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Drosophila Fruit Flies


One way to identify genes that directly regulate aging is to experimentally increase or decrease their expression, and then assay for effects on life span. Decreased life span is problematic, as it is likely to result from novel pathologies that do not normally limit life span. In contrast, increased life span can only result from alterations in limiting processes, and is more likely to identify genes directly related to aging. A strength of the D. melanogaster model system is that there are a variety of transgenic methods for increasing or decreasing the expression of specific genes under well-controlled conditions.

Extensive correlative evidence suggests that, for most organisms, oxidative damage may be a primary cause of aging and functional decline. Reactive oxygen species (ROS) are toxic forms of oxygen that are generated as a byproduct of normal metabolism. One of the most common is superoxide, produced as a byproduct of the mitochondria. ROS can damage cellular components, and such oxidatively damaged molecules and organelles have been found to accumulate in all aging organisms, at least those that have been examined, including D. melanogaster. Not surprisingly, the genes tested for effects on life span in D. melanogaster have been ones involved in preventing or repairing oxidative damage. The gene hsp70 was originally identified as a gene induced in response to heat and oxidative stress. Hsp70-family proteins can help prevent or repair protein damage caused by heat or ROS by preventing protein aggregation, facilitating protein refolding, and facilitating breakdown of damaged proteins. The enzymes superoxide dismutase (SOD) and catalase work together to detoxify ROS in cells. SOD exists in two forms: cytoplasmic (Cu/ZnSOD) and mitochondrial (Mn-SOD). SOD converts superoxide to hydrogen peroxide, and catalase converts hydrogen peroxide to water and oxygen. Another important defense against ROS involves the enzyme glutathione reductase. This enzyme generates reduced glutathione, which is an abundant small molecule that detoxifies ROS.

If increased expression of a gene increases life span, that gene is, by definition, a positive regulator of life span. Transgenic D. melanogaster containing an extra copy of the catalase, CuZnSOD, MnSOD, hsp70, or glutathione reductase genes generally exhibit increased gene expression, but have not been found to exhibit any consistent increase in life span under normal culture conditions. However, extra copies of hsp70 have produced small increases in life span after mild heat stress, and extra glutathione reductase has increased survival in an atmosphere of increased oxygen concentration—a condition known to increase oxidative stress.

Relatively large increases in life span have recently been achieved using more complex methods to control the expression of transgenes. The GAL4/UAS system was used to express human Cu/ZnSOD in a tissue-specific pattern during D. melanogaster development and aging, with expression in the adult occurring primarily in motorneurons. In other studies a system called FLP-out was used to express Cu/ZnSOD specifically in the adult fly. These experiments yielded increases in average life span of up to 48 percent.

At least two negative regulators of D. melanogaster life span have also been identified. In these cases, life span is increased when the gene is disrupted or its expression is decreased. A mutation in the methuselah gene increases life span by up to 35 percent, and also increases body size and stress resistance. Mutation of the Indy gene also increases life span.

The success in identifying genes regulating aging in D. melanogaster, each of which is related to genes in humans, suggests that the fruit fly will continue to be a leading model for aging research.



ARKING, R.; BURDE, V.; GRAVES, K.; HARI, R.; FELDMAN, E.; ZEEVI, A.; SOLIMON, S.; SARAIYA, A.; BUCK, S.; VETTRAINO, J.; SATHRASALA, K.; WEHR, N.; and LEVINE, R. L. "Forward and Reverse Selection for Longevity in Drosophila is Characterized by Alteration of Antioxidant Gene Expression and Oxidative Damage Patterns." Expermental Gerontology 35 (2000): 167–185.

BAKER, G. T.; JACOBSEN, M.; and MOKRYNSKI, G. "Aging in Drosophila." In Cell Biology Handbook in Aging. Edited by V. Crisotfalo. Boca Raton, Fla.: CRC Press, 1989. Pages 511–578.

KING, V., and TOWER, J. "Aging-Specific Expression of Drosophila hsp22." Developmental Biology 207 (1994): 107–118.

KIRKWOOD, T. B. L., and AUSTAD, S. N. "Why Do We Age?" Nature 409 (2000): 233–238.

KURAPATI, R.; PASSANANTI, H. B.; ROSE, M. R.; and TOWER, J. "Increased hsp22 RNA Levels in Drosophila Lines Genetically Selected for Increased Longevity." Journal of Gerontology: Biological. Sciences 55A (2000): B1–B8.

LIN, Y.-J.; SEROUDE, L.; and BENZER, S. "Extended Life-Span and Stress Resistance in the Drosophila Mutant methuselah." Science 282 (1998): 943–946.

NUZHDIN, S. V.; PASYUKOVA, E. G.; DILDA, C. L.; ZENG, Z.-B.; and MACKAY, T. F. C. "Sex-Specific Quantitative Trait Loci Affecting Longevity in Drosophila melanogaster." Proceedings of the National Academy of Sciences USA 94 (1997): 9734–9739.

PARKES, T. L.; ELIA, A. J.; DICKSON, D.; HILLIKER, A. J.; PHILLIPS, J. P.; and BOULIANNE, G. L. "Extension of Drosophila Lifespan by Overexpression of Human SOD1 in Motorneurons." Nature Genetics 19 (1998): 171–174.

ROGINA, B., and HELFAND, S. L. "Spatial and Temporal Pattern of Expression of the Wing-less and Engailed Genes in the Adult Antenna is Regulated by Age-Dependent Mechanisms." Mechanisms of Development 63 (1997): 89–97.

ROGINA, B.; REENAN, R. A.; NILSEN, S. P.; and HELFAND, S. "Extended Life-Span Conferred by Cotransporter Gene Mutations in Drosophila." Science 290 (2000): 2137–2140.

SOHAL, R. S.; MOCKETT, R. J.; and ORR, W. C. "Current Issues Concerning the Role of Oxidative Stress in Aging: A Perspective." In Results and Problems in Cell Differentiation, vol. 29. Berlin: Springer-Verlag, 2000.

SPRADLING, A. C.; STERN, D. M.; KISS, I.; ROOTE, J.; LAVERTY, T.; and RUBIN, G. M. "Gene Disruptions Using P Transposable Elements: An Integral Component of the Drosophila Genome Project." Procedures of the National Academy of Sciences USA 92 (1995): 10824–10830.

SUN, J., and TOWER, J. "FLP Recombinase-Mediated Induction of Cu/Zn-Superoxide Dismutase Transgene Expression Can Extend the Life Span of Adult Drosophila Melanogaster Flies." Molecular Cellular Biology 19 (1999): 216–228.

TATAR, M. "Transgenes in the Analysis of Life Span and Fitness." The American Naturalist 154 (1999): S67–S81.

TOWER, J. "Aging Mechanisms in Fruit Flies." Bioessays 18 (1996): 799–807.

TOWER, J. "Transgenic Methods for Increasing Drosophila Life Span." Mechanisms of Ageing and Development 118 (2000): 1–14.

WHEELER, J. C.; BIESCHKE, E. T.; and TOWER, J. "Muscle-Specific Expression of Drosophila hsp70 in Response to Aging and Oxidative Stress." Proceedings of the National Academy of Science USA 92 (1995): 10408–10412.

WHEELER, J. C.; KING, V.; and TOWER, J. "Sequence Requirements for Upregulated Expression of Drosophila hsp70 Transgenes during Aging." Neurobiology of Aging 20 (1999): 545–553.

Additional topics

Medicine EncyclopediaAging Healthy - Part 2Drosophila Fruit Flies - Selection Experiments And Quantitative Trait Loci, Changes In Gene Expression During Aging, Transgenics