scholarly journals DAF-18 is required for the age-dependent increase in DAF-16 activity in Caenorhabditis elegans

2020 ◽  
Author(s):  
Kali Carrasco ◽  
Matthew J. Youngman
Keyword(s):  
Caenorhabditis Elegans ◽  
Functional Characterization ◽  
Growth Factor Signaling ◽  
Dynamic Activity ◽  
Post Translational Modifications ◽  
C Elegans ◽  
Regulatory Module ◽  
Phospholipid Signaling ◽  
Age Dependent ◽  
Foxo Transcription Factors

ABSTRACTThe insulin/insulin-like growth factor signaling (IIS) pathway modulates growth, survival, and lifespan by regulating FOXO transcription factors. In Caenorhabditis elegans, IIS maintains DAF-16/FOXO in an inactive state unless animals are challenged by environmental stress. Recent evidence suggests that DAF-16 becomes activated as part of normal aging in C. elegans, yet the regulatory module responsible for this phenomenon is largely undefined. Embedded within IIS is phospholipid signaling in which PIP3 produced by the PI3 kinase AGE-1 is an upstream event in DAF-16 inhibition. Countering AGE-1 is DAF-18, an ortholog of human PTEN phosphatase that dephosphorylates PIP3. Although it is required for normal lifespan in C. elegans, functional characterization of DAF-18 has primarily focused on its roles during development in the germline and neurons. In this study we asked whether DAF-18 plays a role in the age-dependent activation of DAF-16, and specifically in DAF-16-mediated immunity. Our data show that DAF-18 is expressed in multiple tissues during adulthood. We found that DAF-18 contributes to host defense in adult animals by functioning in the neurons and intestine, likely working through DAF-16 which acts in those same tissues to confer immunity. Supporting this possibility, DAF-18 was required for increased DAF-16 transcriptional activity during aging. Post-translational modifications including ubiquitination and sumoylation appear to be required for the function of DAF-18 during aging in C. elegans, indicating that strategies to modulate PTEN activity are evolutionarily conserved. Our results establish an important role for DAF-18 later in life and imply that it is a critical component of a neuroendocrine signaling circuit that governs the dynamic activity of DAF-16.

scholarly journals DAF-16 and SMK-1 Contribute to Innate Immunity During Adulthood in Caenorhabditis elegans

2020 ◽  
Vol 10 (5) ◽  
pp. 1521-1539 ◽  
Author(s):  
Daniel R. McHugh ◽  
Elena Koumis ◽  
Paul Jacob ◽  
Jennifer Goldfarb ◽  
Michelle Schlaubitz-Garcia ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Caenorhabditis Elegans ◽  
Host Defense ◽  
Insulin Signaling ◽  
Bacterial Pathogens ◽  
C Elegans ◽  
Link Type ◽  
Age Dependent ◽  
Over Time

Aging is accompanied by a progressive decline in immune function termed “immunosenescence”. Deficient surveillance coupled with the impaired function of immune cells compromises host defense in older animals. The dynamic activity of regulatory modules that control immunity appears to underlie age-dependent modifications to the immune system. In the roundworm Caenorhabditis elegans levels of PMK-1 p38 MAP kinase diminish over time, reducing the expression of immune effectors that clear bacterial pathogens. Along with the PMK-1 pathway, innate immunity in C. elegans is regulated by the insulin signaling pathway. Here we asked whether DAF-16, a Forkhead box (FOXO) transcription factor whose activity is inhibited by insulin signaling, plays a role in host defense later in life. While in younger C. elegansDAF-16 is inactive unless stimulated by environmental insults, we found that even in the absence of acute stress the transcriptional activity of DAF-16 increases in an age-dependent manner. Beginning in the reproductive phase of adulthood, DAF-16 upregulates a subset of its transcriptional targets, including genes required to kill ingested microbes. Accordingly, DAF-16 has little to no role in larval immunity, but functions specifically during adulthood to confer resistance to bacterial pathogens. We found that DAF-16-mediated immunity in adults requires SMK-1, a regulatory subunit of the PP4 protein phosphatase complex. Our data suggest that as the function of one branch of the innate immune system of C. elegans (PMK-1) declines over time, DAF-16-mediated immunity ramps up to become the predominant means of protecting adults from infection, thus reconfiguring immunity later in life.

