factors—such as long working hours, shift work, insufficient compensation for effort, and frequent exposure to emotionally charged patient interactions—further exacerbate stress in this profession [ 3 ]. Prolonged exposure to such stressors has been identified as a major determinant of both physical and psychological health deterioration. Recent evidence indicates that psychological stress is closely associated with cellular and biological aging processes and age-related diseases [ 5 – 7 ]. In response to stressors, the autonomic nervous system (ANS) and the hypothalamic–pituitary–adrenal (HPA) axis serve as primary physiological pathways that regulate adaptive stress responses. However, chronic or repeated stress exposure can lead to cumulative physiological burden, commonly referred to as allostatic load, thereby increasing vulnerability to disease [ 8 , 9 ]. Allostatic load represents a state of physiological dysregulation resulting from repeated or prolonged stress-induced “wear and tear” on regulatory systems [ 8 , 10 ]. Persistent allostatic load is characterized by dysregulation of the ANS and HPA axis, leading to excessive secretion of catecholamines, glucocorticoids, pro-inflammatory cytokines, and reactive oxygen species (ROS), with insufficient termination of these responses [ 8 , 11 , 12 ]. These biological mediators contribute to tissue injury and cellular damage and form the mechanistic basis through which psychological stress influences the development of chronic diseases, including cardiovascular disorders [ 8 ]. Telomere length and mitochondrial function have emerged as key biomarkers reflecting cellular aging. Telomeres are protective nucleoprotein structures that maintain chromosomal stability, and their progressive shortening contributes to genomic instability and cellular senescence [ 13 ]. Shortened telomere length has been associated with inflammation, oxidative stress, impaired telomerase activity, and repeated cell division [ 14 , 15 ]. Mitochondrial DNA copy number (mtDNAcn), an index of mitochondrial biogenesis and function, is considered a reliable biomarker of mitochondrial health [ 16 ]. The interaction between telomere dynamics and mitochondrial function plays a critical role in cellular aging. Telomere dysfunction impairs mitochondrial biogenesis and energy production and increases ROS generation, thereby accelerating cellular damage [ 16 , 17 ]. Psychological stress has been shown to influence both telomeres and mitochondria through shared biological pathways involving inflammation and oxidative stress [ 18 ]. Based on the evidence, the overall scheme of the mechanism by which psychological stress can contribute cellular aging is summarized as shown in Fig. 1 . Given these mechanisms, effective stress management interventions that target physiological stress-response pathways are essential for nurses. Numerous non-pharmacological interventions—such as relaxation therapy, mindfulness-based practices, and structured physical activity—aim to restore autonomic balance [ 19 , 20 ]. However, most previous studies have relied primarily on patient-reported outcomes, with limited assessment of physiological or cellular aging markers [ 21 – 23 ]. Heart rate variability (HRV) biofeedback training has demonstrated efficacy in improving both physiological and psychological outcomes by regulating ANS activity [ 24 ]. Also, a meta-analysis reported that cognitive behavioral therapy combined with relaxation therapy was more effective than cognitive behavioral therapy alone or relaxation therapy in reducing occupational stress among teachers [ 25 ]. On the basis of this evidence, the integrated stress response reduction intervention ( i SRI) was developed to restore autonomic balance and potentially mitigate stress-induced cellular aging. This study aimed to examine the effects of the 12-week ISRI intervention in middle-aged nurses. To our knowledge, few studies have investigated interventions targeting stress-related mechanisms at the cellular level, as well as associated biochemical markers. Methods Study design This study employed a non-randomized controlled pilot study to examine the psychological and physiological effects of the i SRI among middle-aged nurses. Study setting and participants Among three tertiary hospitals of similar size and organizational characteristics located in a metropolitan city, two hospitals were randomly selected using a coin-toss method. After obtaining approval from the nursing department directors at both hospitals, a second independent coin toss conducted by a third party not involved in the study was used to allocate one hospital to the intervention group and the other to the control group. Using a convenience sampling approach, nurses working at the participating hospitals were invited to enroll. Inclusion criteria were nurses who (1) were aged 45–60 years, (2) had a Perceived Stress Scale (PSS) score greater than 16—based on evidence indicating a mean PSS score of 16.1 in the Korean general population [ 26 , 27 ]—and (3) had not participated in any formal stress-relief intervention within the previous three months. Exclusion criteria included nurses (1) with central or peripheral nervous system disorders or neuropsychiatric conditions that could affect ANS, (2) who had been diagnosed with a psychiatric disorder or were receiving related pharmacological treatment, and (3) who were taking sleep medication for a diagnosed sleep disorder. The age range was restricted because telomere length and mtDNAcn—both key biomarkers of cellular aging—are strongly associated with chronological age. These indicators typically decline with advancing age, and prior studies suggest that the rate of decline becomes more pronounced beginning in midlife [ 28 , 29 ]. In addition, exposure to stressful life events during childhood has been associated with shorter telomere length; however, evidence suggests that the influence of early-life stress on telomere length is no longer detectable after approximately age 45 [ 30 ]. Sample size calculation Sample size was calculated using the G*Power software version 3.1.9.6 [ 31 ]. Based on a two-tailed independent t-test with an effect size of 0.80, a significance level of 0.05, and statistical power of 0.80, a minimum of 26 participants per group was required. Allowing for a potential attrition rate of 15%, a total sample size of at least 60 participants was determined. Intervention The i SRI was developed following a comprehensive review of the literature on stress-reduction interventions and biofeedback training. The intervention was designed to mitigate physiological stress responses that underlie stress-related cellular aging mechanisms. Content validity of the initial program was evaluated by an expert panel consisting of two nursing professors with expertise in autonomic balance–based interventions, two nursing professors specializing in intervention research, and one clinical public health nurse. Based on feedback from the expert panel, the intervention content and delivery methods were refined. The revised program was subsequently pilot-tested with six clinical nurses, leading to further simplification of weekly themes and clarification of intervention procedures. The i SRI is a multicomponent, group-based intervention comprising cognitive–behavioral education, relaxation therapy, mindfulness practice, and individualized heart rate variability biofeedback training. Excluding one week each for pre- and post-intervention assessments, the intervention was delivered over a 12-week period. The principal investigator conducted weekly 60-minute group education sessions focusing on stress mechanisms, ANS regulation, lifestyle modification, and coping strategies, including physical activity and relaxation techniques. To enhance adherence, individual telephone counseling sessions lasting 5–10 minutes were conducted twice weekly. Participants recorded daily stress-management practices in logs provided at the beginning of the intervention. In the seventh week, participants’ logs were reviewed, and experiences were shared during the group session. A participant demonstrating the greatest improvement in stress management was identified and received a small monetary incentive. Weekly individualized biofeedback training commenced in the second intervention week. Initial respiration rate was set at 10 breaths per minute, after which individualized respiration rates producing optimal autonomic responses were determined and maintained throughout the intervention period. Each biofeedback session lasted 20 minutes and was administered once weekly using a biofeedback device (ProComp Infiniti; Thought Technology Ltd., Quebec, Canada) in a controlled environment with minimal visual and auditory stimulation. Intervention fidelity was ensured through standardized training of research personnel, use of a detailed intervention manual, and monitoring adherence using session checklists. Participant adherence was also evaluated through regular review of daily practice logs. Control group Participants in the control group received a single 30-minute group education session on general stress management following completion of baseline assessments. In addition, participants were provided with a wearable activity-tracking device to encourage and monitor daily physical activity. Data collection procedure Pre-intervention assessments were initiated after the principal investigator obtained participants’ signed and dated informed consent forms. Upon arrival at the data collection site, participants rested for 30 minutes before a registered nurse, who was a member of the research team, administered self-report questionnaires and collected venous blood samples for biochemical analyses and DNA extraction. Post-intervention assessments were conducted 12 weeks after baseline, following the same procedures used for pre-intervention data collection. Participants in both the intervention and control groups, as well as research team members responsible for data collection, were blinded to group allocation. The principal investigator delivered the intervention but did not participate in data collection to minimize potential bias that could influence study outcomes. Measures Perceived psychological stress. Perceived psychological stress was measured using the Korean version of the Perceived Stress Scale (PSS), which was originally developed by Cohen et al. [ 26 ] and later validated in Korean populations [ 27 ]. The PSS consists of 10 items rated on a Likert scale, with total scores ranging from 0 to 40, where higher scores indicate higher levels of perceived stress. In the original development study, Cronbach’s