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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
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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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    • "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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    ABSTRACT: The cornea protects the anterior eye and accounts for two thirds of the eyes refractive capacity. The homeostasis of corneal epithelium is thought to be maintained by putative stem cells residing in the epithelial basal layer. As a tissue constantly exposed to environmental stress, the cornea is hypothesised to accumulate persistent DNA damage events with time in stem cell populations. Recently, telomere associated DNA damage foci (TAF) have been suggested as a marker for persistent DNA damage which can be used to detect senescent cells during ageing. Dietary restriction (DR) is the only known non-genetic intervention that is able to increase both life and health span among various animal species. The aim of this study was to analyse changes in corneal properties with age and under 16 months of DR. We employed immunofluorescence staining for ɣH2A.X together with telomere fluorescence in situ hybridisation (immuno-FISH) on mouse corneas from young, old ad libitum fed (AL) as well as dietary restricted (DR) mice. Our data show that the central corneas of old mice had significantly more general and telomere-associated DNA damage compared to young mice while DR treatment was able to reduce the amount of DNA damage significantly. We also found that the thickness of the peripheral region of the cornea, where the putative stem cells may reside, decreased with age regardless of whether the animals underwent DR treatment or not. Number of bullae, which indicates corneal edema, accumulated in old corneas in the central area and DR treatment mitigated the formation of these bullae. Moreover, the protein levels of the stem cell marker TAp63 decreased with age only in the central but not the peripheral region of the cornea. This finding suggests that epithelial progenitors might be better maintained in the peripheral than the central cornea during ageing. Together with the finding that the peripheral corneal showed no increase in DNA damage during age, we speculate that in mice, like humans, the putative stem cells reside in the peripheral cornea. Copyright © 2015. Published by Elsevier Inc.
    Experimental gerontology 04/2015; 67. DOI:10.1016/j.exger.2015.04.014 · 3.53 Impact Factor
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    • "DR is sufficient to reduce mTORC1 activity in each of the organisms where it has been shown to increase lifespan, and epistasis studies have placed DR in the same genetic pathway as mTORC1 with respect to lifespan in yeast (Kaeberlein et al., 2005; Steffen et al., 2008), nematodes (Ching et al., 2010), and fruit flies (Kapahi et al., 2004; Zid et al., 2009). These observations, along with the fact that mTORC1 inhibition is sufficient to extend lifespan in each of these species, has led to the general consensus that inhibition of mTORC1 plays a direct role in promoting longevity and healthspan in response to DR (Kapahi et al., 2010; Kaeberlein, 2013a). As of early 2014, at least seven independent studies have reported lifespan extension from rapamycin in wild type mice (Table 1), with most studies using a dietary formulation where rapamycin is encapsulated for enteric release (Nadon et al., 2008). "
    Journal of Genetics and Genomics 09/2014; 41(9). DOI:10.1016/j.jgg.2014.06.009 · 2.92 Impact Factor
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    • "The results described here point to ceramide as a novel regulator of protein synthesis in C2C12 cells. The rate of protein synthesis is governed by a number of cellular controls, including signaling by the mTOR and eIF2 pathways (Kennedy & Kaeberlein, 2009; Kapahi et al., 2010; Kaeberlein & Kennedy, 2011). At variance with in vitro observations (Deldicque et al., 2010), but in line with in vivo data (Khamzina et al., 2005), the activity of the mTOR pathway, on which insulin and amino acid availability exert a positive influence, was unaffected in the present study. "
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    ABSTRACT: Obesity and aging are characterized by decreased insulin sensitivity (IS) and muscle protein synthesis. Intramuscular ceramide accumulation has been implicated in insulin resistance during obesity. We aimed to measure IS, muscle ceramide level, protein synthesis, and activation of intracellular signaling pathways involved in translation initiation in male Wistar young (YR, 6-month) and old (OR, 25-month) rats receiving a low- (LFD) or a high-fat diet (HFD) for 10 weeks. A corresponding cellular approach using C2C12 myotubes treated with palmitate to induce intracellular ceramide deposition was taken. A decreased ability of adipose tissue to store lipids together with a reduced adipocyte diameter and a development of fibrosis were observed in OR after the HFD. Consequently, OR fed the HFD were insulin resistant, showed a strong increase in intramuscular ceramide level and a decrease in muscle protein synthesis associated with increased eIF2α phosphorylation. The accumulation of intramuscular lipids placed a lipid burden on mitochondria and created a disconnect between metabolic and regulating pathways in skeletal muscles of OR. In C2C12 cells, palmitate-induced ceramide accumulation was associated with a decreased protein synthesis together with upregulated eIF2α phosphorylation. In conclusion, a reduced ability to expand adipose tissues was found in OR, reflecting a lower lipid buffering capacity. Muscle mitochondrial activity was affected in OR conferring a reduced ability to oxidize fatty acids entering the muscle cell. Hence, OR were more prone to ectopic muscle lipid accumulation than YR, leading to decreased muscle protein anabolism. This metabolic change is a potential therapeutic target to counter sarcopenic obesity.
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