• Activation of G Signaling Enhances Memory Consolidation and Slows Cognitive Decline.

    Rachel N. Arey; Geneva M. Stein; Rachel Kaletsky; Amanda Kauffman; Coleen T. Murphy
    Journal Article

    Perhaps the most devastating decline with age is the loss of memory. Therefore, identifying mechanisms to restore memory function with age is critical. Using C. elegans associative learning and memory assays, we identified a gain-of-function G signaling pathway mutant that forms a long-term (cAMP response element binding protein [CREB]-...

  • Aging: miRacles of longevity?

    Coleen T. Murphy
    Journal Article

    The inventory of processes that miRNAs regulate has continued to expand since their relatively recent discovery. A new study reveals not only that the expression of miRNAs changes with age, but also that these miRNAs can act in both pro- and anti-longevity regulatory pathways.

  • The C. elegans adult neuronal IIS/FOXO transcriptome reveals adult phenotype regulators.

    Rachel Kaletsky; Vanisha Lakhina; Rachel Arey; April Williams; Jessica Landis; Jasmine Ashraf; Coleen T. Murphy
    Journal Article

    Insulin/insulin-like growth factor signalling (IIS) is a critical regulator of an organism's most important biological decisions from growth, development, and metabolism to reproduction and longevity. It primarily does so through the activity of the DAF-16 transcription factor (forkhead box O (FOXO) homologue), whose global targets were...

  • C. elegans maximum velocity correlates with healthspan and is maintained in worms with an insulin receptor mutation.

    Jeong-Hoon Hahm; Sunhee Kim; Race DiLoreto; Cheng Shi; Seung-Jae V. Lee; Coleen T. Murphy; Hong Gil Nam
    Journal Article

    Ageing is marked by physical decline. Caenorhabditis elegans is a valuable model for identifying genetic regulatory mechanisms of ageing and longevity. Here we report a simple method to assess C. elegans' maximum physical ability based on the worms' maximum movement velocity. We show maximum velocity declines with age, correlates well with...

  • C. elegans pathogenic learning confers multigenerational pathogen avoidance

    Rebecca S. Moore; Rachel Kaletsky; Coleen Tara Murphy
    Journal Article
    The ability to pass on learned information to progeny could present an evolutionary advantage for many generations. While apparently evolutionarily conserved, transgenerational epigenetic inheritance (TEI) is not well understood at the molecular or behavioral levels. Here we describe our discovery that C. elegans can pass on a learned pathogenic...
  • C. elegans positive butanone learning, short-term, and long-term associative memory assays.

    Amanda Kauffman; Lance Parsons; Geneva Stein; Airon Wills; Rachel Kaletsky; Coleen Murphy
    Journal Article

    The memory of experiences and learned information is critical for organisms to make choices that aid their survival. C. elegans navigates its environment through neuron-specific detection of food and chemical odors, and can associate nutritive states with chemical odors, temperature, and the pathogenicity of a food source. Here, we describe...

  • C. elegans positive olfactory associative memory is a molecularly conserved behavioral paradigm.

    Geneva M. Stein; Coleen T. Murphy
    Journal Article

    While it is thought that short-term memory arises from changes in protein dynamics that increase the strength of synaptic signaling, many of the underlying fundamental molecular mechanisms remain unknown.Our lab developed a Caenorhabditis elegans assay of positive olfactory short-term associative memory (STAM), in which worms learn to associate...

  • The C. elegans TGF-beta Dauer pathway regulates longevity via insulin signaling.

    Wendy M. Shaw; Shijing Luo; Jessica Landis; Jasmine Ashraf; Coleen T. Murphy
    Journal Article

    BACKGROUND: Previous genetic evidence suggested that the C. elegans TGF-beta Dauer pathway is responsible solely for the regulation of dauer formation, with no role in longevity regulation, whereas the insulin/IGF-1 signaling (IIS) pathway regulates both dauer formation and longevity.

    RESULTS: We have uncovered a significant longevity-...

  • Caenorhabditis elegans reproductive aging: Regulation and underlying mechanisms.

    Shijing Luo; Coleen T. Murphy
    Journal Article

    Female reproductive decline is one of the first aging phenotypes in humans, manifested in increasing rates of infertility, miscarriage, and birth defects in children of mothers over 35. Recently, Caenorhabditis elegans (C. elegans) has been developed as a model to study reproductive aging, and several studies have advanced our knowledge of...

