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The Anticonvulsant Ethosuximide Disrupts Sensory Function to Extend C. elegans Lifespan  [PDF]
James J. Collins,Kimberley Evason,Christopher L. Pickett,Daniel L. Schneider,Kerry Kornfeld
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000230
Abstract: Ethosuximide is a medication used to treat seizure disorders in humans, and we previously demonstrated that ethosuximide can delay age-related changes and extend the lifespan of the nematode Caenorhabditis elegans. The mechanism of action of ethosuximide in lifespan extension is unknown, and elucidating how ethosuximide functions is important for defining endogenous processes that influence lifespan and for exploring the potential of ethosuximide as a therapeutic for age-related diseases. To identify genes that mediate the activity of ethosuximide, we conducted a genetic screen and identified mutations in two genes, che-3 and osm-3, that cause resistance to ethosuximide-mediated toxicity. Mutations in che-3 and osm-3 cause defects in overlapping sets of chemosensory neurons, resulting in defective chemosensation and an extended lifespan. These findings suggest that ethosuximide extends lifespan by inhibiting the function of specific chemosensory neurons. This model is supported by the observation that ethosuximide-treated animals displayed numerous phenotypic similarities with mutants that have chemosensory defects, indicating that ethosuximide inhibits chemosensory function. Furthermore, ethosuximide extends lifespan by inhibiting chemosensation, since the long-lived osm-3 mutants were resistant to the lifespan extension caused by ethosuximide. These studies demonstrate a novel mechanism of action for a lifespan-extending drug and indicate that sensory perception has a critical role in controlling lifespan. Sensory perception also influences the lifespan of Drosophila, suggesting that sensory perception has an evolutionarily conserved role in lifespan control. These studies highlight the potential of ethosuximide and related drugs that modulate sensory perception to extend lifespan in diverse animals.
Telomeres, Age and Reproduction in a Long-Lived Reptile  [PDF]
Virginie Plot, Fran?ois Criscuolo, Sandrine Zahn, Jean-Yves Georges
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040855
Abstract: A major interest has recently emerged in understanding how telomere shortening, mechanism triggering cell senescence, is linked to organism ageing and life history traits in wild species. However, the links between telomere length and key history traits such as reproductive performances have received little attention and remain unclear to date. The leatherback turtle Dermochelys coriacea is a long-lived species showing rapid growth at early stages of life, one of the highest reproductive outputs observed in vertebrates and a dichotomised reproductive pattern related to migrations lasting 2 or 3 years, supposedly associated with different environmental conditions. Here we tested the prediction of blood telomere shortening with age in this species and investigated the relationship between blood telomere length and reproductive performances in leatherback turtles nesting in French Guiana. We found that blood telomere length did not differ between hatchlings and adults. The absence of blood telomere shortening with age may be related to an early high telomerase activity. This telomere-restoring enzyme was formerly suggested to be involved in preventing early telomere attrition in early fast-growing and long-lived species, including squamate reptiles. We found that within one nesting cycle, adult females having performed shorter migrations prior to the considered nesting season had shorter blood telomeres and lower reproductive output. We propose that shorter blood telomeres may result from higher oxidative stress in individuals breeding more frequently (i.e., higher costs of reproduction) and/or restoring more quickly their body reserves in cooler feeding areas during preceding migration (i.e., higher foraging costs). This first study on telomeres in the giant leatherback turtle suggests that blood telomere length predicts not only survival chances, but also reproductive performances. Telomeres may therefore be a promising new tool to evaluate individual reproductive quality which could be useful in such species of conservation concern.