scholarly journals Expression of β-1,4-galactosyltransferases during Aging in Caenorhabditis elegans

Gerontology ◽  
2020 ◽  
Vol 66 (6) ◽  
pp. 571-581
Author(s):  
Jennifer Kremer ◽  
Cornelia Brendel ◽  
Elisabeth Karin Maria Mack ◽  
Hildegard Isolde Dietlinde Mack
Keyword(s):  
Caenorhabditis Elegans ◽  
Model Organism ◽  
Mrna Levels ◽  
Germline Stem Cells ◽  
Wild Type ◽  
Activity Increase ◽  
C Elegans ◽  
Targeted Analysis ◽  
Age Dependent ◽  
Plasma Activity

<b><i>Background:</i></b> Altered plasma activity of β-1,4-galac­tosyl­transferases (B4GALTs) is a novel candidate biomarker of human aging. B4GALT1 is assumed to be largely responsible for this activity increase, but how it modulates the aging process is unclear at present. <b><i>Objectives:</i></b> To determine how expression of B4GALT1 and other B4GALT enzymes changes during aging of an experimentally tractable model organism, <i>Caenorhabditis elegans</i>. <b><i>Methods:</i></b> Targeted analysis of mRNA levels of all 3 <i>C. elegans</i> B4GALT family members was performed by qPCR in wild-type and in long-lived <i>daf-2</i> (insulin/IGF1-like receptor)-deficient or germline-deficient animals. <b><i>Results:</i></b> <i>bre-4</i> (<i>B4GALT1/2/3/4</i>) is the only B4GALT whose expression increases during aging in wild-type worms. In addition, <i>bre-4</i> levels also rise during aging in long-lived <i>daf-2</i>-deficient worms, but not in animals that are long-lived due to the lack of germline stem cells. On the other hand, expression of <i>sqv-3 (B4GALT7)</i> and of <i>W02B12.11 (B4GALT5/6)</i> appears decreased or constant, respectively, in all backgrounds during aging. <b><i>Conclusions:</i></b> The age-dependent <i>bre-4</i> mRNA increase in <i>C. elegans</i> parallels the age-dependent B4GALT activity increase in humans and is consistent with <i>C. elegans</i> being a suitable experimental organism to define potentially conserved roles of B4GALT1 during aging.

scholarly journals Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Sunitha Rangaraju ◽  
Gregory M Solis ◽  
Ryan C Thompson ◽  
Rafael L Gomez-Amaro ◽  
Leo Kurian ◽  
...  
Keyword(s):  
Young Adults ◽  
Caenorhabditis Elegans ◽  
Functional Groups ◽  
Expression Patterns ◽  
Older Age ◽  
C Elegans ◽  
Age Dependent ◽  
Effects Of Aging

Longevity mechanisms increase lifespan by counteracting the effects of aging. However, whether longevity mechanisms counteract the effects of aging continually throughout life, or whether they act during specific periods of life, preventing changes that precede mortality is unclear. Here, we uncover transcriptional drift, a phenomenon that describes how aging causes genes within functional groups to change expression in opposing directions. These changes cause a transcriptome-wide loss in mRNA stoichiometry and loss of co-expression patterns in aging animals, as compared to young adults. Using Caenorhabditis elegans as a model, we show that extending lifespan by inhibiting serotonergic signals by the antidepressant mianserin attenuates transcriptional drift, allowing the preservation of a younger transcriptome into an older age. Our data are consistent with a model in which inhibition of serotonergic signals slows age-dependent physiological decline and the associated rise in mortality levels exclusively in young adults, thereby postponing the onset of major mortality.

scholarly journals Loss of SET1/COMPASS methyltransferase activity reduces lifespan and fertility in Caenorhabditis elegans

