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Aging in Caenorhabditis elegans is characterized by widespread physiological and molecular changes, but the mechanisms that determine the rate at which these changes occur are not well understood. In this study, we identify a novel link between reproductive aging and somatic aging in C. elegans. By measuring global age-related changes in the proteome, we identify a previously uncharacterized group of secreted proteins in the adult uterus that dramatically increase in abundance with age. This accumulation is blunted in animals with an extended reproductive period and accelerated in sterile animals lacking a germline. Uterine proteins are not removed in old post-reproductive animals or in young vulvaless worms, indicating that egg-laying is necessary for their rapid removal in wild-type young animals. Together, these results suggest that age-induced infertility contributes to extracellular protein accumulation in the uterus with age. Finally, we show that knocking down multiple age-increased proteins simultaneously extends lifespan. These results provide a mechanistic example of how the cessation of reproduction contributes to detrimental changes in the soma, and demonstrate how the timing of reproductive decline can influence the rate of aging. 相似文献
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Paola Sebastiani Monty Montano Annibale Puca Nadia Solovieff Toshio Kojima Meng C. Wang Efthymia Melista Micah Meltzer Sylvia E. J. Fischer Stacy Andersen Stephen H. Hartley Amanda Sedgewick Yasumichi Arai Aviv Bergman Nir Barzilai Dellara F. Terry Alberto Riva Chiara Viviani Anselmi Alberto Malovini Aya Kitamoto Motoji Sawabe Tomio Arai Yasuyuki Gondo Martin H. Steinberg Nobuyoshi Hirose Gil Atzmon Gary Ruvkun Clinton T. Baldwin Thomas T. Perls 《PloS one》2009,4(12)
Background
The strong familiality of living to extreme ages suggests that human longevity is genetically regulated. The majority of genes found thus far to be associated with longevity primarily function in lipoprotein metabolism and insulin/IGF-1 signaling. There are likely many more genetic modifiers of human longevity that remain to be discovered.Methodology/Principal Findings
Here, we first show that 18 single nucleotide polymorphisms (SNPs) in the RNA editing genes ADARB1 and ADARB2 are associated with extreme old age in a U.S. based study of centenarians, the New England Centenarian Study. We describe replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) that collectively support an association of ADARB1 and ADARB2 with longevity. Some SNPs in ADARB2 replicate consistently in the four populations and suggest a strong effect that is independent of the different genetic backgrounds and environments. To evaluate the functional association of these genes with lifespan, we demonstrate that inactivation of their orthologues adr-1 and adr-2 in C. elegans reduces median survival by 50%. We further demonstrate that inactivation of the argonaute gene, rde-1, a critical regulator of RNA interference, completely restores lifespan to normal levels in the context of adr-1 and adr-2 loss of function.Conclusions/Significance
Our results suggest that RNA editors may be an important regulator of aging in humans and that, when evaluated in C. elegans, this pathway may interact with the RNA interference machinery to regulate lifespan. 相似文献6.
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Cocaine, a potent addictive substance, is an inhibitor of monoamine transporters, including DAT (dopamine transporter), SERT (serotonin transporter) and NET (norepinephrine transporter). Cocaine administration induces complex behavioral alterations in mammals, but the underlying mechanisms are not well understood. Here, we tested the effect of cocaine on C. elegans behavior. We show for the first time that acute cocaine treatment evokes changes in C. elegans locomotor activity. Interestingly, the neurotransmitter serotonin, rather than dopamine, is required for cocaine response in C. elegans. The C. elegans SERT MOD-5 is essential for the effect of cocaine, consistent with the role of cocaine in targeting monoamine transporters. We further show that the behavioral response to cocaine is primarily mediated by the ionotropic serotonin receptor MOD-1. Thus, cocaine modulates locomotion behavior in C. elegans primarily by impinging on its serotoninergic system. 相似文献
