Mechanisms of Longevity Regulation by Dmp53 in Insulin-Producing Cells
We have recently
shown that inhibition of Dmp53, the fly ortholog of the mammalian tumor
suppressor p53, significantly extends Drosophila
life span. This function of Dmp53 resides in only 14 cells of the fly nervous
system, the insulin-producing cells (IPC). IPC are the equivalent of β-cells in
the mammalian pancreas. They are nutrient responsive and secrete Drosophila insulin-like peptides (dILP)
into the fly hemolymph. Reduction of Dmp53 activity in these cells leads to a
decrease of dILP2 mRNA levels.
Through a combination of genetics, molecular biology and cell biology, we are currently investigation how reduction of Dmp53 activity in the 14 IPC leads to altered IPC functionality and increased fly longevity.
Identification of Novel Longevity Genes and Pathways
We recently identified the Drosophila melanogaster gene takeout (to) in a microarray enrichment screen for mediators of longevity. Overexpression of takeout specifically in the adult fly fat body extends longevity by up to ~40%, but does not lead to other phenotypes often associated with longevity, such as increased stress resistance. However, takeout long-lived flies show severe defects in male mating behavior and female egg laying.
We hypothesize that takeout-dependent signaling events are crucial mediators in the trade-off between fertility and longevity. This trade-off may be affected via alteration of male fertility or behavior. On a molecular level, these effects may be mediated through modulation of Juvenile Hormone (JH) signaling. We are currently investigating how takeout may interfere with JH signaling.
Nutrition, Life Span and Health Span
Dietary Restriction (DR) extends life span of a multitude of organisms and has been shown to provide numerous health benefits. For example, DR has been shown to lower insulin levels and increase insulin sensitivity. Any pharmacologic intervention that mimics DR may thus also be useful in improving health parameters or treating ageing-related deseases, such as diabetes. In order to develop such interventions, we need not only to understand the molecular pathways mediating the DR effects, but also how DR changes the physiology of animals. We are using Drosophila to dissect the physiology of the DR response, investigate the nutritional requirements of fruit flies and develop interventions that may mimic DR and improve general fly health.
Chhabra, R., Kolli, S., and Bauer, J.H. (2013) Organically grown food provides health benefits to Drosophila melanogaster. PLoS ONE , 8(1):e52988. PMCID: 3541339.
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. (2012) takeout-dependent longevity is associated with altered Juvenile Hormone signaling. Mech Ageing Dev 133(11-12): 637-46. PMCID: 3518612.
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.
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): 193-201
Bauer 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
Bauer JH, Poon PC, Glatt-Deeley H, Abrams JM, Helfand SL (2005) Neuronal expression of p53 dominant-negative proteins in adult Drosophila melanogaster extends life span. Curr Biol 15(22): 2063-2068