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Fernández, Álvaro F; Sebti, Salwa; Wei, Yongjie; Zou, Zhongju; Shi, Mingjun; McMillan, Kathryn L; He, Congcong; Ting, Tabitha; Liu, Yang; Chiang, Wei-Chung; Marciano, Denise K; Schiattarella, Gabriele G; Bhagat, Govind; Moe, Orson W; Hu, Ming Chang; Levine, Beth
Nature (London), 06/2018, Letnik: 558, Številka: 7708Journal Article
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 ) 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 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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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