α ranged from 0.84 to 0.86, and a reliability coefficient of 0.81 was reported in a previous study involving Korean adults [ 32 ]. Biochemical markers. Biochemical markers included serum cortisol, interleukin-6 (IL-6), and superoxide dismutase (SOD). Serum cortisol levels were measured using venous blood samples. To account for diurnal variation in cortisol secretion, all blood samples were collected between 8:00 and 10:00 a.m. The reference range for serum cortisol is 3.7–19.4 µg/dL for samples collected between 6:00 and 10:00 a.m. SOD and IL-6 concentrations were assessed using 3 mL of venous blood drawn from the antecubital vein after a minimum of 12 hours of fasting. Blood samples were centrifuged at 3,000 rpm for 10 minutes at 4°C and subsequently analyzed at Seoul Clinical Laboratories. Cellular aging markers. Leukocyte telomere length (LTL) and mtDNAcn are commonly used as biomarkers for assessing biological or cellular aging. Because white blood cells (leukocytes) are easily obtained from peripheral blood, sufficient amounts of DNA for such measurements can be extracted from them. Thus, genomic DNA was extracted from the buffy coat of 1 mL of whole blood collected on the same day using a DNA isolation kit (QIAamp DNA Blood Midi Kit; Qiagen, Hilden, Germany). The extracted DNA was aliquoted into 1.5-mL microcentrifuge tubes and stored at − 24°C until analysis. To measure LTL and mtDNAcn, quantitative real-time polymerase chain reaction (qRT-PCR) was performed using a commercial assay kit (Absolute Human Telomere Length Quantification qPCR Assay Kit; ScienCell Research Laboratories, Carlsbad, CA, USA). LTL and mtDNAcn were calculated from the obtained quantification cycle (Cq) values. The specificity of qRT-PCR amplification was verified by melt-curve analysis. All measurements were performed in triplicate as previously described [ 33 ]. Ethical considerations This study was approved by the Institutional Review Board of K University prior to data collection (IRB No. 40525-202212-BR-085-06). All potential participants received detailed information regarding the study’s purpose, procedures, duration, eligibility criteria, potential benefits, confidentiality measures, and incentives. Written informed consent was obtained from all participants who voluntarily agreed to participate. Participants were informed that they could withdraw from the study at any time without penalty and that their anonymity would be strictly protected. Access to personal information was restricted to the principal investigator and authorized research personnel only, and all collected data were securely disposed of upon completion of the study. Results Participant characteristics and homogeneity testing A total of 129 nurses were assessed for eligibility, of whom 66 were excluded based on the inclusion and exclusion criteria. During the 12-week intervention period, three participants withdrew from the study (one due to nonattendance and two due to refusal to complete post-intervention assessments). Data from 60 participants were included in the final analysis, with 31 nurses in the intervention group and 29 in the control group (Fig. 2 ). All participants in both the intervention and control groups were women. The mean age of participants was 50.2 years in the intervention group and 53.0 years in the control group. More than half of the participants held a master’s degree or higher. Mean clinical experience was 340.3 months for the intervention group and 375.9 months for the control group. Significant baseline differences were observed between the two groups in mean age, clinical experience, alcohol consumption status, and perceived current stress. No significant differences were identified for other demographic characteristics. Homogeneity testing of outcome variables at baseline revealed significant between-group differences in SOD levels and LTL, whereas no significant differences were observed for other outcome measures (Table 1 ). Table 1 Baseline Characteristics of Participants (N = 60) Variable Category Intervention (n = 31) Control (n = 29) z/t/χ 2 p Mean (SD) or n (%) Age (year) 50.23 (3.63) 53.00 (.76) -2.93 * .003 Education College 7 (22.6) 11 (37.9) 1.68 .195 ≥ Graduate school 24 (77.4) 18 (62.1) Spouse No 5 (16.1) 2 (6.9) 1.24 .426 Yes 26 (83.9) 27 (93.1) Religion No 6 (19.4) 12 (41.4) 3.46 .063 Yes 25 (80.6) 17 (58.6) Working department Ward 12 (38.7) 9 (31.0) 1.62 .445 Operation room/Outpatient 9 (29.0) 13 (44.8) Administration 10 (32.3) 7 (24.2) Clinical experience (month) 340.32 (47.04) 375.97 (51.98) -2.78 .007 Shift work No 21 (67.7) 20 (69.0) 0.01 .919 Yes 10 (32.3) 9 (31.0) Alcohol drinking No 14 (45.2) 21 (72.4) 4.58 .032 Yes 17 (54.8) 8 (27.6) Chronic disease No 17 (54.8) 18 (62.1) 0.32 .570 Yes 14 (45.2) 11 (37.9) Menopause No 14 (45.2) 20 (69.0) 3.46 .063 Yes 17 (54.8) 9 (31.0) Current stress No 5 (16.1) 13 (44.8) 5.87 .015 Yes 26 (83.9) 16 (55.2) PSS 20.48 (3.53) 18.86 (3.85) 1.70 .094 Serum cortisol (µg/dL) 7.77 (2.77) 8.66 (2.83) -1.22 .226 IL-6 (pg/mL) 1.65 (1.49) 1.31 (0.71) -0.30 * .762 SOD (unit) 1.06 (0.23) 1.21 (0.22) -2.26 * .024 LTL 1.78 (0.59) 2.04 (0.37) -2.04 .047 Mitochondria copy number 468.26 (154.57) 461.10 (143.81) 0.19 .854 Note. SD = standard deviation; PSS = Perceived Stress Scale; * Mann-Whitney U test; IL-6 = Interleukin-6; LTL= Leukocyte Telomere Length; SOD = Superoxide Dismutase Effects of the intervention on psychological stress Table 2 shows changes in PSS scores from baseline to 12 weeks. Following the 12-week i SRI intervention, PSS levels decreased significantly in the intervention group, whereas no significant change was observed in the control group. Effects of the intervention on biochemical markers Regarding biochemical outcomes, both groups demonstrated a significant increase in serum cortisol levels over time (Table 2). However, no significant between-group differences were observed for serum cortisol or IL-6 levels following the intervention. IL-6 levels showed a slight decrease in the intervention group and a slight increase in the control group, but the between-group difference was not statistically significant. Both groups exhibited significant within-group changes in SOD levels. Table 2. Changes in psychological stress, biochemical markers, cellular aging markers (N=60) Variable Intervention (n=31) Control (n=29) Difference between groups z/t (p) Baseline 12 weeks t (p) Baseline 12 weeks t (p) Mean (SD) Mean (SD) PSS 20.48 (3.53) 17.06 (4.19) 3.65 (.001) 18.86 (3.85) 17.97 (3.75) 1.13 (.269) -2.04 (.046) Serum cortisol (μg/dL) 7.77 (2.77) 8.55 (2.27) -1.73 (< .001) 8.66 (2.83) 10.28 (3.75) -2.65 (.013) -1.68 * (.093) IL-6 (pg/mL) 1.73 (1.51) 1.70 (1.10) -3.76 (.001) 1.31 (0.71) 1.32 (0.92) -0.06 (.952) -0.12 (.907) SOD (unit) 1.06 (0.23) 1.66 (0.35) -10.43 (< .001) 1.21 (0.22) 1.60 (0.18) -8.37 (< .001) 2.96 (.005) LTL 1.78 (0.59) 1.81 (0.39) -0.22 (.831) 2.04 (0.37) 1.66 (0.35) 5.58 (< .001) -2.74* (.006) Mitochondria copy number 468.26 (154.57) 448.68 (89.25) 0.76 (.452) 461.10 (143.81) 426.97 (103.56) 0.94 (.355) 0.33 (.745) Note. SD = Standard deviation; PSS = Perceived Stress Scale; *Mann-Whitney U test; IL-6 = Interleukin-6; LTL= Leukocyte Telomere Length; SOD = Superoxide Dismutase Notably, the increase in SOD was significantly greater in the intervention group than in the control group, indicating a favorable effect of the intervention on antioxidant status. Effects of the intervention on cellular aging markers With respect to cellular aging indicators, LTL showed a slight, non-significant increase in the intervention group, whereas a significant decrease was observed in the control group (Figure 3A, 3B). The between-group difference in LTL change was statistically significant. In contrast, no significant within-group or between-group differences were identified in mtDNAcn following the intervention period. Discussion This study examined the effects of a 12-week i SRI on psychological stress, physiological responses, and cellular aging biomarkers among middle-aged nurses. The findings indicate that the i SRI was effective in reducing perceived stress levels and improving specific biochemical and cellular aging indicators, supporting the potential of mechanism-based stress management interventions in nursing populations. Following the intervention, perceived stress levels in the intervention group decreased significantly. However, post-intervention stress levels remained higher than those reported in the Korean general population [ 27 ]. This finding is consistent with previous studies demonstrating that although mindfulness- or relaxation-based interventions can significantly reduce perceived stress among nurses, stress levels often remain elevated due to persistent occupational demands [ 34 ]. These results underscore the chronic and structural nature of occupational stress in nursing and highlight the need for sustained or intensified interventions, as well as organizational-level strategies to reduce stressors in the work environment. In contrast to studies reporting significant reductions in serum cortisol following meditation or relaxation interventions, the present study did not observe significant between-group differences in cortisol levels [ 35 ]. This discrepancy may reflect the complex relationship between cortisol secretion and psychological stress, as cortisol reactivity is influenced by multiple factors including sex, duration of stress exposure, symptom severity, and circadian rhythm [ 36 , 37 ]. Given that all participants in this study were women, future investigations incorporating more diverse populations and longer follow-up periods may be required to elucidate intervention-related changes in cortisol dynamics. Although no significant differences were observed in IL-6 levels, SOD levels increased significantly in the intervention group compared with the control group. Psychological stress activates the sympathetic nervous system and HPA axis, leading to increased allostatic load and enhanced secretion of inflammatory cytokines and reactive oxygen species [ 8 , 38 , 39 ]. Elevated oxidative stress is a key contributor to cellular damage and aging [ 40 ]. The significant increase in SOD observed in the intervention group suggests that the i SRI may attenuate oxidative stress by restoring autonomic balance and reducing excessive physiological stress responses. A primary objective of this study was to determine whether the i SRI could influence cellular aging markers associated with psychological stress. Notably, LTL increased slightly in the intervention group while significantly decreasing in the control group, resulting in a significant between-group difference. This