Disruption of the beclin 1–BCL2 autophagy regulatory complex promotes longevity in mice
Álvaro F. Fernández,
Salwa Sebti,
Yongjie Wei,
Zhongju Zou,
Mingjun Shi,
Kathryn L. McMillan,
Congcong He,
Tabitha Ting,
Yang Liu,
Wei-Chung Chiang,
Denise K. Marciano,
Gabriele G. Schiattarella,
Govind Bhagat,
Orson W. Moe,
Ming Chang Hu () and
Beth Levine ()
Additional contact information
Álvaro F. Fernández: University of Texas Southwestern Medical Center
Salwa Sebti: University of Texas Southwestern Medical Center
Yongjie Wei: University of Texas Southwestern Medical Center
Zhongju Zou: University of Texas Southwestern Medical Center
Mingjun Shi: University of Texas Southwestern Medical Center
Kathryn L. McMillan: University of Texas Southwestern Medical Center
Congcong He: Northwestern University
Tabitha Ting: University of Texas Southwestern Medical Center
Yang Liu: University of Texas Southwestern Medical Center
Wei-Chung Chiang: University of Texas Southwestern Medical Center
Denise K. Marciano: University of Texas Southwestern Medical Center
Gabriele G. Schiattarella: University of Texas Southwestern Medical Center
Govind Bhagat: Columbia University Medical Center and New York Presbyterian Hospital
Orson W. Moe: University of Texas Southwestern Medical Center
Ming Chang Hu: University of Texas Southwestern Medical Center
Beth Levine: University of Texas Southwestern Medical Center
Nature, 2018, vol. 558, issue 7708, 136-140
Abstract:
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.
Date: 2018
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DOI: 10.1038/s41586-018-0162-7
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