Manipulating insulin signaling to enhance mosquito reproduction
Anam J Arik, Jason L Rasgon, Kendra M Quicke, Michael A Riehle
BMC Physiology , 2009, DOI: 10.1186/1472-6793-9-15
Abstract: Knockdown of AaegPTEN or its specific splice variant AaegPTEN6 (the splice variant thought to regulate reproduction in the ovary and fat body) using RNAi led to a 15–63% increase in egg production with no adverse effects on egg viability during the first reproductive cycle. Knockdown of AaegPTEN3, expressed predominantly in the head, had no effect on reproduction. We also characterized the protein expression patterns of these two splice variants during development and in various tissues during a reproductive cycle.Previous studies in a range of organisms, including Drosophila melanogaster and Caenorhabditis elegans, have demonstrated that disruption of the IIS cascade leads to decreased reproduction or sterility. In this study we demonstrate that knockdown of the IIS inhibitor PTEN can actually increase reproduction in the mosquito, at least during the first reproductive cycle.Mosquito-borne diseases such as dengue, malaria and lymphatic filariasis are an increasing global health problem. Dengue, along with dengue hemorrhagic fever (DHF), is transmitted by the mosquito Aedes aegypti and is becoming an increasing threat in more than one hundred countries [1]. A better understanding of the mosquito's reproductive physiology could lead to novel control strategies that could complement or replace current methods of control. It has been theorized that increased reproductive effort results in a trade-off with lifespan. Such a trade-off is supported by studies conducted on a wide range of organisms, including birds, mammals, fruit flies and roundworms [2-4]. However, recent studies also indicate that lifespan and reproduction can be uncoupled [5]. The insulin/insulin growth factor I signaling (IIS) cascade lies at the heart of this interplay between reproduction and lifespan in eukaryotic organisms [6-8]. Studies in Caenorhabditis elegans and Drosophila melanogaster show that gene mutations in signaling molecules within the IIS cascade affect lifespan and reproduction [9-1
No Influence of Indy on Lifespan in Drosophila after Correction for Genetic and Cytoplasmic Background Effects  [PDF]
Janne M Toivonen,Glenda A Walker,Pedro Martinez-Diaz,Ivana Bjedov,Yasmine Driege,Howard T Jacobs,David Gems,Linda Partridge
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030095
Abstract: To investigate whether alterations in mitochondrial metabolism affect longevity in Drosophila melanogaster, we studied lifespan in various single gene mutants, using inbred and outbred genetic backgrounds. As positive controls we included the two most intensively studied mutants of Indy, which encodes a Drosophila Krebs cycle intermediate transporter. It has been reported that flies heterozygous for these Indy mutations, which lie outside the coding region, show almost a doubling of lifespan. We report that only one of the two mutants lowers mRNA levels, implying that the lifespan extension observed is not attributable to the Indy mutations themselves. Moreover, neither Indy mutation extended lifespan in female flies in any genetic background tested. In the original genetic background, only the Indy mutation associated with altered RNA expression extended lifespan in male flies. However, this effect was abolished by backcrossing into standard outbred genetic backgrounds, and was associated with an unidentified locus on the X chromosome. The original Indy line with long-lived males is infected by the cytoplasmic symbiont Wolbachia, and the longevity of Indy males disappeared after tetracycline clearance of this endosymbiont. These findings underscore the critical importance of standardisation of genetic background and of cytoplasm in genetic studies of lifespan, and show that the lifespan extension previously claimed for Indy mutants was entirely attributable to confounding variation from these two sources. In addition, we saw no effects on lifespan of expression knockdown of the Indy orthologues nac-2 and nac-3 in the nematode Caenorhabditis elegans.
