title: Astrocytic metabolic and inflammatory changes as a function of age.
abstract: This study examines age-dependent metabolic-inflammatory axis in primary astrocytes isolated from brain cortices of 7-, 13-, and 18-month-old Sprague-Dawley male rats. Astrocytes showed an age-dependent increase in mitochondrial oxidative metabolism respiring on glucose and/or pyruvate substrates; this increase in mitochondrial oxidative metabolism was accompanied by increases in COX3/18SrDNA values, thus suggesting an enhanced mitochondrial biogenesis. Enhanced mitochondrial respiration in astrocytes limits the substrate supply from astrocytes to neurons; this may be viewed as an adaptive mechanism to altered cellular inflammatory-redox environment with age. These metabolic changes were associated with an age-dependent increase in hydrogen peroxide generation (largely ascribed to an enhanced expression of NOX2) and NFκB signaling in the cytosol as well as its translocation to the nucleus. Astrocytes also displayed augmented responses with age to inflammatory cytokines, IL-1β, and TNFα. Activation of NFκB signaling resulted in increased expression of nitric oxide synthase 2 (inducible nitric oxide synthase), leading to elevated nitric oxide production. IL-1β and TNFα treatment stimulated mitochondrial oxidative metabolism and mitochondrial biogenesis in astrocytes. It may be surmised that increased mitochondrial aerobic metabolism and inflammatory responses are interconnected and support the functionality switch of astrocytes, from neurotrophic to neurotoxic with age.
authors.affiliation: Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089-9121, USA.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Jiang
authors.forename: Enrique
authors.initials: E
authors.lastname: Cadenas
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D053583:Interleukin-1beta / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4
keywords: NFκB; astrocytes; cytokines; hydrogen peroxide; inflammation; mitochondria; mitochondrial biogenesis; nitric oxide