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 3

Sarcopenia, myocyte dropout, and progressive fibrotic remodeling in the heart of the KO mouse.

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Sarcopenia, myocyte dropout, and progressive fibrotic remodeling in the ...
(A) Vacuolar degeneration and blanching of the myocardia, consistent with marked sarcopenia and myocyte dropout, are apparent in the H&E-stained hearts of KO mice. Original magnification, ×400; scale bar: 20 μm. (B) Fibrotic remodeling is shown in the Masson’s trichrome-stained sections. Original magnification, ×400; scale bar: 20 μm. (C) Additional H&E-stained images show myocyte dropout and fibrosis that is readily apparent as early as 12 months of age in the KO mice. The arrow indicates area of myocyte dropout. Original magnification, ×200; scale bar: 100 μm. (D) Representative transmission electron micrographs in the heart at 2, 12, and 24 months of age. There are markedly swollen mitochondria, with marked disruption of sarcomeres, in the KO mice at 12 months of age, worsening at 24 months, at which point there is loss of mitochondria and myofibrils. Original magnification, ×10,000 (top row); ×5,000 (middle row); ×4,400 (bottom row); scale bar: 1 μm. (E) Increased superoxide production in KO mice. (F) Increased p16 expression in the hearts of KO mice.