  • Caenorhabditis elegans sperm carry a histone-based epigenetic memory of both spermatogenesis and oogenesis.

    Tomoko M. Tabuchi; Andreas Rechtsteiner; Tess E. Jeffers; Thea A. Egelhofer; Coleen T. Murphy; Susan Strome
    Journal Article

    Paternal contributions to epigenetic inheritance are not well understood. Paternal contributions via marked nucleosomes are particularly understudied, in part because sperm in some organisms replace the majority of nucleosome packaging with protamine packaging. Here we report that in Caenorhabditis elegans sperm, the genome is packaged in...

  • The cell biology of aging.

    Race DiLoreto; Coleen T. Murphy
    Journal Article

    One of the original hypotheses of organismal longevity posits that aging is the natural result of entropy on the cells, tissues, and organs of the animal--a slow, inexorable slide into nonfunctionality caused by stochastic degradation of its parts. We now have evidence that aging is instead at least in part genetically regulated. Many mutations...

  • Cell biology of disease and aging: a two-way street

    Craig Blackstone; Coleen T. Murphy
    Journal Article
  • Cell-Specific Transcriptional Profiling of Ciliated Sensory Neurons Reveals Regulators of Behavior and Extracellular Vesicle Biogenesis.

    Juan Wang; Rachel Kaletsky; Malan Silva; April Williams; Leonard A. Haas; Rebecca J. Androwski; Jessica N. Landis; Cory Patrick; Alina Rashid; Dianaliz Santiago-Martinez; Maria Gravato-Nobre; Jonathan Hodgkin; David H. Hall; Coleen T. Murphy; Maureen M. Barr
    Journal Article

    Cilia and extracellular vesicles (EVs) are signaling organelles [1]. Cilia act as cellular sensory antennae, with defects resulting in human ciliopathies. Cilia both release and bind to EVs [1]. EVs are sub-micron-sized particles released by cells and function in both short- and long-range intercellular communication. In C. elegans and mammals...

  • Cell-Type-Specific Transcriptome Analysis in the Drosophila Mushroom Body Reveals Memory-Related Changes in Gene Expression.

    Amanda Crocker; Xiao-Juan Guan; Coleen T. Murphy; Mala Murthy
    Journal Article

    Learning and memory formation in Drosophila rely on a network of neurons in the mushroom bodies (MBs). Whereas numerous studies have delineated roles for individual cell types within this network in aspects of learning or memory, whether or not these cells can also be distinguished by the genes they express remains unresolved. In addition, the...

  • Comparing genomic expression patterns across species identifies shared transcriptional profile in aging.

    Steven A. McCarroll; Coleen T. Murphy; Sige Zou; Scott D. Pletcher; Chen-Shan Chin; Yuh Nung Jan; Cynthia Kenyon; Cornelia I. Bargmann; Hao Li
    Journal Article

    We developed a method for systematically comparing gene expression patterns across organisms using genome-wide comparative analysis of DNA microarray experiments. We identified analogous gene expression programs comprising shared patterns of regulation across orthologous genes. Biological features of these patterns could be identified as highly...

  • Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf.

    Riva P. Oliveira; Jess Porter Abate; Kieran Dilks; Jessica Landis; Jasmine Ashraf; Coleen T. Murphy; Keith Blackwell
    Journal Article

    Studies in model organisms have identified regulatory processes that profoundly influence aging, many of which modulate resistance against environmental or metabolic stresses. In Caenorhabditis elegans, the transcription regulator SKN-1 is important for oxidative stress resistance and acts in multiple longevity pathways. SKN-1 is the ortholog...

  • Conserved regulators of cognitive aging: From worms to humans.

    Rachel N. Arey; Coleen T. Murphy
    Journal Article

    Cognitive decline is a major deficit that arises with age in humans. While some research on the underlying causes of these problems can be done in humans, harnessing the strengths of small model systems, particularly those with well-studied longevity mutants, such as the nematode C. elegans, will accelerate progress. Here we review the...

  • DAF-16 and PQM-1: partners in longevity.

    Ronald G. Tepper; Coleen T. Murphy; Harmen J. Bussemaker
    Journal Article
  • Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity.

