Review Volume 13, Issue 1 pp 1510—1527

PAM (PIK3/AKT/mTOR) signaling in glia: potential contributions to brain tumors in aging

PAM (PIK3/AKT/mTOR) Signaling in glia during aging may contribute to glioma pathology. Astrocytes take up glucose, convert it to lactate (i.e. aerobic glycolysis) via lactate dehydrogenase (LDH) and transport it via monocarboxylate transporters (MCT) to neurons (i.e. Lactate Shuttle) where it serves as an energy substrate. These glia can alter their metabolism and also re-uptake glutamate in response to neuronal firing activity. Interestingly, the aerobic glycolysis in astrocytes is reminiscent of energy production in cancer cells, including gliomas. Furthermore, variation in metabolic activity and/or insulin stimulation in astrocytes corresponds with activation of PAM (PIK3/AKT/mTOR), a pathway linked to oncogenic processes in tumor cells (e.g. aberrant cell cycle progression, impaired autophagy, neuroinflammation). Thus, metabolic fluctuations in the central nervous system (CNS) during aging (e.g. insulin dysregulation, deficits in glucose utilization) may aberrantly potentiate PAM signaling in these glia, given their prominent role in metabolic homeostasis. In turn, this could contribute to pathogenic processes of gliomas and facilitate poor prognosis in elderly individuals. Created with <a href="http://Biorender.com" target="

Figure 1. PAM (PIK3/AKT/mTOR) Signaling in glia during aging may contribute to glioma pathology. Astrocytes take up glucose, convert it to lactate (i.e. aerobic glycolysis) via lactate dehydrogenase (LDH) and transport it via monocarboxylate transporters (MCT) to neurons (i.e. Lactate Shuttle) where it serves as an energy substrate. These glia can alter their metabolism and also re-uptake glutamate in response to neuronal firing activity. Interestingly, the aerobic glycolysis in astrocytes is reminiscent of energy production in cancer cells, including gliomas. Furthermore, variation in metabolic activity and/or insulin stimulation in astrocytes corresponds with activation of PAM (PIK3/AKT/mTOR), a pathway linked to oncogenic processes in tumor cells (e.g. aberrant cell cycle progression, impaired autophagy, neuroinflammation). Thus, metabolic fluctuations in the central nervous system (CNS) during aging (e.g. insulin dysregulation, deficits in glucose utilization) may aberrantly potentiate PAM signaling in these glia, given their prominent role in metabolic homeostasis. In turn, this could contribute to pathogenic processes of gliomas and facilitate poor prognosis in elderly individuals. Created with Biorender.com.