DAF-16/FoxO in Caenorhabditis elegans and Its Role in Metabolic Remodeling

DAF-16, the only forkhead box transcription factors class O (FoxO) homolog in Caenorhabditis elegans, integrates signals from upstream pathways to elicit transcriptional changes in many genes involved in aging, development, stress, metabolism, and immunity. The major regulator of DAF-16 activity is the insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway, reduction of which leads to lifespan extension in worms, flies, mice, and humans. In C. elegans daf-2 mutants, reduced IIS leads to a heterochronic activation of a dauer survival program during adulthood. This program includes elevated antioxidant defense and a metabolic shift toward accumulation of carbohydrates (i.e., trehalose and glycogen) and triglycerides, and activation of the glyoxylate shunt, which could allow fat-to-carbohydrate conversion. The longevity of daf-2 mutants seems to be partially supported by endogenous trehalose, a nonreducing disaccharide that mammals cannot synthesize, which points toward considerable differences in downstream mechanisms by which IIS regulates aging in distinct groups.

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The Effect of Mianserin on Lifespan of Caenorhabditis elegans is Abolished by Glucose

Current Aging Science ◽

10.2174/1874609813999210104203614 ◽

2021 ◽

Vol 13 ◽

Author(s):

Abdullah Almotayri ◽

Jency Thomas ◽

Mihiri Munasinghe ◽

Markandeya Jois

Keyword(s):

Caenorhabditis Elegans ◽

Scaffolding Protein ◽

Lifespan Extension ◽

Wild Type ◽

E Coli ◽

C Elegans ◽

Risk Of Death ◽

Increased Risk ◽

Antidepressant Use ◽

Extension Effect

Background: The antidepressant mianserin has been shown to extend the lifespan of Caenorhabditis elegans (C. elegans), a well-established model organism used in aging research. The extension of lifespan in C. elegans was shown to be dependent on increased expression of the scaffolding protein (ANK3/unc-44). In contrast, antidepressant use in humans is associated with an increased risk of death. The C. elegans in the laboratory are fed Escherichia coli (E. coli), a diet high in protein and low in carbohydrate, whereas a typical human diet is high in carbohydrates. We hypothesized that dietary carbohydrates might mitigate the lifespan-extension effect of mianserin. Objective: To investigate the effect of glucose added to the diet of C. elegans on the lifespan-extension effect of mianserin. Methods: Wild-type Bristol N2 and ANK3/unc-44 inactivating mutants were cultured on agar plates containing nematode growth medium and fed E. coli. Treatment groups included (C) control, (M50) 50 μM mianserin, (G) 73 mM glucose, and (M50G) 50 μM mianserin and 73 mM glucose. Lifespan was determined by monitoring the worms until they died. Statistical analysis was performed using the Kaplan-Meier version of the log-rank test. Results: Mianserin treatment resulted in a 12% increase in lifespan (P<0.05) of wild-type Bristol N2 worms but reduced lifespan by 6% in ANK3/unc-44 mutants, consistent with previous research. The addition of glucose to the diet reduced the lifespan of both strains of worms and abolished the lifespan-extension by mianserin. Conclusion: The addition of glucose to the diet of C. elegans abolishes the lifespan-extension effects of mianserin.

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PES-1 is expressed during early embryogenesis in Caenorhabditis elegans and has homology to the fork head family of transcription factors

Development ◽

10.1242/dev.120.3.505 ◽

1994 ◽

Vol 120 (3) ◽

pp. 505-514 ◽

Cited By ~ 4

Author(s):

I.A. Hope

Keyword(s):

Transcription Factors ◽

Caenorhabditis Elegans ◽

Cell Lineage ◽

Embryonic Cell ◽

Early Embryogenesis ◽

C Elegans ◽

Promoter Trapping ◽

Fork Head ◽

Initiation Of Transcription ◽

Beta Galactosidase

Promoter trapping has identified a gene, pes-1, which is expressed during C. elegans embryogenesis. The beta-galactosidase expression pattern, directed by the pes-1/lacZ fusion through which this gene was cloned, has been determined precisely in terms of the embryonic cell lineage and has three components. One component is in a subset of cells of the AB founder cell lineage during early embryogenesis, suggesting pes-1 may be regulated both by cell autonomous determinants and by intercellular signals. Analysis of cDNA suggests pes-1 has two sites for initiation of transcription and the two transcripts would encode related but distinct proteins. The predicted PES-1 proteins have homology to the fork head family of transcription factors and therefore may have important regulatory roles in early embryogenesis.