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Roxani Gatsi Bettina Schulze María Jesús Rodríguez-Palero Blanca Hernando-Rodríguez Ralf Baumeister Marta Artal-Sanz 《PloS one》2014,9(9)
Lifespan regulation by mitochondrial proteins has been well described, however, the mechanism of this regulation is not fully understood. Amongst the mitochondrial proteins profoundly affecting ageing are prohibitins (PHB-1 and PHB-2). Paradoxically, in C. elegans prohibitin depletion shortens the lifespan of wild type animals while dramatically extending that of metabolically compromised animals, such as daf-2-insulin-receptor mutants. Here we show that amongst the three kinases known to act downstream of daf-2, only loss of function of sgk-1 recapitulates the ageing phenotype observed in daf-2 mutants upon prohibitin depletion. Interestingly, signalling through SGK-1 receives input from an additional pathway, parallel to DAF-2, for the prohibitin-mediated lifespan phenotype. We investigated the effect of prohibitin depletion on the mitochondrial unfolded protein response (UPRmt). Remarkably, the lifespan extension upon prohibitin elimination, of both daf-2 and sgk-1 mutants, is accompanied by suppression of the UPRmt induced by lack of prohibitin. On the contrary, gain of function of SGK-1 results in further shortening of lifespan and a further increase of the UPRmt in prohibitin depleted animals. Moreover, SGK-1 interacts with RICT-1 for the regulation of the UPRmt in a parallel pathway to DAF-2. Interestingly, prohibitin depletion in rict-1 loss of function mutant animals also causes lifespan extension. Finally, we reveal an unprecedented role for mTORC2-SGK-1 in the regulation of mitochodrial homeostasis. Together, these results give further insight into the mechanism of lifespan regulation by mitochondrial function and reveal a cross-talk of mitochondria with two key pathways, Insulin/IGF and mTORC2, for the regulation of ageing and stress response. 相似文献
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Background
Antibodies are critical tools in many avenues of biological research. Though antibodies can be produced in the research laboratory setting, most research labs working with vertebrates avail themselves of the wide array of commercially available reagents. By contrast, few such reagents are available for work with model organisms.Methodology/Principal Findings
We report the production of monoclonal antibodies directed against a wide range of proteins that label specific subcellular and cellular components, and macromolecular complexes. Antibodies were made to synaptobrevin (SNB-1), a component of synaptic vesicles; to Rim (UNC-10), a protein localized to synaptic active zones; to transforming acidic coiled-coil protein (TAC-1), a component of centrosomes; to CENP-C (HCP-4), which in worms labels the entire length of their holocentric chromosomes; to ORC2 (ORC-2), a subunit of the DNA origin replication complex; to the nucleolar phosphoprotein NOPP140 (DAO-5); to the nuclear envelope protein lamin (LMN-1); to EHD1 (RME-1) a marker for recycling endosomes; to caveolin (CAV-1), a marker for caveolae; to the cytochrome P450 (CYP-33E1), a resident of the endoplasmic reticulum; to β-1,3-glucuronyltransferase (SQV-8) that labels the Golgi; to a chaperonin (HSP-60) targeted to mitochondria; to LAMP (LMP-1), a resident protein of lysosomes; to the alpha subunit of the 20S subcomplex (PAS-7) of the 26S proteasome; to dynamin (DYN-1) and to the α-subunit of the adaptor complex 2 (APA-2) as markers for sites of clathrin-mediated endocytosis; to the MAGUK, protein disks large (DLG-1) and cadherin (HMR-1), both of which label adherens junctions; to a cytoskeletal linker of the ezrin-radixin-moesin family (ERM-1), which localized to apical membranes; to an ERBIN family protein (LET-413) which localizes to the basolateral membrane of epithelial cells and to an adhesion molecule (SAX-7) which localizes to the plasma membrane at cell-cell contacts. In addition to working in whole mount immunocytochemistry, most of these antibodies work on western blots and thus should be of use for biochemical fractionation studies.Conclusions/Significance
We have produced a set of monoclonal antibodies to subcellular components of the nematode C. elegans for the research community. These reagents are being made available through the Developmental Studies Hybridoma Bank (DSHB). 相似文献11.
