Extended Life-Span Conferred by Cotransporter Gene Mutations in Drosophila

Department of Genetics and Developmental Biology, School of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington CT 06030, USA.
Science (Impact Factor: 33.61). 01/2001; 290(5499):2137-40. DOI: 10.1126/science.290.5499.2137
Source: PubMed


Aging is genetically determined and environmentally modulated. In a study of longevity in the adult fruit fly,Drosophila melanogaster, we found that five independent P-element insertional mutations in a single gene resulted in a near doubling of the average
adult life-span without a decline in fertility or physical activity. Sequence analysis revealed that the product of this gene,
named Indy (for I'm not dead yet), is most closely related to a mammalian sodium dicarboxylate cotransporter—a membrane protein that transports Krebs cycle
intermediates. Indy was most abundantly expressed in the fat body, midgut, and oenocytes: the principal sites of intermediary metabolism in the
fly. Excision of the P element resulted in a reversion to normal life-span. These mutations may create a metabolic state that
mimics caloric restriction, which has been shown to extend life-span.

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    • "In Drosophila, loss-of-function mutations in the fly homolog of NaCT (named INDY for " I'm Not Dead Yet " ) result in an 80–100% increase in the average lifespan of both adult male and female Drosophila flies (Rogina et al., 2000). Studies in Caenorhabditis elegans also revealed that the disruption of transporters with similar transport properties as NaCT extends the animal's lifespan (Fei et al., 2003). "
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    ABSTRACT: The citric acid cycle intermediate citrate plays a crucial role in metabolic processes such as fatty acid synthesis, glucose metabolism, and b-oxidation. Citrate is imported from the circulation across the plasma membrane into liver cells mainly by the sodium-dependent citrate transporter (NaCT; SLC13A5). Deletion of NaCT from mice led to metabolic changes similar to caloric restriction; therefore, NaCT has been proposed as an attractive therapeutic target for the treatment of obesity and type 2 diabetes. In this study, we expressed mouse and human NaCT into Xenopus oocytes and examined some basic functional properties of those transporters. Interestingly, striking differences were found between mouse and human NaCT with respect to their sensitivities to citric acid cycle intermediates as substrates for these transporters. Mouse NaCT had at least 20-to 800-fold higher affinity for these intermediates than human NaCT. Mouse NaCT is fully active at physiologic plasma levels of citrate, but its human counterpart is not. Replacement of extracellular sodium by other monovalent cations revealed that human NaCT was markedly less dependent on extracellular sodium than mouse NaCT. The low sensitivity of human NaCT for citrate raises questions about the translatability of this target from the mouse to the human situation and raises doubts about the validity of this transporter as a therapeutic target for the treatment of metabolic diseases in humans.
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    • "Food availability and nutritional content is well known to be a major selective force in natural populations. There is strong experimental evidence to show that diet can mediate a trade-off between fecundity and longevity in worms and flies (Pennisi 2000; Rogina et al. 2000; Walker et al. 2000; Marden et al. 2003). Here, we provide evidence that diet can differentially influence the fitness of animals and cells harbouring specific mtDNA mutations. "
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    ABSTRACT: 1. The vast majority of studies employing mtDNA in evolutionary biology and ecology have used it as a means to infer demographic and historical patterns without pondering the underly-ing functional implications. In contrast, the biochemical and medical communities often aim to understand the influence of specific mtDNA mutations on mitochondrial functions, but rarely consider the evolutionary and ecological implications. 2. Ongoing research has shown that mtDNA mutations can profoundly affect mitochondrial function in humans and other animals. If the mutation (or set of mutations) is pathogenic, mitochondrial malfunction may be detected from early age. In nature, however, most muta-tions are not highly deleterious and may exist at intermediate frequency in populations. 3. In this review, we suggest that knowledge of the underlying biochemistry and functions of mitochondria can facilitate a more complete determination of the evolutionary dynamics of mtDNA and its influence on the life-history traits of organisms. With this approach, it is possi-ble to use biochemistry to link the genotype with the phenotype. 4. After reviewing the literature, we conclude that there can be physiological and evolutionary trade-offs in the way that mitochondrial mutations can affect age classes and/or fitness compo-nents and that these effects may depend on the environment. Through these trade-offs, it may be possible for specific mtDNA mutations to have unequal fitness in different nuclear genetic backgrounds and also in different environments.
    Functional Ecology 12/2013; 28(1). DOI:10.1111/1365-2435.12177 · 4.83 Impact Factor
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    • "Studies in flies and mice support this hypothesis mainly by showing similarities between the physiology of Indy mutant flies and mIndy knockout mice on high calorie food and control flies and mice on CR (Wang et al., 2009; Birkenfeld et al., 2011). It has recently been reported that longevity was not extended in worms with decreased levels of the Indy or in fruit flies with one of the alleles utilized by Rogina et al. (2000) and Toivonen et al. (2007). Toivonen et al. (2007), attributed the life span extension in Indy to the genetic background and bacterial infection (Toivonen et al., 2007). "
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    ABSTRACT: Decreased expression of the fly and worm Indy genes extends longevity. The fly Indy gene and its mammalian homolog are transporters of Krebs cycle intermediates, with the highest rate of uptake for citrate. Cytosolic citrate has a role in energy regulation by affecting fatty acid synthesis and glycolysis. Fly, worm, and mice Indy gene homologs are predominantly expressed in places important for intermediary metabolism. Consequently, decreased expression of Indy in fly and worm, and the removal of mIndy in mice exhibit changes associated with calorie restriction, such as decreased levels of lipids, changes in carbohydrate metabolism and increased mitochondrial biogenesis. Here we report that several Indy alleles in a diverse array of genetic backgrounds confer increased longevity.
    Frontiers in Genetics 04/2013; 4(47):47. DOI:10.3389/fgene.2013.00047
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