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

Item Type:Article
Title:Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice
Creators Name:Fernández, Á.F. and Sebti, S. and Wei, Y. and Zou, Z. and Shi, M. and McMillan, K.L. and He, C. and Ting, T. and Liu, Y. and Chiang, W.C. and Marciano, D.K. and Schiattarella, G.G. and Bhagat, G. and Moe, O.W. and Hu, M.C. and Levine, B.
Abstract: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.
Keywords:Aging, Autophagosomes, Autophagy, Beclin-1, Cultured Cells, Fibroblasts, Gene Knock-In Techniques, Glucuronidase, HeLa Cells, Health, Inbred C57BL Mice, Longevity, Mutation, Proto-Oncogene Proteins c-bcl-2, Animals, Mice
Publisher:Nature Publishing Group
Page Range:136-140
Date:7 June 2018
Additional Information:Erratum in: Nature 561(7723): E30.
Official Publication:https://doi.org/10.1038/s41586-018-0162-7
PubMed:View item in PubMed

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