Mechanism of biofilm-mediated stress resistance and lifespan extension in C. elegans.
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ABSTRACT:
SUBMITTER: Smolentseva O
PROVIDER: S-EPMC5540977 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The mechanism whereby lactic acid bacteria extend the lifespan of Caenorhabditis elegans has previously been elucidated. However, the role of Weissella species has yet not been studied. We show that Weissella koreensis and Weissella cibaria significantly (p < 0.05) extend the lifespan of C. elegans compared with Escherichia coli OP50 and induce the expression of several genes related to lifespan extension (daf-16, aak-2, jnk-1, sod-3 and hif-1). Oral administration of Weissella altered reactive oxygen species (ROS) production and lowered the accumulation of lipofuscin and increased locomotor activity (which translates to a delay in ageing). Moreover, Weissella-fed C. elegans had decreased body sizes, brood sizes, ATP levels and pharyngeal pumping rates compared with E. coli OP50-fed worms. Furthermore, mutations in sod-3, hif-1 or skn-1 did not alter lifespan extension compared with wild-type C. elegans. However, C. elegans failed to display lifespan extension in loss-of-function mutants of daf-16, aak-2 and jnk-1, which highlights the potential role of these genes in Weissella-induced longevity in C. elegans. Weissella species extend C. elegans lifespan by activating DAF-16 via the c-Jun N-terminal kinase (JNK) pathway, which is related to stress response, and the AMP-activated protein kinase (AMPK)-pathway that is activated by dietary restriction.
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Project description:The translation initiation factor eIF3 is a multi-subunit protein complex that coordinates the assembly of the 43S pre-initiation complex in eukaryotes. Prior studies have demonstrated that not all subunits of eIF3 are essential for the initiation of translation, suggesting that some subunits may serve regulatory roles. Here, we show that loss-of-function mutations in the genes encoding the conserved eIF3k and eIF3l subunits of the translation initiation complex eIF3 result in a 40% extension in lifespan and enhanced resistance to endoplasmic reticulum (ER) stress in Caenorhabditis elegans. In contrast to previously described mutations in genes encoding translation initiation components that confer lifespan extension in C. elegans, loss-of-function mutations in eif-3.K or eif-3.L are viable, and mutants show normal rates of growth and development, and have wild-type levels of bulk protein synthesis. Lifespan extension resulting from EIF-3.K or EIF-3.L deficiency is suppressed by a mutation in the Forkhead family transcription factor DAF-16. Mutations in eif-3.K or eif-3.L also confer enhanced resistance to ER stress, independent of IRE-1-XBP-1, ATF-6, and PEK-1, and independent of DAF-16. Our data suggest a pivotal functional role for conserved eIF3k and eIF3l accessory subunits of eIF3 in the regulation of cellular and organismal responses to ER stress and aging.
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Project description:Hormesis occurs when a low level stress elicits adaptive beneficial responses that protect against subsequent exposure to severe stress. Recent findings suggest that mild oxidative and thermal stress can extend lifespan by hormetic mechanisms. Here we show that the botanical pesticide plumbagin, while toxic to C. elegans nematodes at high doses, extends lifespan at low doses. Because plumbagin is a naphthoquinone that can generate free radicals in vivo, we investigated whether it extends lifespan by activating an adaptive cellular stress response pathway. The C. elegans cap'n'collar (CNC) transcription factor, SKN-1, mediates protective responses to oxidative stress. Genetic analysis showed that skn-1 activity is required for lifespan extension by low-dose plumbagin in C. elegans. Further screening of a series of plumbagin analogs identified three additional naphthoquinones that could induce SKN-1 targets in C. elegans. Naphthazarin showed skn-1dependent lifespan extension, over an extended dose range compared to plumbagin, while the other naphthoquinones, oxoline and menadione, had differing effects on C. elegans survival and failed to activate ARE reporter expression in cultured mammalian cells. Our findings reveal the potential for low doses of naturally occurring naphthoquinones to extend lifespan by engaging a specific adaptive cellular stress response pathway.
