SUMO promotes longevity and maintains mitochondrial homeostasis during ageing in Caenorhabditis elegans

Abstract The insulin/IGF signalling pathway impacts lifespan across distant taxa, by controlling the activity of nodal transcription factors. In the nematode Caenorhabditis elegans, the transcription regulators DAF-16/FOXO and SKN-1/Nrf function to promote longevity under conditions of low insulin/IGF signalling and stress. The activity and subcellular localization of both DAF-16 and SKN-1 is further modulated by specific posttranslational modifications, such as phosphorylation and ubiquitination. Here, we show that ageing elicits a marked increase of SUMO levels in C. elegans. In turn, SUMO fine-tunes DAF-16 and SKN-1 activity in specific C. elegans somatic tissues, to enhance stress resistance. SUMOylation of DAF-16 modulates mitochondrial homeostasis by interfering with mitochondrial dynamics and mitophagy. Our findings reveal that SUMO is an important determinant of lifespan, and provide novel insight, relevant to the complexity of the signalling mechanisms that influence gene expression to govern organismal survival in metazoans.

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Balanced mRNA storage and degradation regulates mitochondrial homeostasis, ageing and stress resistance in Caenorhabditis elegans

10.12681/eadd/47121 ◽

2020 ◽

Author(s):

Ιωάννα Δασκαλάκη

Keyword(s):

Caenorhabditis Elegans ◽

Stress Resistance ◽

C Elegans ◽

Mitochondrial Homeostasis

Ο αριθμός των μιτοχονδρίων σε συνδυασμό με την λειτουργία τους αποτελούν σημαντικούς ρυθμιστές της υγείας των ατόμων αλλά και του προσδόκιμου ζωής αυτών σε ποικίλους οργανισμούς, από απλούς όπως ο νηματώδης C. elegans έως και πολύ πολύπλοκους όπως είναι ο άνθρωπος. Συγκεκριμένα, η διατάραξή τους συσχετίζεται συχνά με παθολογικές καταστάσεις όπως τα λυσοσωμικά αθροιστικά νοσήματα, η καρδιαγγειακή νόσος, ο νευροεκφυλισμός και σακχαρώδης διαβήτης τύπου 2, μεταξύ άλλων. Ο αριθμός των μιτοχονδρίων ελέγχεται στενά από δύο αντίθετες διαδικασίες, την βιογένεση των μιτοχονδρίων και τη μιτοφαγία. Σε αντίθεση με τη μιτοφαγία, η οποία έχει μελετηθεί εκτεταμένα, οι μηχανισμοί μιτοχονδριακής βιογένεσης εξακολουθούν να είναι ως επί το πλείστον ανεξερεύνητοι. Η ημι-αυτόνομη φύση των μιτοχονδρίων καθιστά τη βιογένεσή τους μια πολύπλοκη διαδικασία που βασίζεται στον συντονισμό σηματοδότησης από τα μιτοχόνδρια προς τον πυρήνα και από τον πυρήνα προς τα μιτοχόνδρια. Η τοπική μετάφραση των μεταγραφημάτων μιτοχονδριακών πρωτεϊνών που κωδικοποιούνται από το πυρηνικό DNA (NEMTTs) κοντά στα μιτοχόνδρια, είναι θεμελιώδης για τη βιογένεση των μιτοχονδρίων. Παρόλο που αναμένεται ότι κυτταροπλασματικοί παράγοντες θα πρέπει κυρίως να ρυθμίζουν την τοπική μετάφραση υπό κανονικές συνθήκες και ως απόκριση σε στρες, οι παράγοντες αυτοί παραμένουν ασαφείς. Στόχος της παρούσας διατριβής είναι η διαλεύκανση αυτών των παραγόντων χρησιμοποιώντας ως πρότυπο οργανισμό το C. elegans. Στα πλαίσια αυτή, αποκαλύπτουμε ότι κυτταροπλασματικοί παράγοντες που σχετίζονται με το μονοπάτι 5'-3' αποικοδόμησης των αγγελιοφόρων RNA (mRNA), αποτελούν νέους, βασικούς ρυθμιστές του αριθμού και της λειτουργίας των μιτοχονδρίων στο νηματώδη. Πιο συγκεκριμένα, δείχνουμε ότι το πρωτεϊνικό σύμπλοκο που πραγματοποιεί την αφαίρεση του καλύμματος των mRNA και τo σύμπλοκo αποαδενυλίωσης (CCR-4 / NOT) εμπεριέχονται σε ξεχωριστούς σχηματισμούς που έχουν φυσική αλληλεπίδραση με τα μιτοχόνδρια και ρυθμίζουν αντίθετα τον αριθμό τους κατά τη διάρκεια της γήρανσης. Ο μηχανισμός μέσω του οποίου επιτυγχάνουν κάτι τέτοιο βασίζεται στη μετα-μεταγραφική ρύθμιση των NEMTTs που πραγματοποιείται κοντά στο οργανίδιο. Η ισορροπημένη αποικοδόμηση και αποθήκευση των NEMTTs-στόχων είναι αναγκαία για τη ρύθμιση του αριθμού και της λειτουργίας των μιτοχονδρίων. Η επίτευξη μιας τέτοιας ισορροπίας τελικά προάγει την απόκριση σε στρες και τη μακροβιότητα ατόμων C. elegans. Τα ευρήματά μας αποκαλύπτουν ένα νέο ρόλο των παραγόντων μεταβολισμού των mRNAs στη βιογένεση των οργανιδίων και με αυτό τον τρόπο οδηγούν στην ταυτοποίηση των κυτταροπλασματικών συστατικών που συντονίζουν την τοπική μετάφραση κατά τη διάρκεια της γήρανσης και υπό συνθήκες στρες στο C. elegans.

