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      Stem cell aging: mechanisms, regulators and therapeutic opportunities

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      Nature Medicine

      Springer Science and Business Media LLC

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          Abstract

          Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both supporting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic 'memory' that is indelibly written or one that can be reset.

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          Most cited references 189

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          Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases.

          A range of human degenerative conditions, including Alzheimer's disease, light-chain amyloidosis and the spongiform encephalopathies, is associated with the deposition in tissue of proteinaceous aggregates known as amyloid fibrils or plaques. It has been shown previously that fibrillar aggregates that are closely similar to those associated with clinical amyloidoses can be formed in vitro from proteins not connected with these diseases, including the SH3 domain from bovine phosphatidyl-inositol-3'-kinase and the amino-terminal domain of the Escherichia coli HypF protein. Here we show that species formed early in the aggregation of these non-disease-associated proteins can be inherently highly cytotoxic. This finding provides added evidence that avoidance of protein aggregation is crucial for the preservation of biological function and suggests common features in the origins of this family of protein deposition diseases.
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            Stem cells and niches: mechanisms that promote stem cell maintenance throughout life.

            Niches are local tissue microenvironments that maintain and regulate stem cells. Long-predicted from mammalian studies, these structures have recently been characterized within several invertebrate tissues using methods that reliably identify individual stem cells and their functional requirements. Although similar single-cell resolution has usually not been achieved in mammalian tissues, principles likely to govern the behavior of niches in diverse organisms are emerging. Considerable progress has been made in elucidating how the microenvironment promotes stem cell maintenance. Mechanisms of stem cell maintenance are key to the regulation of homeostasis and likely contribute to aging and tumorigenesis when altered during adulthood.
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              mTOR signaling in growth control and disease.

              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. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Nature Medicine
                Nat Med
                Springer Science and Business Media LLC
                1078-8956
                1546-170X
                August 2014
                August 6 2014
                August 2014
                : 20
                : 8
                : 870-880
                Article
                10.1038/nm.3651
                4160113
                25100532
                © 2014

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