Search For Evolutionarily Conserved Genetic Mechanisms Affecting Lifespan

Drosophila has been used to identify evolutionarily conserved aging mechanisms by assessment of whether particular genes/genetic pathways that extend lifespan in other organisms such as yeast and nematodes also work in flies. Any mechanisms that are conserved across distant species are likely to have implications for humans.

Genes in the insulin/insulin-like growth factor signaling pathway have been examined based on the knowledge that homologues such as daf-2 extend lifespan in C. elegans. The Drosophila equivalent of daf-2 (Inr), chico, a Drosophila insulin receptor substrate, were also found to extend lifespan in flies when mutated, suggesting conserved mechanisms of the IIS pathway in the control of lifespan.

Another example is the role of the sirtuin family of genes. SIR2 is a NAD-dependent histone deacetylase that is involved in silencing at mating type loci in yeast. In yeast, a single extra copy of SIR2 increases lifespan, whereas its deletion shortens lifespan, and SIR2 also mediates the effect of dietary restriction. In C. elegans, the closest homologue is sir-2.1, and increased dosage extended lifespan in a daf-2-dependent manner. Following these findings, effects of increasing Drosophila Sir2 (dSir2) were examined; dSir2 was also reported to regulate lifespan in flies, and the effect was linked with that of dietary restriction (Rogina and Helfand, 2004). Again, it suggests that there is a conserved mechanism of Sir2 in the regulation of lifespan.

Phenotype screening, candidate locus approaches, and QTL mapping have resulted in discovery of a number of genes in Drosophila that extend lifespan. The first example of such a gene was methuselah (mth), which codes for a G-coupled membrane receptor-like protein, reported in 1998 (Lin et al., 1998) by longevity screens. Since then almost 50 additional genes have been identified. Whether these genes also affect lifespan in other species is yet to be determined, but just as Drosophila has served as a test species for genes identified in other organisms, others may serve to explore patterns initially found in Drosophila.

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