Abstract
The glycogen synthase kinase-3 (GSK-3) family of protein kinases consists of two highly related isoforms, α and β. The GSK-3 family has been reported to regulate an astonishing variety of physiological and pathophysiological processes, whereas virtually nothing is known as for whether they regulate aging. Aging, defined as the progressive loss of function accompanied by decreasing fertility and increasing mortality with advancing age, is a complex biological process, controlled by multiple genetic, epigenetic and environmental factors. We now present the first studies defining the role of GSK-3α in the aging process using germline GSK-3α knockout (KO) mice at age of 3, 6, 12, and 24 mos. Age-matched wildtype (WT) mice served as control. Kaplan-Meier analysis shows that percent survivals (WT vs. KO) was 73.33 vs. 42.11 ‡ at 24 mos of age. In the heart we find cardiac hypertrophy, marked cell loss with replacement fibrosis, contractile dysfunction with profound abnormalities of mitochondrial structure, and impaired autophagy (assessed by Beclin1/ATG6), all becoming evident after 6 mos of age. Echocardiographic LV mass (in mg) is as follows (4 time points): 124.0±3.15 vs. 132.4±3.93, 136.2±4.75 vs. 171.5±7.57 ‡ , 169.2±8.53 vs. 203.5±8.18 ‡ , 195.4±9.82 vs. 257.4±7.24 ‡ ; ejection factor: 60.6±1.08 vs. 62.5±1.52, 64.3±1.10 vs. 60.7±1.61*, 58.5±1.74 vs. 52.2±1.41 ‡ , 55.5±0.96 vs. 49.4±1.02 ‡ ; invasive hemodynamic dP/dt+: 6863.8±673.8 vs. 6999.4±473.2, 7115.4±392.9 vs. 6012.6±407.3*, 7509.6±419.6 vs. 4291.6±473.5*, 6889.0±460.9 vs. 3955.5±306.9 ‡ . We also observed increased BrdU positive nuclei in isolated cardiomyocytes from the KO at 6 mos of age, and increased stem cells at every time-point, compared with age-matched WT. In the small intestine, we find marked senescence-associated β-galactosidase (SA-β-GAL) activity associated with thinning of the crypts, consistent with reduced cell cycling in this tissue. The results imply accelerated development of age-related pathologies in the KO heart and small bowel. These phenotypes are associated with a reduced lifespan in the mouse. Thus GSK-3α is a novel regulator of aging which retards age-related pathologies and prolongs lifespan of the organism. (*, P<0.05; ‡, P<0.01 KO vs. WT)
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