finding aligns with previous evidence indicating that stress-reduction interventions, including mindfulness-based approaches, can slow telomere shortening or enhance telomere maintenance mechanisms [ 41 , 42 ]. Elevated psychological stress has been consistently associated with shorter telomere length, and both subjective and biological stress measures appear to exert comparable effects on telomere dynamics [ 43 , 44 ]. The underlying mechanism is thought to involve stress-induced activation of inflammatory and oxidative pathways, which accelerate telomere attrition beyond that attributable to chronological aging alone [ 45 , 46 ]. The i SRI may interrupt this cascade and contribute to the preservation or restoration of telomere length. These findings support the conceptual framework that intervention strategies targeting stress-response mechanisms can exert measurable effects at the cellular level. Stress, telomere dynamics, and mitochondrial function are known to influence one another [ 18 , 47 ]. However, no significant changes were observed in mtDNAcn. Telomere function and mitochondrial health are closely interconnected, and chronic stress is known to disrupt both through shared biological pathways [ 16 , 18 ]. However, evidence suggests that telomere shortening may occur earlier or recover more rapidly than alterations in mitochondrial markers, which may require prolonged or sustained intervention to demonstrate measurable change [ 17 , 48 ]. The absence of mtDNAcn change in the present study may reflect a temporal lag between improvements in telomere maintenance and mitochondrial adaptation, indicating the need for longer follow-up periods or repeated intervention exposure. Strengths and limitations This study represents, to our knowledge, the first investigation to demonstrate that a stress management intervention grounded in physiological stress mechanisms can influence cellular aging biomarkers in nurses. By integrating autonomic regulation, cognitive–behavioral strategies, and biofeedback training, the i SRI provides a comprehensive approach to stress reduction that extends beyond subjective outcomes to include biochemical and cellular indicators. Nevertheless, several limitations should be considered. First, the use of convenience sampling may introduce selection bias, potentially favoring participants who were more motivated or receptive to stress management. However, as most primary outcomes were objective physiological measures, the influence of self-selection bias is likely limited. Second, the study sample consisted exclusively of middle-aged nurses, many of whom were not engaged in rotating shift work. Therefore, the findings may not be generalizable to younger nurses or those working irregular shifts, who often experience higher levels of occupational stress [ 1 , 3 ]. Third, because this study was a pilot study with a small sample size and employed a non-randomized controlled trial design, generalizability of the findings is limited. Implications for future research and practice Future studies employing longitudinal and randomized controlled trial is warranted to clarify the causal relationship between stress reduction interventions and cellular aging trajectories. Extending the intervention duration or incorporating booster sessions may help determine whether sustained improvements in mitochondrial function can be achieved. Additionally, examining the effectiveness of the i SRI in younger nurses, shift workers, or individuals with chronic stress-related conditions would further enhance its applicability. From a practice perspective, the demonstrated benefits of the i SRI suggest that healthcare organizations should consider implementing structured, evidence-based stress management programs as part of occupational health strategies. Although biofeedback-based interventions require initial investment in equipment, training, and time allocation, their potential to mitigate stress-related health deterioration among nurses may justify institutional support, particularly when integrated into flexible or technology-assisted delivery models. Conclusions The i SRI was significantly effective in reducing perceived stress levels and alleviating stress responses. These findings are significant in that the non-pharmacological i SRI, which targets stress-related mechanisms, successfully improved antioxidant capacity and cellular aging markers, as well as perceived psychological stress. Further research should be conducted among younger nurses working three-shift schedules and providing direct patient care. Examination of the long-term effects of the i SRI may reveal sustained reductions in stress responses and clearer evidence of its efficacy on cellular aging markers. Abbreviations ANS: Autonomic Nervous System HPA: Hypothalamic-Pituitary-Adrenal HRV: Heart rate variability IL-6: Interleukin-6 i SRI: Integrated Stress Response Reduction Intervention LTL: Leukocyte Telomere Length mtDNAcn: Mitochondrial DNA Copy Number PSS: Perceived Stress Scale SOD: Superoxide Dismutase Declarations Ethics approval and consent to participate This study was conducted in accordance with the principles of the Declaration of Helsinki. This study was approved by the Institutional Review Board of K University prior to data collection (IRB No. 40525-202212-BR-085-06). Consent for publication Not applicable. Availability of data and materials The datasets generated and analysed during the current study are not publicly available due to the protection of participants’ privacy but are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This work was supported by the National Research Foundation of Korea (grant number: 2020R1A2C1006590). The funding body had no role in the study design, data collection, analysis, interpretation, manuscript writing, or decision to submit the paper for publication. Authors' contributions Conceptualization; NK, Data curation; HC, NK, Formal analysis; HC, MS, Investigation; NK, HC, HK Methodology; HC, NK, Project administration; HC, NK, Resources; HK, NK, Supervision; NK, Validation; HK, MS, NK, Visualization; HK, MS, Roles/Writing - original draft; HC, HK, Writing - review & editing: HK, NK. 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The effect of a biofeedback-based integrated program on improving orthostatic hypotension in community-dwelling older adults: A pilot study. J Cardiovasc Nurs. 2025;40(1):E24–36. 10.1097/JCN.0000000000001026 . McCraty R, Atkinson M, Lipsenthal L, Arguelles L. New hope for correctional officers: an innovative program for reducing stress and health risks. Appl Psychophysiol Biofeedback. 2009;34(4):251–72. 10.1007/s10484-009-9087-0 . Aguilar-Raab C, Stoffel M, Hernández C, Rahn S, Moessner M, Steinhilber B, et al. Effects of a mindfulness-based intervention on mindfulness, stress, salivary alpha-amylase and cortisol in everyday life. Psychophysiology. 2021;58(12):e13937. 10.1111/psyp.13937 . Van der Zwan JE, de Vente W, Huizink AC, Bögels SM, de Bruin EI. Physical activity, mindfulness meditation, or heart rate variability biofeedback for stress reduction: a randomized controlled trial. Appl Psychophysiol Biofeedback. 2015;40(4):257–68. 10.1007/s10484-015-9293-x . Goessl VC, Curtiss JE, Hofmann SG. The effect of heart rate variability biofeedback training on stress and anxiety: a meta-analysis. Psychol Med. 2017;47(15):2578–86. 10.1017/s0033291717001003 . Denuwara B, Gunawardena N, Dayabandara M, Samaranayake D. Effectiveness of individual-level interventions to reduce occupational stress perceptions among teachers: a systematic review and meta-analysis. Arch Environ Occup Health. 2022;77(7):530–44. 10.1080/19338244.2021.1958738 . Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav. 1983;24(4):385–96. Park S, Joe SH, Kim SH, Han CS, Ham BJ, Ko YH. Association with socio-demographic and clinical variables in a working population. Korean J Psychosom Med. 2014;22(1). Mengel-From J, Thinggaard M, Dalgård C, Kyvik KO, Christensen K, Christiansen L. Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly. Hum Genet. 2014;133(9):1149–59. 10.1007/s00439-014-1458-9 . Parks CG, Miller DB, McCanlies EC, Cawthon RM, Andrew ME, DeRoo LA, Sandler DP. Telomere length, current perceived stress, and urinary stress hormones in women. Cancer Epidemiol Biomarkers Prev. 2009;18(2):551–60. 10.1158/1055-9965.epi-08-0614 . McFarland MJ, Taylor J, Hill TD, Friedman KL. Stressful life events in early life and leukocyte telomere length in adulthood. Adv Life Course Res. 2018;35:37–45. 10.1016/j.alcr.2017.12.002 . Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009;41(4):1149–60. 10.3758/brm.41.4.1149 . Kim AY, Kim N. Associations of perceived stress level, serum cortisol level, and telomere length of community-dwelling adults in Korea. J Korean Biol Nurs Sci. 2022;24(4):235–42. 10.7586/jkbns.2022.24.4.235 . Kim N, Sung JY, Park JY, Kong ID, Hughes TL, Kim DK. Association between internet gaming addiction and leukocyte telomere length in Korean male adolescents. Soc Sci Med. 2019;222:84–90. 10.1016/j.socscimed.2018.12.026 . Sarazine J, Heitschmidt M, Vondracek H, Sarris S, Marcinkowski N, Kleinpell R. Mindfulness workshops effects on nurses' burnout, stress, and mindfulness skills. Holist Nurs Pract. 32021;5(1):10–18. Mohan A, Sharma R, Bijlani RL. Effect of meditation on stress-induced changes in cognitive functions. J Altern Complement Med. 2011;17(3):207–12. Zorn JV, Schür RR, Boks MP, Kahn RS, Joëls M, Vinkers CH. Cortisol stress reactivity across psychiatric disorders: A systematic review and meta-analysis. Psychoneuroendocrinology. 2017;77:25–36. Faresjö Å, Theodorsson E, Chatziarzenis M, Sapouna V, Claesson HP, Koppner J, Faresjö T. Higher perceived stress but lower cortisol levels found among young Greek adults living in a stressful social environment in comparison with Swedish young adults. PLoS ONE. 2013;8(9):e73828. doi.org/10.1371/journal.pone.0073828 . Escoter-Torres L, Caratti G, Mechtidou A, Tuckermann J, Uhlenhaut NH, Vettorazzi S. Fighting the fire: mechanisms of inflammatory gene regulation by the glucocorticoid receptor. Front Immunol. 2019;10:1859. 10.3389/fimmu.2019.01859 . Lin J, Epel E. Stress and telomere shortening: Insights from cellular mechanisms. Ageing Res Rev. 2022;73:101507. 10.1016/j.arr.2021.101507 . Choi J, Fauce SR, Effros RB. Reduced telomerase activity in human T lymphocytes exposed to cortisol. Brain Behav Immun. 2008;22(4):600–5. Carlson LE, Beattie TL, Giese-Davis J, Faris P, Tamagawa R, Fick LJ, Degelman ES, Speca M. Mindfulness‐based cancer recovery and supportive‐expressive therapy maintain telomere length relative to controls in distressed breast cancer survivors. Cancer. 