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

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Item Type:	Article
Title:	Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice
Creators Name:	Fernández, Á.F., Sebti, S., Wei, Y., Zou, Z., Shi, M., McMillan, K.L., He, C., Ting, T., Liu, Y., Chiang, W.C., Marciano, D.K., Schiattarella, G.G., Bhagat, G., Moe, O.W., 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
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	558
Number:	7708
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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