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Streblus asper Lour. exerts MAPK and SKN-1 mediated anti-aging, anti-photoaging activities and imparts neuroprotection by ameliorating Aβ in Caenorhabditis elegans

Nutrition and Healthy Aging ◽

10.3233/nha-210121 ◽

2021 ◽

pp. 1-17

Author(s):

Mani Iyer Prasanth ◽

James Michael Brimson ◽

Dicson Sheeja Malar ◽

Anchalee Prasansuklab ◽

Tewin Tencomnao

Keyword(s):

Oxidative Stress ◽

Caenorhabditis Elegans ◽

Stress Resistance ◽

Vital Role ◽

Transgenic Strain ◽

Wild Type ◽

Neuroprotective Effects ◽

C Elegans ◽

Streblus Asper

BACKGROUND: Streblus asper Lour., has been reported to have anti-aging and neuroprotective efficacies in vitro. OBJECTIVE: To analyze the anti-aging, anti-photoaging and neuroprotective efficacies of S. asper in Caenorhabditis elegans. METHODS: C. elegans (wild type and gene specific mutants) were treated with S. asper extract and analyzed for lifespan and other health benefits through physiological assays, fluorescence microscopy, qPCR and Western blot. RESULTS: The plant extract was found to increase the lifespan, reduce the accumulation of lipofuscin and modulate the expression of candidate genes. It could extend the lifespan of both daf-16 and daf-2 mutants whereas the pmk-1 mutant showed no effect. The activation of skn-1 was observed in skn-1::GFP transgenic strain and in qPCR expression. Further, the extract can extend the lifespan of UV-A exposed nematodes along with reducing ROS levels. Additionally, the extract also extends lifespan and reduces paralysis in Aβ transgenic strain, apart from reducing Aβ expression. CONCLUSIONS: S. asper was able to extend the lifespan and healthspan of C. elegans which was independent of DAF-16 pathway but dependent on SKN-1 and MAPK which could play a vital role in eliciting the anti-aging, anti-photoaging and neuroprotective effects, as the extract could impart oxidative stress resistance and neuroprotection.

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Effects of Orange Extracts on Longevity, Healthspan, and Stress Resistance in Caenorhabditis elegans

Molecules ◽

10.3390/molecules25020351 ◽

2020 ◽

Vol 25 (2) ◽

pp. 351 ◽

Cited By ~ 4

Author(s):

Jing Wang ◽

Na Deng ◽

Hong Wang ◽

Tong Li ◽

Ling Chen ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Stress Resistance ◽