2015;121(3):476–84. 10.1002/cncr.29063 . Arévalo-Flechas LC, Flores BP, Wang H, Liang H, Li Y, Gelfond J, Espinoza S, Lewis SL, Musi N, Yeh CK. Stress‐Busting Program for Family Caregivers: Validation of the Spanish version using biomarkers and quality‐of‐life measures. Res Nurs Health. 2022;45(2):205–17. 10.1002/nur.22216 . Han S, Jun S, Kim N. Association of psychological stress with telomere length as a biomarker of cellular aging: a systematic review. Korean J Adult Nurs. 2022;34(5):450–65. 10.7475/kjan.2022.34.5.450 . Damjanovic AK, Yang Y, Glaser R, Kiecolt-Glaser JK, Nguyen H, Laskowski B, Zou Y, Beversdorf DQ, Weng NP. Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer’s disease patients. J Immunol. 2007;179(6):4249–54. Epel ES. Psychological and metabolic stress: a recipe for accelerated cellular aging? Hormones. 2009;8(1):7–22. Shimanoe C, Hara M, Nishida Y, Nanri H, Horita M, Yamada Y, Li YS, Kasai H, Kawai K, Higaki Y, Tanaka K. Perceived stress, depressive symptoms, and oxidative DNA damage. Psychosom Med. 2018;80(1):28–33. 10.1097/psy.0000000000000513 . Cai N, Chang S, Li Y, Li Q, Hu J, Liang J, Song L, Kretzschmar W, Gan X, Nicod J, Rivera M. Molecular signatures of major depression. Curr Biol. 2015;25(9):1146–56. 10.1016/j.cub.2015.03.008 . Verhoeven JE, Révész D, Epel ES, Lin J, Wolkowitz OM, Penninx BWJH. Depression, telomeres and mitochondrial DNA: between- and within-person associations from a 10-year longitudinal study. Mol Psychiatry. 2018;23:850–7. 10.1038/mp.2017.48 . Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9303641","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":626144941,"identity":"e14662d8-0298-4357-ba76-9e8a1e477419","order_by":0,"name":"Hwasook Cho","email":"","orcid":"","institution":"Keimyung University Dongsan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Hwasook","middleName":"","lastName":"Cho","suffix":""},{"id":626144942,"identity":"cc70aeee-0438-4ada-a0bb-ec09262e7bd6","order_by":1,"name":"Hyunwook Kang","email":"","orcid":"","institution":"Kangwon National University","correspondingAuthor":false,"prefix":"","firstName":"Hyunwook","middleName":"","lastName":"Kang","suffix":""},{"id":626144943,"identity":"97d5e9dc-d8ba-457f-a9ac-a02ed1a674f7","order_by":2,"name":"MeiLing Song","email":"","orcid":"","institution":"Daegu Health College","correspondingAuthor":false,"prefix":"","firstName":"MeiLing","middleName":"","lastName":"Song","suffix":""},{"id":626144944,"identity":"2482a037-1ca3-452c-b89d-cd8cf0385ae7","order_by":3,"name":"Nahyun Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAArElEQVRIiWNgGAWjYDCCA2wMBxgqEmA8orWcIVULA2MbKVr4bh9LPHRzXlq0wQHmhx8YztwjrEXyXNqBw7nbcnI3HGAzlmC4UUxYi8EZ9gaglgqgFgYzBoYPCQR1QLXMAWlh/0asFjagwxpADuMB2nKDCC2SZ9gSDuccS8udeZinWCIBHtp4AN8ZNuPPOTXJuX3H2zd++HCMCC0IwAzEJGkYBaNgFIyCUYAbAAAcaUH+u6m0WwAAAABJRU5ErkJggg==","orcid":"","institution":"Keimyung University","correspondingAuthor":true,"prefix":"","firstName":"Nahyun","middleName":"","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2026-04-02 13:11:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9303641/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9303641/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107619762,"identity":"4f207b65-5525-4ad9-b517-b5bbd859eb30","added_by":"auto","created_at":"2026-04-23 09:32:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":95598,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic diagram of the mechanism summarizing the association of psychological stress and cellular aging. Prolonged-excessive psychological stress causes allostatic overload, including dysregulation of ANS and HPA axis. Changes in these two main systems contribute to the production of inflammatory cytokines and ROS accumulation. These allostatic overloads resulted in genetic instabilities and subsequently cellular aging. ANS, autonomic nervous system; HPA, hypothalamic pituitary adrenal; ROS, reactive oxygen species.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9303641/v1/c1a25607dd508472ffe80110.png"},{"id":107619763,"identity":"f6349044-b033-4997-a46a-e42fa345c201","added_by":"auto","created_at":"2026-04-23 09:32:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":34046,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram depicting selection process for study participants\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9303641/v1/1969bcb1906280f1404f143b.png"},{"id":107706778,"identity":"3a37a064-ca2a-479a-a8d9-135527aefe5f","added_by":"auto","created_at":"2026-04-24 09:18:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":37945,"visible":true,"origin":"","legend":"\u003cp\u003eA. Within group pre-post changes of leukocyte telomere length (*p\u0026lt;.05)\u003c/p\u003e\n\u003cp\u003eB. Between group pre-post changes of leukocyte telomere length (*p\u0026lt;.05)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9303641/v1/3df8755cd5591476aa85bb95.png"},{"id":107869169,"identity":"5f0da9a4-dc42-4b76-a1a5-701dcdbcfa63","added_by":"auto","created_at":"2026-04-27 07:36:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":530593,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9303641/v1/410ff491-9459-48af-8c88-d0d988b801da.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Effect of the Integrated Stress Response Reduction Intervention on Cellular Aging in Middle-aged Nurses: A Pilot Study","fulltext":[{"header":"Background","content":"\u003cp\u003eNurses constitute a major workforce in healthcare systems worldwide. Although they deliver essential care across diverse clinical settings, nursing work environments are widely recognized as highly stressful and are associated with adverse health outcomes among nurses, ultimately threatening the quality of patient care [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. International reports consistently identify nursing as one of the most stressful occupations, characterized by high emotional demands and sustained workload pressure [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrimary sources of occupational stress for nurses include caring responsibilities for patients and their families, interpersonal conflicts with colleagues, and excessive workload demands [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Additionally, organizational and environmental factors\u0026mdash;such as long working hours, shift work, insufficient compensation for effort, and frequent exposure to emotionally charged patient interactions\u0026mdash;further exacerbate stress in this profession [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Prolonged exposure to such stressors has been identified as a major determinant of both physical and psychological health deterioration.\u003c/p\u003e \u003cp\u003eRecent evidence indicates that psychological stress is closely associated with cellular and biological aging processes and age-related diseases [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In response to stressors, the autonomic nervous system (ANS) and the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis serve as primary physiological pathways that regulate adaptive stress responses. However, chronic or repeated stress exposure can lead to cumulative physiological burden, commonly referred to as allostatic load, thereby increasing vulnerability to disease [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAllostatic load represents a state of physiological dysregulation resulting from repeated or prolonged stress-induced \u0026ldquo;wear and tear\u0026rdquo; on regulatory systems [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Persistent allostatic load is characterized by dysregulation of the ANS and HPA axis, leading to excessive secretion of catecholamines, glucocorticoids, pro-inflammatory cytokines, and reactive oxygen species (ROS), with insufficient termination of these responses [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. These biological mediators contribute to tissue injury and cellular damage and form the mechanistic basis through which psychological stress influences the development of chronic diseases, including cardiovascular disorders [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTelomere length and mitochondrial function have emerged as key biomarkers reflecting cellular aging. Telomeres are protective nucleoprotein structures that maintain chromosomal stability, and their progressive shortening contributes to genomic instability and cellular senescence [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Shortened telomere length has been associated with inflammation, oxidative stress, impaired telomerase activity, and repeated cell division [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Mitochondrial DNA copy number (mtDNAcn), an index of mitochondrial biogenesis and function, is considered a reliable biomarker of mitochondrial health [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe interaction between telomere dynamics and mitochondrial function plays a critical role in cellular aging. Telomere dysfunction impairs mitochondrial biogenesis and energy production and increases ROS generation, thereby accelerating cellular damage [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Psychological stress has been shown to influence both telomeres and mitochondria through shared biological pathways involving inflammation and oxidative stress [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBased on the evidence, the overall scheme of the mechanism by which psychological stress can contribute cellular aging is summarized as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGiven these mechanisms, effective stress management interventions that target physiological stress-response pathways are essential for nurses. Numerous non-pharmacological interventions\u0026mdash;such as relaxation therapy, mindfulness-based practices, and structured physical activity\u0026mdash;aim to restore autonomic balance [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, most previous studies have relied primarily on patient-reported outcomes, with limited assessment of physiological or cellular aging markers [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHeart rate variability (HRV) biofeedback training has demonstrated efficacy in improving both physiological and psychological outcomes by regulating ANS activity [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Also, a meta-analysis reported that cognitive behavioral therapy combined with relaxation therapy was more effective than cognitive behavioral therapy alone or relaxation therapy in reducing occupational stress among teachers [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. On the basis of this evidence, the integrated stress response reduction intervention (\u003cem\u003ei\u003c/em\u003eSRI) was developed to restore autonomic balance and potentially mitigate stress-induced cellular aging.