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Int J Hyperthermia,
2013]
Heat shock proteins (HSP) are molecular chaperones and have been implicated in longevity and aging in many species. Their major functions include chaperoning misfolded or newly synthesised polypeptides, protecting cells from proteotoxic stress, and processing of immunogenic agents. These proteins are expressed constitutively and can be induced by stresses such as heat, oxidative stress and many more. The induction of HSP in aging could potentially maintain protein homeostasis and longevity by refolding the damaged proteins which accumulate during aging and are toxic to cells. HSP are shown to increase life span in model organisms such as Caenorhabditis elegans and decrease aging-related proteotoxicity. Thus, decrease in HSP in aging is associated with disruption of cellular homeostasis which causes diseases such as cancer, cell senescence and neurodegeneration. HSP levels are decreased with aging in most organs including neurons. Aging also causes attenuation or alteration of many signalling pathways as well as the expression of transcription factors such as heat shock factor (HSF). The alteration in regulation and synthesis of Forkhead box O3a (FoxO3a) family of transcription factors as well as major antioxidant enzymes (manganese superoxide dismutase, catalase) are also seen in aging. Among many signalling mechanisms involved in altering longevity and aging, the insulin/IGF-1 pathway and the Sir2 deacetylase are highly significant. This review enquires into the role of some of these pathways in longevity/aging along with HSP.
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Curr Biol,
2003]
The DAF-16 transcription factor controls aging in C. elegans as part of an insulin-like signaling pathway. Identification of a target of DAF-16 has opened a new window into the aging process.
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Cell Cycle,
2006]
A conserved
sir2 deacetylase gene can determine longevity of yeast, flies and worms. Recently we have reported a molecular mechanism of action of the C. elegans homologue
sir-2.1. Our study revealed a novel stress-dependent pathway for lifespan determination in which SIR-2.1 binds to 14-3-3 proteins and a forkhead transcription factor DAF-16 to activate transcription of DAF-16 target genes. DAF-16 has long been known as a central protein in the regulation of lifespan that interfaces with multiple pathways. Recent studies by us and other laboratories suggest that DAF-16 requires co-factors for full activity. In this prospective we review recent literature highlighting the role of SIR-2.1, 14-3-3 and other DAF-16 co-factors in DAF-16 activation.
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Dev Dyn,
2010]
In a remarkably conserved insulin signaling pathway that is well-known for its regulation of longevity in worms, flies, and mammals, the major C. elegans effector of this pathway, DAF-16/FOXO, also modulates many other physiological processes. This raises the question of how DAF-16/FOXO chooses the correct targets to achieve the appropriate response in a particular context. Here, we review current knowledge of tissue-specificity and interacting partners that modulate DAF-16/FOXO functional output.
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Exp Gerontol,
2006]
In Caenorhabditis elegans, the insulin/IGF-1 signaling pathway controls many biological processes such as life span, fat storage, dauer diapause, reproduction and stress response . This pathway is comprised of many genes including the insulin/IGF-1 receptor (DAF-2) that signals through a conserved PI 3-kinase/AKT pathway and ultimately down-regulates DAF-16, a forkhead transcription factor (FOXO). DAF-16 also receives input from several other pathways that regulate life span such as the germline and the JNK pathway [Hsin, H., Kenyon, C., 1999. Signals from the reproductive system regulate the lifespan of C. elegans. Nature 399, 362-366; Oh, S.W., Mukhopadhyay, A., Svrzikapa, N., Jiang, F., Davis, R.J., Tissenbaum, H.A., 2005. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc. Natl. Acad. Sci. USA 102, 4494-4499]. Therefore, DAF-16 integrates signals from multiple pathways and regulates its downstream target genes to control diverse processes. Here, we discuss the signals to and from DAF-16, with a focus on life span regulation.
