Journal
EXPERIMENTAL GERONTOLOGY
Volume 173, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.exger.2023.112091
Keywords
AKT; GDC0068; Senescence amelioration; Lysosome; Mitochondria
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Senescence is caused by alterations in cellular organelles and is the primary cause of aging and aging-related diseases. Recent studies have revealed that oncogene-induced senescence is driven by activation of serine/threonine protein kinases (AKT1, AKT2, and AKT3). In this study, GDC0068 was found to have a senescence-ameliorating effect by restoring lysosomal and mitochondrial function through modulation of AKT activity.
Senescence is a phenomenon defined by alterations in cellular organelles and is the primary cause of aging and aging-related diseases. Recent studies have shown that oncogene-induced senescence is driven by activation of serine/threonine protein kinases (AKT1, AKT2 and AKT3). In this study, we evaluated twelve AKT inhibitors and revealed GDC0068 as a potential agent to ameliorate senescence. Senescence-ameliorating effect was evident from the finding that GDC0068 yielded lysosomal functional recovery as observed by reduction in lysosomal mass and induction in autophagic flux. Furthermore, GDC0068-mediated restoration of lysosomal function activated the removal of dysfunctional mitochondria, resulting in restoration of mitochondrial function. Together, our findings revealed a unique mechanism by which senescence is recovered by functional restoration of lysosomes and mitochondria through modulation of AKT activity.
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