Abstract
Astrocytes are central to brain homeostasis, supporting neuronal metabolism, synaptic activity, and the blood-brain barrier. With aging, these glial cells undergo molecular and functional changes that weaken support functions and promote neuroinflammation, contributing to neurodegeneration. Yet the systems-level mechanisms by which astrocytes respond to aging-related stressors remain poorly defined in human models. Because aging also heightens risk for cardiovascular disease, cognitive impairment, type 2 diabetes, and systemic inflammation, clarifying shared astrocytic pathways is critical for understanding brain-body crosstalk. Using an in vitro human astrocyte model exposed to sublethal oxidative stress (10 µM H₂O₂) as a proxy for age-related cellular stress, we profiled transcriptomic changes and identified differentially expressed genes across antioxidant defenses, proteostasis, transcriptional regulation, vesicular trafficking, and inflammatory signaling. We then performed network-prioritization analyses on a curated human protein-protein interactome: one seeded with the astrocyte oxidative stress responsive genes and six with phenotype-associated gene sets (Alzheimer's disease, cardiovascular disease, cognitive impairment, type 2 diabetes, oxidative stress, and inflammation). Intersecting the top 5 % scoring genes from each run yielded a 127-gene core shared across all seven, enriched for proteostasis, DNA repair, mitochondrial regulation, and telomere and nuclear envelope maintenance. Structure-guided analyses highlighted vulnerable interfaces, including lamin A/C-lamin B1, α-actinin-filamins, 14-3-3 dimers, and aminoacyl-tRNA synthetase assemblies, where pathogenic variants are predicted to destabilize or aberrantly stabilize protein interactions. Structure-based interface predictions also highlight potential interactions between amyloid precursor protein (APP) and valosin-containing protein (VCP), and between p53 and 14-3-3ζ, potentially linking proteostasis and stress signaling. Together, these analyses identify a conserved astrocyte-centered network signature that may relate neurodegenerative and cardiovascular processes, and prioritize structurally testable candidates for biomarker and intervention hypothesis testing.