Faculty & Research
Molecular Mechanisms of Lifespan Regulation
A major research focus of the lab is the molecular dissection of signaling pathways that regulate longevity. We have recently shown that downregulation of the activity of the Drosophila melanogaster ortholog of the tumor suppressor p53, Dmp53, significantly extends fly longevity. Reduction of p53 activity was achieved by expressing dominant-negative (DN) versions of Dmp53 in the adult fly only. Expressing DN-Dmp53 in the adult nervous system, but not in other fly tissues, extended fly longevity by up to 26%. Furthermore, when DN-Dmp53 expression is restricted to a set of fourteen insulin-producing neurons (IPC), the same life span extension is observed.
A three-dimensional image of IPC stained with GFP. The IPC cell bodies are located in two clusters of seven cells each in the anterior part of the adult fly brain. Their axons extend along the esophagus to the fly heart.
Interestingly, while DN-Dmp53 long-lived flies show a reduction in insulin/insulin-like signaling pathway (IIS) activity, expression of DN-Dmp53 in flies lacking dFoxo, a downstream mediator of IIS, still extends lifespan. In contrast, the DN-Dmp53-dependent longevity increase is completely abolished in flies lacking 4E-BP, a downstream component of the TOR pathway. These data suggest that DN-Dmp53 utilizes TOR signaling to modulate longevity. We are currently investigating Dmp53 function inside the fourteen insulin-producing neurons and the events that lead to longevity extension.
Recently, we have identified takeout, a Drosophila protein that may be involved in Juvenile Hormone signaling. takeout expression is upregulated in a variety of longevity interventions, suggesting that takeout may have a central role in the modulation of longevity determination. Overexpression of takeout in the fly fat body extends lifespan by up to 40%. Interestingly, takeout long-lived flies have greatly reduced fertility and male courtship behavior. These data suggest that takeout may be a crucial player in the trade-off between longevity and fertility.
Development of Type 2 diabetes in Drosophila melanogaster
According to the CDC (National Diabetes Fact Sheet for 2007), approximately 7.8% of the U.S. population has diabetes, with a higher prevalence among minorities. In 2006, diabetes accounted for over 75,000 deaths, making it the 7th leading cause of death in the U.S. Complications associated with diabetes led to an additional ~230,000 deaths, mostly due to causing or aggravating other health conditions, such as heart disease, high blood pressure, stroke or neuropathies that can also lead to blindness. The treatment of diabetes and its symptoms has been estimated to cost $116 billion dollars in 2007 alone, with an additional $58 billion lost to disability, work loss or premature mortality (‘Economic costs of diabetes in the U.S. in 2007’, American Diabetes Association).
Adult fat body cells stained with a marker for IIS activity. Strong plasma membrane staining indicates active IIS within these cells.
The realization that flies possess similar neuroendocrine cellular and molecular architecture as mammals has generated a lot of interest in utilizing flies as a cost-effective and rapid alternative to investigate molecular mechanisms of metabolic dysregulation. We are thus developing Drosophila as a cost-effective and rapid alternative model system for diabetes research. Drosophila has been spectacularly successful as a model system for a variety of human diseases, ranging from Alzheimer’s Disease to alcoholism. Advantages of the fly system are its rapid generation time and its low cost. However, the greatest strengths of the fly system are the powerful genetic tools that allow for rapid dissection of molecular disease mechanisms.
Work in our laboratory has demonstrated the development of diabetes-like phenotypes in flies fed a western-style diet. Under these conditions flies gain excessive weight, show metabolic abnormalities and develop insulin-resistance in peripheral tissues. Similar phenotypes are observed in aging flies. Importantly, anti-diabetic drugs reverse some of these phenotypes.
With these benchmarks established, the Drosophila system can provide a quick and inexpensive screening tool for pharmacologic and genetic interventions that modify the diabetic phenotype.
BIOL 2101 - Introductory Research
This course takes place in a research laboratory. Students will be part of a team of scientists performing research into the molecular biology of the aging process. Successful completion of this course is a prerequisite for an independent undergraduate research project in the lab that may lead to admission to the Departmental Distinction Program.
BIOL 5310 - Biological Chemistry
BIOL 5110 - Biological Chemistry Lab
Chamseddin, K., Khan, S.Q., Nguyen, M.L.H., Antosh, M., Morris, S.N., Kolli, S., Neretti, N., Helfand, S.L. and Bauer, J.H., takeout-dependent longevity is associated with altered Juvenile Hormone signaling. (Mech Ageing Dev, in press)
Morris, S., Coogan, C., Chamseddin, K., Fernandez-Kim, S.O., Kolli, S., Keller, J.N., and Bauer, J.H. (2012). Development of diet-induced insulin resistance in adult Drosophila melanogaster. Biochim Biophys Acta-Molecular Basis of Disease, 1822: 1230-1237.
Antosh M, Whitaker R, Kroll A, Hosier S, Chang C, Bauer J, Cooper L, Neretti N, Helfand SL (2011) Comparative transcriptional pathway bioinformatic analysis of Dietary Restriction, Sir2, p53 and resveratrol life span extension in Drosophila. Cell Cycle 10(6), in press
Bauer J*, Antosh M*, Chang C, Schorl C, Kolli S, Neretti N, Helfand SL (2010) Comparative transcriptional profiling identifies takeout as a gene that regulates life span. Aging 2(5): 298-310
Bauer JH, Chang C, Bae G, Morris SN, Helfand SL (2010) Dominant-negative Dmp53 extends life span through the dTOR pathway in D. melanogaster. Mech Ageing Dev 131(3): 193-201Bauer JH, Morris SN, Chang C, Flatt T, Wood JG, Helfand SL (2009) dSir2 and Dmp53 interact to mediate aspects of CR-dependent life span extension in D. melanogaster. Aging 1(1): 38-48