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      Disruption of the beclin 1/Bcl-2 autophagy regulatory complex promotes longevity in mice

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          Abstract

          Autophagy increases 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 F121A ( Becn1 F121A/F121A) mutation in beclin 1 that decreases its interaction with the negative regulator, Bcl-2. We demonstrate that beclin 1/Bcl-2 interaction is disrupted in multiple tissues in Becn1 F121A/F121A knock-in (KI) mice in association with higher levels of basal autophagic flux. Compared to wild-type (WT) littermates, the lifespan of both male and female KI mice is significantly increased. The healthspan of the KI mice also improves as aging-related phenotypes are diminished, including age-related renal and cardiac pathological changes and spontaneous tumorigenesis. Moreover, mice deficient in the anti-aging protein, Klotho 3 , have increased beclin 1/Bcl-2 interaction, decreased autophagy, premature lethality and infertility which are rescued by the beclin 1 F121A mutation. Taken together, our data demonstrate that disruption of the beclin 1/Bcl-2 complex is an effective mechanism to increase autophagy, prevent premature aging, improve healthspan and promote longevity in mammals.

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          Most cited references17

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          Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network.

          Autophagy is an intracellular bulk protein degradation system. Beclin is known to be involved in this process; however, its role is unclear. In this study, we showed that Beclin was co-immunoprecipitated with phosphatidylinositol (PtdIns) 3-kinase, which is also required for autophagy, suggesting that Beclin is a component of the PtdIns 3-kinase complex. Quantitative analyses using a cross-linker showed that all Beclin forms a complex with PtdIns 3-kinase, whereas approximately 50% of PtdIns 3-kinase remains free from Beclin. Indirect immunofluorescence microscopy demonstrated that the majority of Beclin and PtdIns 3-kinase localize to the trans-Golgi network (TGN). Some PtdIns 3-kinase is also distributed in the late endosome. These results suggest that Beclin and PtdIns 3-kinase control autophagy as a complex at the TGN.
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            Essential role for autophagy in life span extension.

            Life and health span can be prolonged by calorie limitation or by pharmacologic agents that mimic the effects of caloric restriction. Both starvation and the genetic inactivation of nutrient signaling converge on the induction of autophagy, a cytoplasmic recycling process that counteracts the age-associated accumulation of damaged organelles and proteins as it improves the metabolic fitness of cells. Here we review experimental findings indicating that inhibition of the major nutrient and growth-related signaling pathways as well as the upregulation of anti-aging pathways mediate life span extension via the induction of autophagy. Furthermore, we discuss mounting evidence suggesting that autophagy is not only necessary but, at least in some cases, also sufficient for increasing longevity.
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              Klotho and aging.

              The klotho gene encodes a single-pass transmembrane protein that forms a complex with multiple fibroblast growth factor (FGF) receptors and functions as an obligatory co-receptor for FGF23, a bone-derived hormone that induces negative phosphate balance. Defects in either Klotho or Fgf23 gene expression cause not only phosphate retention but also a premature-aging syndrome in mice, unveiling a potential link between phosphate metabolism and aging. In addition, the extracellular domain of Klotho protein is clipped on the cell surface and secreted into blood stream, potentially functioning as an endocrine factor. The secreted Klotho protein has a putative sialidase activity that modifies glycans on the cell surface, which may explain the ability of secreted Klotho protein to regulate activity of multiple ion channels and growth factors including insulin, IGF-1, and Wnt. Secreted Klotho protein also protects cells and tissues from oxidative stress through a mechanism yet to be identified. Thus, the transmembrane and secreted forms of Klotho protein have distinct functions, which may collectively affect aging processes in mammals.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                2 May 2018
                30 May 2018
                June 2018
                30 November 2018
                : 558
                : 7708
                : 136-140
                Affiliations
                [1 ]Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA 75390
                [2 ]Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA 75390
                [3 ]Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA 75390
                [4 ]Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA 75390
                [5 ]Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA 75390
                [6 ]Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA 75390
                [7 ]Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 60611
                [8 ]Department of Pathology and Cell Biology, Columbia University Medical Center and New York Presbyterian Hospital, New York, New York 10032
                Author notes
                [+]

                These authors contributed equally to this work. The order of these authors was determined by a coin toss.

                Article
                NIHMS960525
                10.1038/s41586-018-0162-7
                5992097
                29849149
                687250b7-bba6-4a59-be40-527ba1934408

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