2021 ◽  
Vol 5 (3) ◽  
pp. e202101140
Author(s):  
Matthieu Caron ◽  
Loïc Gely ◽  
Steven Garvis ◽  
Annie Adrait ◽  
Yohann Couté ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
H3k4 Methylation ◽  
Methyltransferase Activity ◽  
Post Translational Modifications ◽  
C Elegans ◽  
Histone 3 ◽  
Inactive Form ◽  
Extended Lifespan ◽  
Fat Stores

Changes in histone post-translational modifications are associated with aging through poorly defined mechanisms. Histone 3 lysine 4 (H3K4) methylation at promoters is deposited by SET1 family methyltransferases acting within conserved multiprotein complexes known as COMPASS. Previous work yielded conflicting results about the requirement for H3K4 methylation during aging. Here, we reassessed the role of SET1/COMPASS–dependent H3K4 methylation in Caenorhabditis elegans lifespan and fertility by generating set-2(syb2085) mutant animals that express a catalytically inactive form of SET-2, the C. elegans SET1 homolog. We show that set-2(syb2085) animals retain the ability to form COMPASS, but have a marked global loss of H3K4 di- and trimethylation (H3K4me2/3). Reduced H3K4 methylation was accompanied by loss of fertility, as expected; however, in contrast to earlier studies, set-2(syb2085) mutants displayed a significantly shortened, not extended, lifespan and had normal intestinal fat stores. Other commonly used set-2 mutants were also short-lived, as was a cfp-1 mutant that lacks the SET1/COMPASS chromatin-targeting component. These results challenge previously held views and establish that WT H3K4me2/3 levels are essential for normal lifespan in C. elegans.

scholarly journals The PP2A/4/6 subfamily of phosphoprotein phosphatases regulates DAF-16 during aging and confers resistance to environmental stress in postreproductive adult C. elegans

2020 ◽  
Author(s):  
Rebecca S. Rivard ◽  
Julia M. Morris ◽  
Matthew J. Youngman
Keyword(s):  
Environmental Stress ◽  
Transcriptional Activity ◽  
Reverse Genetics ◽  
Dependent Manner ◽  
C Elegans ◽  
Forkhead Box ◽  
Phosphoprotein Phosphatases ◽  
Complex Functions ◽  
Age Dependent ◽  
Foxo Transcription Factors

AbstractInsulin and insulin-like growth factors are longevity determinants that negatively regulate Forkhead box class O (FoxO) transcription factors. In C. elegans mutations that constitutively activate DAF-16, the ortholog of mammalian FoxO3a, extend lifespan by two-fold. While environmental insults induce DAF-16 activity in younger animals, it also becomes activated in an age-dependent manner in the absence of stress, modulating gene expression well into late adulthood. The mechanism by which DAF-16 activity is regulated during aging has not been defined. Since phosphorylation of DAF-16 generally leads to its inhibition, we asked whether phosphatases might be necessary for its increased transcriptional activity in adult C. elegans. We focused on the PP2A/4/6 subfamily of phosphoprotein phosphatases, members of which had been implicated to regulate DAF-16 under low insulin signaling conditions but had not been investigated during aging in wildtype animals. Using reverse genetics, we functionally characterized all C. elegans orthologs of human catalytic, regulatory, and scaffolding subunits of PP2A/4/6 holoenzymes in postreproductive adults. We found that PP2A complex constituents PAA-1 and PPTR-1 regulate DAF-16 during aging and that they cooperate with the catalytic subunit LET-92 to protect adult animals from ultraviolet radiation. PP4 complex members PPH-4.1/4.2, SMK-1, and PPFR-2 also appear to regulate DAF-16 in an age-dependent manner, and they contribute to innate immunity. Interestingly, SUR-6 but no other subunit of the PP2A complex was necessary for the survival of pathogen-infected animals, suggesting that a heterotypic PP4 complex functions during aging. Finally, we found that PP6 complex constituents PPH-6 and SAPS-1 contribute to host defense during aging, apparently without affecting DAF-16 transcriptional activity. Our studies indicate that a set of PP2A/4/6 complexes protect adult C. elegans from environmental stress, thus preserving healthspan. Therefore, along with their functions in cell division and development, the PP2A/4/6 phosphatases also appear to play critical roles later in life.

scholarly journals Systematic Functional Characterization of Human 21st Chromosome Orthologs in Caenorhabditis elegans

