摘要：

Although cellular senescence is a natural biological process,its role in living organisms is not well -understood and the specific molecular mechanisms underlying biological aging remain largely uncharacterized. Sirtuins are a family of proteins possessing anti-aging activities in yeast,drosophila and worms.Mammalian sirtuins appear to mediate the anti-aging effects of caloric restriction.One of them,SIRT1,is progressively down-regulated during the senescence process in primary endothelial cultures.Replenishment of SIRT1 restores the proliferative capacities and functions of the senescent endothelial cells.By contrast,AMP - activated protein kinase or AMPK,a master regulator of energy metabolism,is hyper - activated in senescent endothelial cells.While activation of AMPK signaling protects cells against energy stress,this pathway can also cause endothelial senescence and cell cycle arrest.SIRT1 is known to act as a stress and energy sensor and activated by an increased NAD/NADH ratio.AMPK senses AMP/ATP levels through its upstream kinase LKB1.Interactions between SIRT1 and AMPK pathways occur in endothelial cells and coordinately support cell survival and vascular homeostasis.As a deacetylase,SIRT1 antagonizes LKB1-dependent AMPK activation by promoting the deacetylation,ubiquintination and proteasome - mediated degradation of LKB1. Meanwhile,hyper - activation of LKB1 - AMPK pathway negatively regulates the enzymatic activity of SIRT1 by promoting the posttranslational modification of this anti - aging protein.This counterbalancing mechanism helps to integrate nutrient/energy availability and the survival/proliferative capability of the endothelial cells. Interrupting of this circle may turn anoriginally pro - survival strategy into a pro - aging mechanism,which ultimately leads to the progressive degeneration and irreversible cellular senescence.

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