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Nature. 2018 Jun;558(7708):136-140. doi: 10.1038/s41586-018-0162-7. Epub 2018 May 30.

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

Author information

1
Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
2
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
3
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
4
Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
5
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
6
Department of Pathology and Cell Biology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.
7
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
8
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. ming-chang.hu@utsouthwestern.edu.
9
Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, USA. ming-chang.hu@utsouthwestern.edu.
10
Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX, USA. beth.levine@utsouthwestern.edu.
11
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. beth.levine@utsouthwestern.edu.
12
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. beth.levine@utsouthwestern.edu.
13
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. beth.levine@utsouthwestern.edu.

Abstract

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 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 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.

PMID:
29849149
PMCID:
PMC5992097
DOI:
10.1038/s41586-018-0162-7
[Indexed for MEDLINE]
Free PMC Article

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