2017 ◽  
Author(s):  
Sarah K. Nordquist ◽  
Sofia R. Smith ◽  
Jonathan T. Pierce
Keyword(s):  
Nervous System ◽  
Down Syndrome ◽  
Caenorhabditis Elegans ◽  
Functional Characterization ◽  
System Function ◽  
Loss Of Function ◽  
C Elegans ◽  
Genes Encoding ◽  
Nervous System Function ◽  
Encoding Protein

ABSTRACTIndividuals with Down syndrome have neurological and muscle impairments due to an additional copy of the human 21st chromosome (HSA21). Only a few of ~200 HSA21 genes encoding protein have been linked to specific Down syndrome phenotypes, while the remainder are understudied. To identify poorly characterized HSA21 genes required for nervous system function, we studied behavioral phenotypes caused by loss-of-function mutations in conserved HSA21 orthologs in the nematode Caenorhabditis elegans. We identified ten HSA21 orthologs that are required for neuromuscular behaviors: cle-1 (COL18A1), cysl-2 (CBS), dnsn-1 (DONSON), eva-1 (EVA1C), mtq-2 (N6ATM1), ncam-1 (NCAM2), pad-2 (POFUT2), pdxk-1 (PDXK), rnt-1 (RUNX1), and unc-26 (SYNJ1). We also found that three of these genes are required for normal release of the neurotransmitter acetylcholine. This includes a known synaptic gene unc-26 (SYNJ1), as well as uncharacterized genes pdxk-1 (PDXK) and mtq-2 (N6ATM1). As the first systematic functional analysis of HSA21 orthologs, this study may serve as a platform to understand genes that underlie phenotypes associated with Down syndrome.ARTICLE SUMMARYDown syndrome causes neurological and muscle dysfunction due to an extra 21st chromosome. This chromosome has over 200 genes, most of which are understudied. To address this, we studied whether reducing function of these gene equivalents in the worm C. elegans caused neuronal or muscle defects. We identified ten genes conserved between human and worm that mediate function of behaviors. Among these, we show the uncharacterized genes mtq-2 and pdxk-1 are important for synaptic transmission and are exclusively expressed in nervous system. Our analysis may reveal functions of poorly studied genes that affect nervous system function in Down syndrome.

scholarly journals CAMKII and Calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Li Tao ◽  
Qi Xie ◽  
Yue-He Ding ◽  
Shang-Tong Li ◽  
Shengyi Peng ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Nuclear Localization ◽  
Insulin Signaling ◽  
Mammalian Cells ◽  
Nuclear Translocation ◽  
Type Ii ◽  
Wild Type ◽  
C Elegans ◽  
Foxo Transcription Factors ◽  
Lifespan Regulation

The insulin-like signaling pathway maintains a relatively short wild-type lifespan in Caenorhabditis elegans by phosphorylating and inactivating DAF-16, the ortholog of the FOXO transcription factors of mammalian cells. DAF-16 is phosphorylated by the AKT kinases, preventing its nuclear translocation. Calcineurin (PP2B phosphatase) also limits the lifespan of C. elegans, but the mechanism through which it does so is unknown. Herein, we show that TAX-6•CNB-1 and UNC-43, the C. elegans Calcineurin and Ca2+/calmodulin-dependent kinase type II (CAMKII) orthologs, respectively, also regulate lifespan through DAF-16. Moreover, UNC-43 regulates DAF-16 in response to various stress conditions, including starvation, heat or oxidative stress, and cooperatively contributes to lifespan regulation by insulin signaling. However, unlike insulin signaling, UNC-43 phosphorylates and activates DAF-16, thus promoting its nuclear localization. The phosphorylation of DAF-16 at S286 by UNC-43 is removed by TAX-6•CNB-1, leading to DAF-16 inactivation. Mammalian FOXO3 is also regulated by CAMKIIA and Calcineurin.

scholarly journals Calreticulin, a Calcium-binding Molecular Chaperone, Is Required for Stress Response and Fertility in Caenorhabditis elegans

