Brain cells normally respond adaptively to oxidative stress or bioenergetic challenges, resulting from ongoing activity in neuronal circuits. During aging and in neurodegenerative disorders, these mechanisms are compromised. In fact, neurons show unique age-related changes in functions and metabolism, resulting in greater susceptibility to insults and disease. Aging affects the nervous system as well as other organs. More precisely, as the nervous system ages, neuron metabolism may change, inducing glucose hypometabolism, impaired transport of critical substrates underlying metabolism, alterations in calcium signaling, and mitochondrial dysfunction. Moreover, in neuronal aging, an accumulation of impaired and aggregated proteins in the cytoplasm and in mitochondria is observed, as the result of oxidative stress: reduced antioxidant defenses and/or increase of reactive oxygen species (ROS). These changes lead to greater vulnerability of neurons in various regions of the brain and increased susceptibility to several diseases. Specifically, the first part of the review article will focus on the major neuronal cells’ rearrangements during aging in response to changes in metabolism and oxidative stress, while the second part will cover the neurodegenerative disease areas in detail.

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Among all solid tumors, the high-grade glioma appears to be the most vascularized one. In fact, “microvascular hyperplasia” is a hallmark of GBM. An altered vascular network determines irregular blood flow, so that tumor cells spread rapidly beyond the diffusion distance of oxygen in the tissue, with the consequent formation of hypoxic or anoxic areas, where the bulk of glioblastoma stem cells (GSCs) reside. The response to this event is the induction of angiogenesis, a process mediated by hypoxia inducible factors. However, this new capillary network is not efficient in maintaining a proper oxygen supply to the tumor mass, thereby causing an oxygen gradient within the neoplastic zone. This microenvironment helps GSCs to remain in a “quiescent” state preserving their potential to proliferate and differentiate, thus protecting them by the effects of chemo- and radiotherapy. Recent evidences suggest that responses of glioblastoma to standard therapies are determined by the microenvironment of the niche, where the GSCs reside, allowing a variety of mechanisms that contribute to the chemo- and radioresistance, by preserving GSCs. It is, therefore, crucial to investigate the components/factors of the niche in order to formulate new adjuvant therapies rendering more efficiently the gold standard therapies for this neoplasm.

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