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Piceatannol, a Natural Stilbene, Extends the Lifespan of Caenorhabditis elegans Under Fasting Through Inhibition of Lipolysis

Current Developments in Nutrition ◽

10.1093/cdn/nzaa040_038 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 38-38

Author(s):

Jang Miran ◽

Zhang Yuan ◽

Bai Juan ◽

Jun-Bae An ◽

Park Yeonhwa ◽

...

Keyword(s):

Lipid Metabolism ◽

Caenorhabditis Elegans ◽

Negative Energy ◽

Hormone Sensitive Lipase ◽

Pcr Analysis ◽

Lifespan Extension ◽

Mrna Levels ◽

Free Glycerol ◽

C Elegans ◽

Glycerol Level

Abstract Objectives Lipolysis is the catabolic process that hydrolyzes triglyceride (TG) to free fatty acids (FFAs) and glycerol under negative energy balance such as fasting. In adipocytes, adipose TG lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase play key roles in a series of TG hydrolysis reactions in mammals. However, overly activated adipose lipolysis is believed to contribute to link between obesity and systemic inflammation and oxidative stress. We previously demonstrated that piceatannol (PIC), a natural resveratrol analogue, inhibits adipogenesis in cultured adipocytes and lipogenesis in Caenorhabditis elegans. Furthermore, we showed that PIC extends the lifespan of C. elegans via the insulin/IGF-1 signaling. However, the effects of PIC on lipid metabolism during fasting state is unknown. Methods We conducted Oil-Red-O assay, Enzyme assay (TG and Free glycerol contents), PCR analysis and lifespan assay. Results In this study, we demonstrated that PIC-treated C. elegans exhibited suppressed lipolysis under fasting as judged by increased lipid accumulation and TG levels with decreased free glycerol level. Consistent with these findings, PIC treatment resulted in decreased mRNA levels of genes involved lipolysis such as atgl-1, hosl-1 and aak-2 in fasted C. elegans. Also, PIC treatment augmented fasting-induced lifespan of C. elegans by an increased daf-16 gene expression. However, such effect was abolished when atgl-1, aak-2, and daf-16 mutants were treated with PIC. In addition, we also found that autophagy is required for PIC-induced lifespan in C. elegans during fasting since autophagy inhibitor treatments and autophagy gene deficient worms resulted in blunting the lifespan extension effect of PIC. Conclusions Collectively, our results indicate that PIC contributes to lifespan extension in C. elegans during fasting possibly through regulating lipolysis- and/or autophagy-dependent lipid metabolism. Funding Sources 1. The National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2019R1A2C1086146) and (2019R1A6A3A03033878) 2. The Rural Development Administration of the Republic of Korea.

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Antiaging Effects of Vicatia thibetica de Boiss Root Extract on Caenorhabditis elegans and Doxorubicin-Induced Premature Aging in Adult Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9942090 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Wenwen Liu ◽

Yunhui Guan ◽

Sicong Qiao ◽

Jiqun Wang ◽

Keting Bao ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Stress Resistance ◽

Chinese Herb ◽

Premature Aging ◽

Lifespan Extension ◽

Root Extract ◽

Antioxidant Ability ◽

C Elegans ◽

Adult Mice ◽

Heat Stress Resistance

The roots of Vicatia thibetica de Boiss are a kind of Chinese herb with homology of medicine and food. This is the first report showing the property of the extract of Vicatia thibetica de Boiss roots (HLB01) to extend the lifespan as well as promote the healthy parameters in Caenorhabditis elegans (C. elegans). For doxorubicin- (Doxo-) induced premature aging in adult mice, HLB01 counteracted the senescence-associated biomarkers, including P21 and γH2AX. Interestingly, HLB01 promoted the expression of collagen in C. elegans and mammalian cell systemically, which might be one of the essential factors to exert the antiaging effects. In addition, HLB01 was also found as a scavenger of free radicals, thereby performing the antioxidant ability. Lifespan extension by HLB01 was also dependent on DAF-16 and HSF-1 via oxidative stress resistance and heat stress resistance. Taken together, overall data suggested that HLB01 could extend the lifespan and healthspan of C. elegans and resist Doxo-induced senescence in mice via promoting the expression of collagen, antioxidant potential, and stress resistance.