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Project description:Dietary restriction (DR) extends lifespan in various species and also slows the onset of age-related diseases. Previous studies from flies and yeast have demonstrated that the target of rapamycin (TOR) pathway is essential for longevity phenotypes resulting from DR. TOR is a conserved protein kinase that regulates growth and metabolism in response to nutrients and growth factors. While some of the downstream targets of TOR have been implicated in regulating lifespan, it is still unclear whether additional targets of this pathway also modulate lifespan. It has been shown that the hypoxia inducible factor-1 (HIF-1) is one of the targets of the TOR pathway in mammalian cells. HIF-1 is a transcription factor complex that plays key roles in oxygen homeostasis, tumor formation, glucose metabolism, cell survival, and inflammatory response. Here, we describe a novel role for HIF-1 in modulating lifespan extension by DR in Caenorhabditis elegans. We find that HIF-1 deficiency results in extended lifespan, which overlaps with that by inhibition of the RSKS-1/S6 kinase, a key component of the TOR pathway. Using a modified DR method based on variation of bacterial food concentrations on solid agar plates, we find that HIF-1 modulates longevity in a nutrient-dependent manner. The hif-1 loss-of-function mutant extends lifespan under rich nutrient conditions but fails to show lifespan extension under DR. Conversely, a mutation in egl-9, which increases HIF-1 activity, diminishes the lifespan extension under DR. This deficiency is rescued by tissue-specific expression of egl-9 in specific neurons and muscles. Increased lifespan by hif-1 or DR is dependent on the endoplasmic reticulum (ER) stress regulator inositol-requiring protein-1 (IRE-1) and is associated with lower levels of ER stress. Therefore, our results demonstrate a tissue-specific role for HIF-1 in the lifespan extension by DR involving the IRE-1 ER stress pathway.
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Project description:A high-sugar diet has been associated with reduced lifespan in organisms ranging from worms to mammals. However, the mechanisms underlying the harmful effects of glucose are poorly understood. Here we establish a causative relationship between endogenous glucose storage in the form of glycogen, resistance to oxidative stress and organismal aging in Caenorhabditis elegans. We find that glycogen accumulated on high dietary glucose limits C. elegans longevity. Glucose released from glycogen and used for NADPH/glutathione reduction renders nematodes and human hepatocytes more resistant against oxidative stress. Exposure to low levels of oxidants or genetic inhibition of glycogen synthase depletes glycogen stores and extends the lifespan of animals fed a high glucose diet in an AMPK-dependent manner. Moreover, glycogen interferes with low insulin signalling and accelerates aging of long-lived daf-2 worms fed a high glucose diet. Considering its extensive evolutionary conservation, our results suggest that glycogen metabolism might also have a role in mammalian aging.
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Project description:Reducing protein synthesis slows growth and development but can increase adult lifespan. We demonstrate that knock-down of eukaryotic translation initiation factor 4G (eIF4G), which is down-regulated during starvation, results in differential translation of genes important for growth and longevity in C. elegans. Genome-wide mRNA translation state analysis showed that inhibition of IFG-1, the C. elegans ortholog of eIF4G, results in a relative increase in ribosomal loading and translation of stress response genes. Some of these genes are required for lifespan extension when IFG-1 is inhibited and are new determinants of longevity. Furthermore, enhanced ribosomal loading of certain mRNAs upon IFG-1 inhibition was correlated with increased mRNA length. This association was supported by changes in the proteome assayed via quantitative mass spectrometry. Our results support a role for IFG-1 in mediating the antagonistic effects on growth and somatic maintenance by modulating translation of a specific class of mRNA based on transcript length. 24 experimental samples were analyzed using custom oligo microarrays. A wild type sample pool was used as the Cy3 reference/control for all experimetal samples. All extracted RNA prior to array analysis was fractioned (via a sucrose gradient) based on ribosomal loading and pooled into ribosomal and free RNA (Fraction1), light polysomes (Fraction2) and heavy polysomes (Fraction3) as described in the experimental procedures. The control RNAi is ‘empty’ vector L4440 RNAi feeding vector plasmid (1999 Firelab vector kit) transformed HT115(DE3), which was obtained from the Caenorhabditis Genetics Center (University of Wisconsin).