Survival Rates ◽

Intracellular Reactive Oxygen Species ◽

Ultraviolet B ◽

Oxygen Species ◽

Aging Effects ◽

C Elegans ◽

Anti Cancer ◽

The Mean

Orange, with various bioactive phytochemicals, exerts various beneficial health effects, including anti-cancer, antioxidant, and anti-inflammatory properties. However, its anti-aging effects remain unclear. In this study, the Caenorhabditis elegans (C. elegans) model was used to evaluate the effects of orange extracts on lifespan and stress resistance. The results indicated that orange extracts dose-dependently increased the mean lifespan of C. elegans by 10.5%, 18.0%, and 26.2% at the concentrations of 100, 200, and 400 mg/mL, respectively. Meanwhile, orange extracts promoted the healthspan by improving motility, and decreasing the accumulation of age pigment and intracellular reactive oxygen species (ROS) levels without damaging fertility. The survival rates of orange extract-fed worms were obviously higher than those of untreated worms against thermal and ultraviolet-B (UV-B) stress. Moreover, the activities of superoxide dismutase (SOD) and catalase (CAT) were significantly enhanced while malondialdehyde (MDA) contents were diminished. Further investigation revealed that worms supplemented with orange extracts resulted in upregulated levels of genes, including daf-16, sod-3, gst-4, sek-1, and skn-1, and the downregulation of age-1 expression. These findings revealed that orange extracts have potential anti-aging effects through extending the lifespan, enhancing stress resistance, and promoting the healthspan.

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Interplay between mitochondria and diet mediates pathogen and stress resistance inC. elegans

10.1101/154393 ◽

2017 ◽

Author(s):

Alexey V. Revtovich ◽

Ryan Lee ◽

Natalia V. Kirienko

Keyword(s):

Stress Resistance ◽

Vitamin B12 Deficiency ◽

E Coli ◽

C Elegans ◽

Mitochondrial Homeostasis ◽

Physiological Consequence ◽

Organismal Biology ◽

Host Health ◽

B12 Deficiency ◽

Dietary Deficiency

SummaryDiet is a crucial determinant of organismal biology. Here we demonstrate the dramatic impact of a subtle shift in diet on the ability ofCaenorhabditis elegansto survive pathogenic or abiotic stress. Interestingly, this shift occurs independently of canonical host defense pathways, arising instead from improvements in mitochondrial health. Using a variety of assays, we reveal that the most commonC. elegansfood source (E. coliOP50) results in a vitamin B12 deficiency that compromises mitochondrial homeostasis. Increasing B12 supply by feeding onE. coliHT115 or by supplementing bacterial media with methylcobalamin restored mitochondrial function, even if the bacteria were dead. B12 supplementation also efficiently increased host health without adversely affecting lifespan. Our study forges a molecular link between a dietary deficiency (nutrition/microbiota) and a physiological consequence (host sensitivity), using the host-microbiota-diet framework. The ubiquity of B12 deficiency (~10-40% of US adults) highlights the importance of our findings.

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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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Genes implicated in Caenorhabditis elegans and human health regulate stress resistance and physical abilities in aged Caenorhabditis elegans

Biology Letters ◽

10.1098/rsbl.2020.0916 ◽

2021 ◽

Vol 17 (6) ◽

pp. 20200916

Author(s):

Jessica Dysarz ◽

Georg Fuellen ◽

Steffen Möller ◽

Walter Luyten ◽

Christian Schmitz-Linneweber ◽

...

Keyword(s):

Heat Stress ◽

Caenorhabditis Elegans ◽

Stress Resistance ◽

Bioinformatics Analyses ◽

C Elegans ◽

Swim Performance ◽

Health Related ◽

Physical Abilities ◽

Heat Stress Resistance ◽

Literature Curation

Recently, nine Caenorhabditis elegans genes, grouped into two pathways/clusters, were found to be implicated in healthspan in C. elegans and their homologues in humans, based on literature curation, WormBase data mining and bioinformatics analyses. Here, we further validated these genes experimentally in C. elegans . We downregulated the nine genes via RNA interference (RNAi), and their effects on physical function (locomotion in a swim assay) and on physiological function (survival after heat stress) were analysed in aged nematodes. Swim performance was negatively affected by the downregulation of acox-1.1 , pept-1 , pak-2 , gsk-3 and C25G6.3 in worms with advanced age (twelfth day of adulthood) and heat stress resistance was decreased by RNAi targeting of acox-1.1 , daf-22 , cat-4 , pig-1 , pak-2 , gsk-3 and C25G6.3 in moderately (seventh day of adulthood) or advanced aged nematodes. Only one gene, sad-1 , could not be linked to a health-related function in C. elegans with the bioassays we selected. Thus, most of the healthspan genes could be re-confirmed by health measurements in old worms.