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Kynurenine Metabolism Lifespan Extension Mediated by Oxidative Stress Response and Hypoxic Response in C. elegans

Innovation in Aging ◽

10.1093/geroni/igab046.2552 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. 684-684

Author(s):

Raul Castro-Portuguez ◽

Jeremy Meyers ◽

Sam Freitas ◽

Hope Dang ◽

Emily Turner ◽

...

Keyword(s):

Oxidative Stress ◽

Transcription Factors ◽

Stress Response ◽

Aging Process ◽

De Novo ◽

Kynurenine Pathway ◽

Oxidative Stress Response ◽

Lifespan Extension ◽

Hypoxic Stress ◽

C Elegans

Abstract Aging is characterized by a progressive decline in the normal physiological functions of an organism, ultimately leading to mortality. Metabolic changes throughout the aging process disrupt the balance and homeostasis of the cell. The kynurenine metabolic pathway is the sole de novo biosynthetic pathway for producing NAD+ from ingested tryptophan. Altered kynurenine pathway activity is associated with both aging and a variety of age-associated diseases, and kynurenine-based interventions can extend lifespan in Caenorhabditis elegans. Our laboratory recently demonstrated knockdown of the kynurenine pathway enzymes kynureninase (KYNU) or 3-hydroxyanthranilic acid dioxygenase (HAAO) increases lifespan by 20-30% in C elegans. However, the mechanism of how these interventions may modulate response against different stressors during the aging process has yet to be explored. Fluorescent reporter strains show the stress-responsive transcription factors skn-1 (ortholog of NRF2/NFE2L2; oxidative stress response) and hif-1 (ortholog of HIF1A; hypoxic stress response) to be highly upregulated when the kynurenine pathway is inhibited. We also demonstrated the increase expression of gst-4 and gcs-1 (transcriptional targets skn-1), which are involved in production of the antioxidant glutathione (GSH), as well as upregulation of cysl-2 (transcriptional target of hif-1), a regulator of cysteine biosynthesis from serine. We hypothesize that lifespan extension resulting from kynurenine pathway inhibition is mediated, at least in part, by upregulation of these transcription factors, providing elevated defense against oxidative stress and hypoxic stress.

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Piecemeal regulation of convergent neuronal lineages by bHLH transcription factors in Caenorhabditis elegans

Development ◽

10.1242/dev.199224 ◽

2021 ◽

Vol 148 (11) ◽

Author(s):

Neda Masoudi ◽

Eviatar Yemini ◽

Ralf Schnabel ◽

Oliver Hobert

Keyword(s):

Transcription Factors ◽

Caenorhabditis Elegans ◽

Contralateral Side ◽

Mirror Image ◽

Neuronal Markers ◽

C Elegans ◽

Helix Loop Helix ◽

Distinct Lineage ◽

Bhlh Transcription Factors ◽

Identity Transformations

ABSTRACT Cells of the same type can be generated by distinct cellular lineages that originate in different parts of the developing embryo (‘lineage convergence’). Several Caenorhabditis elegans neuron classes composed of left/right or radially symmetric class members display such lineage convergence. We show here that the C. elegans Atonal homolog lin-32 is differentially expressed in neuronal lineages that give rise to left/right or radially symmetric class members. Loss of lin-32 results in the selective loss of the expression of pan-neuronal markers and terminal selector-type transcription factors that confer neuron class-specific features. Another basic helix-loop-helix (bHLH) gene, the Achaete-Scute homolog hlh-14, is expressed in a mirror image pattern relative to lin-32 and is required to induce neuronal identity and terminal selector expression on the contralateral side of the animal. These findings demonstrate that distinct lineage histories converge via different bHLH factors at the level of induction of terminal selector identity determinants, which thus serve as integrators of distinct lineage histories. We also describe neuron-to-neuron identity transformations in lin-32 mutants, which we propose to also be the result of misregulation of terminal selector gene expression.

