With TOR, Less is more: a key role for the conserved nutrient-sensing TOR pathway in Aging

Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA.
Cell metabolism (Impact Factor: 16.75). 06/2010; 11(6):453-65. DOI: 10.1016/j.cmet.2010.05.001
Source: PubMed

ABSTRACT Target of rapamycin (TOR) is an evolutionarily conserved nutrient-sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Studies in flies, worms, yeast, and mice support the notion that the TOR signaling network modulates aging. TOR is also emerging as a robust mediator of the protective effects of various forms of dietary restriction (DR), which can extend life span and slow the onset of certain age-related diseases across species. Here we discuss how modulating TOR signaling slows aging through downstream processes including mRNA translation, autophagy, endoplasmic reticulum (ER) stress signaling, stress responses, and metabolism. Identifying the mechanisms by which the TOR signaling network works as a pacemaker of aging is a major challenge and may help identify potential drug targets for age-related diseases, thereby facilitating healthful life span extension in humans.

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Available from: Subhash D Katewa, Dec 17, 2013
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    • "IGF and insulin pathways are activated via their cognate membrane receptors inducing a signaling cascade centered in the AKT family of protein kinases that is related to a reduction in life span in model organisms (Miyauchi et al. 2004). On the other hand, the nutrient-dependent activation of mTOR pathway induces a metabolic alteration toward cell growth upon regulation of catabolism mediated by autophagy (Kapahi et al. 2010). Inhibition of this pathway extends life span in model organisms and confers protection against a wide range of age-related pathologies (Johnson et al. 2013). "
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    • "These include the evolutionarily conserved key regulators mTOR, AMPactivated protein kinase (AMPK), insulin/IGF1 and sirtuins. Both calories and macronutrients influence these pathways which have evolved to respond to periods of famine by switching cells and organism from their focus on growth and reproduction, towards survival and resilience (Fig. 3; Kapahi et al. 2010, Speakman & Mitchell 2011, Le Couteur et al. 2012). Although there are at least four key nutrient-sensing pathways implicated in longevity , these interact and share many downstream targets "
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    • "Dietary restriction (DR), the process of reducing caloric intake while maintaining sustainable levels of nutrition, has been shown to delay the onset of ageing and can extend mean and maximum lifespan in various model organisms (Heestand et al., 2013; Wu et al., 2013). However, the mechanisms behind the beneficial effects of DR are still controversial and the decreases of the insulin/IGFR pathway (Kenyon et al., 1993), reactive oxygen species (ROS) generation (Mayhew et al., 1998; Zainal et al., 2000; Wang et al., 2010), regulation of sirtuins (Kaeberlein et al., 1999) and inhibition of the mTOR pathway (Kapahi et al., 2010) have all been suggested. In addition, there seems to be a large influence of the genotype on longevity after DR (Liao et al., 2010). "
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