    Collin Y. Ewald; Jess N. Landis; Jess Porter Abate; Coleen T. Murphy; Keith Blackwell
    Journal Article

    Interventions that delay ageing mobilize mechanisms that protect and repair cellular components, but it is unknown how these interventions might slow the functional decline of extracellular matrices, which are also damaged during ageing. Reduced insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile...

  • Dictyostelium myosin 25-50K loop substitutions specifically affect ADP release rates.

    C T. Murphy; J A. Spudich
    Journal Article

    While most of the sequence of myosin's motor domain is highly conserved among various organisms and tissue types, the junctions between the 25 and 50 kDa domains and the 50 and 20 kDa domains are strikingly divergent. The 50-20K loop is positioned to interact with actin, while the 25-50K loop is situated nearer the ATP binding site [Rayment, I...

  • EGF signalling activates the ubiquitin proteasome system to modulate C. elegans lifespan.

    Gang Liu; Jason Rogers; Coleen T. Murphy; Christopher Rongo
    Journal Article

    Epidermal growth factor (EGF) signalling regulates growth and differentiation. Here, we examine the function of EGF signalling in Caenorhabditis elegans lifespan. We find that EGF signalling regulates lifespan via the Ras-MAPK pathway and the PLZF transcription factors EOR-1 and EOR-2. As animals enter adulthood, EGF signalling upregulates the...

  • The endocrine regulation of aging in Caenorhabditis elegans.

    G A. Kleemann; C T. Murphy
    Journal Article

    In recent years, there has been significant growth in our understanding of the regulation of longevity. The most notable change is the identification and detailed description of a number of molecular pathways modulating the rate of aging. A good portion of this new data has come from studies using the genetic model organism Caenorhabditis...

  • Enrichment of regulatory motifs upstream of predicted DAF-16 targets.

    Cynthia Kenyon; Coleen T. Murphy
    Journal Article
  • The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO.

    Gizem Rizki; Terri Naoko Iwata; Ji Li; Christian G. Riedel; Colette Lafontaine Picard; Max Jan; Coleen T. Murphy; Siu Sylvia Lee
    Journal Article

    The conserved DAF-16/FOXO transcription factors and SIR-2.1/SIRT1 deacetylases are critical for diverse biological processes, particularly longevity and stress response; and complex regulation of DAF-16/FOXO by SIR-2.1/SIRT1 is central to appropriate biological outcomes. Caenorhabditis elegans Host Cell Factor 1 (HCF-1) is a longevity...

  • Feeding the germline.

    Cheng Shi; Coleen T. Murphy
    Journal Article

    Nucleotides are required in order to replicate DNA in the developing germline. Here, Chi and colleagues (pp. 307-320) have used Caernohabditis elegans to identify a GLP-1-dependent checkpoint that senses food (bacterially)-supplied nucleotide levels, arresting reproductive development in the absence of sufficient nucleotide supplies.

  • For longevity, perception is everything.

    Vanisha Lakhina; Coleen T. Murphy
    Journal Article

    Aging is a risk factor for chronic diseases, and identifying targets for intervention is a goal of the aging field. Burkewitz et al. now describe a mechanism that mediates the specific role for AMPK in longevity, whereby its activity in neurons modulates metabolism and mitochondrial integrity in peripheral tissues.

  • Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans.

    Coleen T. Murphy; Steven A. McCarroll; Cornelia I. Bargmann; Andrew Fraser; Ravi S. Kamath; Julie Ahringer; Hao Li; Cynthia Kenyon
    Journal Article

    Ageing is a fundamental, unsolved mystery in biology. DAF-16, a FOXO-family transcription factor, influences the rate of ageing of Caenorhabditis elegans in response to insulin/insulin-like growth factor 1 (IGF-I) signalling. Using DNA microarray analysis, we have found that DAF-16 affects expression of a set of genes during early adulthood,...

  • Genome Sequencing Fishes out Longevity Genes.

    Vanisha Lakhina; Coleen T. Murphy
    Journal Article

    Understanding the molecular basis underlying aging is critical if we are to fully understand how and why we age-and possibly how to delay the aging process. Up until now, most longevity pathways were discovered in invertebrates because of their short lifespans and availability of genetic tools. Now, Reichwald et al. and Valenzano et al....

  • Genome-wide functional analysis of CREB/long-term memory-dependent transcription reveals distinct basal and memory gene expression programs.