\u003c/p\u003e \u003cp\u003eThis study aimed to examine the effects of the 12-week ISRI intervention in middle-aged nurses. To our knowledge, few studies have investigated interventions targeting stress-related mechanisms at the cellular level, as well as associated biochemical markers.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis study employed a non-randomized controlled pilot study to examine the psychological and physiological effects of the \u003cem\u003ei\u003c/em\u003eSRI among middle-aged nurses.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy setting and participants\u003c/h3\u003e\n\u003cp\u003eAmong three tertiary hospitals of similar size and organizational characteristics located in a metropolitan city, two hospitals were randomly selected using a coin-toss method. After obtaining approval from the nursing department directors at both hospitals, a second independent coin toss conducted by a third party not involved in the study was used to allocate one hospital to the intervention group and the other to the control group.\u003c/p\u003e \u003cp\u003eUsing a convenience sampling approach, nurses working at the participating hospitals were invited to enroll. Inclusion criteria were nurses who (1) were aged 45\u0026ndash;60 years, (2) had a Perceived Stress Scale (PSS) score greater than 16\u0026mdash;based on evidence indicating a mean PSS score of 16.1 in the Korean general population [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u0026mdash;and (3) had not participated in any formal stress-relief intervention within the previous three months. Exclusion criteria included nurses (1) with central or peripheral nervous system disorders or neuropsychiatric conditions that could affect ANS, (2) who had been diagnosed with a psychiatric disorder or were receiving related pharmacological treatment, and (3) who were taking sleep medication for a diagnosed sleep disorder.\u003c/p\u003e \u003cp\u003eThe age range was restricted because telomere length and mtDNAcn\u0026mdash;both key biomarkers of cellular aging\u0026mdash;are strongly associated with chronological age. These indicators typically decline with advancing age, and prior studies suggest that the rate of decline becomes more pronounced beginning in midlife [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In addition, exposure to stressful life events during childhood has been associated with shorter telomere length; however, evidence suggests that the influence of early-life stress on telomere length is no longer detectable after approximately age 45 [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eSample size calculation\u003c/h3\u003e\n\u003cp\u003eSample size was calculated using the G*Power software version 3.1.9.6 [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Based on a two-tailed independent t-test with an effect size of 0.80, a significance level of 0.05, and statistical power of 0.80, a minimum of 26 participants per group was required. Allowing for a potential attrition rate of 15%, a total sample size of at least 60 participants was determined.\u003c/p\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cp\u003eThe \u003cem\u003ei\u003c/em\u003eSRI was developed following a comprehensive review of the literature on stress-reduction interventions and biofeedback training. The intervention was designed to mitigate physiological stress responses that underlie stress-related cellular aging mechanisms.\u003c/p\u003e \u003cp\u003eContent validity of the initial program was evaluated by an expert panel consisting of two nursing professors with expertise in autonomic balance\u0026ndash;based interventions, two nursing professors specializing in intervention research, and one clinical public health nurse. Based on feedback from the expert panel, the intervention content and delivery methods were refined. The revised program was subsequently pilot-tested with six clinical nurses, leading to further simplification of weekly themes and clarification of intervention procedures.\u003c/p\u003e \u003cp\u003eThe \u003cem\u003ei\u003c/em\u003eSRI is a multicomponent, group-based intervention comprising cognitive\u0026ndash;behavioral education, relaxation therapy, mindfulness practice, and individualized heart rate variability biofeedback training. Excluding one week each for pre- and post-intervention assessments, the intervention was delivered over a 12-week period. The principal investigator conducted weekly 60-minute group education sessions focusing on stress mechanisms, ANS regulation, lifestyle modification, and coping strategies, including physical activity and relaxation techniques.\u003c/p\u003e \u003cp\u003eTo enhance adherence, individual telephone counseling sessions lasting 5\u0026ndash;10 minutes were conducted twice weekly. Participants recorded daily stress-management practices in logs provided at the beginning of the intervention. In the seventh week, participants\u0026rsquo; logs were reviewed, and experiences were shared during the group session. A participant demonstrating the greatest improvement in stress management was identified and received a small monetary incentive.\u003c/p\u003e \u003cp\u003eWeekly individualized biofeedback training commenced in the second intervention week. Initial respiration rate was set at 10 breaths per minute, after which individualized respiration rates producing optimal autonomic responses were determined and maintained throughout the intervention period. Each biofeedback session lasted 20 minutes and was administered once weekly using a biofeedback device (ProComp Infiniti; Thought Technology Ltd., Quebec, Canada) in a controlled environment with minimal visual and auditory stimulation.\u003c/p\u003e \u003cp\u003eIntervention fidelity was ensured through standardized training of research personnel, use of a detailed intervention manual, and monitoring adherence using session checklists. Participant adherence was also evaluated through regular review of daily practice logs.\u003c/p\u003e\n\u003ch3\u003eControl group\u003c/h3\u003e\n\u003cp\u003eParticipants in the control group received a single 30-minute group education session on general stress management following completion of baseline assessments. In addition, participants were provided with a wearable activity-tracking device to encourage and monitor daily physical activity.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData collection procedure\u003c/h2\u003e \u003cp\u003e Pre-intervention assessments were initiated after the principal investigator obtained participants\u0026rsquo; signed and dated informed consent forms. Upon arrival at the data collection site, participants rested for 30 minutes before a registered nurse, who was a member of the research team, administered self-report questionnaires and collected venous blood samples for biochemical analyses and DNA extraction.\u003c/p\u003e \u003cp\u003ePost-intervention assessments were conducted 12 weeks after baseline, following the same procedures used for pre-intervention data collection. Participants in both the intervention and control groups, as well as research team members responsible for data collection, were blinded to group allocation. The principal investigator delivered the intervention but did not participate in data collection to minimize potential bias that could influence study outcomes.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMeasures\u003c/h3\u003e\n\u003cp\u003e \u003cb\u003ePerceived psychological stress.\u003c/b\u003e Perceived psychological stress was measured using the Korean version of the Perceived Stress Scale (PSS), which was originally developed by Cohen et al. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] and later validated in Korean populations [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The PSS consists of 10 items rated on a Likert scale, with total scores ranging from 0 to 40, where higher scores indicate higher levels of perceived stress. In the original development study, Cronbach\u0026rsquo;s α ranged from 0.84 to 0.86, and a reliability coefficient of 0.81 was reported in a previous study involving Korean adults [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cb\u003eBiochemical markers.\u003c/b\u003e Biochemical markers included serum cortisol, interleukin-6 (IL-6), and superoxide dismutase (SOD). Serum cortisol levels were measured using venous blood samples. To account for diurnal variation in cortisol secretion, all blood samples were collected between 8:00 and 10:00 a.m. The reference range for serum cortisol is 3.7\u0026ndash;19.4 \u0026micro;g/dL for samples collected between 6:00 and 10:00 a.m.\u003c/p\u003e \u003cp\u003eSOD and IL-6 concentrations were assessed using 3 mL of venous blood drawn from the antecubital vein after a minimum of 12 hours of fasting. Blood samples were centrifuged at 3,000 rpm for 10 minutes at 4\u0026deg;C and subsequently analyzed at Seoul Clinical Laboratories.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCellular aging markers.\u003c/b\u003e Leukocyte telomere length (LTL) and mtDNAcn are commonly used as biomarkers for assessing biological or cellular aging. Because white blood cells (leukocytes) are easily obtained from peripheral blood, sufficient amounts of DNA for such measurements can be extracted from them. Thus, genomic DNA was extracted from the buffy coat of 1 mL of whole blood collected on the same day using a DNA isolation kit (QIAamp DNA Blood Midi Kit; Qiagen, Hilden, Germany). The extracted DNA was aliquoted into 1.5-mL microcentrifuge tubes and stored at \u0026minus;\u0026thinsp;24\u0026deg;C until analysis.\u003c/p\u003e \u003cp\u003eTo measure LTL and mtDNAcn, quantitative real-time polymerase chain reaction (qRT-PCR) was performed using a commercial assay kit (Absolute Human Telomere Length Quantification qPCR Assay Kit; ScienCell Research Laboratories, Carlsbad, CA, USA). LTL and mtDNAcn were calculated from the obtained quantification cycle (Cq) values. The specificity of qRT-PCR amplification was verified by melt-curve analysis. All measurements were performed in triplicate as previously described [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eEthical considerations\u003c/h3\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board of K University prior to data collection (IRB No. 40525-202212-BR-085-06). All potential participants received detailed information regarding the study\u0026rsquo;s purpose, procedures, duration, eligibility criteria, potential benefits, confidentiality measures, and incentives. Written informed consent was obtained from all participants who voluntarily agreed to participate.