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


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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    • "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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    ABSTRACT: Drosophila is one of the most convenient model organisms in the genetics of aging and longevity. Unlike the nematodes, which allow for the detection of new pro-aging genes by knockout and RNAi-mediated knock-down, Drosophila also provides an opportunity to find new pro-longevity genes by driver-induced overexpression. Similar studies on other models are extremely rare. In this review we focused on genes whose overexpression prolongs the life of fruit flies. The majority of longevity-associated genes regulates metabolism and stress resistance, and belong to the IGF-1R, PI3K, PKB, AMPK and TOR metabolic regulation cluster and the FOXO, HDAC, p53 stress response cluster. Copyright © 2015. Published by Elsevier B.V.
    Ageing research reviews 08/2015; DOI:10.1016/j.arr.2015.08.005 · 4.94 Impact Factor
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    • "As has been indicated before, mutants in eat-2 and eat- 6 eat less than wild type worms due to pharyngeal pumping defects creating a chronic CR state in the worm (Lakowski and Hekimi 1998; Raizen et al. 1995). TOR signalling pathway have been consistently related to CR since longevity effects caused by TOR downregulation cannot be further extended by CR (Hansen et al. 2008; Kaeberlein et al. 2005c; Kapahi et al. 2004; Toth et al. 2008). Interestingly, inhibition of TOR by rapamycin reduces protein translation, however mitochondrial respiratory chain components are resistant to this reduction of protein production and respiration actually increases in response to TOR inhibition in flies (Zid et al. 2009). "
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    ABSTRACT: Ageing is accompanied by the accumulation of damaged molecules in cells due to the injury produced by external and internal stressors. Among them, reactive oxygen species produced by cell metabolism, inflammation or other enzymatic processes are considered key factors. However, later research has demonstrated that a general mitochondrial dysfunction affecting electron transport chain activity, mitochondrial biogenesis and turnover, apoptosis, etc., seems to be in a central position to explain ageing. This key role is based on several effects from mitochondrial-derived ROS production to the essential maintenance of balanced metabolic activities in old organisms. Several studies have demonstrated caloric restriction, exercise or bioactive compounds mainly found in plants, are able to affect the activity and turnover of mitochondria by increasing biogenesis and mitophagy, especially in postmitotic tissues. Then, it seems that mitochondria are in the centre of metabolic procedures to be modified to lengthen life- or health-span. In this review we show the importance of mitochondria to explain the ageing process in different models or organisms (e.g. yeast, worm, fruitfly and mice). We discuss if the cause of aging is dependent on mitochondrial dysfunction of if the mitochondrial changes observed with age are a consequence of events taking place outside the mitochondrial compartment.
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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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    ABSTRACT: Dietary restriction (DR) attenuates many detrimental effects of aging and consequently promotes health and increases longevity across organisms. While over the last 15 years extensive research has been devoted towards understanding the biology of aging, the precise mechanistic aspects of DR are yet to be settled. Abundant experimental evidence indicates that the DR effect on stimulating health impinges several metabolic and stress-resistance pathways. Downstream effects of these pathways include a reduction in cellular damage induced by oxidative stress, enhanced efficiency of mitochondrial functions and maintenance of mitochondrial dynamics and quality control, thereby attenuating age-related declines in mitochondrial function. However, the literature also accumulates conflicting evidence regarding how DR ameliorates mitochondrial performance and whether that is enough to slow age-dependent cellular and organismal deterioration. Here, we will summarize the current knowledge about how and to which extent the influence of different DR regimes on mitochondrial biogenesis and function contribute to postpone the detrimental effects of aging on healthspan and lifespan. Copyright © 2015. Published by Elsevier B.V.
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