    Vanisha Lakhina; Rachel N. Arey; Rachel Kaletsky; Amanda Kauffman; Geneva Stein; William Keyes; Daniel Xu; Coleen T. Murphy
    Journal Article

    Induced CREB activity is a hallmark of long-term memory, but the full repertoire of CREB transcriptional targets required specifically for memory is not known in any system. To obtain a more complete picture of the mechanisms involved in memory, we combined memory training with genome-wide transcriptional analysis of C. elegans CREB mutants....

  • Global prediction of tissue-specific gene expression and context-dependent gene networks in Caenorhabditis elegans.

    Maria D. Chikina; Curtis Huttenhower; Coleen T. Murphy; Olga G. Troyanskaya
    Journal Article

    Tissue-specific gene expression plays a fundamental role in metazoan biology and is an important aspect of many complex diseases. Nevertheless, an organism-wide map of tissue-specific expression remains elusive due to difficulty in obtaining these data experimentally. Here, we leveraged existing whole-animal Caenorhabditis elegans microarray...

  • Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression.

    Seung-Jae Lee; Coleen T. Murphy; Cynthia Kenyon
    Journal Article

    Many studies have addressed the effect of dietary glycemic index on obesity and diabetes, but little is known about its effect on life span itself. We found that adding a small amount of glucose to the medium (2%) shortened the life span of C. elegans by inhibiting the activities of life span-extending transcription factors that are also...

  • Insulin signaling and dietary restriction differentially influence the decline of learning and memory with age.

    Amanda L. Kauffman; Jasmine M. Ashraf; Ryan Corces-Zimmerman; Jessica N. Landis; Coleen T. Murphy
    Journal Article

    Of all the age-related declines, memory loss is one of the most devastating. While conditions that increase longevity have been identified, the effects of these longevity-promoting factors on learning and memory are unknown. Here we show that the C. elegans Insulin/IGF-1 receptor mutant daf-2 improves memory performance early in adulthood and...

  • Insulin Signaling Regulates Oocyte Quality Maintenance with Age via Cathepsin B Activity.

    Nicole M. Templeman; Shijing Luo; Rachel Kaletsky; Cheng Shi; Jasmine Ashraf; William Keyes; Coleen T. Murphy
    Journal Article

    A decline in female reproduction is one of the earliest hallmarks of aging in many animals, including invertebrates and mammals [1-4]. The insulin/insulin-like growth factor-1 signaling (IIS) pathway has a conserved role in regulating longevity [5] and also controls reproductive aging [2, 6]. Although IIS transcriptional targets that regulate...

  • Insulin/insulin-like growth factor signaling in C. elegans.

    Coleen T. Murphy; Patrick J. Hu
    Journal Article

    The C. elegans insulin/IGF-1 signaling (IIS) pathway connects nutrient levels to metabolism, growth, development, longevity, and behavior. This fundamental pathway is regulated by insulin-like peptide ligands that bind to the insulin/IGF-1 transmembrane receptor (IGFR) ortholog DAF-2. DAF-2/IGFR controls the activity of a conserved...

  • An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology.

    Diana Andrea Fer de Abreu; Antonio Caballero; Pascal Fardel; Nicholas Stroustrup; Zhunan Chen; Kyunghwa Lee; William D. Keyes; Zachary M. Nash; Isaac F. López-Moyado; Federico Vaggi; Astrid Cornils; Martin Regenass; Anca Neagu; Ivan Ostojic; Chang Liu; Yongmin Cho; Deniz Sifoglu; Yu Shen; Walter Fontana; Hang Lu; Attila Csikasz-Nagy; Coleen T. Murphy; Adam Antebi; Eric Blanc; Javier Apfeld; Yun Zhang; Joy Alcedo; Queelim Ch'ng
    Journal Article

    Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies...

  • Integration of diverse inputs in the regulation of Caenorhabditis elegans DAF-16/FOXO.

    Jessica N. Landis; Coleen T. Murphy
    Journal Article

    In a remarkably conserved insulin signaling pathway that is well-known for its regulation of longevity in worms, flies, and mammals, the major C. elegans effector of this pathway, DAF-16/FOXO, also modulates many other physiological processes. This raises the question of how DAF-16/FOXO chooses the correct targets to achieve the appropriate...

  • An integrative tissue-network approach to identify and test human disease genes.