We develop a new hidden Markov model-based method to analyze C elegans locomotive behavior and use this method to quantitatively characterize behavioral states. In agreement with previous work, we find states corresponding to roaming, dwelling, and quiescence. However, we also find evidence for a continuum of intermediate states. We suggest that roaming, dwelling, and quiescence may best be thought of as extremes which, mixed in any proportion, define the locomotive repertoire of C elegans foraging and feeding behavior. 相似文献
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Naoko Sakai Ryo Iwata Saori Yokoi Rebecca A. Butcher Jon Clardy Masahiro Tomioka Yuichi Iino 《PloS one》2013,8(7)
In sexually reproducing animals, mating is essential for transmitting genetic information to the next generation and therefore animals have evolved mechanisms for optimizing the chance of successful mate location. In the soil nematode C. elegans, males approach hermaphrodites via the ascaroside pheromones, recognize hermaphrodites when their tails contact the hermaphrodites'' body, and eventually mate with them. These processes are mediated by sensory signals specialized for sexual communication, but other mechanisms may also be used to optimize mate location. Here we describe associative learning whereby males use sodium chloride as a cue for hermaphrodite location. Both males and hermaphrodites normally avoid sodium chloride after associative conditioning with salt and starvation. However, we found that males become attracted to sodium chloride after conditioning with salt and starvation if hermaphrodites are present during conditioning. For this conditioning, which we call sexual conditioning, hermaphrodites are detected by males through pheromonal signaling and additional cue(s). Sex transformation experiments suggest that neuronal sex of males is essential for sexual conditioning. Altogether, these results suggest that C. elegans males integrate environmental, internal and social signals to determine the optimal strategy for mate location. 相似文献
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Evgeny V. Berdyshev Irina Gorshkova Anastasia Skobeleva Robert Bittman Xuequan Lu Steven M. Dudek Tamara Mirzapoiazova Joe G. N. Garcia Viswanathan Natarajan 《The Journal of biological chemistry》2009,284(9):5467-5477
Novel immunomodulatory molecule FTY720 is a synthetic analog of myriocin,
but unlike myriocin FTY720 does not inhibit serine palmitoyltransferase.
Although many of the effects of FTY720 are ascribed to its phosphorylation and
subsequent sphingosine 1-phosphate (S1P)-like action through
S1P1,3–5 receptors, studies on modulation of intracellular
balance of signaling sphingolipids by FTY720 are limited. In this study, we
used stable isotope pulse labeling of human pulmonary artery endothelial cells
with l-[U-13C, 15N]serine as well as in
vitro enzymatic assays and liquid chromatography-tandem mass spectrometry
methodology to characterize FTY720 interference with sphingolipid de
novo biosynthesis. In human pulmonary artery endothelial cells, FTY720
inhibited ceramide synthases, resulting in decreased cellular levels of
dihydroceramides, ceramides, sphingosine, and S1P but increased levels of
dihydrosphingosine and dihydrosphingosine 1-phosphate (DHS1P). The
FTY720-induced modulation of sphingolipid de novo biosynthesis was
similar to that of fumonisin B1, a classical inhibitor of ceramide synthases,
but differed in the efficiency to inhibit biosynthesis of short-chain
versus long-chain ceramides. In vitro kinetic studies
revealed that FTY720 is a competitive inhibitor of ceramide synthase 2 toward
dihydrosphingosine with an apparent Ki of 2.15
μm. FTY720-induced up-regulation of DHS1P level was mediated by
sphingosine kinase (SphK) 1, but not SphK2, as confirmed by experiments using
SphK1/2 silencing with small interfering RNA. Our data demonstrate for the
first time the ability of FTY720 to inhibit ceramide synthases and modulate
the intracellular balance of signaling sphingolipids. These findings open a
novel direction for therapeutic applications of FTY720 that focuses on
inhibition of ceramide biosynthesis, ceramide-dependent signaling, and the
up-regulation of DHS1P generation in cells.FTY7202 is a
synthetic analog of sphingosine and is currently being studied as a potent
immunosuppressive and immunomodulatory agent
(1–3).