Lifespan and Glucose Metabolism in Insulin Receptor Mutant Mice  [PDF]
Takahiko Shimizu,Tomonori Baba,Midori Ogawara,Takuji Shirasawa
Journal of Aging Research , 2011, DOI: 10.4061/2011/315640
Abstract: Insulin/insulin-like growth factor type 1 signaling regulates lifespan and resistance to oxidative stress in worms, flies, and mammals. In a previous study, we revealed that insulin receptor (IR) mutant mice, which carry a homologous mutation found in the long-lived daf-2 mutant of Caenorhabditis elegans, showed enhanced resistance to oxidative stress cooperatively modulated by sex hormones and dietary signals (Baba et al., (2005)). We herein investigated the lifespan of IR mutant mice to evaluate the biological significance of insulin signaling in mice. Under normoxia, mutant male mice had a lifespan comparable to that of wild-type male mice. IR mutant female mice also showed a lifespan similar to that of wild-type female mice, in spite of the fact that the IR mutant female mice acquired more resistance to oxidative stress than IR mutant male mice. On the other hand, IR mutant male and female mice both showed insulin resistance with hyperinsulinemia, but they did not develop hyperglycemia throughout their entire lifespan. These data indicate that the IR mutation does not impact the lifespan in mice, thus suggesting that insulin signaling might have a limited effect on the lifespan of mice. 1. Introduction Accumulating evidence indicates that insulin/insulin-like growth factor type 1 (IGF-1) signaling regulates lifespan in worms, flies, and mammals [1, 2]. In Caenorhabditis elegans, a mutation of the daf-2 gene that encodes an insulin/IGF-1 receptor ortholog significantly extended the lifespan and enhanced the resistance of the worms to oxidative stress [3, 4]. The lifespan extension caused by daf-2 mutations required the activity of daf-16 [3], which encodes a FOXO family transcription factor [5, 6]. Insulin/IGF-1 receptor mutations can also increase the lifespan of Drosophila [7]. In addition, mutations in chico, a downstream insulin receptor (IR) substrate-like signaling protein, increased the lifespan of the flies [8]. In mice, long-lived hereditary dwarf mice have been described [9]. Low levels of circulating growth hormone (GH) and IGF-1 in the Ames and Snell dwarf mice, which have pituitary defects, were associated with an extension of their lifespan [9]. Mutations in upstream genes that regulate insulin and IGF-1 also extended lifespan. For example, Little mice harbor a mutation in the GH-releasing hormone receptor and display reduced GH, as well as prolactin secretion [10]. Little mice also show reduced IGF-1 in blood, and have an increased mean and maximal lifespan [9]. Furthermore, GH receptor (GHR) mutant mice showed reduced circulating
Identification of a Lifespan Extending Mutation in the Schizosaccharomyces pombe Cyclin Gene clg1+ by Direct Selection of Long-Lived Mutants  [PDF]
Bo-Ruei Chen, Yanhui Li, Jessica R. Eisenstatt, Kurt W. Runge
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069084
Abstract: Model organisms such as budding yeast, worms and flies have proven instrumental in the discovery of genetic determinants of aging, and the fission yeast Schizosaccharomyces pombe is a promising new system for these studies. We devised an approach to directly select for long-lived S. pombe mutants from a random DNA insertion library. Each insertion mutation bears a unique sequence tag called a bar code that allows one to determine the proportion of an individual mutant in a culture containing thousands of different mutants. Aging these mutants in culture allowed identification of a long-lived mutant bearing an insertion mutation in the cyclin gene clg1+. Clg1p, like Pas1p, physically associates with the cyclin-dependent kinase Pef1p. We identified a third Pef1p cyclin, Psl1p, and found that only loss of Clg1p or Pef1p extended lifespan. Genetic and co-immunoprecipitation results indicate that Pef1p controls lifespan through the downstream protein kinase Cek1p. While Pef1p is conserved as Pho85p in Saccharomyces cerevisiae, and as cdk5 in humans, genome-wide searches for lifespan regulators in S. cerevisiae have never identified Pho85p. Thus, the S. pombe system can be used to identify novel, evolutionarily conserved lifespan extending mutations, and our results suggest a potential role for mammalian cdk5 as a lifespan regulator.
Prolonged manganese exposure induces severe deficits in lifespan, development and reproduction possibly by altering oxidative stress response in Caenorhabditis elegans

XIAO Jing,RUI Qi,GUO Yuling,CHANG Xingya,WANG Dayong,

环境科学学报(英文版) , 2009,
Abstract: We examined the possible multiple defects induced by acute and prolonged exposure to high levels of manganese (Mn) solution by monitoring the endpoints of lifespan,development,reproduction,and stress response.Our data suggest that acute exposure (6 h) to Mn did not cause severe defects of life span,development,and reproduction.Similarly,no significant defects could be found for the life span,development,and reproduction in animals exposed to a low concentration of Mn (2.5 μmol/L) for 48 h.In contrast,prolonged exposure (48-h) to high concentrations of Mn (75 and 200 μmol/L) resulted in significant defects of life span,development,and reproduction,as well as the increase of the percentage of population with hsp-16.2::gfp expression indicating the obvious induction of stress responses in exposed animals.Moreover,prolonged exposure (48-h) to high concentrations (75 and 200 μmol/L) of Mn decreased the expression levels of antioxidant genes of sod-1,sod-2,sod-3,and sod-4 compared to control.Therefore,prolonged exposure to high concentrations of Mn will induce the severe defects of life span,development,and reproduction in nematodes possibly by affecting the stress response and expression of antioxidant genes in Caenorhabditis elegans.
