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. IntroductionAging is usually defined as the progressive loss of function accompanied by decreasing fertility and increasing mortality with advancing age (1). It is a complex biological process controlled by multiple genetic, epigenetic, and environmental factors. In order to explain how aging occurs at the molecular level, numerous theories have been proposed, but as yet, a unifying theory has not emerged. There are four main theories that are accepted more widely. (a) The telomere loss theory proposes that telomere shortening represents a cell-intrinsic mechanism, leading to DNA damage accumulation and activation of DNA damage checkpoints in aging cells. Activation of DNA damage checkpoints in response to telomere dysfunction results in induction of cellular senescence (2-4). (b) The somatic mutation theory states that aging proceeds if somatic mutations and other forms of DNA damage exceed the capacity for DNA repair (5). (c) The mitochondrial theory suggests that accumulation of mutations in mitochondrial DNA with age impairs ATP production, resulting in impaired bioenergetics (4). (d) The waste accumulation theory proposes that aging results from the accumulation of damaged proteins or superfluous or dysfunctional organelles due to age-related impairment of degradative processes, including the ubiquitin-proteasome system and, especially, lysosome-mediated autophagy (6, 7).Many conserved signaling pathways and regulatory proteins are reported to regulate life span and rate of aging of eukaryotic organisms. They include, but are not limited to, the insulin/IGF-1 pathway, the mTOR pathway, the WNT signaling pathway, and the p53/sestrin si...

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