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


  • Á.F. Fernández
  • S. Sebti
  • Y. Wei
  • Z. Zou
  • M. Shi
  • K.L. McMillan
  • C. He
  • T. Ting
  • Y. Liu
  • W.C. Chiang
  • D.K. Marciano
  • G.G. Schiattarella
  • G. Bhagat
  • O.W. Moe
  • M.C. Hu
  • B. Levine


  • Nature


  • Nature 558 (7708): 136-140


  • Autophagy increases the 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 Phe121Ala mutation in beclin 1 (Becn1(F121A/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 Becn1(F121A/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 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.