Pamela L. Larsen, Ph.D.Associate Professor
Vanderbilt University, Nashville, 1986
Dr. Larsen joined the Department of Cellular and Structural Biology in December 2002. She is currently an Ellison Medical Foundation Senior Scholar in Aging. She was the inaugural chairholder of the Paul F. Glenn Foundation Chair in Cellular and Molecular Gerontology at the University of Southern California. In the past, she has received fellowships from the American Federation for Aging, the Brookdale Foundation, and the American Cancer Society.
Research Interests - The focus of the laboratory is on understanding the biological mechanisms for the efficient life maintenance, in development and adulthood in C. elegans. It is generally believed that genetic and environmental manipulations result in life span extension by controlling metabolism and resistance to stress. We are interested in understanding the mechanisms of longevity by both means. The genetic focus is the daf-2 pathway in the nematode C. elegans, which is homologous to insulin/IGF1 signaling pathways. The environmental focus is on cultivation temperature because it controls life span with cooler temperatures yielding longer life spans. Both cooler temperatures and reduction of the daf-2/insulin/IGF-1 signaling pathway show longevity in multiple species.
Currently, we are identifying genes regulated by reduction of cultivation temperature and/or by reduction of DAF-2 signaling. It is unknown whether the molecular and metabolic consequences of altering DAF-2 signaling and temperature are similar mechanistically. A molecular genetic approach will be used to sort candidate genes for life span effects. Importantly, we will gain insight into genes contributing to both the short-life of wild type and the long-life of daf-2 mutants. In addition, we are studying biochemical and physiological differences between the short-lived wild type and the long-lived mutants in adults and in dauer larvae. We are investigating the 39 insulin-like genes and fatty acid metabolism because dauer larvae and daf-2 mutant adults are obese compared to wild-type adults. The dysregulation of lipid metabolism may contribute to the longevity. Furthermore, changing the cultivation temperature alters lipid composition. Increased longevity by reduction of cultivation temperature and/or by reduction of DAF-2 signaling could be via increased triglyceride availability and utilization, since feeding declines dramatically in all genotypes upon cessation of reproduction and the rate of body size diminution correlates with longevity. Alternatively, changes in which polyunsaturated fatty acids are produced could alter the membrane phospholipids and increase survival. Finally, most of our studies include different genotypes at temperatures, with the goal being to define environmental and genetic interactions with regard to adult life span.
C. elegans culture and genetics
Transgenic strain construction
PCR and Real-time PCR
Curran, S. P., E. P. Leverich, C. M. Koehler, and P. L. Larsen, 2004. Defective mitochondrial protein translocation precludes normal Caenorhabditis elegans development. J. Biol. Chem. 279, 54655-54662.
Jonassen T, Davis DE, Larsen PL, Clarke CF. Reproductive fitness and quinone content of Caenorhabditis elegans clk-1 mutants fed coenzyme Q isoforms of varying length. J Biol Chem. 2003 Dec 19;278(51):51735-42. Epub 2003 Oct 06.
Jonassen, T., B. N. Marbois, K. F. Faull, C. F. Clarke, and P. L. Larsen, 2002. Development and fertility in C. elegans clk-1 mutants depends upon transport of dietary coenzyme Q8 to mitochondria. JBC 2002, Nov 22; 277(47): 45020-7
Larsen, P. L. and C. F. Clarke, 2002. Extension of life span in C. elegans by a diet lacking coenzyme Q. Science 295, 120-123.
Jonassen, T., P. L. Larsen, and C. F. Clarke, 2001. A dietary source of coenzyme Q is essential for survival of long-lived C. elegans clk-1 mutants. Proc. Natl. Acad. Sci. USA 98, 421-426.
Yu, H. and P. L. Larsen, 2001. DAF-16- Dependent and -Independent Expression Targets of DAF-2 Insulin Receptor-like Pathway in Caenorhabditis elegans Include FKBPs. J. Mol. Biol. 314, 1017-1028.