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 2

Cardiac abnormalities in the Gsk3a KO mouse.

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Cardiac abnormalities in the Gsk3a KO mouse. Deletion of GSK-3α leads ...
Deletion of GSK-3α leads to exaggerated cardiac hypertrophy, contractile dysfunction, and impaired diastolic relaxation. Mice were examined for cardiac abnormalities at (A and B) 6 months and 24 months of age or (C–I) at 3, 6, 12, and 24 months. (A) Representative images of hearts of KO and WT mice. Original magnification, ×2; scale bar: 4 mm. (B) Quantification of hypertrophy using heart weight normalized to tibial length (HW/TL). Hypertrophy as determined by (C) transthoracic echocardiographic assessment of LV posterior wall thickness or by (D) direct measurement of LV mass. (E–G) Hemodynamic parameters determined at cardiac catheterization: (E) LV systolic pressure (LVSP), (F) +dP/dt (a measure of contractile function), and (G) –dP/dt (a measure of the ability of the heart to relax) are all impaired in the KO mouse. (H) Contractile function, as assessed by echocardiography, is impaired. (I) EDD, a marker of dilatation of the LV, is increased in the KO mouse.