Geropotency: Increased malignant potential of aging neural progenitors

human adult gliomas increased patient age is a robust predictor of malignant clinical behavior evidenced by increased incidence, histologic grade, resistance to therapy and shortened patient survival [1]. Despite these associations, the mechanisms responsible for age-related increases in glioma malignancy are poorly understood; a deficiency compounded by the lack of informative animal models. Neural stem/progenitor (NSPCs) cells are the presumed cells of glioma origin. Using a syngeneic mouse glioma model we showed that the " age " of neural stem and progenitor cells (i.e., the age of donors from which NSPCs were isolated prior to transformation) dictated survival in same-aged hosts and differently-aged (3mo and 20mo) hosts [1]. Surprisingly, host age had no significant effect on survival [1]. After malignant transformation, aging in NSPCs translated to increased invasive potential, genomic instability, resistance to genotoxic stress (radiation and alkylating chemotherapy) and tolerance of hypoxia. These observations suggest that aging related changes in putative glioma cells of origin contribute to increased malignant potential. However, many aging associated changes observed in normal NSPCs would seem more likely to inhibit malignant potential. For example, with aging there is an overall attrition of NSPCs associated with acquisition of a senescent phenotype with decreased overall proliferation and self-renewal [2]. How then does a senescing cell population generate a more robust cancer cell? Emerging understanding of aging NSPCs suggests that mechanisms associated with aging may actually prime NSPCs for enhanced malignant potential. Conceivably, the increased genomic instability and tolerance of hypoxic stress with aging could enhance NSPC " malignant fitness " or potential [1]. In addition, although less proliferative overall, a small sub-population of aging NSPCs display an increased propensity to re-enter the cell cycle and by conferring a selection advantage could also enhance their malignant potential [3]. Presumably, after malignant transformation the age-dependent state of malignant " pre-conditioning " present in normal NSPCs translates into differential growth advantages within the brain and glioma micro-environment. Genomic insta-Editorial bility and hypoxia are speculated to be among the mechanisms fundamental for defining malignant potential and its manifestations of increased invasion, proliferation and treatment resistance. Genomic instability could drive emergence and selection of hypoxia tolerant and responsive cells in the aging brain microenvironment while activation of hypoxic responses in turn could foster acquisition of or enhancement of genomic instability. Finally, senescent and malignant states share common features of altered chromatin structure, epigenetic changes and DNA damage. Therefore, age-dependent mechanisms that …