Coleen T Murphy et al. (2003) International Worm Meeting "Genes that act downstream of DAF-16 to influence C. elegans lifespan."

Ravi S Kamath, Steven A McCarroll, Cynthia J Kenyon, Julie Ahringer, Jason D Lieb, Andrew Fraser, Cornelia I Bargmann, Coleen T Murphy, Hao Li

[International Worm Meeting, 2003]

DAF-16, a FOXO-family transcription factor, influences the rate of aging of C. elegans in response to insulin/IGF-1 signaling. Using DNA microarray analysis, we found that DAF-16 affects the expression of a set of genes during early adulthood, the time at which this pathway is known to influence aging. We also found that many of these genes influence the aging process. Several of these genes are novel longevity factors, and we are currently working to characterize these processes in further detail. Additionally, we observed that both the canonical DAF-16 binding site and a novel sequence are overrepresented in the promoters of the daf-2-regulated genes. We are now performing chromatin IP microarray (ChIP/chip) experiments to distinguish direct and indirect DAF-16 targets. The insulin/IGF-1 pathway functions cell-nonautonomously to regulate lifespan, and our findings suggest that it signals other cells, at least in part, by feedback regulation of an insulin/IGF-1 homolog. Our findings suggest that the insulin/IGF-1 pathway ultimately exerts its effect on lifespan by up-regulating a wide variety of genes, including cellular stress-response and anti-microbial genes, and by down-regulating specific life-shortening genes.

Coleen T Murphy et al. (2001) International C. elegans Meeting "GENE EXPRESSION ANALYSIS OF C. elegans LIFESPAN MUTANTS"

Cynthia Kenyon, Coleen T Murphy

[International C. elegans Meeting, 2001]

The discovery of long-lived mutants in various systems suggests that aging is a regulated process. C. elegans, a soil nematode whose lifespan is on the order of weeks and whose genome has been fully sequenced, is an ideal organism in which to study the genetic basis of aging. Mutants of the daf-2 insulin-like receptor pathway have been found to extend lifespan in C. elegans. This pathway is presumed to affect the output of an HNF/forkhead transcription factor, DAF-16; daf-16 mutants suppress the life extension of daf-2 and age-1 mutants. Signals from the sensory neurons and the reproductive system of the worm affect lifespan, acting through this signaling pathway. In an effort to monitor changes in gene expression during the aging process, we have built a full-genome C. elegans microarray containing PCR fragments of almost 20,000 predicted genes. We are using these microarrays to analyze the transcriptional output of aging worms and lifespan mutants to define the group of genes whose expression is necessary for long life.

Coleen T Murphy et al. (2004) West Coast Worm Meeting "Feed-forward regulation of the DAF-2 pathway by two opposing insulins."

Coleen T Murphy, Cynthia Kenyon

[West Coast Worm Meeting, 2004]

Alic N (2016) Cell Metab "Of FOXes and Forgetful Worms."

Alic N

[Cell Metab, 2016]

Age-related cognitive decline is one of the most haunting aspects of human aging. In a recent publication, Coleen Murphy and colleagues (Kaletsky et al., 2016) describe the transcriptional program that maintains youthful function of aging neurons in the nematode worm.

Coleen T Murphy et al. (2005) International Worm Meeting "Organism-wide coordination of the insulin/IGF-1 pathway through the regulation and activity of the INS-7 insulin-like peptide"

Coleen T Murphy, Cynthia Kenyon, Seung-Jae Lee

[International Worm Meeting, 2005]

The insulin/IGF-1 pathway has been shown to be a key regulator of lifespan in many organisms, including mammals. In C. elegans, this pathway uses a cell non-autonomous mechanism to regulate both longevity and dauer formation. The molecules that mediate this coordination have not yet been identified, but insulins, of which there are 38 in C. elegans, are attractive candidates for this role. In a microarray study, we found that the insulin-like peptide ins-7 is regulated transcriptionally by the DAF-2 insulin/IGF-1 receptor and the downstream DAF-16/FOXO transcription factor. Despite the fact that insulin-like peptides are widely expressed in neurons, we find that the intestine is the major site of DAF-2/DAF-16-regulated ins-7 transcription. We also find that INS-7 allows the activity of the insulin/IGF-1 pathway in one tissue to influence its activity elsewhere. Interestingly, feedback regulation of ins-18 may help ins-7 to coordinate the activity of the DAF-2/DAF-16 pathway throughout the animal. Finally, we find that a second major regulator of lifespan, the heat-shock factor HSF-1, also dramatically affects the intestinal expression of ins-7. Thus, directly or indirectly, INS-7 responds to multiple transcriptional inputs to coordinate the rate of aging among the different tissues of the animal.

Coleen T Murphy et al. (2002) West Coast Worm Meeting "Discovery of DAF-16 Targets and Novel Lifespan Genes: Microarray Analysis of the C. elegans DAF-2 Pathway"

Hao Li, Coleen T Murphy, Steven A McCarroll, Cynthia J Kenyon

[West Coast Worm Meeting, 2002]

The C. elegans DAF-2 IGF/insulin-like receptor pathway controls dauer formation, progeny production, stress response, and lifespan through its regulation of the DAF-16 HNF/forkhead transcription factor. While Daf-2 pathway components upstream of daf-16 have been well studied, few targets of DAF-16 have been identified, and the cellular and biochemical processes that are needed to prolong lifespan through this pathway have not yet been explored. We used microarray analysis of mutants and dsRNA-interference-treated worms to identify genes downstream of DAF-16. At the transcriptome level, general aging effects outweigh daf-2-specific changes, indicating that transcriptional differences in a relatively small number of genes and cellular processes are required to achieve the profound physical differences that result in the long lifespan of daf-2 mutants. At the single gene level, we found that reducing the activity of putative DAF-16-induced targets shortens the lifespan of daf-2 worms, but not of wild type worms, while activity reduction of genes with the opposite transcriptional profile lengthens lifespan. Thus, with this approach we have been able to analyze the transcriptional output of DAF-16 at the transcriptome, biochemical process, and individual gene levels, and we have used the predictive power of transcriptional profiling to discover new lifespan-determining genes.

