Article

Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway

Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125, USA.
Current Biology (Impact Factor: 9.57). 06/2004; 14(10):885-90. DOI: 10.1016/j.cub.2004.03.059
Source: PubMed

ABSTRACT

In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.

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    • "Decreasing the activity of TORC1 either with caloric restriction (CR), genetic manipulation or inhibitors leads in general to an increase in lifespan. In D. melanogaster, down-regulation of dTor or up-regulation of dTsc2 and the combination of these two, increased the lifespan significantly , as shown with expression of a dominant-negative form of S6K (Kapahi et al., 2004 ). Inhibition of CeTor by RNAi increased lifespan profoundly (Vellai et al., 2003). "
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    ABSTRACT: Ageing is the organisms increased susceptibility to death, which is linked to accumulated damage in the cells and tissues. Ageing is a complex process regulated by crosstalk of various pathways in the cells. Ageing is highly regulated by the Target of Rapamycin (TOR) pathway activity. TOR is an evolutionary conserved key protein kinase in the TOR pathway that regulates growth, proliferation and cell metabolism in response to nutrients, growth factors and stress. Comparing the ageing process in invertebrate model organisms with relatively short lifespan with mammals provides valuable information about the molecular mechanisms underlying the ageing process faster than mammal systems. Inhibition of the TOR pathway activity via either genetic manipulation or rapamycin increases lifespan profoundly in most invertebrate model organisms. This contribution will review the recent findings in invertebrates concerning the TOR pathway and effects of TOR inhibition by rapamycin on lifespan. Besides some contradictory results, the majority points out that rapamycin induces longevity. This suggests that administration of rapamycin in invertebrates is a promising tool for pursuing the scientific puzzle of lifespan prolongation.
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    • "The first evidence that reduced mTORC1 signaling is sufficient to increase life span came from studies in yeast, in which mutation of the S6 kinase homolog Sch9 was shown to extend chronological life span (Fabrizio et al. 2001); although, at the time, the link between Sch9 and mTORC1 was not appreciated. A few years later, genetic inhibition of mTOR itself, as well as other components of the mTORC1 complex , was found to extend life span in worms (Vellai et al. 2003; Jia et al. 2004), flies (Kapahi et al. 2004), and, soon thereafter, replicative life span in yeast (Kaeberlein et al. 2005a). "
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    • "Two Drosophila homologues of tuberous sclerosis complex genes, dTsc1 and dTsc2, are growth and size regulators, which inhibit TOR-mediated amino acid availability to S6 kinase and translation initiation. Their ubiquitous as well as muscle-and fat tissue-specific overactivation significantly extends lifespan (Kapahi et al., 2004). Ectopic expression of dPTEN (a phosphatase and tensin homologue) in the fat body prolongs fruit fly life (Hwangbo et al., 2004). "
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