\u003c/p\u003e \u003cp\u003eParticipants were informed that they could withdraw from the study at any time without penalty and that their anonymity would be strictly protected. Access to personal information was restricted to the principal investigator and authorized research personnel only, and all collected data were securely disposed of upon completion of the study.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eParticipant characteristics and homogeneity testing\u003c/h2\u003e \u003cp\u003eA total of 129 nurses were assessed for eligibility, of whom 66 were excluded based on the inclusion and exclusion criteria. During the 12-week intervention period, three participants withdrew from the study (one due to nonattendance and two due to refusal to complete post-intervention assessments). Data from 60 participants were included in the final analysis, with 31 nurses in the intervention group and 29 in the control group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAll participants in both the intervention and control groups were women. The mean age of participants was 50.2 years in the intervention group and 53.0 years in the control group. More than half of the participants held a master\u0026rsquo;s degree or higher. Mean clinical experience was 340.3 months for the intervention group and 375.9 months for the control group. Significant baseline differences were observed between the two groups in mean age, clinical experience, alcohol consumption status, and perceived current stress. No significant differences were identified for other demographic characteristics.\u003c/p\u003e \u003cp\u003eHomogeneity testing of outcome variables at baseline revealed significant between-group differences in SOD levels and LTL, whereas no significant differences were observed for other outcome measures (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics of Participants (N\u0026thinsp;=\u0026thinsp;60)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ez/t/χ\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eMean (SD) or n (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50.23 (3.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e53.00 (.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-2.93\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eEducation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCollege\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (22.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11 (37.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e.195\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge; Graduate school\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24 (77.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18 (62.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSpouse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (16.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2 (6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e.426\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26 (83.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27 (93.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eReligion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (19.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12 (41.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e3.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e.063\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25 (80.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e17 (58.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eWorking department\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWard\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12 (38.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (31.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e.445\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOperation room/Outpatient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (29.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13 (44.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdministration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (32.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7 (24.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical experience (month)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e340.32 (47.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e375.97 (51.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-2.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eShift work\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21 (67.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20 (69.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e.919\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (32.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (31.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAlcohol drinking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14 (45.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e21 (72.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e4.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e.032\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17 (54.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8 (27.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eChronic disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17 (54.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18 (62.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e.570\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14 (45.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11 (37.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMenopause\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14 (45.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20 (69.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e3.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e.063\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17 (54.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (31.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCurrent stress\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (16.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13 (44.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e5.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26 (83.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16 (55.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20.48 (3.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.86 (3.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum cortisol\u003c/p\u003e \u003cp\u003e(\u0026micro;g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.77 (2.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.66 (2.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.226\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003cp\u003e(pg/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.65 (1.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.31 (0.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.30\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.762\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOD (unit)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.06 (0.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.21 (0.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-2.26\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.024\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLTL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.78 (0.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.04 (0.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-2.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMitochondria copy number\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e468.26 (154.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e461.10 (143.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.854\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cem\u003eNote.\u003c/em\u003e SD\u0026thinsp;=\u0026thinsp;standard deviation; PSS\u0026thinsp;=\u0026thinsp;Perceived Stress Scale; \u003csup\u003e*\u003c/sup\u003eMann-Whitney U test; IL-6\u0026thinsp;=\u0026thinsp;Interleukin-6; LTL= Leukocyte Telomere Length; SOD\u0026thinsp;=\u0026thinsp;Superoxide Dismutase\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u003cstrong\u003eEffects of the intervention on psychological stress\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 shows changes in PSS scores from baseline to 12 weeks. Following the 12-week \u003cem\u003ei\u003c/em\u003eSRI intervention, PSS levels decreased significantly in the intervention group, whereas no significant change was observed in the control group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEffects of the intervention on biochemical markers\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegarding biochemical outcomes, both groups demonstrated a significant increase in serum cortisol levels over time (Table 2). However, no significant between-group differences were observed for serum cortisol or IL-6 levels following the intervention. IL-6 levels showed a slight decrease in the intervention group and a slight increase in the control group, but the between-group difference was not statistically significant. Both groups exhibited significant within-group changes in SOD levels.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Changes in psychological stress, biochemical markers, cellular aging markers (N=60)\u003c/p\u003e\n\u003ctable style=\"width: 4.7e+2pt\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\"\u003e\n \u003cp\u003eIntervention (n=31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\"\u003e\n \u003cp\u003eControl (n=29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\"\u003e\n \u003cp\u003eDifference between groups\u003c/p\u003e\n \u003cp\u003ez/t (p)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003et (p)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003et (p)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePSS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20.48 (3.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17.06 (4.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.65 (.001)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18.86 (3.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17.97 (3.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.13\u003c/p\u003e\n \u003cp\u003e(.269)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-2.04\u003c/p\u003e\n \u003cp\u003e(.046)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSerum cortisol\u003c/p\u003e\n \u003cp\u003e(\u0026mu;g/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.77 (2.