    Victoria Yao; Rachel Kaletsky; William Keyes; Danielle E. Mor; Aaron K. Wong; Salman Sohrabi; Coleen T. Murphy; Olga G. Troyanskaya
    Journal Article

    Effective discovery of causal disease genes must overcome the statistical challenges of quantitative genetics studies and the practical limitations of human biology experiments. Here we developed diseaseQUEST, an integrative approach that combines data from human genome-wide disease studies with in silico network models of tissue- and cell-type...

  • The Intersection of Aging, Longevity Pathways, and Learning and Memory in C. elegans.

    Geneva M. Stein; Coleen T. Murphy
    Journal Article

    Our understanding of the molecular and genetic regulation of aging and longevity has been greatly augmented through studies using the small model system, C. elegans. It is important to test whether mutations that result in a longer life span also extend the health span of the organism, rather than simply prolonging an aged state. C. elegans can...

  • Investigating Mechanisms that Control Ubiquitin-Mediated DAF-16/FOXO Protein Turnover.

    Thomas Heimbucher; Coleen T. Murphy
    Journal Article

    Protein turnover of FOXO family transcription factors is regulated by the ubiquitin-proteasome system. A complex interplay of factors that covalently attach certain types of ubiquitin chains (E3-ubiquitin ligases), and enzymes that are able to remove ubiquitin conjugates (deubiquitylases), regulate the degradation of FOXO proteins by the...

  • Mating and male pheromone kill \textitCaenorhabditis males through distinct mechanisms

    Cheng Shi; Alexi M. Runnels; Coleen T. Murphy
    Journal Article
    Differences in longevity between sexes is a mysterious yet general phenomenon across great evolutionary distances. To test the roles of responses to environmental cues and sexual behaviors in longevity regulation, we examined \textitCaenorhabditis male lifespan under solitary, grouped, and mated conditions. We find that neurons and the germline...
  • Mating induces shrinking and death in Caenorhabditis mothers.

    Cheng Shi; Coleen T. Murphy
    Journal Article

    Interactions between the germ line and the soma help optimize reproductive success. We discovered a phenomenon linking reproductive status to longevity: In both hermaphroditic and gonochoristic Caenorhabditis, mating leads to female shrinking and death, compressing postreproductive life span. Male sperm induces germline- and DAF-9/DAF-12-...

  • Mating-induced Male Death and Pheromone Toxin-regulated Androstasis

    Cheng Shi; Alexi M. Runnels; Coleen T. Murphy
    Journal Article
    How mating affects male lifespan is poorly understood. Using single worm lifespan assays, we discovered that males live significantly shorter after mating in both androdioecious (male and hermaphroditic) and gonochoristic (male and female) Caenorhabditis. Germline-dependent shrinking, glycogen loss, and ectopic expression of vitellogenins...
  • A microfluidic device and automatic counting system for the study of C. elegans reproductive aging.

    Siran Li; Howard A. Stone; Coleen T. Murphy
    Journal Article

    The nematode Caenorhabditis elegans (C. elegans) is an excellent model to study reproductive aging because of its short life span, its cessation of reproduction in mid-adulthood, and the strong conservation of pathways that regulate longevity. During its lifetime, a wild-type C. elegans hermaphrodite usually lays about 200-300 self-fertilized...

  • A myosin II mutation uncouples ATPase activity from motility and shortens step size.

    C T. Murphy; R S. Rock; J A. Spudich
    Journal Article

    It is thought that Switch II of myosin, kinesin and G proteins has an important function in relating nucleotide state to protein conformation. Here we examine a myosin mutant containing an S456L substitution in the Switch II region. In this protein, mechanical activity is uncoupled from the chemical energy of ATP hydrolysis so that its gliding...

  • The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory.

    Ling-Bo Li; Haoyun Lei; Rachel N. Arey; Pengpeng Li; Jianfeng Liu; Coleen T. Murphy; X Z.Shawn Xu; Kang Shen
    Journal Article

    Aging is the greatest risk factor for a number of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Furthermore, normal aging is associated with a decline in sensory, motor, and cognitive functions. Emerging evidence suggests that synapse alterations, rather than neuronal cell death, are the causes of neuronal...

  • A new system for comparative functional genomics of Saccharomyces yeasts.

