Clustering metabolic and behavioral risk factors for hypertension: evidence from a longitudinal cohort in western Iran.

Major depressive disorder (MDD) is a prevalent psychiatric condition characterized by persistent low mood, anxiety, anhedonia, and diminished self-worth, which collectively impair social and occupational functioning [–]. In recent years, the incidence of clinically diagnosed depression has increased among younger populations, with young adults exhibiting the highest rates across age groups [–]. Although MDD can manifest at any stage of life, onset most commonly occurs between the ages of 15 and 29 years, a critical developmental window referred to as young adulthood [, ]. Early life stress is strongly associated with increased vulnerability to psychiatric disorders, including MDD and post-traumatic stress disorder [, ]. The brain undergoes rapid structural and functional maturation from childhood through adolescence, accompanied by extensive epigenetic remodeling. These changes render the brain particularly sensitive to the long-term effects of early life stress, potentially resulting in disrupted neural connectivity and impaired cognitive and emotional regulation []. Given these vulnerabilities, early detection and intervention in young adults are essential to mitigate adverse outcomes, such as recurrent episodes, chronic symptomatology, and long-term functional impairments []. Despite the increasing clinical burden, the neurobiological mechanisms underlying MDD in young adulthood remain poorly understood, and age-specific preclinical and clinical studies are limited. Astrocytes, the most abundant glial cells in the central nervous system, play key roles in maintaining brain homeostasis, regulating neurotransmitter metabolism, and supporting synaptic plasticity [, ]. Increasing evidence implicates astrocyte dysfunction in the pathophysiology of MDD, with both structural and functional abnormalities observed in affected individuals [, ]. Notably, reductions in glial fibrillary acidic protein (GFAP)-positive astrocytes have been reported in the prefrontal cortex (PFC) of young adult patients with MDD, whereas such reductions appear less pronounced or absent in older individuals []. Consistent findings have been reported in animal models, where chronic stress reduces GFAP mRNA expression in the PFC []. In addition to astrocyte loss or marker downregulation, functional impairments, such as disrupted neurovascular coupling and altered glutamate homeostasis, have been identified in both clinical and preclinical contexts, including magnetic resonance imaging (MRI)-based studies []. These findings suggest that astrocytic dysfunction in the PFC contributes to the neurobiology of depression, particularly in young adults.