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.55 (2.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-1.73\u003c/p\u003e\n \u003cp\u003e(\u0026lt; .001)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.66 (2.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.28 (3.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-2.65\u003c/p\u003e\n \u003cp\u003e(.013)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-1.68\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e(.093)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eIL-6\u003c/p\u003e\n \u003cp\u003e(pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.73 (1.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.70 (1.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-3.76\u003c/p\u003e\n \u003cp\u003e(.001)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.31 (0.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.32 (0.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.06\u003c/p\u003e\n \u003cp\u003e(.952)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.12\u003c/p\u003e\n \u003cp\u003e(.907)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSOD (unit)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.06 (0.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.66 (0.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-10.43\u003c/p\u003e\n \u003cp\u003e(\u0026lt; .001)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.21 (0.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.60 (0.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-8.37\u003cbr\u003e\u0026nbsp;(\u0026lt; .001)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.96\u003c/p\u003e\n \u003cp\u003e(.005)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLTL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.78 (0.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.81 (0.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.22\u003c/p\u003e\n \u003cp\u003e(.831)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.04 (0.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.66 (0.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.58\u003c/p\u003e\n \u003cp\u003e(\u0026lt; .001)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-2.74*\u003c/p\u003e\n \u003cp\u003e(.006)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMitochondria copy number\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e468.26 (154.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e448.68 (89.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003cp\u003e(.452)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e461.10 (143.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e426.97 (103.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003cp\u003e(.355)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003cp\u003e(.745)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eNote.\u0026nbsp;\u003c/em\u003eSD = Standard deviation; PSS = Perceived Stress Scale; *Mann-Whitney U test; IL-6 = Interleukin-6; LTL= Leukocyte Telomere Length; SOD = Superoxide Dismutase\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNotably, the increase in SOD was significantly greater in the intervention group than in the control group, indicating a favorable effect of the intervention on antioxidant status.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEffects of the intervention on cellular aging markers\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWith respect to cellular aging indicators, LTL showed a slight, non-significant increase in the intervention group, whereas a significant decrease was observed in the control group (Figure 3A, 3B). The between-group difference in LTL change was statistically significant.\u003c/p\u003e\n\u003cp\u003eIn contrast, no significant within-group or between-group differences were identified in mtDNAcn following the intervention period.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study examined the effects of a 12-week \u003cem\u003ei\u003c/em\u003eSRI on psychological stress, physiological responses, and cellular aging biomarkers among middle-aged nurses. The findings indicate that the \u003cem\u003ei\u003c/em\u003eSRI was effective in reducing perceived stress levels and improving specific biochemical and cellular aging indicators, supporting the potential of mechanism-based stress management interventions in nursing populations.\u003c/p\u003e \u003cp\u003eFollowing the intervention, perceived stress levels in the intervention group decreased significantly. However, post-intervention stress levels remained higher than those reported in the Korean general population [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This finding is consistent with previous studies demonstrating that although mindfulness- or relaxation-based interventions can significantly reduce perceived stress among nurses, stress levels often remain elevated due to persistent occupational demands [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. These results underscore the chronic and structural nature of occupational stress in nursing and highlight the need for sustained or intensified interventions, as well as organizational-level strategies to reduce stressors in the work environment.\u003c/p\u003e \u003cp\u003eIn contrast to studies reporting significant reductions in serum cortisol following meditation or relaxation interventions, the present study did not observe significant between-group differences in cortisol levels [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. This discrepancy may reflect the complex relationship between cortisol secretion and psychological stress, as cortisol reactivity is influenced by multiple factors including sex, duration of stress exposure, symptom severity, and circadian rhythm [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Given that all participants in this study were women, future investigations incorporating more diverse populations and longer follow-up periods may be required to elucidate intervention-related changes in cortisol dynamics.\u003c/p\u003e \u003cp\u003eAlthough no significant differences were observed in IL-6 levels, SOD levels increased significantly in the intervention group compared with the control group. Psychological stress activates the sympathetic nervous system and HPA axis, leading to increased allostatic load and enhanced secretion of inflammatory cytokines and reactive oxygen species [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Elevated oxidative stress is a key contributor to cellular damage and aging [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The significant increase in SOD observed in the intervention group suggests that the \u003cem\u003ei\u003c/em\u003eSRI may attenuate oxidative stress by restoring autonomic balance and reducing excessive physiological stress responses.\u003c/p\u003e \u003cp\u003eA primary objective of this study was to determine whether the \u003cem\u003ei\u003c/em\u003eSRI could influence cellular aging markers associated with psychological stress. Notably, LTL increased slightly in the intervention group while significantly decreasing in the control group, resulting in a significant between-group difference. This finding aligns with previous evidence indicating that stress-reduction interventions, including mindfulness-based approaches, can slow telomere shortening or enhance telomere maintenance mechanisms [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Elevated psychological stress has been consistently associated with shorter telomere length, and both subjective and biological stress measures appear to exert comparable effects on telomere dynamics [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe underlying mechanism is thought to involve stress-induced activation of inflammatory and oxidative pathways, which accelerate telomere attrition beyond that attributable to chronological aging alone [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. The \u003cem\u003ei\u003c/em\u003eSRI may interrupt this cascade and contribute to the preservation or restoration of telomere length. These findings support the conceptual framework that intervention strategies targeting stress-response mechanisms can exert measurable effects at the cellular level.\u003c/p\u003e \u003cp\u003eStress, telomere dynamics, and mitochondrial function are known to influence one another [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. However, no significant changes were observed in mtDNAcn. Telomere function and mitochondrial health are closely interconnected, and chronic stress is known to disrupt both through shared biological pathways [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, evidence suggests that telomere shortening may occur earlier or recover more rapidly than alterations in mitochondrial markers, which may require prolonged or sustained intervention to demonstrate measurable change [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. The absence of mtDNAcn change in the present study may reflect a temporal lag between improvements in telomere maintenance and mitochondrial adaptation, indicating the need for longer follow-up periods or repeated intervention exposure.\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eThis study represents, to our knowledge, the first investigation to demonstrate that a stress management intervention grounded in physiological stress mechanisms can influence cellular aging biomarkers in nurses. By integrating autonomic regulation, cognitive\u0026ndash;behavioral strategies, and biofeedback training, the \u003cem\u003ei\u003c/em\u003eSRI provides a comprehensive approach to stress reduction that extends beyond subjective outcomes to include biochemical and cellular indicators.\u003c/p\u003e \u003cp\u003eNevertheless, several limitations should be considered. First, the use of convenience sampling may introduce selection bias, potentially favoring participants who were more motivated or receptive to stress management. However, as most primary outcomes were objective physiological measures, the influence of self-selection bias is likely limited. Second, the study sample consisted exclusively of middle-aged nurses, many of whom were not engaged in rotating shift work. Therefore, the findings may not be generalizable to younger nurses or those working irregular shifts, who often experience higher levels of occupational stress [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Third, because this study was a pilot study with a small sample size and employed a non-randomized controlled trial design, generalizability of the findings is limited.