Age modulates the link between stress-related neural activity and mortality.

Stress-related neural activity (SNA), as measured by amygdala metabolism, has been linked in prior work to all-cause mortality and major adverse cardiovascular events. In this study, we sought to clarify SNA determinants and test whether age modifies its association with all-cause mortality. Using 2-[18 F]fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET), we quantified amygdala metabolism, a surrogate for SNA, in 1,336 patients (mean age 59.4 ± 15.6 years, 37.8% women). Assessing demographic and imaging confounders, associations between SNA and mortality were evaluated in a subgroup of 960 participants with a median 5-year follow-up (IQR 3-9). Higher SNA appears independently associated with greater all-cause mortality across all age groups (HR 1.45, 95% CI 1.08-1.95; p = 0.012). The association is strongest in younger, healthier individuals (HR 7.86, 95% CI 2.92-21.21; p < 0.001) and attenuates with advancing age. Mediation analysis indicates that SNA accounts for 38.2% (95% CI 15.7%-60.7%) of the age-mortality link. Here, we find that SNA is independently associated with all-cause mortality, with effect sizes that diminish with age; if confirmed, incorporating SNA into risk models alongside conventional factors may improve mortality prediction and help identify younger adults, who appear low risk by standard criteria, for closer follow-up and preventive strategies.