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Flavonoids’ Effects on Caenorhabditis elegans’ Longevity, Fat Accumulation, Stress Resistance and Gene Modulation Involve mTOR, SKN-1 and DAF-16

Antioxidants ◽

10.3390/antiox10030438 ◽

2021 ◽

Vol 10 (3) ◽

pp. 438

Author(s):

María Alejandra Guerrero-Rubio ◽

Samanta Hernández-García ◽

Francisco García-Carmona ◽

Fernando Gandía-Herrero

Keyword(s):

Caenorhabditis Elegans ◽

Stress Resistance ◽

Inflammatory Diseases ◽

Biological Effects ◽

Molecular Targets ◽

Mechanistic Studies ◽

C Elegans ◽

Nutraceutical Compounds ◽

Age Related ◽

Health Promoting

Flavonoids are potential nutraceutical compounds present in diary food. They are considered health-promoting compounds and promising drugs for different diseases, such as neurological and inflammatory diseases, diabetes and cancer. Therefore, toxicological and mechanistic studies should be done to assert the biological effects and identify the molecular targets of these compounds. In this work we describe the effects of six structurally-related flavonoids—baicalein, chrysin, scutellarein, 6-hydroxyflavone, 6,7-dihydroxyflavone and 7,8-dihydroxyflavone—on Caenorhabditis elegans’ lifespan and stress resistance. The results showed that chrysin, 6-hydroxyflavone and baicalein prolonged C. elegans’ lifespan by up to 8.5%, 11.8% and 18.6%, respectively. The lifespan extensions caused by these flavonoids are dependent on different signaling pathways. The results suggested that chrysin’s effects are dependent on the insulin signaling pathway via DAF-16/FOXO. Baicalein and 6-hydroxyflavone’s effects are dependent on the SKN-1/Nfr2 pathway. In addition, microarray analysis showed that baicalein downregulates important age-related genes, such as mTOR and PARP.

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Gengnianchun Extends the Lifespan of Caenorhabditis elegans via the Insulin/IGF-1 Signalling Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4740739 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Fanhui Meng ◽

Jun Li ◽

Yanqiu Rao ◽

Wenjun Wang ◽

Yan Fu

Keyword(s):

Thermal Stress ◽

Caenorhabditis Elegans ◽

Chinese Medicine ◽

Stress Resistance ◽

Antioxidant Properties ◽

Signalling Pathway ◽

Rna Seq ◽

C Elegans ◽

Beneficial Effects ◽

Mutant Strains

Gengnianchun (GNC), a traditional Chinese medicine (TCM), is believed to have beneficial effects on ageing-related diseases, such as antioxidant properties and effects against Aβ-induced toxicity. We previously found that GNC extended the lifespan of Caenorhabditis elegans. However, the mechanism underlying this effect was unclear. In this study, we further explored the mechanisms of GNC using a C. elegans model. GNC significantly increased the lifespan of C. elegans and enhanced oxidative and thermal stress resistance. Moreover, chemotaxis increased after GNC treatment. RNA-seq analysis showed that GNC regulated genes associated with longevity. We also conducted lifespan assays with a series of worm mutants. The results showed that GNC significantly extended the lifespan of several mutant strains, including eat-2 (ad465), rsks-1 (ok1255), and glp-1 (e2144), suggesting that the prolongevity effect of GNC is independent of the function of these genes. However, GNC failed to extend the lifespan of daf-2 (e1370), age-1 (hx546), and daf-16 (mu86) mutant strains. Our findings suggest that GNC extends the lifespan of C. elegans via the insulin/IGF-1 signalling pathway and may be a potential antiageing agent.

