Improved WNT signaling may accelerate aging through stimulating mitochondrial biogenesis and protein translation and inducing ROS generation. Re-establishing mTOR inhibition downstream of GSK 3 by everolimus hdac1 inhibitor restores autophagy as well as contractile function, especially in the setting of high level age. Discussion Herein, we provide evidence showing that GSK 3 is a suppressor of aging that retards age related pathologies, thus increasing expected life in the mouse. Other organ systems were affected as well, including the belly, liver, and bone and joints, although we concentrated more on organs with striated muscle. In fact, with the exception of skin, which had no clear aging related pathologies, every system we examined had significant abnormalities. Although little has been noted regarding GSK 3s in aging, cues can be found in published reports that suggest that GSK 3s have a potential role. For instance, GSK 3s are key negative regulators of WNT signaling. But in comparison to those studies, we’ve not observed major derangements in WNT signaling in the hearts of the Gsk3a KO mice, suggesting that WNT signaling is probable not a major issue in the Inguinal canal accelerated aging in the KO heart. We did observe significant increases in ROS in the heart and skeletal muscle of the KO mouse, and this may promote senescence. Having said that, it’s not clear how removal of GSK 3 may possibly cause increased ROS production, and determining the system is beyond the scope of this work. We do, however, have mechanistic information on dysregulation of 2 important pathways, both that importantly impinge upon autophagy. Inactivating mutations in IRS proteins, central aspects of natural product libraries the insulin/IGF 1 signaling pathway, increase life span in various species. IRS 1 is reported to be phosphorylated by GSK 3, resulting in its ubiquitination and proteasomal degradation, and, indeed, we found a significant escalation in IRS 1 expression in the heart of the Gsk3a KO mouse. Nevertheless, this didn’t seem to result in enhanced activity of key elements downstream in the IRS 1 pathway, including Akt. Ergo, activation of Akt doesn’t seem to be a significant mechanism where autophagy is impaired in the KO mouse. However, an additional system, and one that we show to become crucial to the aging phenotypes, is via the lack of immediate regulation of mTORC1 by GSK 3 in the KO mouse. Suppressing the mTOR pathway has been shown to slow aging related pathologies and increase life time. GSK 3, acting via TSC2, results in inhibition of mTORC1. Our published data have confirmed increased mTORC1 activity in the small Gsk3a KO mouse, and this difference between KO and WT mice is exaggerated with advancing age. This activation of mTORC1 contributes to a profound inhibition of autophagy. Each one of the 3 markers of autophagy that we examined, p62, LC3 I/II, and beclin 1, were markedly dysregulated, and all indicate impaired autophagy.