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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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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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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.
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Exp Gerontol,
2006]
The insulin/IGF-1 receptor (IIR)/FOXO pathway is remarkably conserved in worms, flies, and mammals, and downregulation of signaling in this pathway has been shown to extend lifespan in all of these animals. FOXO-mediated transcription is required for the long lifespan of IIR mutants; thus, there is great interest in identifying FOXO target genes, as they may carry out the biochemical activities that extend longevity. A number of approaches have been used to identify the transcriptional targets of FOXO. Thus far, the best data available on the components downstream of this pathway are from experiments involving the Caenorhabditis elegans FOXO transcription factor, DAF-16; some of these targets have been tested for their contributions to longevity, dauer formation, and fat storage. Here, I examine and compare the approaches used to identify DAF-16/FOXO targets, review the genes regulated by DAF-16, and discuss the processes that may be at work to extend lifespan in IIR mutants. Rather than upregulating every possible beneficial gene, DAF-16 appears to selectively upregulate genes that contribute to specific protective mechanisms, while simultaneously downregulating potentially deleterious genes. In addition to genes that carry out expected roles in stress protection, many previously unknown targets have been identified in these studies, suggesting that some mechanisms of lifespan extension still await discovery. These mechanisms may act cooperatively or cumulatively to increase longevity, and are likely to be at least partially conserved in higher organisms.
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Ann Bot,
2017]
BACKGROUND: Plant-parasitic nematode interactions occur within a vast molecular plant immunity network. Following initial contact with the host plant roots, plant-parasitic nematodes (PPNs) activate basal immune responses. Defence priming involves the release in the apoplast of toxic molecules derived from reactive species or secondary metabolism. In turn, PPNs must overcome the poisonous and stressful environment at the plant-nematode interface. The ability of PPNs to escape this first line of plant immunity is crucial and will determine its virulence. SCOPE: Nematodes trigger crucial regulatory cytoprotective mechanisms, including antioxidant and detoxification pathways. Knowledge of the upstream regulatory components that contribute to both of these pathways in PPNs remains elusive. In this review, we discuss how PPNs probably orchestrate cytoprotection to resist plant immune responses, postulating that it may be derived from ancient molecular mechanisms. The review focuses on two transcription factors, DAF-16 and SKN-1, which are conserved in the animal kingdom and are central regulators of cell homeostasis and immune function. Both regulate the unfolding protein response and the antioxidant and detoxification pathways. DAF-16 and SKN-1 target a broad spectrum of Caenorhabditis elegans genes coding for numerous protein families present in the secretome of PPNs. Moreover, some regulatory elements of DAF-16 and SKN-1 from C. elegans have already been identified as important genes for PPN infection. CONCLUSION: DAF-16 and SKN-1 genes may play a pivotal role in PPNs during parasitism. In the context of their hub status and mode of regulation, we suggest alternative strategies for control of PPNs through RNAi approaches.
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Exp Gerontol,
2007]
The nematode Caenorhabditis elegans has proven to be a very useful tool for studying the genetics of longevity. Over 70 genes have been found to influence lifespan in this worm. Those related to the Ins/IGF signaling pathway are among the best studied and will be focused on in this review. The master regulator of this pathway, the forkhead transcription factor DAF-16, can activate an enhanced life maintenance program in response to environmental and gonadal inputs. DAF-16 up- and downregulates expression of many genes leading to metabolic alterations and increased stress and microbial resistance. This is generally confirmed by biochemical and physiological data. Longevity mutants are not hypometabolic and probably produce more reactive oxygen species than wild type. However, their high antioxidant capacity may result in lower oxidative damage. Enhanced molecular turnover rates may also play a role in their longevity phenotype.