Areas of Research: Molecular mechanisms of aging
- Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics
148 Carl C. Icahn Laboratory
Molecular mechanisms of aging
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.
- Lakhina V, Murphy CT. (2015) For longevity, perception is everything. Cell. 160:807-9. Pubmed
- Lakhina V, Arey RN, Kaletsky R,..Murphy CT. (2015) Genome-wide functional analysis of CREB/long-term memory-dependent transcription reveals distinct basal and memory gene expression programs. Neuron. 85:330-45. Pubmed
- Shi C, Murphy CT. (2014) Mating induces shrinking and death in Caenorhabditis mothers. Science. 343: 536-40. Pubmed
- Tepper RG, Murphy CT, Bussemaker HJ. (2014) DAF-16 and PQM-1: Partners in longevity. Aging (Albany NY) 6: 5-6 Pubmed
- Murphy CT, Hu PJ. (2013) Insulin/insulin-like growth factor signaling in C. elegans. WormBook. 1-43. Pubmed
- Tepper RG, Ashraf J, Kaletsky R, Kleemann G, Murphy CT, Bussemaker HJ. (2013) PQM-1 complements DAF-16 as a key transcriptional regulator of DAF-2-mediated development and longevity. Cell. 154: 676-90. PubMed
- Blackstone C, Murphy CT. (2012) Cell biology of disease and aging: a two-way street. Mol Biol Cell. 23: 975.
- Stein GM, Murphy CT. (2012) The intersection of aging, longevity pathways, and learning and memory in C. elegans. Front Genet. 3: 259. Pubmed
- Rizki G, Iwata TN, Li J,...Murphy CT, Lee SS. (2011) The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet. 7:e1002235. PubMed
- Liu G, Rogers J, Murphy CT, Rongo C. (2011) EGF signaling activates the ubiquitin proteasome system to modulate C. elegans lifespan. EMBO J. 30: 2990-3003. Pubmed
- Kauffman A, Parsons L, Stein G, Wills A, Kaletsky R, Murphy C. (2011) C. elegans positive butanone learning, short-term, and long-term associative memory assays. J Vis Exp. pii: 2490. Pubmed
- Luo S, Murphy CT. (2011) C. elegans reproductive aging: Regulation and underlying mechanisms. Genesis. 49: 53-65. PubMed
- Murphy CT. (2010) Aging: miRacles of Longevity? Curr Biol. 20: R1076-78. PubMed
- Luo S, Kleemann GA, Ashraf JM, Shaw WM, Murphy CT. (2010) TGF-β and insulin signaling regulate reproductive aging via oocyte and germline quality maintenance. Cell. 143: 299-312. PubMed
- Kauffman AL, Ashraf JM, Corces-Zimmerman MR, Landis JN, Murphy CT. (2010) Insulin signaling and dietary restriction differentially influence the decline of learning and memory with age. PLoS Biol. 8: e1000372. PubMed
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