James A. Elkins, Jr. Professor in the Life Sciences, Professor of Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics
Director of Paul F. Glenn Laboratories for Aging Research

Contact

ctmurphy@princeton.edu
609-258-9396
609-258-7070
Icahn Laboratory, 148
Murphy Lab

Research Area

Genetics & Genomics

Research Focus

Molecular mechanisms of aging



Research
Selected Publications
Honors & Awards
My lab is focused on the process of aging, which remains one of the fundamental mysteries of biology. While aging may appear to be simply an unfortunate consequence of living, recent genetic breakthroughs suggest that aging is a regulated process, rather than the result of cumulative cellular damage. Many chronic and degenerative disorders, such as diabetes, cancer, and neurodegenerative diseases develop in an age-related manner. Because more than 20% of U.S. citizens will be over the age of 65 by the year 2050, there is a growing need to better understand the mechanisms involved in aging and age-associated diseases.
The emergence of model systems to study aging and the development of whole-genome approaches is providing an unprecedented glimpse into the processes underlying aging. Our understanding of aging at the molecular level will progress from identifying these global regulators, to defining the genes that they control, to describing the biochemical events that carry out the business of keeping an organism's cells alive. The goal of my lab is to enrich our understanding of the molecular basis of aging process by first identifying the genes that are controlled by these global regulators and then elucidating the cell biological and biochemical mechanisms used by these genes to affect lifespan.

A model for aging: C. elegans

We have chosen the nematode C. elegans as our model system of aging. For our purposes C. elegans is ideal because lives two-three weeks, making lifespan experiments feasible, and during this time it exhibits many obvious phenotypes of aging, such as slowed motility and tissue deterioration. Importantly, C. elegans mutants with dramatically extended longevity have been identified; the genetic dissection of the pathways contributing to these mutants' longevity can shed light on the mechanisms of aging. The genes that regulate lifespan are conserved from worms to mammals, making our findings relevant for humans, as well.

Transcriptional analysis of longevity pathways

The initial work in my lab will use microarray techniques to identify transcriptional targets of longevity pathways. For this purpose, we have built both PCR product arrays and 60-mer oligo arrays for the almost 20,000 open reading frames in C. elegans. My previous work identified the genes that act downstream of the C. elegans insulin receptor/FOXO transcription factor pathway, and found that this pathway is likely to be regulated through a feed-forward mechanism; now we would like to determine when the target genes are expressed and distinguish direct from indirect targets. Because downregulation of the insulin receptor pathway is only one of the mechanisms that increase the longevity of C. elegans, we will also use microarrays and genomic analysis to discover transcriptional targets that are shared between multiple longevity pathways.

Functional analysis of candidate lifespan genes

Once the targets have been identified, we can use the extremely tractable C. elegans experimental system to test these genes for their roles in longevity. For example, C. elegans is susceptible to RNA interference by bacterial feeding, allowing us to quickly knock down gene activity and test the requirement for that gene in lifespan extension. Now that we know which genes act downstream of the insulin receptor/FOXO pathway to affect lifespan, we would like to identify the sites of action of these genes in the worm. Using fluorescent gene fusions, we can identify the localization and time of expression of specific proteins in the animal to better understand the gene's organismal role. Finally, in vitro studies will be carried out on the most interesting candidate genes to understand their biochemical functions.
Additionally, my lab will carry out genetic screens to identify novel genes that are critical to aging-related processes. The combination of a classic genetic system that recapitulates aging in higher organisms with powerful genomic approaches and fast functional analysis should help us to elucidate the multigenic mechanisms involved in aging.




