Exercise Increases Neural Stem Cell Number in a Growth Hormone-Dependent Manner, Augmenting the Regenerative Response in Aged Mice

Abstract

The exercise-induced enhancement of learning and memory, and its ability to slow age-related cognitive decline in humans led us to investigate whether running stimulates periventricular (PVR) neural stem cells (NSCs) in aging mice, thereby augmenting the regenerative capacity of the brain. To establish a benchmark of normal aging on endogenous NSCs, we harvested the PVR from serial vibratome sections through the lateral ventricles of juvenile (6-8 weeks), 6-, 12-, 18-, and 24-month-old mice, culturing the cells in the neural colony-forming cell assay. A significant decline in NSC frequency was apparent by 6 months ($40%), ultimately resulting in a $90% reduction by 24 months. Concurrent with this decline was a progressive loss in regenerative capacity, as reflected by an incomplete repopulation of neurosphere-forming cells following gamma cell irradiation-induced depletion of the PVR. However, voluntary exercise (i.e., 21 days of running) significantly increased NSC frequency in mice ! 18 months of age, augmenting the regeneration of irradiation-ablated periventricular cells and restoring NSC numbers to youthful levels. Importantly, and consistent with the demonstrated ability of growth hormone (GH) to increase NSC proliferation, and the elevated secretion of GH during exercise, exercise failed to stimulate NSCs in GH receptor-null mice. These findings now provide a novel basis for understanding the ability of exercise to delay the onset and rate of decline in neurodegenerative conditions not typically associated with the hippocampus and suggest that the GH-dependent activation of endogenous NSCs may be effective in reversing or preventing age-related neurodegeneration in humans. STEM CELLS

When stem cells grow old: phenotypes and mechanisms of stem cell aging

“…In support of a beneficial role for reduced levels of insulin and IGF-1, dampening of insulin-IGF signaling specifically in fly ISCs improves gut homeostasis and extends lifespan, whereas reduced IGF-1 levels are associated with improved HSC self-renewal (Biteau et al, 2010;Cheng et al, 2014). These results in mice and flies are seemingly in opposition to the fact that insulin, IGF-1 and growth hormone increase the number of NSCs and GSCs in aged animals (Blackmore et al, 2009;Hsu and Drummond-Barbosa, 2009;Lichtenwalner et al, 2001). One explanation is that the increase in NSCs and GSCs might come at the expense of long-term self-renewal or impact homeostatic processes that are not yet known.…”

“…Unlike other stem cells, however, the in vitro function of aged NSCs on a per-cell basis is not substantially impaired with age (Ahlenius et al, 2009), which implies that cell-extrinsic factors are largely at play. Indeed, heterochronic parabiosis (the joining of the circulatory systems of two animals of different age) and restoring the levels of IGF-1, GH, Wnt3, TGF-β or GDF11 in old mice to those found in young mice improves neurogenesis (Blackmore et al, 2009;Katsimpardi et al, 2014;Lichtenwalner et al, 2001;Okamoto et al, 2011;Pineda et al, 2013;Villeda et al, 2014). An age-dependent change in the senescence of NSCs also contributes to their declining numbers (Molofsky et al, 2006;Nishino et al, 2008) and might underlie learning and memory deficits in the elderly (Zhao et al, 2008a).…”

Microglia Modulate Hippocampal Neural Precursor Activity in Response to Exercise and Aging

“…Rodents with access to a running wheel exhibit significantly enhanced cell proliferation and neurogenesis within the SGZ, as well as improved performance in spatial memory and learning tasks (van Praag et al, 1999a,b). Importantly, voluntary exercise also counteracts the decline in NPC activity that normally occurs with aging (Blackmore et al, 2009;Jinno, 2011) and slows the associated cognitive impairment (van Praag et al, 2005;Sahay et al, 2011).…”

Cell Sorting of Neural Stem and Progenitor Cells from the Adult Mouse Subventricular Zone and Live-imaging of their Cell Cycle Dynamics

“…Most studies agree on a progressive reduction in the number of proliferating progenitor cells in the SGZ and SVZ [15][16][17][18][19][20] . The consequences are not innocuous as the age-related decline in neurogenesis in the SVZ provokes a diminution of newborn neurons in the olfactory bulbs of the aged brain, ultimately leading to impairment in olfactory discrimination in aged mice .…”