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Untangling Longevity, Dauer, and Healthspan in Caenorhabditis elegans Insulin/IGF-1-Signalling

Gerontology ◽

10.1159/000480504 ◽

2017 ◽

Vol 64 (1) ◽

pp. 96-104 ◽

Cited By ~ 15

Author(s):

Collin Yvès Ewald ◽

Jorge Iván Castillo-Quan ◽

T. Keith Blackwell

Keyword(s):

Caenorhabditis Elegans ◽

Healthy Aging ◽

Receptor Gene ◽

Recent Analysis ◽

Lifespan Extension ◽

Extension Programs ◽

Subsequent Work ◽

C Elegans ◽

Downstream Processes ◽

Shed Light

The groundbreaking discovery that lower levels of insulin/IGF-1 signaling (IIS) can induce lifespan extension was reported 24 years ago in the nematode Caenorhabditis elegans. In this organism, mutations in the insulin/IGF-1 receptor gene daf-2 or other genes in this pathway can double lifespan. Subsequent work has revealed that reduced IIS (rIIS) extends lifespan across diverse species, possibly including humans. In C. elegans, IIS also regulates development into the diapause state known as dauer, a quiescent larval form that enables C. elegans to endure harsh environments through morphological adaptation, improved cellular repair, and slowed metabolism. Considerable progress has been made uncovering mechanisms that are affected by C. elegans rIIS. However, from the beginning it has remained unclear to what extent rIIS extends C. elegans lifespan by mobilizing dauer-associated mechanisms in adults. As we discuss, recent work has shed light on this question by determining that rIIS can extend C. elegans lifespan comparably through downstream processes that are either dauer-related or -independent. Importantly, these two lifespan extension programs can be distinguished genetically. It will now be critical to tease apart these programs, because each may involve different longevity-promoting mechanisms that may be relevant to higher organisms. A recent analysis of organismal “healthspan” has questioned the value of C. elegans rIIS as a paradigm for understanding healthy aging, as opposed to simply extending life. We discuss other work that argues strongly that C. elegans rIIS is indeed an invaluable model and consider the likely possibility that dauer-related processes affect parameters associated with health under rIIS conditions. Together, these studies indicate that C. elegans and analyses of rIIS in this organism will continue to provide unexpected and exciting results, and new paradigms that will be valuable for understanding healthy aging in humans.

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The symbiotic relationship between Caenorhabditis elegans and members of its microbiome contributes to worm fitness and lifespan extension

BMC Genomics ◽

10.1186/s12864-021-07695-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Orçun Haçariz ◽

Charles Viau ◽

Farial Karimian ◽

Jianguo Xia

Keyword(s):

Caenorhabditis Elegans ◽

Signaling Pathways ◽

Vitamin B6 ◽

Genomic Diversity ◽

Glutathione Metabolism ◽

Lifespan Extension ◽

Promising Alternative ◽

Host Fitness ◽

C Elegans ◽

Cellular Detoxification

Abstract Background A healthy microbiome influences host physiology through a mutualistic relationship, which can be important for the host to cope with cellular stress by promoting fitness and survival. The mammalian microbiome is highly complex and attributing host phenotypes to a specific member of the microbiome can be difficult. The model organism Caenorhabditis elegans and its native microbiome, discovered recently, can serve as a more tractable, experimental model system to study host-microbiome interactions. In this study, we investigated whether certain members of C. elegans native microbiome would offer a benefit to their host and putative molecular mechanisms using a combination of phenotype screening, omics profiling and functional validation. Results A total of 16 members of C. elegans microbiome were screened under chemically-induced toxicity. Worms grown with Chryseobacterium sp. CHNTR56 MYb120 or Comamonas sp. 12022 MYb131, were most resistant to oxidative chemical stress (SiO2 nanoparticles and juglone), as measured by progeny output. Further investigation showed that Chryseobacterium sp. CHNTR56 positively influenced the worm’s lifespan, whereas the combination of both isolates had a synergistic effect. RNAseq analysis of young adult worms, grown with either isolate, revealed the enrichment of cellular detoxification mechanisms (glutathione metabolism, drug metabolism and metabolism of xenobiotics) and signaling pathways (TGF-beta and Wnt signaling pathways). Upregulation of cysteine synthases (cysl genes) in the worms, associated with glutathione metabolism, was also observed. Nanopore sequencing uncovered that the genomes of the two isolates have evolved to favor the specific route of the de novo synthesis pathway of vitamin B6 (cofactor of cysl enzymes) through serC or pdxA2 homologs. Finally, co-culture with vitamin B6 extended worm lifespan. Conclusions In summary, our study indicates that certain colonizing members of C. elegans have genomic diversity in vitamin B6 synthesis and promote host fitness and lifespan extension. The regulation of host cellular detoxification genes (i.e. gst) along with cysl genes at the transcriptome level and the bacterium-specific vitamin B6 synthesis mechanism at the genome level are in an agreement with enhanced host glutathione-based cellular detoxification due to this interspecies relationship. C. elegans is therefore a promising alternative model to study host-microbiome interactions in host fitness and lifespan.

