The anti-ageing effects of caloric restriction may involve stimulation of macroautophagy and lysosomal degradation, and can be intensified pharmacologically

Bergamini, Ettore; Cavallini, Gabriella; Donati, Alessio; Gori, Zina

doi:10.1016/s0753-3322(03)00048-9

Cited by 131 publications

(79 citation statements)

References 44 publications

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“…Antiageing strategies may involve, in particular, a reduction of oxidative damage by the administration of antioxidants and iron chelators, and the stimulation of cellular degradation systems, including different forms of autophagy, proteasomes, and cytosolic as well as mitochondrial proteases. Although no effective pharmacological anti-ageing agents have so far been proposed, the above-mentioned strategies are supported by studies of long-lived Caenorhabditis elegans mutants and calorie-restricted rodents, showing both reduced oxidative stress [106,107] and enhanced autophagy [108,109].…”

Section: Resultsmentioning

confidence: 99%

Autophagy, organelles and ageing

Terman

Gustafsson

Brunk

2007

The Journal of Pathology

263

210

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As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy and other degradative systems, long-lived postmitotic cells, such as cardiac myocytes, neurons and retinal pigment epithelial cells, progressively accumulate biological 'garbage' ('waste' materials). The latter include lipofuscin (a non-degradable intralysosomal polymeric substance), defective mitochondria and other organelles, and aberrant proteins, often forming aggregates (aggresomes). An interaction between senescent lipofuscin-loaded lysosomes and mitochondria seems to play a pivotal role in the progress of cellular ageing. Lipofuscin deposition hampers autophagic mitochondrial turnover, promoting the accumulation of senescent mitochondria, which are deficient in ATP production but produce increased amounts of reactive oxygen species. Increased oxidative stress, in turn, further enhances damage to both mitochondria and lysosomes, thus diminishing adaptability, triggering mitochondrial and lysosomal pro-apoptotic pathways, and culminating in cell death.

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Section: Resultsmentioning

confidence: 99%

Autophagy, organelles and ageing

Terman

Gustafsson

Brunk

2007

The Journal of Pathology

263

210

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“…This phenomenon enables cells to survive long periods of starvation. However, in higher eukaryotes autophagy also plays an important role in developmental changes (Levine and Klionsky, 2004), regulation of lifespan (Bergamini et al, 2003;Longo and Finch, 2003;Melendez et al, 2003;Vellai et al, 2003), cancer (Qu et al, 2003;Yue et al, 2003;Gozuacik and Kimchi, 2004), and in neurodegenerative disorders like Huntington's, Parkinson's, or Alzheimer's disease (Yuan et al, 2003). It is also part of the innate immune system assisting in eliminating intracellular pathogens after infection (Gutierrez et al, 2004;Nakagawa et al, 2004;Ogawa et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

The Vacuolar Transporter Chaperone (VTC) Complex Is Required for Microautophagy

Uttenweiler

Schwarz

Neumann

et al. 2007

MBoC

107

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Microautophagy involves direct invagination and fission of the vacuolar/lysosomal membrane under nutrient limitation.This occurs by an autophagic tube, a specialized vacuolar membrane invagination that pinches off vesicles into the vacuolar lumen. In this study we have identified the VTC (vacuolar transporter chaperone) complex as required for microautophagy. The VTC complex is present on the ER and vacuoles and at the cell periphery. On induction of autophagy by nutrient limitation the VTC complex is recruited to and concentrated on vacuoles. The VTC complex is inhomogeneously distributed within the vacuolar membranes, showing an enrichment on autophagic tubes. Deletion of the VTC complex blocks microautophagic uptake into vacuoles. The mutants still form autophagic tubes but the production of microautophagic vesicles from their tips is impaired. In line with this, affinity-purified antibodies to the Vtc proteins inhibit microautophagic uptake in a reconstituted system in vitro. Our data suggest that the VTC complex is an important constituent of autophagic tubes and that it is required for scission of microautophagic vesicles from these tubes. INTRODUCTIONAutophagy occurs in all eukaryotic cells (Reggiori and Klionsky, 2002). In yeast it has mainly been characterized as an adaptation to nutrient stress such as nitrogen limitation: during autophagy large portions of cytosolic and membraneous material are delivered to the lysosome (in yeast called vacuole) for degradation and recycling (Takeshige et al., 1992). This phenomenon enables cells to survive long periods of starvation. However, in higher eukaryotes autophagy also plays an important role in developmental changes (Levine and Klionsky, 2004), regulation of lifespan (Bergamini et al., 2003;Longo and Finch, 2003;Melendez et al., 2003;Vellai et al., 2003), cancer (Qu et al., 2003;Yue et al., 2003;Gozuacik and Kimchi, 2004), and in neurodegenerative disorders like Huntington's, Parkinson's, or Alzheimer's disease (Yuan et al., 2003). It is also part of the innate immune system assisting in eliminating intracellular pathogens after infection (Gutierrez et al., 2004;Nakagawa et al., 2004;Ogawa et al., 2005).Macroautophagy in yeast is defined as the uptake of cytosolic contents by fusion of double-layered vesicles (autophagosomes) with vacuoles (Baba et al., 1994). Autophagosomes originate from a preautophagosomal structure (PAS) in the vicinity of the vacuole and, during their formation, enwrap portions of cytosol. Fusion of the outer autophagosomal layer with the vacuolar membrane liberates autophagic bodies (single-layered intravacuolar vesicles) into the vacuolar lumen for degradation (Takeshige et al., 1992). Relevant actors of macroautophagy (Atg proteins; Klionsky et al., 2003) have been identified, mainly by genetic screens (Tsukada and Ohsumi, 1993;Thumm et al., 1994;Harding et al., 1995Harding et al., , 1996Titorenko et al., 1995) and have been studied intensively over the last decade.Little is known about microautophagy, a process consisting of a di...

