Cellular senescence changes and their association with brain structure in schizophrenia and major depressive disorder

Individuals with schizophrenia (SZ) and major depressive disorder (MDD) may experience accelerated biological aging, potentially linked to cellular senescence and the senescence-associated secretory phenotype (SASP). While the SASP index has been reported to be elevated in MDD, its status in SZ and its relationship with brain structure remain unclear. This study investigated whether the SASP index, a composite biomarker-based measure, is elevated in SZ and MDD, and examined its associations with brain-predicted age difference (brain-PAD) and regional brain morphology across SZ, MDD, and healthy controls (HCs). A total of 119 subjects (29 individuals with SZ, 40 individuals with MDD, and 50 HCs) underwent both peripheral blood collection and MRI scanning. First, across all subjects, the effects of diagnostic groups on SASP indices were assessed. Second, associations between age-adjusted SASP indices and brain-PAD were examined within each diagnostic group. Third, exploratory analyses tested associations between SASP indices and subcortical volumes as well as cortical thickness and surface area in each diagnostic group. We found a significant main effect of diagnostic group on SASP indices and significantly elevated SASP indices in both SZ and MDD. Although no significant associations were observed between SASP indices and brain-PAD in any diagnostic group, negative associations were identified in SZ between SASP indices and the surface area of the left transverse temporal gyrus and the right inferior frontal gyrus pars triangularis, regions that play pivotal roles in auditory and language processing alterations observed in SZ. These findings suggest that SASP-related processes may contribute to the neural underpinnings of SZ through localized, rather than global, alterations in brain structure.