Endocrine regulation of aging and reproduction in Drosophila

Hormonal signals can modulate lifespan and reproductive capacity across the animal kingdom. The use of model organisms such as worms, flies and mice has been fundamentally important for aging research in the discovery of genetic alterations that can extend healthy lifespan. The effects of mutations in the insulin and insulin-like growth factor-like signaling (IIS) pathways are evolutionarily conserved in that they can increase lifespan in all three animal models. Additionally, steroids and other lipophilic signaling molecules modulate lifespan in diverse organisms. Here we shall review how major hormonal pathways in the fruit fly Drosophila melanogaster interact to influence reproductive capacity and aging.     

Longevity mutants do not establish any “new science” of ageing

The biological reasons for ageing are now well known, so it is no longer an unsolved problem in biology. Furthermore, there is only one science of ageing, which is continually advancing. The significance and importance of the mutations that lengthen the lifespan of invertebrates can be assessed only in relationship to previous well-established studies of ageing. The mutant strains of model organisms that increase longevity have altered nutrient signalling pathways similar to the effects of dietary restriction, and so it is likely that there is a shift in the trade-off between reproduction and maintenance of the soma. To believe that the isolation and characterisation of a few invertebrate mutations (as well as those in yeast) will “galvanise” the field and provide new insights into human ageing is an extreme point of view which does not recognize the huge progress in ageing research that has been made in the last 50 years or so.     

Steroid hormone regulation of C. elegans and Drosophila aging and life history

In the last two decades it has become clear that hormones and gene mutations in endocrine signaling pathways can exert major effects on lifespan and related life history traits in worms, flies, mice, and other organisms. While most of this research has focused on insulin/insulin-like growth factor-1 signaling, a peptide hormone pathway, recent work has shown that also lipophilic hormones play an important role in modulating lifespan and other life history traits. Here we review how steroid hormones, a particular group of lipophilic hormones, affect life history traits in the nematode worm (Caenorhabditis elegans) and the fruit fly (Drosophila melanogaster), with a particular focus on longevity. Interestingly, a comparison suggests that parallel endocrine principles might be at work in worms and flies in these species and that steroid hormones interact with the gonad to affect lifespan.     

The GH/IGF-I axis and longevity

Several converging lines of evidence obtained over the last years in a wide variety of experimental model organisms suggest that the ageing process is regulated by genes that encode proteins from the somatotroph axis: longevity genes like daf-2, which were identified using mutant Caenorhabditis elegans strains, turned out to be orthologues of the mammalian genes encoding insulin-like signalling cascade proteins. Transgenic flies with mutations in the corresponding insect genes showed a similar pattern of increased lifespan. Finally, mice with spontaneous mutations leading to pituitary hormone deficiency significantly outlived controls. While these and other genetic models suggest that the downregulation of the somatotroph axis can slow the ageing process, other results from studies using pharmacological administration of growth hormone suggest that such stimulating treatment can restore some of the phenotypic traits associated with youth. To better understand the role of the insulin-like receptors in mammalian lifespan regulation and ageing, we explored the phenotype of heterozygous IGF-I receptor (IGF1R) knockout mice. Compared with control littermates these mutants live longer without any obvious impairment of their health and physiology, except a reduced glucose tolerance that we observed in males. These IGF1R(+/-) mutants were also more resistant to oxidative stress in vivo, and we identified a possible molecular pathway linking underphosphorylation of IGF-I receptors to the lack of activation of p66Shc, a protein capable of increasing resistance to oxidative stress through regulation of a set of downstream genes. These and other results suggest that in mammals too, lifespan can be increased by continuous, long-term downregulation of IGF signalling. Since growth hormone administration normally stimulates IGF production in tissues, the question arises whether the beneficial effects of GH, as reported by others, could be IGF independent. This hypothesis can be addressed, for example, by adequately combining existing transgenic mouse models.     