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Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in C. elegans

eLife ◽

10.7554/elife.55745 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 5

Author(s):

Yanan Sun ◽

Meijiao Li ◽

Dongfeng Zhao ◽

Xin Li ◽

Chonglin Yang ◽

...

Keyword(s):

Transcription Factors ◽

Food Intake ◽

Aging Process ◽

Lifespan Extension ◽

C Elegans ◽

Cathepsin Proteases ◽

Age Dependent ◽

Genes Encoding ◽

Degradation Activity ◽

Lifespan Regulation

Lysosomes play important roles in cellular degradation to maintain cell homeostasis. In order to understand whether and how lysosomes alter with age and contribute to lifespan regulation, we characterized multiple properties of lysosomes during the aging process in C. elegans. We uncovered age-dependent alterations in lysosomal morphology, motility, acidity and degradation activity, all of which indicate a decline in lysosome function with age. The age-associated lysosomal changes are suppressed in the long-lived mutants daf-2, eat-2 and isp-1, which extend lifespan by inhibiting insulin/IGF-1 signaling, reducing food intake and impairing mitochondrial function, respectively. We found that 43 lysosome genes exhibit reduced expression with age, including genes encoding subunits of the proton pump V-ATPase and cathepsin proteases. The expression of lysosome genes is upregulated in the long-lived mutants, and this upregulation requires the functions of DAF-16/FOXO and SKN-1/NRF2 transcription factors. Impairing lysosome function affects clearance of aggregate-prone proteins and disrupts lifespan extension in daf-2, eat-2 and isp-1 worms. Our data indicate that lysosome function is modulated by multiple longevity pathways and is important for lifespan extension.

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Lifespan extension in Caenorhabditis elegans insulin/IGF-1 signalling mutants is supported by non-vertebrate physiological traits

Nematology ◽

10.1163/15685411-00003060 ◽

2017 ◽

Vol 19 (5) ◽

pp. 499-508

Author(s):

Bart P. Braeckman ◽

Ineke Dhondt

Keyword(s):

Caenorhabditis Elegans ◽

Molecular Mechanisms ◽

Genetic Model ◽

Causal Relation ◽

Glyoxylate Cycle ◽

Protein Carbonyls ◽

Lifespan Extension ◽

Turnover Rates ◽

C Elegans ◽

Trehalose Synthesis

The insulin/IGF-1 signalling (IIS) pathway connects nutrient levels to metabolism, growth and lifespan in eukaryotes ranging from yeasts to humans, including nematodes such as the genetic model organismCaenorhabditis elegans. The link between ageing and the IIS pathway has been thoroughly studied inC. elegans; upon reduced IIS signalling, a genetic survival program is activated resulting in a drastic lifespan extension. One of the components of this program is the upregulation of antioxidant activity but experiments failed to show a clear causal relation to longevity. However, oxidative damage, such as protein carbonyls, accumulates at a slower pace in long-livedC. elegansmutants with reduced IIS. This is probably not achieved by increased macroautophagy, a process that sequesters cellular components to be eliminated as protein turnover rates are slowed down in IIS mutants. The IIS mutantdaf-2, bearing a mutation in the insulin/IGF-1 receptor, recapitulates the dauer survival program, including accumulation of fat and glycogen. Fat can be converted into glucose and glycogenviathe glyoxylate shunt, a pathway absent in vertebrates. These carbohydrates can be used as substrates for trehalose synthesis, also absent in mammals. Trehalose, a non-reducing homodimer of glucose, stabilises intracellular components and is responsible for almost half of the lifespan extension in IIS mutants. Hence, the molecular mechanisms by which lifespan is extended under reduced IIS may differ substantially between phyla that have an active glyoxylate cycle and trehalose synthesis, such as ecdysozoans and fungi, and vertebrate species such as mammals.

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