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Focusing the spotlight on GSK-3 in aging.

Zhou J, Force T - Aging (Albany NY) (2013)

View Article: PubMed Central - PubMed

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These mechanisms, that are not mutually exclusive, include shortened telomeres, the induction of the senescence-associated secretory phenotype (SASP), regulation of metabolism by sirtuins, altered mitochondrial metabolism, the mechanistic target of rapamycin (mTOR) signaling pathway and longevity, aging and immune system dysfunction, and aging-associated changes in pancreatic β-cells... Our recent work seems to clearly implicate GSK-3, and specifically the α isoform, in aging... Through targeting GSK-3α in the mouse, we found accelerated development of age-related pathologies in multiple organ systems... But the most striking findings were seen in the heart and skeletal muscle (i.e. striated muscle)... These organ systems developed profound hypertrophy and dysfunction... We confirmed that KO of GSK-3α markedly activated mTOR, and knowing that mTOR suppresses autophagy, we asked if autophagy was dysregulated... We confirmed that it was... The key remaining question was whether this dysregulation of autophagy was leading to (or at least contributing to) the abnormalities of striated muscle... We employed a second generation inhibitor of mTORC1, everolimus, and found that both cardiac contractile abnormalities and skeletal muscle abnormalities were largely corrected... It remains to be seen whether the numerous other organ systems that we found to be dysfunctional in the absence of GSK-3α will also be corrected by mTORC1 inhibition... Given the number of signaling pathways that both influence aging and are regulated, at least in part, by GSK-3, combined with our more preliminary findings with degenerative joint disease, and abnormalities of the gut, and liver, we believe that additional rolls will be identified for GSK-3 in aging.

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Schematic drawing represents the signaling pathways and proteins that have been reported to influence aging are regulated by GSK-3s, implying GSK-3 is a crucial regulator in the aging process.
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Figure 1: Schematic drawing represents the signaling pathways and proteins that have been reported to influence aging are regulated by GSK-3s, implying GSK-3 is a crucial regulator in the aging process.

Mentions: Aging/senescence occurs at both the level of the whole organism and the individual cell. Organismal aging is usually defined as the progressive loss of function accompanied by decreasing fertility and increasing mortality with advancing age [1]. Cellular senescence refers to the permanent arrest of cell division, which is characterized by several cellular markers, identifying senescent cells in vitro and in vivo [2]. These include altered cellular morphology, increased activity of SA-β-GAL, accumulation of DNA damage foci, accumulation of senescence-associated heterochromatic foci (SAHF) [3] and promyelocytic leukemia protein nuclear bodies (PML-NBs) [4], chromosomal instability, and induction of an inflammatory secretome. Aging affects all organisms but to date, it is still unclear whether aging is triggered by genetic programs and/or evolutionary processes (Figure 1).


Focusing the spotlight on GSK-3 in aging.

Zhou J, Force T - Aging (Albany NY) (2013)

Schematic drawing represents the signaling pathways and proteins that have been reported to influence aging are regulated by GSK-3s, implying GSK-3 is a crucial regulator in the aging process.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824406&req=5

Figure 1: Schematic drawing represents the signaling pathways and proteins that have been reported to influence aging are regulated by GSK-3s, implying GSK-3 is a crucial regulator in the aging process.
Mentions: Aging/senescence occurs at both the level of the whole organism and the individual cell. Organismal aging is usually defined as the progressive loss of function accompanied by decreasing fertility and increasing mortality with advancing age [1]. Cellular senescence refers to the permanent arrest of cell division, which is characterized by several cellular markers, identifying senescent cells in vitro and in vivo [2]. These include altered cellular morphology, increased activity of SA-β-GAL, accumulation of DNA damage foci, accumulation of senescence-associated heterochromatic foci (SAHF) [3] and promyelocytic leukemia protein nuclear bodies (PML-NBs) [4], chromosomal instability, and induction of an inflammatory secretome. Aging affects all organisms but to date, it is still unclear whether aging is triggered by genetic programs and/or evolutionary processes (Figure 1).

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

These mechanisms, that are not mutually exclusive, include shortened telomeres, the induction of the senescence-associated secretory phenotype (SASP), regulation of metabolism by sirtuins, altered mitochondrial metabolism, the mechanistic target of rapamycin (mTOR) signaling pathway and longevity, aging and immune system dysfunction, and aging-associated changes in pancreatic β-cells... Our recent work seems to clearly implicate GSK-3, and specifically the α isoform, in aging... Through targeting GSK-3α in the mouse, we found accelerated development of age-related pathologies in multiple organ systems... But the most striking findings were seen in the heart and skeletal muscle (i.e. striated muscle)... These organ systems developed profound hypertrophy and dysfunction... We confirmed that KO of GSK-3α markedly activated mTOR, and knowing that mTOR suppresses autophagy, we asked if autophagy was dysregulated... We confirmed that it was... The key remaining question was whether this dysregulation of autophagy was leading to (or at least contributing to) the abnormalities of striated muscle... We employed a second generation inhibitor of mTORC1, everolimus, and found that both cardiac contractile abnormalities and skeletal muscle abnormalities were largely corrected... It remains to be seen whether the numerous other organ systems that we found to be dysfunctional in the absence of GSK-3α will also be corrected by mTORC1 inhibition... Given the number of signaling pathways that both influence aging and are regulated, at least in part, by GSK-3, combined with our more preliminary findings with degenerative joint disease, and abnormalities of the gut, and liver, we believe that additional rolls will be identified for GSK-3 in aging.

Show MeSH