McIntyre LM, Huertas F, Morse AM, Kaletsky R, Murphy CT, Kalia V, et al. GAIT-GM integrative cross-omics analyses reveal cholinergic defects in a C. elegans model of Parkinson's disease. Sci Rep. 2022 ;12(1):3268. PubMed
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Rahimi M, Sohrabi S, Murphy CT. Novel elasticity measurements reveal C.?elegans cuticle stiffens with age and in a long-lived mutant. Biophys J. 2022 ;121(4):515-524. PubMed
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Sohrabi S, Mor DE, Kaletsky R, Keyes W, Murphy CT. High-throughput behavioral screen in C. elegans reveals Parkinson's disease drug candidates. Commun Biol. 2021 ;4(1):203. PubMed
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Sohrabi S, Moore RS, Murphy CT. CeAid: a smartphone application for logging and plotting Caenorhabditis elegans assays. G3 (Bethesda). 2021 ;11(10). PubMed
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Moore RS, Kaletsky R, Lesnik C, Cota V, Blackman E, Parsons LR, et al. The role of the Cer1 transposon in horizontal transfer of transgenerational memory. Cell. 2021 ;184(18):4697-4712.e18. PubMed
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Lee Y, Jung Y, Jeong D-E, Hwang W, Ham S, Park H-EH, et al. Reduced insulin/IGF1 signaling prevents immune aging via ZIP-10/bZIP-mediated feedforward loop. J Cell Biol. 2021 ;220(5). PubMed
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Baumeister R, Murphy CT, Heimbucher T. Metabolic adaptation to hypoxia: do worms and cancer cells share common metabolic responses to hypoxic stress?. Cell Death Differ. 2021 ;28(4):1434-1436. PubMed
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Moore RS, Kaletsky R, Murphy CT. Protocol for transgenerational learned pathogen avoidance behavior assays in . STAR Protoc. 2021 ;2(1):100384. PubMed
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Choi LS, Shi C, Ashraf J, Sohrabi S, Murphy CT. Oleic Acid Protects Caenorhabditis Mothers From Mating-Induced Death and the Cost of Reproduction. Front Cell Dev Biol. 2021 ;9:690373. PubMed
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Shi C, Murphy CT. Sex and death. Curr Top Dev Biol. 2021 ;144:353-375. PubMed
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Heimbucher T, Hog J, Gupta P, Murphy CT. Author Correction: PQM-1 controls hypoxic survival via regulation of lipid metabolism. Nat Commun. 2020 ;11(1):6018. PubMed
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Mor DE, Sohrabi S, Kaletsky R, Keyes W, Tartici A, Kalia V, et al. Metformin rescues Parkinson's disease phenotypes caused by hyperactive mitochondria. Proc Natl Acad Sci U S A. 2020 ;117(42):26438-26447. PubMed
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Heimbucher T, Hog J, Gupta P, Murphy CT. PQM-1 controls hypoxic survival via regulation of lipid metabolism. Nat Commun. 2020 ;11(1):4627. PubMed
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Kaletsky R, Moore RS, Vrla GD, Parsons LR, Gitai Z, Murphy CT. C.?elegans interprets bacterial non-coding RNAs to learn pathogenic avoidance. Nature. 2020 ;586(7829):445-451. PubMed
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Templeman NM, Cota V, Keyes W, Kaletsky R, Murphy CT. CREB Non-autonomously Controls Reproductive Aging through Hedgehog/Patched Signaling. Dev Cell. 2020 ;54(1):92-105.e5. PubMed
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Murphy CT. Short and sweet. Elife. 2020 ;9. PubMed
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Mor DE, Murphy CT. Mitochondrial hyperactivity as a potential therapeutic target in Parkinson's disease. Transl Med Aging. 2020 ;4:117-120. PubMed
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Kaletsky R, Murphy CT. Transcriptional Profiling of C. elegans Adult Cells and Tissues with Age. Methods Mol Biol. 2020 ;2144:177-186. PubMed
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Arey RN, Kaletsky R, Murphy CT. Nervous system-wide profiling of presynaptic mRNAs reveals regulators of associative memory. Sci Rep. 2019 ;9(1):20314. PubMed
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Murphy CT. Being open to the unexpected. Mol Biol Cell. 2019 ;30(23):2862-2864. PubMed
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Shi C, Booth LN, Murphy CT. Insulin-like peptides and the mTOR-TFEB pathway protect hermaphrodites from mating-induced death. Elife. 2019 ;8. PubMed
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Moore RS, Kaletsky R, Murphy CT. Piwi/PRG-1 Argonaute and TGF-β Mediate Transgenerational Learned Pathogenic Avoidance. Cell. 2019 ;177(7):1827-1841.e12. PubMed
