Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice.
Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice.
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DOI：
10.1038/s41586-018-0162-7
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发表时间：
2018-06
期刊：
影响因子：
64.8
通讯作者：
Levine B
中科院分区：
文献类型：
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作者：
Fernández ÁF;Sebti S;Wei Y;Zou Z;Shi M;McMillan KL;He C;Ting T;Liu Y;Chiang WC;Marciano DK;Schiattarella GG;Bhagat G;Moe OW;Hu MC;Levine B
自噬增加模式生物的寿命;然而，它在促进哺乳动物长寿方面的作用还不太确定。在这里，我们报告了基础自噬增加的小鼠模型的寿命和健康寿命延长。为了确定组成性增加的自噬对哺乳动物健康的影响，我们在beclin 1中产生了具有F121 A（Becn 1F 121 A/F121 A）突变的靶向突变小鼠，该突变降低了其与负调节因子Bcl-2的相互作用。我们证明了Beclin 1/Bcl-2相互作用在Becn 1F 121 A/F121 A基因敲入（KI）小鼠的多个组织中被破坏，与更高水平的基础自噬通量相关。与野生型（WT）同窝仔相比，雄性和雌性KI小鼠的寿命均显著增加。KI小鼠的健康寿命也随着年龄相关表型的减少而改善，包括年龄相关的肾脏和心脏病理变化以及自发性肿瘤发生。此外，缺乏抗衰老蛋白Klotho的小鼠具有增加的beclin 1/Bcl-2相互作用、减少的自噬、过早致死和不育，这是由beclin 1 F121 A突变拯救的。综上所述，我们的数据表明，Beclin 1/Bcl-2复合物的破坏是增加自噬、防止过早衰老、改善健康寿命和促进哺乳动物长寿的有效机制。
Autophagy increases lifespan of model organisms; however, its role in promoting mammalian longevity is less well-established. Here, we report lifespan and healthspan extension in a mouse model with increased basal autophagy. To determine the effects of constitutively increased autophagy on mammalian health, we generated targeted mutant mice with a F121A (Becn1F121A/F121A) mutation in beclin 1 that decreases its interaction with the negative regulator, Bcl-2. We demonstrate that beclin 1/Bcl-2 interaction is disrupted in multiple tissues in Becn1F121A/F121A knock-in (KI) mice in association with higher levels of basal autophagic flux. Compared to wild-type (WT) littermates, the lifespan of both male and female KI mice is significantly increased. The healthspan of the KI mice also improves as aging-related phenotypes are diminished, including age-related renal and cardiac pathological changes and spontaneous tumorigenesis. Moreover, mice deficient in the anti-aging protein, Klotho, have increased beclin 1/Bcl-2 interaction, decreased autophagy, premature lethality and infertility which are rescued by the beclin 1 F121A mutation. Taken together, our data demonstrate that disruption of the beclin 1/Bcl-2 complex is an effective mechanism to increase autophagy, prevent premature aging, improve healthspan and promote longevity in mammals.