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eImplications for future research and practice\u003c/h2\u003e \u003cp\u003eFuture studies employing longitudinal and randomized controlled trial is warranted to clarify the causal relationship between stress reduction interventions and cellular aging trajectories. Extending the intervention duration or incorporating booster sessions may help determine whether sustained improvements in mitochondrial function can be achieved. Additionally, examining the effectiveness of the \u003cem\u003ei\u003c/em\u003eSRI in younger nurses, shift workers, or individuals with chronic stress-related conditions would further enhance its applicability.\u003c/p\u003e \u003cp\u003eFrom a practice perspective, the demonstrated benefits of the \u003cem\u003ei\u003c/em\u003eSRI suggest that healthcare organizations should consider implementing structured, evidence-based stress management programs as part of occupational health strategies. Although biofeedback-based interventions require initial investment in equipment, training, and time allocation, their potential to mitigate stress-related health deterioration among nurses may justify institutional support, particularly when integrated into flexible or technology-assisted delivery models.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe \u003cem\u003ei\u003c/em\u003eSRI was significantly effective in reducing perceived stress levels and alleviating stress responses. These findings are significant in that the non-pharmacological \u003cem\u003ei\u003c/em\u003eSRI, which targets stress-related mechanisms, successfully improved antioxidant capacity and cellular aging markers, as well as perceived psychological stress. Further research should be conducted among younger nurses working three-shift schedules and providing direct patient care. Examination of the long-term effects of the \u003cem\u003ei\u003c/em\u003eSRI may reveal sustained reductions in stress responses and clearer evidence of its efficacy on cellular aging markers.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n \u003cli\u003eANS: Autonomic Nervous System\u003c/li\u003e\n \u003cli\u003eHPA: Hypothalamic-Pituitary-Adrenal\u003c/li\u003e\n \u003cli\u003eHRV: Heart rate variability\u003c/li\u003e\n \u003cli\u003eIL-6: Interleukin-6\u003c/li\u003e\n \u003cli\u003e\u003cem\u003ei\u003c/em\u003eSRI: Integrated Stress Response Reduction Intervention\u003c/li\u003e\n \u003cli\u003eLTL: Leukocyte Telomere Length\u003c/li\u003e\n \u003cli\u003emtDNAcn: Mitochondrial DNA Copy Number\u003c/li\u003e\n \u003cli\u003ePSS: Perceived Stress Scale\u003c/li\u003e\n \u003cli\u003eSOD: Superoxide Dismutase\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board of K University prior to data collection (IRB No. 40525-202212-BR-085-06).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analysed during the current study are not publicly available due to the protection of participants\u0026rsquo; privacy but are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Research Foundation of Korea (grant number: 2020R1A2C1006590). The funding body had no role in the study design, data collection, analysis, interpretation, manuscript writing, or decision to submit the paper for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization; NK, Data curation; HC, NK, Formal analysis; HC, MS,\u0026nbsp;Investigation; NK, HC, HK Methodology; HC, NK, Project administration; HC, NK, Resources; HK, NK, Supervision; NK, Validation; HK, MS, NK, Visualization; HK, MS, Roles/Writing - original draft; HC, HK, Writing - review \u0026amp; editing: HK, NK.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEnglish language editing was assisted by an AI-based tool (ChatGPT, OpenAI). The final manuscript was carefully reviewed and approved by the authors. \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKhamisa N, Oldenburg B, Peltzer K, Ilic D. Work-related stress, burnout, job satisfaction and general health of nurses. Int J Environ Res Public Health. 2015;12(1):652\u0026ndash;66. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/ijerph120100652\u003c/span\u003e\u003cspan address=\"10.3390/ijerph120100652\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBabapour AR, Gahassab-Mozaffari N, Fathnezhad-Kazemi A. Nurses\u0026rsquo; job stress and its impact on quality of life and caring behaviors: a cross-sectional study. 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Mol Psychiatry. 2018;23:850\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/mp.2017.48\u003c/span\u003e\u003cspan address=\"10.1038/mp.2017.48\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nursing","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurs","sideBox":"Learn more about [BMC Nursing](http://bmcnurs.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurs/default.aspx","title":"BMC Nursing","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"biofeedback, cellular senescence, mitochondria, nurses, psychological stress, telomere, non-randomized controlled trial","lastPublishedDoi":"10.21203/rs.3.rs-9303641/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9303641/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNurses experience persistently high levels of occupational stress, which negatively affects their physical and psychological health and compromises the quality of patient care. Chronic psychological stress is closely linked to physiological dysregulation and cellular aging processes through stress-response pathways. However, limited evidence exists regarding whether stress management interventions targeting these mechanisms can influence cellular aging biomarkers in nurses. This study examined the effects of an integrated stress response reduction intervention (\u003cem\u003ei\u003c/em\u003eSRI) on cellular aging among middle-aged nurses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA non-randomized controlled pilot study was conducted with 60 nurses aged 45–60 years recruited from two tertiary hospitals. Participants were allocated to either an intervention group (n = 31) or a control group (n = 29). The 12-week ISRI comprised biofeedback training, group-based cognitive–behavioral education, mindfulness and relaxation practices, and structured physical exercise. Outcomes included perceived psychological stress, biochemical markers associated with the mechanisms through which psychological stress contributes to cellular aging (serum cortisol, interleukin-6, and superoxide dismutase), and cellular aging indicators (leukocyte telomere length and mitochondrial DNA copy number). Assessments were performed at baseline and post-intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePerceived stress levels significantly decreased in the intervention group following the \u003cem\u003ei\u003c/em\u003eSRI, while remaining unchanged in the control group. Although no significant between-group differences were observed in serum cortisol or interleukin-6 levels, superoxide dismutase levels increased significantly in the intervention group compared with the control group. With respect to cellular aging markers, leukocyte telomere length increased slightly in the intervention group but significantly decreased in the control group, resulting in a significant between-group difference. No significant changes were observed in mitochondrial DNA copy number.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe \u003cem\u003ei\u003c/em\u003eSRI was effective in reducing perceived stress and improving antioxidant activity while attenuating telomere shortening among middle-aged nurses. These findings suggest that stress management interventions grounded in physiological stress-response mechanisms may exert beneficial effects extending to cellular aging processes. Incorporating mechanism-based, multicomponent stress reduction programs into occupational health strategies may enhance nurse well-being and long-term health outcomes. Given the demonstrated effectiveness of the \u003cem\u003ei\u003c/em\u003eSRI, administrators should consider integrating regular, evidence-based stress management programs into organizational support systems to promote nurse well-being and sustainable workforce health.\u003c/p\u003e","manuscriptTitle":"The Effect of the Integrated Stress Response Reduction Intervention on Cellular Aging in Middle-aged Nurses: A Pilot Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-23 09:32:02","doi":"10.21203/rs.3.rs-9303641/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-20T09:05:46+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"241486956266281744862381670664897549628","date":"2026-04-17T02:00:08+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-16T18:09:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-16T15:30:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"33938826646881937825124460519459449538","date":"2026-04-16T15:17:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"64593313356971424565117702255149861074","date":"2026-04-16T05:58:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-15T20:29:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"208410551588784540666682772990044292697","date":"2026-04-15T20:22:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-15T20:17:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"164662404218960413914842582069710028745","date":"2026-04-15T18:09:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294677581545063323951296777849250373464","date":"2026-04-15T16:52:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-15T15:52:05+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-07T12:18:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-07T10:02:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-07T10:01:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nursing","date":"2026-04-02T12:58:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nursing","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurs","sideBox":"Learn more about [BMC Nursing](http://bmcnurs.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurs/default.aspx","title":"BMC Nursing","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d55a3a1f-de0f-480c-b293-af966a5d90fe","owner":[],"postedDate":"April 23rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-19T12:09:44+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-23 09:32:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9303641","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9303641","identity":"rs-9303641","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}