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.

p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration

“…One main feature of astrocyte SASP driving neuronal loss is the release of pro-inflammatory cytokines such as IL-6. 53 Consistent with the neurodegenerative role of these SASP cytokines, the induction of SASP in astrocytes either by Δ133p53 knockdown (Figure 3f) or by p53β overexpression (Figure 4e) leads to increased neuronal apoptosis (Figures 5a-d), while the repression of astrocyte SASP by Δ133p53 restoration (Figure 6d) leads to increased neuronal survival (Figures 6e and f). Our data suggest that IL-6 is a therapeutic target in astrocytes to prevent neurotoxicity (Figure 9b).…”

Anti-aging effects of guanosine in glial cells

“…This function may avoid excitotoxicity, whose incidence increases in age-related neurodegenerative diseases [22,34,48]. Thus, we showed that glutamate uptake activity decreased with aging and that guanosine was able to restore glutamate uptake in an agedependent manner, emerging as a promising pharmacological Fig.…”

“…Aging is a natural process that induces numerous changes in the brain functionality, including alterations in synaptic efficacy, changes in neuron-glia communication with consequent impairment in cerebral activities, and increases in reactive oxygen species (ROS) and inflammatory mediators [20][21][22]. Understanding and managing these alterations may be an important strategy to extend a healthy life span.…”

“…Thus, to study features of adult and aged brains, our group has established a routine technique for the primary culture of astrocytes obtained from non-neonatal rats, because the metabolic, oxidative, and inflammatory properties of cells derived from newborn and adult/aged animals are distinctive [21,22,28,29]. We have previously shown that this tool can be employed to study different astrocytic roles in the CNS, as the cells present classical astroglial markers, such as glial fibrillary acidic protein (GFAP), S100B, and glutamine synthetase (GS) expression and activity.…”

Cortical Astrocytes Acutely Exposed to the Monomethylarsonous Acid (MMAIII) Show Increased Pro-inflammatory Cytokines Gene Expression that is Consistent with APP and BACE-1: Over-expression

“…In this sense, it has been proposed that inflammatory responses and increased mitochondrial aerobic metabolism are interconnected in astrocytes. It has been found that the inflammatory cytokines IL-1and TNF-α stimulate astrocytic oxidative mitochondrial metabolism, leading to a decreased lactate supply to neurons [64]. In this way, arsenic may also compromise neurons' energetic metabolism through the activation of astrocytic inflammatory responses.…”