Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice

作者：Fernandez, Alvaro F.; Sebti, Salwa; Wei, Yongjie; Zou, Zhongju; Shi, Mingjun; Mcmillan, Kathryn L.; He, Congcong; Ting, Tabitha; Liu, Yang; Chiang, Wei-Chung; Marciano, Denise K.; Schiattarella, Gabriele G.; Bhagat, Govind; Moe, Orson W.; Hu, Ming Chang^*; Levine, Beth^*

来源：Nature, 2018, 558(7708): 136-+.

DOI：10.1038/s41586-018-0162-7

• LIFE-SPAN EXTENSION
• CLATHRIN-MEDIATED ENDOCYTOSIS
• 1-DEPENDENT AUTOPHAGY
• KLOTHO
• SPERMIDINE
• INDUCTION
• MITOSIS

Autophagy increases the lifespan of model organisms; however, its role in promoting mammalian longevity is less well-established(1,2). 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 (Becn(1F121A/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 Becn(1F121A/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 klotho(3) 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.

• 出版日期2018-6-7
• 单位西北大学