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.

Download full-text


Available from: Brian Matthew Zid, Jul 13, 2015
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Biochimica et Biophysica Acta 05/2015; DOI:10.1016/j.bbabio.2015.05.005 · 4.66 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Advancing age is associated with a progressive loss of skeletal muscle (SkM) mass and function. Given the worldwide aging demographics, this is a major contributor to morbidity, escalating socio-economic costs and ultimately mortality. Previously, it has been established that a decrease in regenerative capacity in addition to SkM loss with age coincides with suppression of insulin/insulin-like growth factor signalling pathways. However, genetic or pharmacological modulations of these highly conserved pathways have been observed to significantly enhance life and healthspan in various species, including mammals. This therefore provides a controversial paradigm in which reduced regenerative capacity of skeletal muscle tissue with age potentially promotes longevity of the organism. This paradox will be assessed and considered in the light of the following: (i) the genetic knockout, overexpression and pharmacological models that induce lifespan extension (e.g. IRS-1/s6K KO, mTOR inhibition) versus the important role of these signalling pathways in SkM growth and adaptation; (ii) the role of the sirtuins (SIRTs) in longevity versus their emerging role in SkM regeneration and survival under catabolic stress; (iii) the role of dietary restriction and its impact on longevity versus skeletal muscle mass regulation; (iv) the crosstalk between cellular energy metabolism (AMPK/TSC2/SIRT1) and survival (FOXO) versus growth and repair of SkM (e.g. AMPK vs. mTOR); and (v) the impact of protein feeding in combination with dietary restriction will be discussed as a potential intervention to maintain SkM mass while increasing longevity and enabling healthy aging. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 04/2015; Early View. DOI:10.1111/acel.12342 · 5.94 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Compelling evidence indicates that the mammalian target of rapamycin (mTOR) signaling pathway is involved in cellular senescence, organismal aging and age-dependent diseases. mTOR is a conserved serine/threonine kinase that is known to be part of two different protein complexes: mTORC1 and mTORC2, which differ in some components and in upstream and downstream signalling. In multicellular organisms, mTOR regulates cell growth and metabolism in response to nutrients, growth factors and cellular energy conditions. Growing studies highlight that disturbance in mTOR signalling in the brain affects multiple pathways including glucose metabolism, energy production, mitochondrial function, cell growth and autophagy. All these events are key players in age-related cognitive decline such as development of Alzheimer disease (AD). The current review discusses the main regulatory roles of mTOR signalling in the brain, in particular focusing on autophagy, glucose metabolism and mitochondrial functions. Targeting mTOR in the CNS can offer new prospective for drug discovery; however further studies are needed for a comprehensive understanding of mTOR, which lies at the crossroads of multiple signals involved in AD etiology and pathogenesis. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 03/2015; 101. DOI:10.1016/j.nbd.2015.03.014 · 5.20 Impact Factor
Show more