Disruption of the beclin 1–BCL2 autophagy regulatory complex promotes longevity in mice,Nature

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Disruption of the beclin 1–BCL2 autophagy regulatory complex promotes longevity in mice
Nature ( IF 50.5 ) Pub Date : 2018-05-30 , DOI: 10.1038/s41586-018-0162-7
Álvaro F Fernández _{1,

2} , Salwa Sebti _{1,

2} , Yongjie Wei _{1,

2,

3} , Zhongju Zou _{1,

2,

3} , Mingjun Shi ₄ , Kathryn L McMillan ₄ , Congcong He ₅ , Tabitha Ting _{1,

2} , Yang Liu _{1,

2,

3} , Wei-Chung Chiang _{1,

2} , Denise K Marciano ₂ , Gabriele G Schiattarella ₂ , Govind Bhagat ₆ , Orson W Moe _{2,

4,

7} , Ming Chang Hu _{2,

4} , Beth Levine _{1,

2,

3,

8}

Affiliation

Autophagy increases the lifespan of model organisms; however, its role in promoting mammalian longevity is less well-established1,2. 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 Phe121Ala mutation in beclin 1 (Becn1F121A/F121A) that decreases its interaction with the negative regulator BCL2. We demonstrate that the interaction between beclin 1 and BCL2 is disrupted in several tissues in Becn1F121A/F121A knock-in mice in association with higher levels of basal autophagic flux. Compared to wild-type littermates, the lifespan of both male and female knock-in mice is significantly increased. The healthspan of the knock-in mice also improves, as phenotypes such as age-related renal and cardiac pathological changes and spontaneous tumorigenesis are diminished. Moreover, mice deficient in the anti-ageing protein klotho3 have increased beclin 1 and BCL2 interaction and decreased autophagy. These phenotypes, along with premature lethality and infertility, are rescued by the beclin 1(F121A) mutation. Together, our data demonstrate that disruption of the beclin 1–BCL2 complex is an effective mechanism to increase autophagy, prevent premature ageing, improve healthspan and promote longevity in mammals.A knock-in mutation in beclin 1 that increases autophagy in mice extends animal lifespan, improves healthspan, and also rescues early lethality in mice deficient in the anti-ageing protein klotho.

中文翻译：

破坏beclin 1-BCL2自噬调节复合物可促进小鼠寿命

自噬增加了模式生物的寿命；然而，它在促进哺乳动物寿命方面的作用尚不明确1,2。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，我们生成了靶向突变小鼠，该小鼠在 beclin 1 (Becn1F121A/F121A) 中具有 Phe121Ala 突变，从而减少了其与负调节因子 BCL2 的相互作用。我们证明 beclin 1 和 BCL2 之间的相互作用在 Becn1F121A/F121A 敲入小鼠的几个组织中被破坏，这与较高水平的基础自噬通量相关。与野生型同窝小鼠相比，雄性和雌性敲入小鼠的寿命均显着增加。敲入小鼠的健康寿命也有所改善，随着年龄相关的肾脏和心脏病理变化以及自发性肿瘤发生等表型减少。此外，缺乏抗衰老蛋白 klotho3 的小鼠增加了 beclin 1 和 BCL2 的相互作用并减少了自噬。这些表型，连同过早致死和不孕症，被 beclin 1(F121A) 突变拯救。总之，我们的数据表明，破坏 beclin 1-BCL2 复合物是增加自噬、防止过早衰老、改善健康寿命和促进哺乳动物寿命的有效机制。beclin 1 中增加小鼠自噬的敲入突变可延长动物寿命，改善健康寿命，并挽救缺乏抗衰老蛋白 klotho 的小鼠的早期致死率。缺乏抗衰老蛋白 klotho3 的小鼠增加了 beclin 1 和 BCL2 的相互作用并减少了自噬。这些表型，连同过早致死和不孕症，被 beclin 1(F121A) 突变拯救。总之，我们的数据表明，破坏 beclin 1-BCL2 复合物是增加自噬、防止过早衰老、改善健康寿命和促进哺乳动物寿命的有效机制。beclin 1 中增加小鼠自噬的敲入突变可延长动物寿命，改善健康寿命，并挽救缺乏抗衰老蛋白 klotho 的小鼠的早期致死率。缺乏抗衰老蛋白 klotho3 的小鼠增加了 beclin 1 和 BCL2 的相互作用并减少了自噬。这些表型，连同过早致死和不孕症，被 beclin 1(F121A) 突变拯救。总之，我们的数据表明，破坏 beclin 1-BCL2 复合物是增加自噬、防止过早衰老、改善健康寿命和促进哺乳动物寿命的有效机制。beclin 1 中增加小鼠自噬的敲入突变可延长动物寿命，改善健康寿命，并挽救缺乏抗衰老蛋白 klotho 的小鼠的早期致死率。

更新日期：2018-05-30

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