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.

Fernández ÁF^1,², Sebti S^1,², Wei Y^1,^2,³, Zou Z^1,^2,³, Shi M⁴, McMillan KL⁴, He C⁵, Ting T^1,², Liu Y^1,^2,³, Chiang WC^1,², Marciano DK², Schiattarella GG², Bhagat G⁶, Moe OW^2,^4,⁷, Hu MC^8,⁹, Levine B^10,^11,^12,¹³.

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.

Erratum in

Author Correction: Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. [Nature. 2018]

Abstract

Autophagy increases the lifespan of model organisms; however, its role in promoting mammalian longevity is less well-established^1,2. 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 (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 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.