    Amy A. Caudy; Yuanfang Guan; Yue Jia; Christina Hansen; Chris DeSevo; Alicia P. Hayes; Joy Agee; Juan R. Alvarez-Dominguez; Hugo Arellano; Daniel Barrett; Cynthia Bauerle; Namita Bisaria; Patrick H. Bradley; Scott Breunig; Erin Bush; David Cappel; Emily Capra; Walter Chen; John Clore; Peter A. Combs; Christopher Doucette; Olukunle Demuren; Peter Fellowes; Sam Freeman; Evgeni Frenkel; Daniel Gadala-Maria; Richa Gawande; David Glass; Samuel Grossberg; Anita Gupta; Latanya Hammonds-Odie; Aaron Hoisos; Jenny Hsi; Yu-Han Huang Hsu; Sachi Inukai; Konrad J. Karczewski; Xiaobo Ke; Mina Kojima; Samuel Leachman; Danny Lieber; Anna Liebowitz; Julia Liu; Yufei Liu; Trevor Martin; Jose Mena; Rosa Mendoza; Cameron Myhrvold; Christian Millian; Sarah Pfau; Sandeep Raj; Matt Rich; Joe Rokicki; William Rounds; Michael Salazar; Matthew Salesi; Rajani Sharma; Sanford Silverman; Cara Singer; Sandhya Sinha; Max Staller; Philip Stern; Hanlin Tang; Sharon Weeks; Maxwell Weidmann; Ashley Wolf; Carmen Young; Jie Yuan; Christopher Crutchfield; Megan McClean; Coleen T. Murphy; Manuel Llinás; David Botstein; Olga G. Troyanskaya; Maitreya J. Dunham
    Journal Article

    Whole-genome sequencing, particularly in fungi, has progressed at a tremendous rate. More difficult, however, is experimental testing of the inferences about gene function that can be drawn from comparative sequence analysis alone. We present a genome-wide functional characterization of a sequenced but experimentally understudied budding yeast...

  • PQM-1 complements DAF-16 as a key transcriptional regulator of DAF-2-mediated development and longevity.

    Ronald G. Tepper; Jasmine Ashraf; Rachel Kaletsky; Gunnar Kleemann; Coleen T. Murphy; Harmen J. Bussemaker
    Journal Article

    Reduced insulin/IGF-1-like signaling (IIS) extends C. elegans lifespan by upregulating stress response (class I) and downregulating other (class II) genes through a mechanism that depends on the conserved transcription factor DAF-16/FOXO. By integrating genome-wide mRNA expression responsiveness to DAF-16 with genome-wide in vivo binding data...

  • Regulation of aging and age-related disease by DAF-16 and heat-shock factor.

    Ao-Lin Hsu; Coleen T. Murphy; Cynthia Kenyon
    Journal Article

    The Caenorhabditis elegans transcription factor HSF-1, which regulates the heat-shock response, also influences aging. Reducing hsf-1 activity accelerates tissue aging and shortens life-span, and we show that hsf-1 overexpression extends lifespan. We find that HSF-1, like the transcription factor DAF-16, is required for daf-2-insulin/IGF-1...

  • Regulation of reproduction and longevity by nutrient-sensing pathways

    Nicole M. Templeman; Coleen T. Murphy
    Journal Article
    Nutrients are necessary for life, as they are a crucial requirement for biological processes including reproduction, somatic growth, and tissue maintenance. Therefore, signaling systems involved in detecting and interpreting nutrient or energy levels—most notably, the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway, mechanistic...
  • RNA surveillance via nonsense-mediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans.

    Heehwa G. Son; Mihwa Seo; Seokjin Ham; Wooseon Hwang; Dongyeop Lee; Seon Woo A. An; Murat Artan; Keunhee Seo; Rachel Kaletsky; Rachel N. Arey; Youngjae Ryu; Chang Man Ha; Yoon Ki Kim; Coleen T. Murphy; Tae-Young Roh; Hong Gil Nam; Seung-Jae V. Lee
    Journal Article

    Long-lived organisms often feature more stringent protein and DNA quality control. However, whether RNA quality control mechanisms, such as nonsense-mediated mRNA decay (NMD), which degrades both abnormal as well as some normal transcripts, have a role in organismal aging remains unexplored. Here we show that NMD mediates longevity in C....

  • The role of insulin/IGF-like signaling in C. elegans longevity and aging.

    Rachel Kaletsky; Coleen T. Murphy
    Journal Article

    Aging is characterized by general physiological decline over time. A hallmark of human senescence is the onset of various age-related afflictions including neurodegeneration, cardiovascular disease and cancer. Although environmental and stochastic factors undoubtedly contribute to the increased incidence of disease with age, recent studies...

