Article

Signaling networks in aging

Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Journal of Cell Science (Impact Factor: 5.33). 03/2008; 121(Pt 4):407-12. DOI: 10.1242/jcs.021519
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Available from: Eric L Greer, Aug 28, 2015
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    • "The main cellular pathways involved in the control of life span in complex organisms are summarized in Fig. 2. All these pathways together form an entangled and interconnected regulatory framework which is part of the aging hallmarks (Lopez-Otin et al. 2013). Insulin, insulin-like growth factor, and mTOR pathways showed crucial roles over organism life span, being highly conserved among species (Greer and Brunet 2008). 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). "
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    ABSTRACT: Aging is a universal phenomenon in metazoans, characterized by a general decline of the organism physiology associated with an increased risk of mortality and morbidity. Aging of an organism correlates with a decline in function of its cells, as shown for muscle, immune, and neuronal cells. As the DNA content of most cells within an organism remains largely identical throughout the life span, age-associated transcriptional changes must be achieved by epigenetic mechanisms. However, how aging may impact on the epigenetic state of cells is only beginning to be understood. In light of a growing number of studies demonstrating that noncoding RNAs can provide molecular signals that regulate expression of protein-coding genes and define epigenetic states of cells, we hypothesize that noncoding RNAs could play a direct role in inducing age-associated profiles of gene expression. In this context, the role of long noncoding RNAs (lncRNAs) as regulators of gene expression might be important for the overall transcriptional landscape observed in aged human cells. The possible functions of lncRNAs and other noncoding RNAs, and their roles in the regulation of aging-related cellular pathways will be analyzed.
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    • "Functional changes are characterized by increased aortic stiffness, endothelial dysfunction, and subsequent systolic hypertension. These alterations are regulated by signaling pathways activated by endogenous and exogenous factors [3] [4] [5]. On a cellular level, decreased protein synthesis, dysfunctional mitochondria, oxidative stress, impaired antioxidant defense mechanisms, disturbed calcium handling, and increased DNA and protein oxidation have been proposed [6] [7] [8] [9]. "
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    ABSTRACT: Aging leads to a number of disadvantageous changes in the cardiovascular system. Deterioration of vascular homoeostasis with increase in oxidative stress, chronic low-grade inflammation, and impaired nitric oxide bioavailability results in endothelial dysfunction, increased vascular stiffness, and compromised arterial-ventricular interactions. A chronic dietary supplementation with the micronutrient nitrate has been demonstrated to improve vascular function. Healthy dietary patterns may regulate gene expression profiles. However, the mechanisms are incompletely understood. The changes that occur at the gene expression level and transcriptional profile following a nutritional modification with nitrate have not been elucidated. To determine the changes of the vascular transcriptome, we conducted gene expression microarray experiments on aortas of old mice, which were treated with dietary nitrate. Our results highlight differentially expressed genes overrepresented in gene ontology categories. Molecular interaction and reaction pathways involved in the calcium-signaling pathway and the detoxification system were identified. Our results provide novel insight to an altered gene-expression profile in old mice following nitrate supplementation. This supports the general notion of nutritional approaches to modulate age-related changes of vascular functions and its detrimental consequences.
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    • "The activation of Foxo in conditions of low insulin signaling can thus shift energy resources from anabolic functions to cellular preservation and repair. This central role as a switch between anabolism and repair is reflected in the importance of the C. elegans Foxo homologue Daf16 in both dauer formation (where developing worms enter developmental and metabolic arrest under nutrient deprivation or stress) and longevity (Kenyon et al., 1993; Giannakou et al., 2004; Hwangbo et al., 2004; Wang et al., 2005; Greer and Brunet, 2008). Highlighting the importance of Foxo in regulating cellular stress responses, its activity is not only controlled by insulin signaling, but can also be stimulated by stress-response signaling pathways. "
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    ABSTRACT: Aging is characterized by a widespread loss of homeostasis in biological systems. An important part of this decline is caused by age-related deregulation of regulatory processes that coordinate cellular responses to changing environmental conditions, maintaining cell and tissue function. Studies in genetically accessible model organisms have made significant progress in elucidating the function of such regulatory processes and the consequences of their deregulation for tissue function and longevity. Here, we review such studies, focusing on the characterization of processes that maintain metabolic and proliferative homeostasis in the fruitfly Drosophila melanogaster. The primary regulatory axis addressed in these studies is the interaction between signaling pathways that govern the response to oxidative stress, and signaling pathways that regulate cellular metabolism and growth. The interaction between these pathways has important consequences for animal physiology, and its deregulation in the aging organism is a major cause for increased mortality. Importantly, protocols to tune such interactions genetically to improve homeostasis and extend lifespan have been established by work in flies. This includes modulation of signaling pathway activity in specific tissues, including adipose tissue and insulin-producing tissues, as well as in specific cell types, such as stem cells of the fly intestine.
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