An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster

Recent advances in aging research have uncovered genes and genetic pathways that influence lifespan in such diverse organisms as yeast, nematodes, flies, and mice. The discovery of genes and drugs that affect lifespan has been delayed by the absence of a phenotype other than survivorship, which depends on the measurement of age at death of individuals in a population. The use of survivorship to identify genetic and pharmacological interventions that prolong life is time-consuming and requires a large number of homogeneous animals. Here, we report the development of an assay in Drosophila melanogaster using the expression of molecular biomarkers that accelerates the ability to evaluate potential lifespan-altering interventions. Coupling the expression of an age-dependent molecular biomarker to a lethal toxin reduces the time needed to perform lifespan studies by 80%. The assay recapitulates the effect of the three best known environmental life-span-extending interventions in the fly: ambient temperature, reproductive status, and calorie reduction. Single gene mutations known to extend lifespan in the fly such as Indy and rpd3 also extend lifespan in this assay. We used this assay as a screen to identify drugs that extend lifespan in flies. Lipoic acid and resveratrol were identified as being beneficial in our assay and shown to extend lifespan under normal laboratory conditions. We propose that this assay can be used to screen pharmacological as well as genetic interventions more rapidly for positive effects on lifespan.     

Ageing in Drosophila: The role of the insulin/Igf and TOR signalling network

A remarkable discovery of recent years is that, despite the complexity of ageing, simple genetic interventions can increase lifespan and improve health during ageing in laboratory animals. The pathways involved have often proved to sense nutrients and to match costly activities of organisms, such as growth, metabolism and reproduction, to nutrient status. For instance, the insulin/insulin-like growth factor and Target of Rapamycin signalling network has proved to play a function in ageing, from yeast to mammals, seemingly including humans. In the fruit fly Drosophila, altered activity of several components of this network can increase lifespan and improve locomotor and cardiac function during ageing. The fly brain, fat body (equivalent of mammalian liver and white adipose tissue) and the germ line are important in determination of lifespan, with considerable communication between different tissues. Cellular detoxification pathways, increased autophagy and altered protein synthesis have all been implicated in increased lifespan from reduced IIS/TOR activity, with the role of defence against oxidative stress unresolved. Reduced IIS/TOR signalling can alter or block the response of lifespan to dietary restriction. Reduced IIS can act acutely to lower death rate, implying that it may ameliorate the effects of ageing-related damage, rather than preventing it.     

Genetic deficiencies of innate immune signalling in human infectious disease

The type-1 cytokine (interleukin 12, interleukin 23, interferon γ, interleukin 17) signalling pathway is triggered during infection by activation of phagocyte-expressed pattern-recognition receptors that recognise specific pathogen-associated molecular patterns. Triggering of this pathway results, among other things, in activation of microbicidal mechanisms in phagocytic cells. Individuals with a deficiency in one of the proteins in the pathway are unusually susceptible to otherwise poorly pathogenic, mostly environmental, mycobacteria and salmonellae. Individuals with deficiencies in other innate immune signalling proteins show unusual susceptibility to pathogens other than mycobacteria or salmonellae. We discuss recent insights into key molecules involved in type-1 cytokine signalling pathways and provide an update on the molecular genetic defects underlying mendelian susceptibility to mycobacterial disease. We also discuss deficiencies in the innate immune signalling proteins that lead to susceptibility to other pathogens. Knowledge of innate immune signalling has allowed the identification of defects in such patients. However, some patients have enhanced susceptibility to pathogens even though no mutations have been found in the candidate genes identified thus far. Whereas a few patients might have autoantibodies against type-1 cytokines, others might harbour mutations in new genes and pathways that still need to be identified.     

The role of autophagy in genetic pathways influencing ageing

Autophagy is a conserved cellular degradation pathway for the breakdown of cytosolic macromolecules and organelles. Constitutive autophagy has a housekeeping role and is essential for survival, development and metabolic regulation. Autophagy is also responsive to stress and can degrade damaged proteins and organelles, oxidized lipids and intracellular pathogens. Defects in the autophagic degradation system are linked to disease pathogenesis and ageing. Different signalling pathways converge on autophagy to regulate lifespan in diverse organisms. We discuss recent findings that provide insight into the cross-talk between this critical regulator of metabolic homeostasis and molecular mechanisms that promote longevity.