Hormones, reproduction and disease in the longest-lived rodent: the naked mole rat  [cached]
Manlio Vinciguerra
Endocrinology Studies , 2011, DOI: 10.4081/es.2011.e4
Abstract: Aging is an inescapable human condition, made of hormonal, physical, and behavioral changes. Age-related illnesses and decline result from the interactions between genes and the environment. Life expectancy dramatically increased in the last century with the improvement in health cares and quality of life in the Western World. Despite these advances, the last 20 years of our life are often accompanied by an increased incidence of hormonalrelated diseases, such as cancer, metabolic, cardiovascular and neurological dysturbances. Aging research recently uncovered many of the molecular pathways involved in nutrients and hormonal regulation, and also involved in organism life span using simple laboratory animal model. However this knowledge did not translate in an ameliorated aging and cure for hormonal diseases in humans. A breakthrough in aging research came from recent studies on the longest-lived rodent [the naked mole rat (NMR)]. NMR are able to reach ~30 years of age in good health. Because of their longevity and sustained health, NMR are a research model for successful aging. The most striking feature of NMR is perhaps their eusociality. Unique among mammals (eusociality is observed in insects such as bees and ants), NMR are organized in highly cooperative colonies. The aim of this review is to summarize our knowledge on hormonal and reproductive aspects in NMR. Furthermore, their resistance to pathological insults will be discussed.
When Stress Predicts a Shrinking Gene Pool, Trading Early Reproduction for Longevity Can Increase Fitness, Even with Lower Fecundity
William C. Ratcliff,Peter Hawthorne,Michael Travisano,R. Ford Denison
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0006055
Abstract: Stresses like dietary restriction or various toxins increase lifespan in taxa as diverse as yeast, Caenorhabditis elegans, Drosophila and rats, by triggering physiological responses that also tend to delay reproduction. Food odors can reverse the effects of dietary restriction, showing that key mechanisms respond to information, not just resources. Such environmental cues can predict population trends, not just individual prospects for survival and reproduction. When population size is increasing, each offspring produced earlier makes a larger proportional contribution to the gene pool, but the reverse is true when population size is declining.
The Metabolic Profile of Long-Lived Drosophila melanogaster  [PDF]
Pernille Sarup, Simon Metz Mariendal Pedersen, Niels Chr. Nielsen, Anders Malmendal, Volker Loeschcke
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047461
Abstract: We investigated the age-related changes in the metabolic profile of male Drosophila melanogaster and compared the metabolic profile of flies selected for increased longevity to that of control flies of equal age. We found clear differences in metabolite composition between selection regimes and among age groups. Contrary to results found in a previous study of the transcriptome of these lines the metabolic profile did not show a younger pattern in longevity-selected (LS) flies than in same aged control (C) flies. Rather, many of the metabolites affected by age had levels common to older control individuals in the young LS flies. Furthermore, ageing affected the metabolome in a different LS specific direction. The selection induced difference increased with age. Some metabolites involved in oxidative phosphorylation changed with age highlighting the importance of mitochondrial function in the ageing process. However, these metabolites were not affected by selection for increased longevity, indicating that improvements of mitochondrial function were not involved in the increased lifespan of LS lines. Of the eight metabolites identified as having a significant difference in relative abundance between selection regimes in our study choline, lysine and glucose also show difference among lifespan phenotypes in C. elegans indicating that the correlation between the concentration of these metabolites and longevity was evolutionary conserved. Links between longevity and choline concentration is also found in mice making this metabolite an obvious target for further study.
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