Abstract
BACKGROUND: Work-related stress is a well-established contributor to mental health decline, particularly in the context of burnout, a state of prolonged exhaustion. Epigenetic clocks, which estimate biological age based on DNA methylation (DNAm) patterns, have been proposed as potential biomarkers of chronic stress and its impact on biological aging and health. However, their role in mediating the relationship between work-related stress, physiological stress markers, and burnout remains unclear. METHODS: Here, we analyzed DNAm data from 296 employed individuals (n(female) = 202; M(age) = 45.4; SD(age) = 11.3; range(age) = 19.5-67.1) from the longitudinally assessed cohort of the Dresden Burnout Study to investigate whether epigenetic aging mediates the relationship between work-related stress (effort-reward imbalance), hair glucocorticoids (cortisol, cortisone), and burnout symptoms. We examined four epigenetic clocks (DNAm Skin&Blood Age, DNAm PhenoAge, DNAm GrimAge, and DNAm GrimAge2) at baseline and follow-up (one year later). Additional mediation analyses were conducted for depressive symptoms to distinguish their potential effects from those specifically associated with burnout symptoms. RESULTS: As expected, work-related stress at baseline significantly predicted burnout (β = .47, p < .001) and depressive symptoms (β = .32, p < .001) at follow-up. However, epigenetic aging did not mediate these relationships, neither cross-sectionally (indirect effects of epigenetic age acceleration [EAA]: ß(burnout) = [-.0008, -.00001]) nor longitudinally (indirect effects of changes in raw clock estimates: ß(burnout) = [-.002, .007]). Furthermore, work-related stress and hair glucocorticoids were not significantly associated with any epigenetic age markers (all p values > .117), and both EAA and changes in epigenetic aging over time were unrelated to burnout or depressive symptoms (all p values > .190). Sensitivity analyses adjusting for blood cell composition and technical variance confirmed these findings. CONCLUSIONS: Consequently, our results do not support the hypothesis that epigenetic aging serves as a biological mechanism linking work-related stress or biological stress markers to burnout symptoms. While work-related stress significantly predicts burnout and depressive symptoms, its association does not appear to be driven by epigenetic aging pathways in a low to moderately burdened population. These findings underscore the need for longer follow-up studies to explore alternative biological and psychosocial pathways that shape the long-term consequences of work-related stress on mental health.