  • The search for DAF-16/FOXO transcriptional targets: approaches and discoveries.

    Coleen T. Murphy
    Journal Article

    The insulin/IGF-1 receptor (IIR)/FOXO pathway is remarkably conserved in worms, flies, and mammals, and downregulation of signaling in this pathway has been shown to extend lifespan in all of these animals. FOXO-mediated transcription is required for the long lifespan of IIR mutants; thus, there is great interest in identifying FOXO target...

  • The sequence of the myosin 50-20K loop affects Myosin's affinity for actin throughout the actin-myosin ATPase cycle and its maximum ATPase activity.

    C T. Murphy; J A. Spudich
    Journal Article

    We are interested in the role that solvent-exposed, proteolytically sensitive surface loops play in myosin function. The 25-50K loop, or loop 1, is near the ATP binding site, while the 50-20K loop (loop 2) is in the actin binding site. Through chimeric studies, we have found that loop 1 affects ADP release [Murphy, C. T., and Spudich, J. A. (...

  • A simple offspring-to-mother size ratio predicts post-reproductive lifespan

    George Maliha; Coleen T. Murphy
    Journal Article
    Why do many animals live well beyond their reproductive period? This seems counter to the theory that the fraction of life spent reproducing should be maximized in order to maximize the number of offspring produced in each generation. To resolve this paradox, hypotheses have been developed that evoke parental or grandparental care as reasons for...
  • TGF-beta Sma/Mab signaling mutations uncouple reproductive aging from somatic aging.

    Shijing Luo; Wendy M. Shaw; Jasmine Ashraf; Coleen T. Murphy
    Journal Article

    Female reproductive cessation is one of the earliest age-related declines humans experience, occurring in mid-adulthood. Similarly, Caenorhabditis elegans' reproductive span is short relative to its total life span, with reproduction ceasing about a third into its 15-20 day adulthood. All of the known mutations and treatments that extend C....

  • TGF-β and insulin signaling regulate reproductive aging via oocyte and germline quality maintenance.

    Shijing Luo; Gunnar A. Kleemann; Jasmine M. Ashraf; Wendy M. Shaw; Coleen T. Murphy
    Journal Article

    Reproductive cessation is perhaps the earliest aging phenotype that humans experience. Similarly, reproduction of Caenorhabditis elegans ceases in mid-adulthood. Although somatic aging has been studied in both worms and humans, mechanisms regulating reproductive aging are not yet understood. Here, we show that TGF-β Sma/Mab and Insulin/IGF-1...

  • Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans.

    Coleen T. Murphy; Seung-Jae Lee; Cynthia Kenyon
    Journal Article

    How are the rates of aging of different tissues coordinated? In Caenorhabditis elegans, decreasing insulin/IGF-1 signaling extends lifespan by activating the transcription factor DAF-16/FOXO. If DAF-16 levels are experimentally increased in one tissue, such as the intestine, DAF-16 activity in other tissues rises. Here we test the hypothesis...

  • Transcriptome analysis of adult Caenorhabditis elegans cells reveals tissue-specific gene and isoform expression.

    Rachel Kaletsky; Victoria Yao; April Williams; Alexi M. Runnels; Alicja Tadych; Shiyi Zhou; Olga G. Troyanskaya; Coleen T. Murphy
    Journal Article

    The biology and behavior of adults differ substantially from those of developing animals, and cell-specific information is critical for deciphering the biology of multicellular animals. Thus, adult tissue-specific transcriptomic data are critical for understanding molecular mechanisms that control their phenotypes. We used adult cell-specific...

  • Using whole-genome transcriptional analyses to identify molecular mechanisms of aging

    Coleen T. Murphy
    Journal Article
    Whole-genome transcriptional analyses of aging organisms and tissues have revealed changes in many genes and biological processes. A comparison of these studies reveals common age-related changes, including the downregulation of metabolic and mitochondrial function, and the upregulation of stress and immune responses. This suggests that much of...
  • Variable surface loops and myosin activity: accessories to a motor.

    C T. Murphy; J A. Spudich
    Journal Article

    The catalytic head of myosin is a globular structure that has historically been divided into three segments of 25, 50, and 20 kDa. The solvent-exposed, proteolytically-sensitive surface loops of myosin that join these three segments are highly variable in their sequences. While surface loops have not traditionally been thought to affect...