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“…The recent progress made in characterization of the molecular mechanism controlling autophagy has brought a renewal of interest for this process (14). There is now evidence for the role of autophagy during development (15-17), in the life span extension (15,18), and in disease such as cancer (19,20), neurodegenerative disease (21, 22), and myopathies (23,24).A family of autophagy-related genes discovered in yeast and almost integrally conserved in all eucaryotic phyla controls the formation of the autophagosome (25). Two conjugation systems (Atg5p-Atg12p and Atg8p lipidation) are involved in the formation of the autophagosome (26) together with a class III phosphatidylinositol 3-kinase (class III PI3K, 1 the homologue of the yeast Vps34) complex (27,28).…”

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confidence: 99%

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confidence: 99%

Ceramide-mediated Macroautophagy Involves Inhibition of Protein Kinase B and Up-regulation of Beclin 1

Scarlatti

Bauvy

Ventruti

et al. 2004

Journal of Biological Chemistry

415

376

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The sphingolipid ceramide is involved in the cellular stress response. Here we demonstrate that ceramide controls macroautophagy, a major lysosomal catabolic pathway. Exogenous C 2 -ceramide stimulates macroautophagy (proteolysis and accumulation of autophagic vacuoles) in the human colon cancer HT-29 cells by increasing the endogenous pool of long chain ceramides as demonstrated by the use of the ceramide synthase inhibitor fumonisin B 1 . Ceramide reverted the interleukin 13-dependent inhibition of macroautophagy by interfering with the activation of protein kinase B. In addition, C 2 -ceramide stimulated the expression of the autophagy gene product beclin 1. Ceramide is also the mediator of the tamoxifen-dependent accumulation of autophagic vacuoles in the human breast cancer MCF-7 cells. Monodansylcadaverine staining and electron microscopy showed that this accumulation was abrogated by myriocin, an inhibitor of de novo synthesis ceramide. The tamoxifen-dependent accumulation of vacuoles was mimicked by 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, an inhibitor of glucosylceramide synthase. 1-Phenyl-2-decanoylamino-3-morpholino-1-propanol, tamoxifen, and C 2 -ceramide stimulated the expression of beclin 1, whereas myriocin antagonized the tamoxifendependent up-regulation. Tamoxifen and C 2 -ceramide interfere with the activation of protein kinase B, whereas myriocin relieved the inhibitory effect of tamoxifen. In conclusion, the control of macroautophagy by ceramide provides a novel function for this lipid mediator in a cell process with major biological outcomes.Macroautophagy or autophagy is an evolutionary conserved lysosomal pathway involved in the turnover of long lived proteins and organelles (1-3). Autophagy starts with the formation of a multilayer membrane-bound autophagosome that sequesters fractions of the cytoplasm (4, 5). In mammalian cells, most of autophagosomes receive inputs from endocytic compartments before fusing with lysosomes where the degradation of the sequestered material is completed (6, 7).The physiological importance of autophagy during starvation has been primarily highlighted in rat liver (8) and then in different cell types (reviewed in Refs. 9 and 10). At the same time, the term autophagic cell death or type II programmed cell death (PCD II) has been introduced (11) to describe a cell death different from apoptosis or type I programmed cell death (PCD I) (reviewed in Refs. 12 and 13). The recent progress made in characterization of the molecular mechanism controlling autophagy has brought a renewal of interest for this process (14). There is now evidence for the role of autophagy during development (15-17), in the life span extension (15,18), and in disease such as cancer (19,20), neurodegenerative disease (21, 22), and myopathies (23,24).A family of autophagy-related genes discovered in yeast and almost integrally conserved in all eucaryotic phyla controls the formation of the autophagosome (25). Two conjugation systems (Atg5p-Atg12p and Atg8p lipidation) are involved in...

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The anti-ageing effects of caloric restriction may involve stimulation of macroautophagy and lysosomal degradation, and can be intensified pharmacologically

Cited by 131 publications

References 44 publications

Autophagy, organelles and ageing

Autophagy, organelles and ageing

The Vacuolar Transporter Chaperone (VTC) Complex Is Required for Microautophagy

Ceramide-mediated Macroautophagy Involves Inhibition of Protein Kinase B and Up-regulation of Beclin 1

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