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Caffeic and Dihydrocaffeic Acids Promote Longevity and Increase Stress Resistance in Caenorhabditis elegans by Modulating Expression of Stress-Related Genes

Molecules ◽

10.3390/molecules26061517 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1517

Author(s):

Sofia M. Gutierrez-Zetina ◽

Susana González-Manzano ◽

Begoña Ayuda-Durán ◽

Celestino Santos-Buelga ◽

Ana M. González-Paramás

Keyword(s):

Oxidative Stress ◽

Caenorhabditis Elegans ◽

Phenolic Compounds ◽

Caffeic Acid ◽

Phenolic Acids ◽

Stress Resistance ◽

C Elegans ◽

High Concentrations ◽

Gene Expression Studies ◽

Stress Related Genes

Caffeic and dihydrocaffeic acid are relevant microbial catabolites, being described as products from the degradation of different phenolic compounds i.e., hydroxycinnamoyl derivatives, anthocyanins or flavonols. Furthermore, caffeic acid is found both in free and esterified forms in many fruits and in high concentrations in coffee. These phenolic acids may be responsible for a part of the bioactivity associated with the intake of phenolic compounds. With the aim of progressing in the knowledge of the health effects and mechanisms of action of dietary phenolics, the model nematode Caenorhabditis elegans has been used to evaluate the influence of caffeic and dihydrocaffeic acids on lifespan and the oxidative stress resistance. The involvement of different genes and transcription factors related to longevity and stress resistance in the response to these phenolic acids has also been explored. Caffeic acid (CA, 200 μM) and dihydrocaffeic acid (DHCA, 300 μM) induced an increase in the survival rate of C. elegans under thermal stress. Both compounds also increased the mean and maximum lifespan of the nematode, compared to untreated worms. In general, treatment with these acids led to a reduction in intracellular ROS concentrations, although not always significant. Results of gene expression studies conducted by RT-qPCR showed that the favorable effects of CA and DHCA on oxidative stress and longevity involve the activation of several genes related to insulin/IGF-1 pathway, such as daf-16, daf-18, hsf-1 and sod-3, as well as a sirtuin gene (sir-2.1).

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Study of the Effect of Neutral Polysaccharides from Rehmannia glutinosa on Lifespan of Caenorhabditis elegans

Molecules ◽

10.3390/molecules24244592 ◽

2019 ◽

Vol 24 (24) ◽

pp. 4592 ◽

Cited By ~ 2

Author(s):

Yanyan Yuan ◽

Nianxin Kang ◽

Qingxia Li ◽

Yali Zhang ◽

Yonggang Liu ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Stress Resistance ◽

Aging Effect ◽

The Elderly ◽

Mrna Levels ◽

Loss Of Function ◽

Rehmannia Glutinosa ◽

Mechanism Study ◽

C Elegans ◽

Natural Medicine

The problem of an aging society is becoming increasingly acute. Diseases related to aging also come with it. There are some diseases that people can’t treat fundamentally. Therefore, people try to find a natural ingredient from natural medicine to treat these diseases and improve the quality of life of the elderly. With the screening of a large number of traditional Chinese medicines, we found that polysaccharides from Rehmannia glutinous (PRG) can prolong the lifespan of Caenorhabditis elegans (C. elegans). Neutral polysaccharide is the main component of PRG. In the present study, we used a C. elegans model to illustrate the stress resistance and lifespan extension effect and mechanism of two kinds of neutral polysaccharide fractions from Rehmannia glutinosa (NPRG), respectively called NPRRP and NPRR. Our data showed that two kinds of neutral polysaccharides fractions could extend the lifespan and delay senescence of wild-type worms. Moreover, the mechanism study revealed that NPRG was able to promote the nuclear localization of DAF-16 resulting in the activation of antioxidant enzymatic systems under oxidative stress. We also observed that NPRG didn’t increase the lifespan of mutants with daf-16 portion loss of function, suggesting NPRG prolonging the lifespan partially required the daf-16 gene on the insulin/IGF-1 signaling pathway (IIS). NPRG was found to have no effect on Escherichia coli OP50 (E. coli OP50) growth and pharyngeal pump movement of nematodes, indicating that the anti-aging effect of NPRG is not realized by the caloric restriction. However, mRNA levels of daf-2 were remarkably decreased after NPRG treatment. Thus daf-2 lost its inhibitory effect on the expression of daf-16 and had a continuous stimulation effect on the IIS, then prolonged the life of nematodes. Overall, our results illustrated the potential utilization of NPRG as a functional pharmaceutical ingredient to increase stress resistance and extend the life of C. elegans via the IIS, which could be developed as a natural supplement agent.

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