2001 ◽  
Vol 12 (9) ◽  
pp. 2835-2845 ◽  
Author(s):  
Byung-Jae Park ◽  
Duk-Gyu Lee ◽  
Jae-Ran Yu ◽  
Sun-ki Jung ◽  
Kyuyeong Choi ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Calcium Binding ◽  
Functional Characterization ◽  
Cellular Functions ◽  
C Elegans ◽  
Behavioral Rhythms ◽  
Somatic Gonad ◽  
Sperm Development ◽  
Body Wall Muscles

Calreticulin (CRT), a Ca2+-binding protein known to have many cellular functions, including regulation of Ca2+ homoeostasis and chaperone activity, is essential for heart and brain development during embryogenesis in mice. Here, we report the functional characterization of Caenorhabditis elegans calreticulin (crt-1). Acrt-1 null mutant does not result in embryonic lethality but shows temperature-dependent reproduction defects. In C. elegans CRT-1 is expressed in the intestine, pharynx, body-wall muscles, head neurons, coelomocytes, and in sperm. crt-1males exhibit reduced mating efficiency and defects late in sperm development in addition to defects in oocyte development and/or somatic gonad function in hermaphrodites. Furthermore, crt-1 anditr-1 (inositol triphosphate receptor) together are required for normal behavioral rhythms. crt-1transcript level is elevated under stress conditions, suggesting that CRT-1 may be important for stress-induced chaperoning function inC. elegans.

Caenorhabditis elegans: a useful tool to decipher neurodegenerative pathways

2010 ◽  
Vol 38 (2) ◽  
pp. 559-563 ◽  
Author(s):  
James R. Johnson ◽  
Robert C. Jenn ◽  
Jeff W. Barclay ◽  
Robert D. Burgoyne ◽  
Alan Morgan
Keyword(s):  
Caenorhabditis Elegans ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Relevant Model ◽  
C Elegans ◽  
Molecular Determinants ◽  
Age Dependent

Neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases affect millions of people. These disorders are age-dependent, progressive and, at present, incurable. A practical and relevant model is needed to investigate the molecular determinants of these debilitating diseases. Mammalian models are often prohibitively expensive, time-consuming and very complex. Given the highly conserved neurological pathways between mammals and invertebrates, Caenorhabditis elegans has emerged as a powerful tool for the investigation of the pathophysiology of these disorders. We describe recent findings in this area and show how C. elegans is being used to broaden our knowledge of human neurodegenerative diseases.

scholarly journals Lactobacilli in a clade ameliorate age-dependent decline of thermotaxis behavior in Caenorhabditis elegans

2020 ◽  
Author(s):  
Satoshi Higurashi ◽  
Sachio Tsukada ◽  
Shunji Nakano ◽  
Ikue Mori ◽  
Kentaro Noma
Keyword(s):  
Caenorhabditis Elegans ◽  
Brain Aging ◽  
Genetic Manipulation ◽  
Aging Research ◽  
E Coli ◽  
C Elegans ◽  
Powerful Approach ◽  
Age Dependent ◽  
Long Time ◽  
Standard Laboratory Diet

AbstractDiet is proposed to affect brain aging. However, the causality and mechanism of dietary effects on brain aging are still unclear due to the long time scales of aging. The nematode Caenorhabditis elegans (C. elegans) has led aging research because of its short lifespan and easy genetic manipulation. When fed the standard laboratory diet, Escherichia coli (E. coli), C. elegans experiences an age-dependent decline in temperature-food associative learning, called thermotaxis. To address if diet ameliorates this decline, we screened 35 different lactic acid bacteria as alternative diets. We found that Lactobacilli in a clade enriched with heterofermentative bacteria ameliorated age-dependent decline. On the other hand, homofermentative Lactobacillus species did not show this beneficial effect. Lactobacilli affected the thermotaxis of aged animals through DAF-16, an ortholog of mammalian FOXO transcription factor, while the effect on the thermotaxis was independent of the lifespan and locomotion. Our results demonstrate that diet can impact brain aging without changing the lifespan and that bacterial screen using C. elegans is a powerful approach to investigate age-dependent behavioral decline.

Sign in / Sign up

Export Citation Format

Share Document