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Heimbucher T, Murphy CT. A PBX/MEIS Complex Balances Reproduction and Somatic Resilience. Dev Cell. 2019 ;49(2):157-158. PubMed
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Heimbucher T, Murphy CT. Investigating Mechanisms that Control Ubiquitin-Mediated DAF-16/FOXO Protein Turnover. Methods Mol Biol. 2019 ;1890:41-49. PubMed
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Yao V, Kaletsky R, Keyes W, Mor DE, Wong AK, Sohrabi S, et al. An integrative tissue-network approach to identify and test human disease genes. Nat Biotechnol. 2018 ;. PubMed
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Tabuchi TM, Rechtsteiner A, Jeffers TE, Egelhofer TA, Murphy CT, Strome S. Caenorhabditis elegans sperm carry a histone-based epigenetic memory of both spermatogenesis and oogenesis. Nat Commun. 2018 ;9(1):4310. PubMed
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Kaletsky R, Yao V, Williams A, Runnels AM, Tadych A, Zhou S, et al. Transcriptome analysis of adult Caenorhabditis elegans cells reveals tissue-specific gene and isoform expression. PLoS Genet. 2018 ;14(8):e1007559. PubMed
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Arey RN, Stein GM, Kaletsky R, Kauffman A, Murphy CT. Activation of G Signaling Enhances Memory Consolidation and Slows Cognitive Decline. Neuron. 2018 ;98(3):562-574.e5. PubMed
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Templeman NM, Luo S, Kaletsky R, Shi C, Ashraf J, Keyes W, et al. Insulin Signaling Regulates Oocyte Quality Maintenance with Age via Cathepsin B Activity. Curr Biol. 2018 ;28(5):753-760.e4. PubMed
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Templeman NM, Murphy CT. Regulation of reproduction and longevity by nutrient-sensing pathways. J Cell Biol. 2018 ;217(1):93-106. PubMed
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Arey RN, Murphy CT. Conserved regulators of cognitive aging: From worms to humans. Behav Brain Res. 2017 ;322(Pt B):299-310. PubMed
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Shi C, Runnels AM, Murphy CT. Mating and male pheromone kill males through distinct mechanisms. Elife. 2017 ;6. PubMed
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Son HG, Seo M, Ham S, Hwang W, Lee D, An SWoo A, et al. RNA surveillance via nonsense-mediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans. Nat Commun. 2017 ;8:14749. PubMed
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Li L-B, Lei H, Arey RN, Li P, Liu J, Murphy CT, et al. The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory. Curr Biol. 2016 ;26(5):605-15. PubMed
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Kaletsky R, Lakhina V, Arey R, Williams A, Landis J, Ashraf J, et al. The C. elegans adult neuronal IIS/FOXO transcriptome reveals adult phenotype regulators. Nature. 2016 ;529(7584):92-6. PubMed
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Shi C, Murphy CT. Feeding the germline. Genes Dev. 2016 ;30(3):249-50. PubMed
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Crocker A, Guan X-J, Murphy CT, Murthy M. Cell-Type-Specific Transcriptome Analysis in the Drosophila Mushroom Body Reveals Memory-Related Changes in Gene Expression. Cell Rep. 2016 ;15(7):1580-1596. PubMed
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Hahm J-H, Kim S, DiLoreto R, Shi C, Lee S-JV, Murphy CT, et al. C. elegans maximum velocity correlates with healthspan and is maintained in worms with an insulin receptor mutation. Nat Commun. 2015 ;6:8919. PubMed
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Wang J, Kaletsky R, Silva M, Williams A, Haas LA, Androwski RJ, et al. Cell-Specific Transcriptional Profiling of Ciliated Sensory Neurons Reveals Regulators of Behavior and Extracellular Vesicle Biogenesis. Curr Biol. 2015 ;25(24):3232-8. PubMed
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DiLoreto R, Murphy CT. The cell biology of aging. Mol Biol Cell. 2015 ;26(25):4524-31. PubMed
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Lakhina V, Murphy CT. Genome Sequencing Fishes out Longevity Genes. Cell. 2015 ;163(6):1312-3. PubMed
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2016

HHMI Faculty Scholar, Howard Hughes Medical Institute

2015

Pioneer Award, National Institutes of Health

2014

Innovation Award, Department of Molecular Biology, Princeton University

2012

Glenn Foundation for Medical Research Award, Glenn Foundation for Medical Research