| First Author | Fernández ÁF | Year | 2018 |
| Journal | Nature | Volume | 558 |
| Issue | 7708 | Pages | 136-140 |
| PubMed ID | 29849149 | Mgi Jnum | J:263555 |
| Mgi Id | MGI:6164747 | Doi | 10.1038/s41586-018-0162-7 |
| Citation | Fernandez AF, et al. (2018) Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature 558(7708):136-140 |
| abstractText | 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. |
