title: 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.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Jibin
authors.initials: J
authors.lastname: Zhou
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Freeman
authors.forename: Firdos
authors.initials: F
authors.lastname: Ahmad
authors.forename: Xiying
authors.initials: X
authors.lastname: Shang
authors.forename: Emily
authors.initials: E
authors.lastname: Mangano
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: John
authors.initials: J
authors.lastname: Farber
authors.forename: Yajing
authors.initials: Y
authors.lastname: Wang
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Ma
authors.forename: James
authors.initials: J
authors.lastname: Woodgett
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Vagnozzi
authors.forename: Hind
authors.initials: H
authors.lastname: Lal
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
mesh_terms: D000375:Aging; D000818:Animals; D001343:Autophagy; D001842:Bone and Bones / Q000473:pathology; D002318:Cardiovascular Diseases / Q000201:enzymology*; D016922:Cellular Senescence; D000068338:Everolimus; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics*; D022781:Hepatocytes / Q000201:enzymology / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D007719:Knee Joint / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008301:Maleimides / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D055948:Sarcopenia / Q000201:enzymology*; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
chemical_list: D007211:Indoles; D008301:Maleimides; D046912:Multiprotein Complexes; D011506:Proteins; C417521:SB 216763; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D020123:Sirolimus
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