Diminished salivary cortisol response to mental stress predict all-cause mortality in general population.

Objectives: To characterize individuals with a diminished salivary cortisol response to mental stress, assess its association with all-cause mortality, and quantify the mediating effects of the most relevant and modifiable factors to identify potential target for prevention.

Methods: Data from MIDUS II study with a 16-year follow-up, were used to categorize 1129 participants as responders or non-responders based on the existence of increase in salivary cortisol under mental stress. LASSO-logistics analysis identified the most relevant factors. Cox regression models and restricted cubic splines evaluated the prognostic impact. Further analyses examined the mediating effects of identified factors on prognosis.

Results: After employing Inverse Probability of Treatment Weighting to adjust for demographic differences between groups, individuals with diminished cortisol responses were found to have higher levels of depressive symptoms (p = 0.050), increased inflammation (IL-6, 2.30 [1.41, 3.79] vs. 1.96[1.33, 3.31], p = 0.011), and were less likely to regularly exercise (74.3 % vs. 79.9 %, p = 0.030). IL-6 (OR: 1.25 [1.04, 1.52]，p = 0.021) and regularly exercising (OR 0.71 [0.51, 0.97], p = 0.032) emerged as significant modifiable factors in multivariate analysis. A notable prognostic association of diminished cortisol response with all-cause mortality (HR = 1.33 [1.01-1.76], p = 0.046) was observed, consistent across various subgroups and supported by non-linear model analysis. Approximately 13 % of the mortality risk associated with diminished cortisol response was mediated by increased IL-6 levels (p = 0.043).

Conclusion: Diminished salivary cortisol response is linked to an increased risk of all-cause mortality, significantly mediated by elevated IL-6. This study offers a new perspective on prognostic prediction while highlighting potential avenues for intervention.