Bacterial Nitric Oxide Extends the Lifespan of C. elegans

Gusarov, Ivan; Gautier, Laurent; Smolentseva, Olga; Shamovsky, Ilya; Eremina, Svetlana; Mironov, A. S.; Nudler, Evgeny

doi:10.1016/j.cell.2012.12.043

Cited by 168 publications

(176 citation statements)

References 66 publications

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“…TSA has been shown chemically to produce NO when it is oxidized (Samuni et al ., 2010) and hence could potentially produce NO in worms. C. elegans have been shown to live longer when fed NO‐producing bacteria in a process that results in hsp16 activation (Gusarov et al ., 2013). Increases in the heat shock protein hsp16 have been shown to increase lifespan in C. elegans in a DAF‐16‐dependent manner (Walker & Lithgow, 2003).…”

Section: Discussionmentioning

confidence: 99%

A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans

et al. 2015

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SummaryCaloric restriction (CR), a reduction in calorie intake without malnutrition, retards aging in several animal models from worms to mammals. Developing CR mimetics, compounds that reproduce the longevity benefits of CR without its side effects, is of widespread interest. Here, we employed the Connectivity Map to identify drugs with overlapping gene expression profiles with CR. Eleven statistically significant compounds were predicted as CR mimetics using this bioinformatics approach. We then tested rapamycin, allantoin, trichostatin A, LY‐294002 and geldanamycin in Caenorhabditis elegans. An increase in lifespan and healthspan was observed for all drugs except geldanamycin when fed to wild‐type worms, but no lifespan effects were observed in eat‐2 mutant worms, a genetic model of CR, suggesting that life‐extending effects may be acting via CR‐related mechanisms. We also treated daf‐16 worms with rapamycin, allantoin or trichostatin A, and a lifespan extension was observed, suggesting that these drugs act via DAF‐16‐independent mechanisms, as would be expected from CR mimetics. Supporting this idea, an analysis of predictive targets of the drugs extending lifespan indicates various genes within CR and longevity networks. We also assessed the transcriptional profile of worms treated with either rapamycin or allantoin and found that both drugs use several specific pathways that do not overlap, indicating different modes of action for each compound. The current work validates the capabilities of this bioinformatic drug repositioning method in the context of longevity and reveals new putative CR mimetics that warrant further studies.

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Section: Discussionmentioning

confidence: 99%

A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans

et al. 2015

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“…Because diet is an important extrinsic cue that modulates aging, we predict that alterations in the physiologic status of the gut microbiome could have an effect on the host lifespan via activation of mitochondrial homeostatic pathways. In fact, several previous studies suggest that the microbial diet may influence aging in C. elegans (7,(45)(46)(47)(48).…”

Section: (E) Feedingmentioning

confidence: 99%

Dialogue between E. coli free radical pathways and the mitochondria of C. elegans

Govindan

Jayamani

Zhang

et al. 2015

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

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The microbial world presents a complex palette of opportunities and dangers to animals, which have developed surveillance and response strategies to hints of microbial intent. We show here that the mitochondrial homeostatic response pathway of the nematode Caenorhabditis elegans responds to Escherichia coli mutations that activate free radical detoxification pathways. Activation of C. elegans mitochondrial responses could be suppressed by additional mutations in E. coli, suggesting that C. elegans responds to products of E. coli to anticipate challenges to its mitochondrion. Out of 50 C. elegans gene inactivations known to mediate mitochondrial defense, we found that 7 genes were required for C. elegans response to a free radical producing E. coli mutant, including the bZip transcription factor atfs-1 (activating transcription factor associated with stress). An atfs-1 lossof-function mutant was partially resistant to the effects of free radical-producing E. coli mutant, but a constitutively active atfs-1 mutant growing on wild-type E. coli inappropriately activated the pattern of mitochondrial responses normally induced by an E. coli free radical pathway mutant. Carbonylated proteins from free radical-producing E. coli mutant may directly activate the ATFS-1/bZIP transcription factor to induce mitochondrial stress response: feeding C. elegans with H 2 O 2 -treated E. coli induces the mitochondrial unfolded protein response, and inhibition of a gut peptide transporter partially suppressed C. elegans response to free radical damaged E. coli. mitochondria | C. elegans | host-microbe dialogue A nimals, plants, and other eukaryotes do not live in a germ-free environment. Their accessible surfaces are in contact with diverse bacterial species, which have relationships that range from benign to mutual to commensal to pathogenic. In fact, given that modern eukaryotes represent multiple probable ancient fusions of archaeal and bacterial cells, there have always been bacteria in the eukaryotic environment, and eukaryotes at the moment of their genesis were in dialogue with the probable symbiotic bacteria that they engulfed. Bacterial microflora is now intensively studied as the gut microbiota of many vertebrates and invertebrates (1). In the gut, microbes are afforded an anaerobic environment, in which a billion years of bacterial evolution before the emergence of oxygenic photosynthesis and 500 million years of animal guts have generated diverse anaerobic bacteria and a relatively safe environment and abundant nutrients in a circadian rhythm as animals feed (2). In return, gut microbes protect the host against pathogens by occupying niches and facilitate digestion, which enables the synthesis and metabolism of nutrients, energy generation, and vitamin biosynthesis. However, the dialogues between microbes and host are only beginning to be understood. Understanding the factors that affect microbial metabolism and signaling may reveal how microbes regulate animal physiology and aging.Here we study the dialogue between the n...

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“…In Gram-positive bacteria, bNOS-produced NO has been found to modulate macromolecules by nitrosylation (8,9), to function as a commensal molecule (10), to protect against oxidative stress (11), and to detoxify antimicrobials (12). Although the biological function of NO varies among bacterial organisms, the unique ability of NO to protect the pathogens Staphyloccocus aureus and Bacillus anthracis against oxidative and antibioticinduced oxidative stress (12) by activation of catalase and by suppression of damaging Fenton chemistry (11,13) implicates bNOS as a potential therapeutic target.…”

mentioning

confidence: 99%

Structural and biological studies on bacterial nitric oxide synthase inhibitors

Holden

Jing³

et al. 2013

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

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Significance Nitric oxide (NO) produced by bacterial nitric oxide synthase has recently been shown to protect the Gram-positive pathogens Bacillus anthracis and Staphylococcus aureus from antibiotics and oxidative stress. Using Bacillus subtilis as a model system, we identified two NOS inhibitors that work in conjunction with an antibiotic to kill B. subtilis . Moreover, comparison of inhibitor-bound crystal structures between the bacterial NOS and mammalian NOS revealed an unprecedented mode of binding to the bacterial NOS that can be further exploited for future structure-based drug design. Overall, this work is an important advance in developing inhibitors against gram-positive pathogens.

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Bacterial Nitric Oxide Extends the Lifespan of C. elegans

Cited by 168 publications

References 66 publications

A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans

A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans

Dialogue between E. coli free radical pathways and the mitochondria of C. elegans

Structural and biological studies on bacterial nitric oxide synthase inhibitors

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