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 C Hu, Beth Levine

Research output: Contribution to journalArticlepeer-review

427 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)136-140
Number of pages5
JournalNature
Volume558
Issue number7708
DOIs
StatePublished - Jun 7 2018

ASJC Scopus subject areas

  • General

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