2011-04-16 | E-GEOD-28665 | biostudies-arrayexpress
Project description:Moderate stress can increase lifespan by hormesis, a beneficial low-level induction of stress response pathways. 5'-fluorodeoxyuridine (FUdR) is commonly used to sterilize Caenorhabditis elegans in aging experiments. However, FUdR alters lifespan in some genotypes and induces resistance to thermal and proteotoxic stress. We report that hypertonic stress in combination with FUdR treatment or inhibition of the FUdR target thymidylate synthase, TYMS-1, extends C. elegans lifespan by up to 30%. By contrast, in the absence of FUdR, hypertonic stress decreases lifespan. Adaptation to hypertonic stress requires diminished Notch signaling and loss of Notch co-ligands leads to lifespan extension only in combination with FUdR. Either FUdR treatment or TYMS-1 loss induced resistance to acute hypertonic stress, anoxia, and thermal stress. FUdR treatment increased expression of DAF-16 FOXO and the osmolyte biosynthesis enzyme GPDH-1. FUdR-induced hypertonic stress resistance was partially dependent on sirtuins and base excision repair (BER) pathways, while FUdR-induced lifespan extension under hypertonic stress conditions requires DAF-16, BER, and sirtuin function. Combined, these results demonstrate that FUdR, through inhibition of TYMS-1, activates stress response pathways in somatic tissues to confer hormetic resistance to acute and chronic stress. C. elegans lifespan studies using FUdR may need re-interpretation in light of this work.
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Project description:One goal of aging research is to find drugs that delay the onset of age-associated disease. Studies in invertebrates, particularly Caenorhabditis elegans, have uncovered numerous genes involved in aging, many conserved in mammals. However, which of these encode proteins suitable for drug targeting is unknown. To investigate this question, we screened a library of compounds with known mammalian pharmacology for compounds that increase C. elegans lifespan. We identified 60 compounds that increase longevity in C. elegans, 33 of which also increased resistance to oxidative stress. Many of these compounds are drugs approved for human use. Enhanced resistance to oxidative stress was associated primarily with compounds that target receptors for biogenic amines, such as dopamine or serotonin. A pharmacological network constructed with these data reveal that lifespan extension and increased stress resistance cluster together in a few pharmacological classes, most involved in intercellular signaling. These studies identify compounds that can now be explored for beneficial effects on aging in mammals, as well as tools that can be used to further investigate the mechanisms underlying aging in C. elegans.
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Project description:Reducing protein synthesis slows growth and development but can increase adult lifespan. We demonstrate that knock-down of eukaryotic translation initiation factor 4G (eIF4G), which is down-regulated during starvation, results in differential translation of genes important for growth and longevity in C. elegans. Genome-wide mRNA translation state analysis showed that inhibition of IFG-1, the C. elegans ortholog of eIF4G, results in a relative increase in ribosomal loading and translation of stress response genes. Some of these genes are required for lifespan extension when IFG-1 is inhibited and are new determinants of longevity. Furthermore, enhanced ribosomal loading of certain mRNAs upon IFG-1 inhibition was correlated with increased mRNA length. This association was supported by changes in the proteome assayed via quantitative mass spectrometry. Our results support a role for IFG-1 in mediating the antagonistic effects on growth and somatic maintenance by modulating translation of a specific class of mRNA based on transcript length.
2011-04-16 | GSE28665 | GEO
Project description:NDG-4 is a predicted transmembrane acyltransferase protein that acts in the distribution of lipophilic factors. Consequently, ndg-4 mutants lay eggs with a pale appearance due to lack of yolk, and they are resistant to sterility caused by dietary supplementation with the long-chain omega-6 polyunsaturated fatty acid dihommogamma-linolenic acid (DGLA). Two other proteins, NRF-5 and NRF-6, a homolog of a mammalian secreted lipid binding protein and a NDG-4 homolog, respectively, have previously been shown to function in the same lipid transport pathway. Here, we report that mutation of the NDG-4 protein results in increased organismal stress resistance and lifespan. When NDG-4 function and insulin/IGF-1 signaling are reduced simultaneously, maximum lifespan is increased almost fivefold. Thus, longevity conferred by mutation of ndg-4 is partially overlapping with insulin signaling. The nuclear hormone receptor NHR-80 (HNF4 homolog) is required for longevity in germline less animals. We find that NHR-80 is also required for longevity of ndg-4 mutants. Moreover, we find that nrf-5 and nrf-6 mutants also have extended lifespan and increased stress resistance, suggesting that altered lipid transport and metabolism play key roles in determining lifespan.
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