FTY720-induced immunosuppression is ascribed, in part, to its protective
effect on endothelial cell barrier function that results in inhibition of
lymphocyte egress from lymph nodes and down-regulation of innate and adaptive
immune responses (4). As
endothelial cells predominantly express the sphingosine 1-phosphate 1
(S1P1) receptor and its activation initiates signaling that results
in the assembly of VE-cadherin-based adherens junctions
(5), it is thought that the
phosphorylation of FTY720 and the binding of FTY720-P to the S1P1
receptor determine its effect on vasculature
(1). Recently it became evident
that the action of FTY720 is more complex as several other direct protein
targets were identified. Thus, FTY720 was found to bind to and inhibit the
cannabinoid CB1 receptor (6),
to inhibit cytosolic phospholipase A2 (cPLA2), and to
counteract ceramide 1-phosphate-induced cPLA2 activation
(7). Additionally FTY720 but
not FTY720-P was shown to inhibit S1P lyase
(8), which degrades S1P to
ethanolamine phosphate and (E)-2-hexadecenal and regulates the
removal of sphingoid bases from the cumulative pool of sphingolipids. These
findings characterize FTY720 as a molecule with a multitargeted mode of action
whose cellular effects are complicated by its metabolic transformation to
FTY720-P, a structural and functional analog of S1P.Phosphorylation of FTY720 to FTY720-P by sphingosine kinases (SphKs) is the
only reported metabolic transformation of FTY720 and has been actively
explored because of its link to S1P-mediated signaling
(1,
2,
9,
10). Recent studies suggest
that the endogenous balance between S1P and ceramide molecules regulates
prosurvival and proapoptotic signaling cascades, which determine the outcome
of cellular response to different stress conditions
(11,
12) or the efficiency of
anticancer therapy
(12–14).
However, despite the fact that FTY720 resembles sphingosine (Sph) and is a
substrate of SphK2
(15–17),
there are no reported studies on the effect of FTY720 on the intrinsic balance
of signaling sphingolipids. Metabolic interconnections between proapoptotic
(ceramides) and prosurvival (dihydrosphingosine 1-phosphate (DHS1P)) molecules
are expected because it is known that fumonisin B1 (FB1), an inhibitor of
(dihydro)ceramide synthases, not only blocks the formation of ceramides and
up-regulates the intracellular content of dihydrosphingosine (DHSph) but also
increases the cellular level of DHS1P
(19,
20).In view of these considerations, it is important to know how compounds with
a potential ability to interfere with the sphingolipidome turnover affect the
DHS1P-S1P/ceramide balance in cells. To address this question we have
investigated the effect of FTY720 on metabolic pathways leading to ceramide
and sphingoid base 1-phosphate generation in human pulmonary artery
endothelial cells (HPAECs) by using a stable isotope pulse labeling approach
and quantitative liquid chromatography-tandem mass spectrometry of signaling
sphingolipids. We demonstrate that treatment of HPAECs with FTY720 results in
the inhibition of de novo ceramide formation with a concomitant
increase in DHSph and DHS1P content in cells. Moreover FTY720 showed a direct
inhibition of ceramide synthases in an in vitro assay, albeit it was
less efficient compared with the classical inhibitor of ceramide synthases,
FB1. Our present findings have identified ceramide synthase isozymes as a
novel molecular target for FTY720 action, opening a new direction for its
potential therapeutic application through the inhibition of ceramide
biosynthesis, ceramide-dependent signaling, and the up-regulation of DHS1P
generation in cells. 相似文献
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Background
LIN-12/Notch signaling is important for cell-cell interactions during development, and mutations resulting in constitutive LIN-12/Notch signaling can cause cancer. Loss of negative regulators of lin-12/Notch activity has the potential for influencing cell fate decisions during development and the genesis or aggressiveness of cancer.Methodology/Principal Findings
We describe two negative modulators of lin-12 activity in C. elegans. One gene, sel-11, was initially defined as a suppressor of a lin-12 hypomorphic allele; the other gene, cdc-42, is a well-studied Rho GTPase. Here, we show that SEL-11 corresponds to yeast Hrd1p and mammalian Synoviolin. We also show that cdc-42 has the genetic properties consistent with negative regulation of lin-12 activity during vulval precursor cell fate specification.Conclusions/Significance
Our results underscore the multiplicity of negative regulatory mechanisms that impact on lin-12/Notch activity and suggest novel mechanisms by which constitutive lin-12/Notch activity might be exacerbated in cancer. 相似文献15.
