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: 9.92). 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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    • "The key components of these pathways also regulate stress resistance and lifespan in higher eukaryotes [15]. For example, both serine/ threonine-specific protein kinases Akt and S6K (ribosomal protein S6 kinase), homologues of yeast SCH9, regulate lifespan in higher eukaryotes and inhibition of TOR/S6K signaling extends lifespan in worms, flies, and mice [16] [17]. Also, mice deficient in elements of the RAS pathway have extended health-and lifespan [18]. "
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    • "In addition to reduced IIS, reduced signalling through the target of rapamycin (TOR) signalling pathway has also been shown to modulate lifespan and increase healthspan in model organisms (Kapahi et al., 2004; Kaeberlein et al., 2005; Powers et al., 2006; Hansen et al., 2007; Harrison et al., 2009; Anisimov et al., 2010; Bjedov et al., 2010; Miller et al., 2011; Robida-Stubbs et al., 2012; Zhang et al., 2014). Longevity in humans is also associated with reduced mTOR signalling (Slagboom et al., 2011; Passtoors et al., 2013). "
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    • "Considering that mTOR signalling pathway is involved in multiple processes regulating neuronal functions, it is an attractive candidate to study age-related cognitive decline (Godoy et al., 2014). In the last decade , several studies focused on the effect of mTOR on lifespan and experimental evidence showed that mutations in mTOR increased the lifespan of yeast (Kaeberlein et al., 2005), C. elegans (Vellai et al., 2003), and Drosophila (Kapahi et al., 2004). These data were the first evidence to demonstrate that increased longevity could be achieved through reduction of mTOR signaling and suggested that rapamycin, a specific TOR inhibitor, might slow aging in different species. "
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