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

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.

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.

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).

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.