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The manner in which the nervous system regulates animal behaviors in natural environments is a fundamental issue in biology. To address this question, C. elegans has been widely used as a model animal for the analysis of various animal behaviors. Previous behavioral assays have been limited to two-dimensional (2-D) environments, confining the worm motion to a planar substrate that does not reflect three-dimensional (3-D) natural environments such as rotting fruits or soil. Here, we develop a 3-D worm tracker (3DWT) for freely moving C. elegans in 3-D environments, based on a stereoscopic configuration. The 3DWT provides us with a quantitative trajectory, including the position and movement direction of the worm in 3-D. The 3DWT is also capable of recording and visualizing postures of the moving worm in 3-D, which are more complex than those in 2-D. Our 3DWT affords new opportunities for understanding the nervous system function that regulates animal behaviors in natural 3-D environments. 相似文献
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Background
The nematode Caenorhabditis elegans has emerged as an important model for studies of the regulation of fat storage. C. elegans feed on bacteria, and various strains of E. coli are commonly used in research settings. However, it is not known whether particular bacterial diets affect fat storage and metabolism.Methodology/Principal Findings
Fat staining of fixed nematodes, as well as biochemical analysis of lipid classes, revealed considerable differences in fat stores in C. elegans growing on four different E. coli strains. Fatty acid composition and carbohydrate levels differ in the E. coli strains examined in these studies, however these nutrient differences did not appear to have a causative effect on fat storage levels in worms. Analysis of C. elegans strains carrying mutations disrupting neuroendocrine and other fat-regulatory pathways demonstrated that the intensity of Nile Red staining of live worms does not correlate well with biochemical methods of fat quantification. Several neuroendocrine pathway mutants and eating defective mutants show higher or lower fat storage levels than wild type, however, these mutants still show differences in fat stores when grown on different bacterial strains. Of all the mutants tested, only pept-1 mutants, which lack a functional intestinal peptide transporter, fail to show differential fat stores. Furthermore, fatty acid analysis of triacylglycerol stores reveals an inverse correlation between total fat stores and the levels of 15-methylpalmitic acid, derived from leucine catabolism.Conclusions
These studies demonstrate that nutritional cues perceived in the intestine regulate fat storage levels independently of neuroendocrine cues. The involvement of peptide transport and the accumulation of a fatty acid product derived from an amino acid suggest that specific peptides or amino acids may provide nutritional signals regulating fat metabolism and fat storage levels. 相似文献19.
It was recently suggested that specific antidepressants of the serotonin-antagonist type, namely mianserin and methiothepin, may exert anti-aging properties and specifically extend lifespan of the nematode C.elegans by causing a state of perceived calorie restriction (Petrascheck M, Ye X, Buck LB: An antidepressant that extends lifespan in adult Caenorhabditis elegans; Nature, Nov 22, 2007;450(7169):553–6, PMID 18033297). Using the same model organism, we instead observe a reduction of life expectancy when employing the commonly used, standardized agar-based solid-phase assay while applying the same or lower concentrations of the same antidepressants. Consistent with a well-known side-effect of these compounds in humans, antidepressants not only reduced lifespan but also increased body fat accumulation in C. elegans reflecting the mammalian phenotype. Taken together and in conflict with previously published findings, we find that antidepressants of the serotonin-antagonist type not only promote obesity, but also decrease nematode lifespan. 相似文献
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Della C. David Noah Ollikainen Jonathan C. Trinidad Michael P. Cary Alma L. Burlingame Cynthia Kenyon 《PLoS biology》2010,8(8)
Aberrant protein aggregation is a hallmark of many age-related diseases, yet little is known about whether proteins aggregate with age in a non-disease setting. Using a systematic proteomics approach, we identified several hundred proteins that become more insoluble with age in the multicellular organism Caenorhabditis elegans. These proteins are predicted to be significantly enriched in β-sheets, which promote disease protein aggregation. Strikingly, these insoluble proteins are highly over-represented in aggregates found in human neurodegeneration. We examined several of these proteins in vivo and confirmed their propensity to aggregate with age. Different proteins aggregated in different tissues and cellular compartments. Protein insolubility and aggregation were significantly delayed or even halted by reduced insulin/IGF-1-signaling, which also slows aging. We found a significant overlap between proteins that become insoluble and proteins that influence lifespan and/or polyglutamine-repeat aggregation. Moreover, overexpressing one aggregating protein enhanced polyglutamine-repeat pathology. Together our findings indicate that widespread protein insolubility and aggregation is an inherent part of aging and that it may influence both lifespan and neurodegenerative disease. 相似文献