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Cited by 119Neurogenesis and neuroplasticity mechanismsNerve injury and regenerationNeuroinflammation and Neurodegeneration Mechanisms

Exercise increases neural stem cell number in a growth hormone-dependent manner, augmenting the regenerative response in aged mice

Blackmore, Daniel G., Golmohammadi, Mohammad G., Large, Beatrice, Waters, Michael J., Rietze, Rodney L.·2009·Stem Cells
DOI 10.1002/stem.120
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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. Disclosure of potential conflicts of interest is found at the end of this article.

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  • In specific conditions, fluoxetine or running activate not only progenitor but also stem cells, which normally are not stimulated.

    “Moreover, in specific conditions, fluoxetine or running activate not only progenitor but also stem cells, which normally are not stimulated; this fact reveals how stem cells have a long-term, hidden ability to self-renew and, more generally, that neurogenesis is subject to complex controls that may play a role in depression, such as the type of neurogenic stimulus or the state of the local niche.”

    From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as Blackmore et al., 2009

    The section on exercise-induced proliferation reports that running increased both neural stem-cell and progenitor-cell measures in mice, particularly in a rostral periventricular region. The paper does not establish that fluoxetine has the same effect, and its findings do not imply that these cells are normally never stimulated. Page numbers were not available in our copy. (LLM, conf=0.86)

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  • An increase of SVZ neurogenesis by running is observed in old mice, when voluntary running is prolonged, in mice with deletion of Btg1, or after stress induced by corticosterone infusion.

    “Yet, an increase of SVZ neurogenesis by running is observed in some conditions, namely, in old mice (Blackmore et al., 2009), or when voluntary running is prolonged (Bednarczyk et al., 2009) or in mice with deletion of Btg1, a gene maintaining quiescence of neural stem cells (Mastrorilli et al., 2017), or also after stress induced by corticosterone infusion (Lee et al., 2016).”

    From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as Blackmore et al., 2009

    The section “Physical Exercise Stimulates the Proliferation of Endogenous NSCs in Extrahippocampal Regions” reports increased periventricular neural stem-cell frequency in 12- and 18-month-old runners. It does not establish increased production of new SVZ neurons, and it reports decreased stem-cell frequency in 24-month-old runners. The other conditions in the citing sentence are attributed to other sources and are not assessed here. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In specific conditions (after stress or ablation of genes that inhibit proliferation), running activates not only progenitor but also stem cells in the dentate gyrus and SVZ.

    “Moreover, in specific conditions, such as after stress or ablation of genes that inhibit proliferation, fluoxetine (in the dentate gyrus, Micheli et al., 2018, andin the SVZ, Hitoshi et al., 2007) or running (in the dentate gyrus as well as in the SVZ; Farioli-Vecchioli et al., 2014b;Blackmore et al., 2009) activate not only progenitor but also stem cells.”

    From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as Blackmore et al., 2009

    The ‘Physical Exercise Stimulates the Proliferation of Endogenous NSCs in Extrahippocampal Regions’ section reports that running increased both neural stem cells and progenitors near the lateral ventricles, supporting the SVZ portion of the claim. This paper does not establish the dentate-gyrus result or test running after stress or ablation of proliferation-inhibiting genes; its ablation experiment used irradiation to deplete dividing cells. (LLM, conf=0.86)

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Authors
Blackmore, D. G., Golmohammadi, M. G., Large, B., Waters, M. J., & Rietze, R. L.
Affiliations
The University of Queensland (AU)
Corresponding author
Rietze, Rodney L.
ORCID
Venue
Stem Cells
Publisher
Oxford University Press (OUP)
Published
2009-05-14
Volume
27
Issue
8
Pages
2044-2052
ISSN
  • 1066-5099 (ISSN-L)
  • 1549-4918
DOI
10.1002/stem.120
OpenAlex
W1988614395
Cited by
119
References
34
Citations by year
2026: 1 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 5 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 8 · 2016: 10 · 2015: 5 · 2014: 6 · 2013: 13 · 2012: 17
FWCI
3.98
Type
journal article
Language
en
Open access
closed
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Stem Cells (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Health and Medical Research Council (511200, 455864)
  • Pfizer Australia Senior Research Fellowship
  • NHMRC Senior Principal Research Fellow
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
physical activity, neural stem cells, growth hormone, aging, voluntary running, periventricular region, neurogenesis, neurosphere formation, GH receptor, age-related neurodegeneration, hippocampus, cognitive decline
MeSH terms
Aging, Animals, Brain, Cells, Cultured, Humans, Mice, Inbred C57BL, Nerve Regeneration, Neurons, Growth Hormone, Stem Cells, Exercise, Lateral Ventricles, Cell Proliferation, Mice, Neurogenesis

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