The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.

mTOR Signaling in Growth Control and Disease

mTOR signaling in growth control and disease.

mTOR Signaling in Growth, Metabolism, and Disease.

Resveratrol (3,5,49-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-c coactivator 1a (PGC-1a) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.

/pdf/resveratrol-improves-health-and-survival-of-mice-on-a-high-nclsf2ace3.pdf

Resveratrol improves health and survival of mice on a high-calorie diet

In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.

/pdf/mtor-from-growth-signal-integration-to-cancer-diabetes-and-503skey4mb.pdf

mTOR: from growth signal integration to cancer, diabetes and ageing

https://www.cell.com/current-biology/pdf/S0960-9822(04)00238-6.pdf

Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway

https://www.cell.com/cell/pdf/S0092-8674(09)00914-3.pdf

4E-BP Extends Lifespan upon Dietary Restriction by Enhancing Mitochondrial Activity in Drosophila

A universal feature of the response to stress and nutrient limitation is transcriptional upregulation of genes that encode proteins important for survival. Under many such conditions, the overall protein synthesis level is reduced, thereby dampening the stress response at the level of protein expression. For example, during glucose starvation in Saccharomyces cerevisiae (yeast), translation is rapidly repressed, yet the transcription of many stress- and glucose-repressed genes is increased. Here we show, using ribosomal profiling and microscopy, that this transcriptionally upregulated gene set consists of two classes: one class produces messenger RNAs that are translated during glucose starvation and are diffusely localized in the cytoplasm, including many heat-shock protein mRNAs; and the other class produces mRNAs that are not efficiently translated during glucose starvation and are concentrated in foci that co-localize with P bodies and stress granules, a class that is enriched for mRNAs involved in glucose metabolism. Surprisingly, the information specifying the differential localization and protein production of these two classes of mRNA is encoded in the promoter sequence: promoter responsiveness to heat-shock factor 1 (Hsf1) specifies diffuse cytoplasmic localization and higher protein production on glucose starvation. Thus, promoter sequences can influence not only the levels of mRNAs but also the subcellular localization of mRNAs and the efficiency with which they are translated, enabling cells to tailor protein production to the environmental conditions.

/pdf/promoter-sequences-direct-cytoplasmic-localization-and-342uqck5wm.pdf

Promoter sequences direct cytoplasmic localization and translation of mRNAs during starvation in yeast

https://escholarship.org/content/qt92z3x04c/qt92z3x04c.pdf?t=onis6m

An Integrated Approach Reveals Regulatory Controls on Bacterial Translation Elongation

In response to stress, cells must quickly reprogram gene expression to adapt and survive. This is achieved in part by altering levels of mRNAs and their translation into proteins. Recently, the formation of two stress-induced messenger ribonucleoprotein (mRNP) assemblies named stress granules and processing bodies has been postulated to directly impact gene expression during stress. These assemblies sequester and concentrate specific proteins and RNAs away from the larger cytoplasm during stress, thereby providing a layer of posttranscriptional gene regulation with the potential to directly impact mRNA levels, protein translation, and cell survival. The function of these granules has generally been ascribed either by the protein components concentrated into them or, more broadly, by global changes that occur during stress. Recent proteome- and transcriptome-wide studies have provided a more complete view of stress-induced mRNP granule composition in varied cell types and stress conditions. However, direct measurements of the phenotypic and functional consequences of stress granule and processing body formation are lacking. This leaves our understanding of their roles during stress incomplete. Continued study into the function of these granules will be an important part in elucidating how cells respond to and survive stressful environmental changes. This article is categorized under: Translation > Translation Regulation RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Export and Localization > RNA Localization.

/pdf/stress-induced-mrnp-granules-form-and-function-of-processing-2hizmqsgv7.pdf

Brian M. Zid

Papers

Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway

4E-BP Extends Lifespan upon Dietary Restriction by Enhancing Mitochondrial Activity in Drosophila

Promoter sequences direct cytoplasmic localization and translation of mRNAs during starvation in yeast

An Integrated Approach Reveals Regulatory Controls on Bacterial Translation Elongation

Stress-induced mRNP granules: Form and function of processing bodies and stress granules.