Shi, Cheng et al. (2021) International Worm Meeting "piRNA pathway-mediated Hedgehog signaling encodes a germline-to-soma pro-aging signal"

Murphy, Coleen, Shi, Cheng

[International Worm Meeting, 2021]

The reproductive system regulates the aging of the soma. Removal of the germline extends somatic lifespan through conserved pathways including Insulin, mTOR, and steroid signaling, while germline hyperactivity cuts lifespan short through mechanisms that are still elusive. Here, we show that mating-induced germline hyperactivity leads to the downregulation of piRNAs, which in turn release silencing on their targets, two Hedgehog-like ligand encoding genes. Germline-originating Hedgehog signaling is perceived by the Patched-related family receptors in the soma, ultimately causing somatic collapse and early death. Our results reveal an unconventional role of the piRNA pathway and Hedgehog signaling in longevity regulation, and suggest that Hedgehog signaling controlled by the tunable piRNA pathway encodes the previous unknown germline-to-soma pro-aging signal.

Shi, Cheng et al. (2013) International Worm Meeting "Mating-induced somatic collapse reveals a novel soma-germline interaction."

Murphy, Coleen, Shi, Cheng

[International Worm Meeting, 2013]

Interactions between the germline and the soma are important to optimize reproduction and to influence somatic aging. The prevailing germline-soma model suggests that the lifespan shortening signal from the germline antagonizes the lifespan lengthening signal in the somatic gonad in C. elegans. Previous studies focused on removal of germline cells and its longevity-repressing activity to reveal the somatic gonad lifespan-extending signal. We have identified a new phenomenon linking reproductive status to longevity and have illustrated the elusive lifespan-shortening signal for the first time: in C. elegans, mating leads to "post-mating somatic collapse" (PMSC), a state in which mated worms shrink pronouncedly and die early, compressing the post-reproductive life span. The post-mating shrinking and lifespan phenomena are genetically separable, and the DAF-12 steroid receptor and DAF-16/FOXO transcription factor are involved in regulating different aspects of PMSC. Components from males contribute differently to PMSC. Likewise, hermaphrodites have germline-dependent and germline-independent responses that process the corresponding male-initiated signals. Post-mating somatic collapse may be an extreme version of the influence that males in many species exert on female behavior to maximize their own reproductive success. Our study provides new insight into the communication between males and the female germline and soma to regulate reproduction and longevity.

Shi, Cheng et al. (2019) International Worm Meeting "Insulin-like peptides and the mTOR-TFEB pathway protect C. elegans hermaphrodites from Mating-induced Death."

Shi, Cheng, Murphy, Coleen

[International Worm Meeting, 2019]

C. elegans lifespan is shortened by mating, but must be delayed long enough for successful reproduction. Susceptibility to brief mating-induced death increases with age; surprisingly, this is not due to declining health, but to loss of protection upon self-sperm depletion. Self-sperm maintains expression of a DAF-2 insulin-like antagonist, INS-37, which promotes the nuclear localization of HLH-30/TFEB, a pro-longevity regulator. Mating induces the agonist INS-8, promoting HLH-30 nuclear exit and subsequent death. In opposition to the protective role of HLH-30 and DAF-16/FOXO, TOR/LET-363 and the IIS-regulated Zn-finger transcription factor PQM-1 promote seminal-fluid-induced killing. Self-sperm maintenance of nuclear HLH-30/TFEB allows hermaphrodites to resist mating-induced death, increasing the chances that mothers will survive through reproduction. The hijacking of the IIS pathway by males is combated by the mother's expression of an insulin antagonist that keeps her healthy through the activity of pro-longevity factors, as long as she has her own sperm to utilize. ** If possible, I would prefer that this abstract please be considered with the abstract submitted by Lauren N. Booth, Travis J. Maures, Robin W. Yeo, and Anne Brunet ("Self-sperm induce resistance to the detrimental effects of sexual encounters with males in hermaphroditic nematodes").

Kleemann, Gunnar et al. (2013) International Worm Meeting "WormView: a library of modular Matlab functions for static and dynamic image analysis."

Parsons, Lance, Kleemann, Gunnar, Murphy, Coleen

[International Worm Meeting, 2013]

We present WormView, a library of Matlab functions, which can be interchangeably combined to conduct automated image analysis and data visualization. WormView is designed to be flexible and easy enough to use that users with little familiarity with programming can construct new applications. The modular architecture of WormView allows a user to rearrange interchangeable parts into novel applications without requiring new code generation. At the same time, the open source Matlab code can be easily modified by more advanced users to generate new functions without affecting the other parts of the program. The components of the WormView library fall into four progressive functional categories (1) particle identification, (2) particle verification (optional), (3) shape and time series analysis, and (4) data compilation and figure generation. In a typical analysis, single images or images in a series are passed into GetWorm. GetWorm collects worm data as binary thresholded images, as well as position, shape and size data. The GetWorm output is passed to through an optional quality assurance step involving manual perusal or automated verification by SVM (a support vector machine; machine learning). The processed dataset is then used collect data on the worm path (WormTrip), worm posture (SpineWorm), and movement patterns. Finally the processed files are passed into a final analysis for compilation of time course data, particle counts, shape and size analysis and figure generation. We will present sample configurations of the library, which can be used to measure aspects of worm shape, size, posture, position and color as they change over time.