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.
View: Text | PDF
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

×

Figure 6

Increased bone mass, knee joint pathology, and inflammatory cytokines in the Gsk3a KO mice.

Options: View larger image (or click on image) Download as PowerPoint
Increased bone mass, knee joint pathology, and inflammatory cytokines in...
(A) Representative micro-CT scans (in blue) and histological images of the knee. BV/TV, analyzed by micro-CT, was increased strikingly in the knees of the KO mice at 12 and 24 months of age. Values indicate BV/TV for each group. Calcification in the aging knees of the KO mice is also evident by both micro-CT and histology. There is fusion of the joint space and meniscus of the knee at 24 months of age. Original magnification, ×40. (B) Representative immunohistochemistry images from the knees of WT or Gsk3a KO mice, stained for inflammatory cytokines MMP-13 and IL-1. MMP-13 staining (brown stain) is increased in the KO bone marrow at 12 months and remains elevated at 24 months. IL-1 staining (brown stain) is also increased in the osteocytes and bone marrow of the KO mice at 12 months, indicating elevated inflammatory cytokines in the KO mice. Original magnification, ×100.