The Drosophila melanogaster gene chico encodes an insulin receptor substrate that functions in an insulin/insulin-like growth factor (IGF) signaling pathway. In the nematode Caenorhabditis elegans , insulin/IGF signaling regulates adult longevity. We found that mutation of chico extends fruit fly median life-span by up to 48% in homozygotes and 36% in heterozygotes. Extension of life-span was not a result of impaired oogenesis in chico females, nor was it consistently correlated with increased stress resistance. The dwarf phenotype of chico homozygotes was also unnecessary for extension of life-span. The role of insulin/IGF signaling in regulating animal aging is therefore evolutionarily conserved.

The maternal transmission of mitochondrial genomes invokes a sex-specific selective sieve, whereby mutations in mitochondrial DNA can only respond to selection acting directly on females. In theory, this enables male-harming mutations to accumulate in mitochondrial genomes when these same mutations are neutral, beneficial, or only slightly deleterious in their effects on females. Ultimately, this evolutionary process could result in the evolution of male-specific mitochondrial mutation loads; an idea previously termed Mother's Curse. Here, we present evidence that the effects of this process are broader than hitherto realized, and that it has resulted in mutation loads affecting patterns of aging in male, but not female Drosophila melanogaster. Furthermore, our results indicate that the mitochondrial mutation loads affecting male aging generally comprise numerous mutations over multiple sites. Our findings thus suggest that males are subject to dramatic consequences that result from the maternal transmission of mitochondrial genomes. They implicate the diminutive mitochondrial genome as a hotspot for mutations that affect sex-specific patterns of aging, thus promoting the idea that a sex-specific selective sieve in mitochondrial genome evolution is a contributing factor to sexual dimorphism in aging, commonly observed across species.

Microbes of the genus Wolbachia are transmitted by their hosts via the maternal parent and are responsible for cytoplasmic incompatibility among insect populations. This phenomenon can result in Wolbachia spreading through natural populations as previously demonstrated in Drosophila simulans. Here we describe another Wolbachia infection in D. simulans that does not cause cytoplasmic incompatibility. This is a property of the Wolbachia rather than the nuclear background. The infection occurs at a low frequency in natural populations from eastern Australia. The infection shows perfect maternal transmission in the field and does not cause any detectable deleterious effects on its host. These findings suggest that the Wolbachia infection behaves like a neutral variant in populations. The infection may represent an evolutionary outcome of interactions between Wolbachia infections and their hosts.

Interventions that slow down aging provide invaluable insights into its causes. But do they act upon common underlying mechanisms? Recent work with a long-lived mutant mouse, the Ames dwarf, showed that its lifespan could be further extended by another intervention, dietary restriction, in which food intake was restricted to about 70% of voluntary levels (1). This finding was taken to demonstrate that the Ames mutation and dietary restriction slow aging by different mechanisms, because the Ames mutation and dietary restriction do not mask each other's effect on life-span. Using the fruit fly Drosophila, we show here that (i) slowing of aging by a mutation in an insulin/insulin-like growth factor (IGF)-like signaling (IIS) pathway and by dietary restriction occurs by overlapping mechanisms and (ii) life-span must be maximized by at least one of the interventions under investigation for a proper test of the hypothesis that the mechanisms of life-span extension differ.Mutations that reduce IIS extend life-span in the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster (2). The chico 1 mutation in the IIS pathway in Drosophila produces dwarf, longlived females at normal nutrition (3). Dietary restriction slows aging in organisms ranging from yeast to mammals (4), probably including primates (5). In rodents, extension of life-span by dietary restriction has been suggested to be attributable to reduced caloric intake. Dietary restriction by food dilution slows aging in Drosophila, with life-span of wild-type females increasing to a peak under dietary restriction as the food is diluted and then dropping with further dilution, presumably as a result of starvation (6). At least part of the response may be attributable to dilution of yeast in the diet (7). If chico 1 extends life-span by an overlapping mechanism with dietary restriction, then we would expect the relation between life-span and nutrition to be different in chico 1 and control flies. chico 1 flies should behave as though they are already to some extent subjected to dietary restriction. They should therefore be more prone than controls to starvation at low levels of nutrition. At the food dilution that maximizes control life-span, chico 1 flies would be malnourished and less long-lived. Life-span of chico 1 females should peak at a higher food concentration than that of controls does, and at this and higher food concentrations, the chico 1 females should be longer lived than controls.We therefore measured the life-span of chico 1 and control flies over a range of food concentrations (Fig. 1). As predicted, the relation between life-span and food concentration was right-shifted in the chico 1 females. Control and chico 1 females showed similar peak lifespans under dietary restriction, but the food concentrations at which these were achieved were different, with chico 1 females peaking on 0.8 times food and controls on 0.65 times food. This shows that chico 1 did not extend life-span beyond the maximum that can be achieved by dietary r...

SummaryMitochondria are thought to play a central role in aging. In humans, specific naturally occurring mitochondrial genetic variants are overrepresented among centenarians, but only in certain populations; therefore, we cannot tell whether this effect is due solely to mitochondrial genetics or to nuclear-mitochondrial gene complexes, nor do we know the magnitude of the effect in terms we can relate to, such as mean lifespan differences. To examine the effects of natural mitochondrial DNA (mtDNA) variation on lifespan, we need to vary the mitochondrial genotype while controlling the nuclear genotype. Here, nuclear genome replacement is achieved using strains of Drosophila melanogaster bearing multiply inverted 'balancer' chromosomes that suppress recombination, and an isogenic donor strain, thus forcing replacement of entire chromosomes in a single cross while suppressing recombination. Lifespans of wild-type mtDNA variants on the chromosome replacement background vary substantially, and sequencing of the entire protein coding mitochondrial genomes indicates that these lifespan differences are sometimes associated with single amino acid differences. On other nuclear genetic backgrounds, the magnitude and direction of these lifespan effects can change dramatically, and this can be due to changes in baseline mortality risk, rate of aging and/or time of onset of aging. The limited mtDNA variation in D. melanogaster makes it an ideal organism for biochemical studies to link genotype and aging phenotype.