Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus

Abstract

To investigate whether dramatically waned dentate neurogenesis during aging is linked to diminution in neural stem/progenitor cell (NSC) number, we counted cells immunopositive for Sox-2 (a putative marker of NSCs) in the subgranular zone (SGZ) of young, middle-aged and aged F344 rats. The young SGZ comprised ~50,000 Sox-2 + cells and this amount did not diminish with aging. Quantity of GFAP + cells and vimentin + radial glia also remained stable during aging in this region. Besides, in all age groups, analogous fractions of Sox-2 + cells expressed GFAP (astrocytes/NSCs), NG-2 (oligodendrocyte-progenitors/NSCs), vimentin (radial glia), S-100β (astrocytes) and doublecortin (new neurons). Nevertheless, analyses of Sox-2 + cells with proliferative markers insinuated an increased quiescence of NSCs with aging. Moreover, the volume of rat-endothelial-cell-antigen-1 + capillaries (vascular-niches) within the SGZ exhibited an age-related decline, resulting in an increased expanse between NSCs and capillaries. Thus, decreased dentate neurogenesis during aging is not attributable to altered number or phenotype of NSCs. Instead, it appears to be an outcome of increased quiescence of NSCs due to changes in NSC milieu.

Epigenetic regulation of aging stem cells

“…Studies examining NSC number both by long-term label retention assays as well as by staining for putative stem/progenitor markers indicate decreases in the neural stem/progenitor pools in the adult SVZ of rodents (Maslov et al, 2004;Molofsky et al, 2006;Ahlenius et al, 2009). In contrast, in the adult hippocampus of rats, the numbers of neural stem and progenitors, defined by expression of markers SOX2 and GFAP, have been reported to remain relatively constant with age (Hattiangady and Shetty, 2008). However, recent studies in mice using more specific stem cell markers, such as HES5, report a slight decrease in hippocampal NSC numbers with age (Lugert et al, 2010).…”

“…In the nervous system, the ability of NSCs to produce new neurons (neurogenesis) declines with age (Kuhn et al, 1996;Tropepe et al, 1997;Bondolfi et al, 2004;Enwere et al, 2004;Hattiangady and Shetty, 2008). Instead, aging is accompanied by increased production of astrocytes and elevated expression of astrocytespecific genes in the brain, indicating a loss of multipotentiality of stem/progenitor cells and astroglial lineage skewing (Peinado et al, 1998;Lee et al, 2000;Bondolfi et al, 2004).…”

Neural stem cell- and neurogenesis-related gene expression profiles in the young and aged dentate gyrus

“…Multiple studies have shown that age-related decrease in neurogenesis is a result of proliferation of far fewer NSCs in the SGZ (Hattiangady and Shetty 2008;Kuhn et al 1996;Nacher et al 2003;Olariu et al 2007;Rao et al 2005Rao et al , 2006. Examination of the putative NSCs using markers such as Sox-2, GFAP, and vimentin over the course of aging has revealed no changes in NSC numbers in the rodent SGZ with aging (Aizawa et al 2011; however, see Encinas et al 2011;Hattiangady and Shetty 2008).…”

“…Examination of the putative NSCs using markers such as Sox-2, GFAP, and vimentin over the course of aging has revealed no changes in NSC numbers in the rodent SGZ with aging (Aizawa et al 2011; however, see Encinas et al 2011;Hattiangady and Shetty 2008). Interestingly, a combined analysis using a birth-dating marker 5′-bromodeoxyuridine and an endogenous proliferation marker Ki-67 has suggested an increased quiescence of NSCs in the aged rat's SGZ (Hattiangady and Shetty 2008).…”

“…Examination of the putative NSCs using markers such as Sox-2, GFAP, and vimentin over the course of aging has revealed no changes in NSC numbers in the rodent SGZ with aging (Aizawa et al 2011; however, see Encinas et al 2011;Hattiangady and Shetty 2008). Interestingly, a combined analysis using a birth-dating marker 5′-bromodeoxyuridine and an endogenous proliferation marker Ki-67 has suggested an increased quiescence of NSCs in the aged rat's SGZ (Hattiangady and Shetty 2008). Additional studies suggest that changes in the milieu, particularly declines in the concentrations of multiple neurotrophic factors that are mitogenic to NSCs in the hippocampus and changes in neurotrophic factor receptors and stem cell niche, likely underlie this change (Chadashvili and Peterson 2006;Hattiangady et al 2005;Shetty et al 2005).…”