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Biochim Biophys Acta,
2010]
The enzymes of O-GlcNAc cycling couple the nutrient-dependent synthesis of UDP-GlcNAc to O-GlcNAc modification of Ser/Thr residues of key nuclear and cytoplasmic targets. This series of reactions culminating in O-GlcNAcylation of targets has been termed the hexosamine signaling pathway (HSP). The evolutionarily ancient enzymes of O-GlcNAc cycling have co-evolved with other signaling effecter molecules; they are recruited to their targets by many of the same mechanisms used to organize canonic kinase-dependent signaling pathways. This co-recruitment of the enzymes of O-GlcNAc cycling drives a binary switch impacting pathways of anabolism and growth (nutrient uptake) and catabolic pathways (nutrient sparing and salvage). The hexosamine signaling pathway (HSP) has thus emerged as a versatile cellular regulator modulating numerous cellular signaling cascades influencing growth, metabolism, cellular stress, circadian rhythm, and host-pathogen interactions. In mammals, the nutrient-sensing HSP has been harnessed to regulate such cell-specific functions as neutrophil migration, and activation of B-cells and T-cells. This review summarizes the diverse approaches being used to examine O-GlcNAc cycling. It will emphasize the impact O-GlcNAcylation has upon signaling pathways that may be become deregulated in diseases of the immune system, diabetes mellitus, cancer, cardiovascular disease, and neurodegenerative diseases.
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Biogerontology,
2015]
In C. elegans, mutations in the conserved insulin/IGF-1 signaling (IIS) pathway lead to a robust extension in lifespan, improved late life health, and protection from age-related disease. These effects are mediated by the FoxO transcription factor DAF-16 which lies downstream of the IIS kinase cascade. Identifying and functionally testing DAF-16 target genes has been a focal point of ageing research for the last 10years. Here, I review the recent advances in identifying and understanding IIS/DAF-16 targets. These studies continue to reveal the intricate nature of the IIS/DAF-16 gene regulation network and are helping us to understand the mechanisms that control lifespan. Ageing and age related disease is an area of intense public interest, and the biochemical characterization of the genes involved will be critical for identifying drugs to improve the health of our ageing population.
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Physiol Genomics,
2003]
Life developed in a stressful environment. Stressors at the cellular level include heat, hypoxia, oxidative or reductive substances, mechanical or osmotic pressure, and toxic compounds like heavy metals. Various molecular pathways, more or less specific for the different stressors, developed during evolution to combat the molecular consequences of cell stress. Thermal stress induces the induction of a highly conserved protein family, the heat shock proteins (HSP).
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Ann N Y Acad Sci,
2010]
In the nematode Caenorhabditis elegans and the fruit fly Drosophila, loss of the germline stem cells activates lifespan-extending FOXO-family transcription factors in somatic tissues and extends lifespan, suggesting the existence of an evolutionarily conserved pathway that links reproductive state and aging. Consistent with this idea, reproductive tissues have been shown to influence the lifespans of mice and humans as well. In C. elegans, loss of the germ cells activates a pathway that triggers nuclear localization of the FOXO transcription factor DAF-16 in endodermal tissue. DAF-16 then acts in the endoderm to activate downstream lifespan-extending genes. DAF-16 is also required for inhibition of insulin/insulin-like growth factor 1 (IGF-1) signaling to extend lifespan. However, the mechanisms by which inhibition of insulin/IGF-1 signaling and germline loss activate DAF-16/FOXO are distinct. As loss of the germ cells further doubles the already-long lifespan of insulin/IGF-1 pathway mutants, a better understanding of this reproductive longevity pathway could potentially suggest powerful ways to increase healthy lifespan in humans.
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Front Pharmacol,
2017]
Aging is associated with age-related diseases and an increase susceptibility of cancer. Dissecting the molecular mechanisms that underlie aging and longevity would contribute to implications for preventing and treating the age-dependent diseases or cancers. Multiple signaling pathways such as the insulin/IGF-1 signaling pathway, TOR signaling, AMPK pathway, JNK pathway and germline signaling have been found to be involved in aging and longevity. And DAF-16/FOXO, as a key transcription factor, could integrate different signals from these pathways to modulate aging, and longevity via shuttling from cytoplasm to nucleus. Hence, understanding how DAF-16/FOXO functions will be pivotal to illustrate the processes of aging and longevity. Here, we summarized how DAF-16/FOXO receives signals from these pathways to affect aging and longevity. We also briefly discussed the transcriptional regulation and posttranslational modifications of DAF-16/FOXO, its co-factors as well as its potential downstream targets participating in lifespan according to the published data in C. elegans and in mammals, and in most cases, we may focus on the studies in C. elegans which has been considered to be a very good animal model for longevity research.