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

Despite a growing proportion of aged individuals at risk for developing cancer in the brain, the prognosis for these conditions remains abnormally poor due to limited knowledge of underlying mechanisms and minimal treatment options. While cancer metabolism in other organs is commonly associated with upregulated glycolysis (i.e. Warburg effect) and hyperactivation of PIK3/AKT/mTOR (PAM) pathways, the unique bioenergetic demands of the central nervous system may interact with these oncogenic processes to promote tumor progression in aging. Specifically, constitutive glycolysis and PIK3/AKT/mTOR signaling in glia may be dysregulated by age-dependent alterations in neurometabolic demands, ultimately contributing to pathological processes otherwise associated with PIK3/AKT/mTOR induction (e.g. cell cycle entry, impaired autophagy, dysregulated inflammation). Although several limitations to this theoretical model exist, the consideration of aberrant PIK3/AKT/mTOR signaling in glia during aging elucidates several therapeutic opportunities for brain tumors, including non-pharmacological interventions.