GSK-3α is a central regulator of age-related pathologies in mice
Jibin Zhou, … , Hind Lal, Thomas Force
Jibin Zhou, … , Hind Lal, Thomas Force
Published March 15, 2013
Citation Information: J Clin Invest. 2013;123(4):1821-1832. https://doi.org/10.1172/JCI64398.
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Research Article Aging

GSK-3α is a central regulator of age-related pathologies in mice

Abstract

Aging is regulated by conserved signaling pathways. The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases regulates several of these pathways, but the role of GSK-3 in aging is unknown. Herein, we demonstrate premature death and acceleration of age-related pathologies in the Gsk3a global KO mouse. KO mice developed cardiac hypertrophy and contractile dysfunction as well as sarcomere disruption and striking sarcopenia in cardiac and skeletal muscle, a classical finding in aging. We also observed severe vacuolar degeneration of myofibers and large tubular aggregates in skeletal muscle, consistent with impaired clearance of insoluble cellular debris. Other organ systems, including gut, liver, and the skeletal system, also demonstrated age-related pathologies. Mechanistically, we found marked activation of mTORC1 and associated suppression of autophagy markers in KO mice. Loss of GSK-3α, either by pharmacologic inhibition or Gsk3a gene deletion, suppressed autophagy in fibroblasts. mTOR inhibition rescued this effect and reversed the established pathologies in the striated muscle of the KO mouse. Thus, GSK-3α is a critical regulator of mTORC1, autophagy, and aging. In its absence, aging/senescence is accelerated in multiple tissues. Strategies to maintain GSK-3α activity and/or inhibit mTOR in the elderly could retard the appearance of age-related pathologies.

Authors

Jibin Zhou, Theresa A. Freeman, Firdos Ahmad, Xiying Shang, Emily Mangano, Erhe Gao, John Farber, Yajing Wang, Xin-Liang Ma, James Woodgett, Ronald J. Vagnozzi, Hind Lal, Thomas Force

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Figure 5

Senescence in the digestive system.

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Senescence in the digestive system. (A) Senescence in the livers (hepato...
(A) Senescence in the livers (hepatocytes) of the KO mice, as determined by phospho-histone H2AX positivity (brown-stained nuclei). Original magnification, ×200; scale bar: 50 μm. (B) SA β-GAL, a marker of cellular senescence, is widespread in the small intestine of the KO mice (note blue areas). Although difficult to quantify, it appears that crypts are thin and villi are sparse in the KO mice, also consistent with senescence. Arrowheads indicate individual SA β-GAL–positive cells. Original magnification, ×100 (top row); ×400 (bottom row); scale bar: 200 μm (top row), 50 μm (bottom row).