Transcriptional regulation of Caenorhabditis elegansFOXO/DAF-16 modulates lifespan

Bansal, Ankita; Kwon, Eun-Soo; Conte, Darryl; Li, Haibo; Gilchrist, Michael J.; MacNeil, Lesley T.; Tissenbaum, Heidi A.

doi:10.1186/2046-2395-3-5

Cited by 57 publications

(54 citation statements)

References 81 publications

(118 reference statements)

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“…Both miR-34 and daf-16 expression levels were shown to be increased upon dauer formation2658 and also in adults in an age-dependent manner5960, suggesting a link between these regulators of gene expression. By engineering promoter truncations we showed that an IRE sequence, which binds DAF-16, is present in mir-34 promoter.…”

Section: Discussionmentioning

confidence: 98%

MicroRNA mir-34 provides robustness to environmental stress response via the DAF-16 network in C. elegans

Isik

Blackwell

Berezikov

2016

Sci Rep

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Diverse stresses and aging alter expression levels of microRNAs, suggesting a role for these posttranscriptional regulators of gene expression in stress modulation and longevity. Earlier studies demonstrated a central role for the miR-34 family in promoting cell cycle arrest and cell death following stress in human cells. However, the biological significance of this response was unclear. Here we show that in C. elegans mir-34 upregulation is necessary for developmental arrest, correct morphogenesis, and adaptation to a lower metabolic state to protect animals against stress-related damage. Either deletion or overexpression of mir-34 lead to an impaired stress response, which can largely be explained by perturbations in DAF-16/FOXO target gene expression. We demonstrate that mir-34 expression is regulated by the insulin signaling pathway via a negative feedback loop between miR-34 and DAF-16/FOXO. We propose that mir-34 provides robustness to stress response programs by controlling noise in the DAF-16/FOXO-regulated gene network.

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Section: Discussionmentioning

confidence: 98%

MicroRNA mir-34 provides robustness to environmental stress response via the DAF-16 network in C. elegans

Isik

Blackwell

Berezikov

2016

Sci Rep

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“…We examined the mechanism by which HEL-1 influenced the expression of DAF-16 target genes by assessing known modes of activation, including physical interaction with cofactors (20), nuclear translocation (24)(25)(26), and induction at the transcriptional level (27). We performed coimmunoprecipitation assays in cultured mammalian cells and found that HEL-1 bound to DAF-16 ( Fig.…”

Section: Hel-1 Extends Lifespan By the Induction Of Daf-16/foxo-depenmentioning

confidence: 99%

RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans

Seo

Hwang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The homeostatic maintenance of the genomic DNA is crucial for regulating aging processes. However, the role of RNA homeostasis in aging processes remains unknown. RNA helicases are a large family of enzymes that regulate the biogenesis and homeostasis of RNA. However, the functional significance of RNA helicases in aging has not been explored. Here, we report that a large fraction of RNA helicases regulate the lifespan of Caenorhabditis elegans. In particular, we show that a DEAD-box RNA helicase, helicase 1 (HEL-1), promotes longevity by specifically activating the DAF-16/forkhead box O (FOXO) transcription factor signaling pathway. We find that HEL-1 is required for the longevity conferred by reduced insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) and is sufficient for extending lifespan. We further show that the expression of HEL-1 in the intestine and neurons contributes to longevity. HEL-1 enhances the induction of a large fraction of DAF-16 target genes. Thus, the RNA helicase HEL-1 appears to promote longevity in response to decreased IIS as a transcription coregulator of DAF-16. Because HEL-1 and IIS are evolutionarily well conserved, a similar mechanism for longevity regulation via an RNA helicase-dependent regulation of FOXO signaling may operate in mammals, including humans.arious genetic and environmental factors, including insulin/ insulin-like growth factor 1 (IGF-1) signaling (IIS), target of rapamycin signaling, dietary restriction, mitochondrial respiration, and reproductive systems, influence aging across phyla (reviewed in refs. 1-3). IIS is one of the most evolutionarily conserved pathways involved in the regulation of aging. Mutations in Caenorhabditis elegans daf-2, which encodes an insulin/IGF-1 receptor homolog, double the lifespan of C. elegans (4). Inhibition of DAF-2 reduces phosphatidylinositide 3 (PI3)-kinase signaling, which upregulates several transcription factors, including DAF-16/forkhead box O (FOXO), heat shock factor-1 (HSF-1), and SKN-1/NRF2 (reviewed in refs. 1, 3, and 5). DAF-16 is one of the best characterized of these longevity factors; reduced PI3-kinase signaling leads to the dephosphorylation and nuclear translocation of DAF-16, which up-regulates the expression of various target genes. DAF-16 target genes contribute to longevity by promoting stress resistance, reproductive span, innate immunity, and protein homeostasis.RNA helicases are essential for biogenesis, maturation, processing, and homeostasis of various types of RNAs (reviewed in ref. 6). In addition, RNA helicases work with factors, such as a CREBbinding protein, RNA polymerases I and II, and histone deacetylases, to regulate transcriptional activity (7,8). For example, DDX5 (p68), a DEAD-box RNA helicase, interacts with Smad3, a transcriptional activator and intracellular effector of TGF-β (9), and with RNA polymerase II to modulate transcriptional activity (10). Because RNA helicases comprise a large family of housekeeping proteins essential for RNA biogenesis and homeostasis, their importanc...

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“…C. elegans with partial loss-of-function mutations in daf-2 , the C. elegans insulin/IGF-1-receptor gene, not only live longer but also maintain more youthful characteristics, such as active movement (Huang et al, 2004; Kenyon et al, 1993), neuronal function (Liu et al, 2013) and memory (Kauffman et al, 2010), indicating an extension of healthspan as well as lifespan. However, a recent study followed functional ability of daf-2 mutants and found that the daf-2 healthspan, though chronologically longer than that of wild type, did not scale with lifespan, resulting in a disproportionately extended period of age-related decrepitude (Bansal et al, 2014). This report was disconcerting because such an outcome would be undesirable in a human society, where population aging has already massively increased healthcare costs (Centers for Medicare & Medicaid Services, 2015; Meara et al, 2004), and also brought into question the validity of C. elegans as a model organism to study healthy life extension.…”

Section: Introductionmentioning

confidence: 99%

How a Mutation that Slows Aging Can Also Disproportionately Extend End-of-Life Decrepitude

2017

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Summary The goal of aging research is to extend healthy, active life. For decades, C. elegans daf-2 insulin/IGF-1 receptor mutants have served as a model for extended lifespan and youthfulness. However, a recent report suggested that their longevity is associated with an undesirable phenotype: a disproportionately long period of decrepitude at the end of life. In a human population, such an outcome would be a burden to society, bringing into question the relevance of daf-2 mutants as a model for life extension. However, here we report that, following an extended period of movement, daf-2 mutants survive longer in a decrepit state because of a beneficial trait: they are resistant to colonization of the digestive tract by dietary bacteria, a condition that leads to premature death in wild type and prevents their manifestation of decrepitude. If bacterial colonization is prevented, daf-2 mutants lead chronologically and proportionately healthier lives relative to wild type.

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Transcriptional regulation of Caenorhabditis elegansFOXO/DAF-16 modulates lifespan

Cited by 57 publications

References 81 publications

MicroRNA mir-34 provides robustness to environmental stress response via the DAF-16 network in C. elegans

MicroRNA mir-34 provides robustness to environmental stress response via the DAF-16 network in C. elegans

RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans

How a Mutation that Slows Aging Can Also Disproportionately Extend End-of-Life Decrepitude

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