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Elevated AEG-1 levels are associated with aging and HAND in human brain.Astrocytes elevate AEG-1 in response to neuroinflammation and are critical players in HAND and the aging brain.H2O2 induces nucleolar translocation of AEG-1 in astrocytes and AEG-1 binds to Nrf-2, a master regulator of oxidative stress.AEG-1 may regulate neuroinflammation, oxidative stress, reactive astrogliosis, mitochondrial damage and ER/nucleolar stress.Future therapeutic approaches may pursue AEG-1 as a novel target for the treatment of HAND and age-related disorders.Recent attempts to analyze human immunodeficiency virus (HIV)-1-induced gene expression changes in astrocytes uncovered a multifunctional oncogene, astrocyte elevated gene-1 (AEG-1). Our previous studies revealed that AEG-1 regulates reactive astrocytes proliferation, migration and inflammation, hallmarks of aging and CNS injury. Moreover, the involvement of AEG-1 in neurodegenerative disorders, such as Huntington's disease and migraine, and its induction in the aged brain suggest a plausible role in regulating overall CNS homeostasis and aging. Therefore, it is important to investigate AEG-1 specifically in aging-associated cognitive decline. In this study, we decipher the common mechanistic links in cancer, aging and HIV-1-associated neurocognitive disorders that likely contribute to AEG-1-based regulation of astrocyte responses and function. Despite AEG-1 incorporation into HIV-1 virions and its induction by HIV-1, tumor necrosis factor-α and interleukin-1β, the specific role(s) of AEG-1 in astrocyte-driven HIV-1 neuropathogenesis are incompletely defined. We propose that AEG-1 plays a central role in a multitude of cellular stress responses involving mitochondria, endoplasmic reticulum and the nucleolus. It is thus important to further investigate AEG-1-based cellular and molecular regulation in order to successfully develop better therapeutic approaches that target AEG-1 to combat cancer, HIV-1 and aging.