Inheritance of pheromone profiles from aged D. melanogaster.

Through aging, D. melanogaster males and females change their social spacing. Flies are initially more social, but reduce sociability as they grow older. This preferred social space is inherited in their progeny. Here, we report that in females, the profiles of cuticular hydrocarbons (CHC), which are known to promote social interaction between individuals, similarly are affected by age. Importantly, for a subset of those CHC, the progeny's CHC levels are comparable to those of their parents, suggesting that parental age influences offspring CHC expression. Those data establish a foundation to identify the relationship between CHC levels and social spacing, and to understand the mechanisms of the inheritance of complex traits.

Sleep-length differences are associated with altered longevity in the fruit fly Drosophila melanogaster.

Sleep deprivation has been shown to negatively impact health outcomes, leading to decreased immune responses, memory loss, increased activity of stress and inflammatory pathways, weight gain, and even behavioral changes. These observations suggest that sleep deprivation substantially interferes with important physiological functions, including metabolic pathways of energy utilization. Many of those phenotypes are correlated with age, suggesting that disrupted sleep may interfere with the aging process. However, little is known about how sleep disruption affects aging and longevity. Here, we investigate this relationship using eight representative fruit fly lines from the Sleep Inbred Panel (SIP). The SIP consists of 39 inbred lines that display extreme short- and long-sleep patterns, and constitutes a crucial Drosophila community resource for investigating the mechanisms of sleep regulation. Our data show that flies with short-sleep periods have ∼16% longer life span, as well as reduced aging rate, compared to flies with long-sleep. In contrast, disrupting normal circadian rhythm reduces fly longevity. Short-sleep SIP flies moreover show slight metabolic differences to long-sleep lines, and to flies with disrupted circadian rhythm. These data suggest that the inbred SIP lines engage sleep mechanisms that are distinct from the circadian clock system.

Altered pheromone biosynthesis is associated with sex-specific changes in life span and behavior in Drosophila melanogaster.

Many insect behaviors, including foraging, aggression, mating or group behavior, are tightly regulated by pheromones. Recently, it has been shown that pheromones may influence extreme longevity in the honeybee Apis mellifera, while changes in pheromone profile have been observed during ageing in Drosophila melanogaster. These data suggest a potential link between the pheromone system, behavior and longevity in insects. Here, we investigate this potential link by examining changes in behavior and longevity in fruit flies with altered pheromone profiles. We demonstrate that oenocyte-specific reduction of desaturase activity is sufficient to dramatically alter the composition of the hydrocarbon mix displayed by the flies. In addition, flies with altered desaturase activity display changes in fecundity and stereotypical mating behavior, and, importantly, extended longevity. These data provide evidence for a potential link between hydrocarbon synthesis and life span, and suggest that longevity may be influenced by behavior.

¹9F magnetic resonance probes for live-cell detection of peroxynitrite using an oxidative decarbonylation reaction.

We report a newly discovered oxidative decarbonylation reaction of isatins that is selectively mediated by peroxynitrite (ONOO(-)) to provide anthranilic acid derivatives. We have harnessed this rapid and selective transformation to develop two reaction-based probes, 5-fluoroisatin and 6-fluoroisatin, for the low-background readout of ONOO(-) using (19)F magnetic resonance spectroscopy. 5-fluoroisatin was used to non-invasively detect ONOO(-) formation in living lung epithelial cells stimulated with interferon-γ (IFN-γ).

Organically grown food provides health benefits to Drosophila melanogaster.

The "organic food" market is the fastest growing food sector, yet it is unclear whether organically raised food is nutritionally superior to conventionally grown food and whether consuming organic food bestows health benefits. In order to evaluate potential health benefits of organic foods, we used the well-characterized fruit fly Drosophila melanogaster as a model system. Fruit flies were raised on a diets consisting of extracts of either conventionally or organically raised produce (bananas, potatoes, raisins, soy beans). Flies were then subjected to a variety of tests designed to assess overall fly health. Flies raised on diets made from organically grown produce had greater fertility and longevity. On certain food sources, greater activity and greater stress resistance was additionally observed, suggesting that organic food bestows positive effects on fly health. Our data show that Drosophila can be used as a convenient model system to experimentally test potential health effects of dietary components. Using this system, we provide evidence that organically raised food may provide animals with tangible benefits to overall health.

takeout-dependent longevity is associated with altered Juvenile Hormone signaling.

In order to understand the molecular mechanisms of longevity regulation, we recently performed a screen designed to enrich for genes common to several longevity interventions. Using this approach, we identified the Drosophila melanogaster gene takeout. takeout is upregulated in a variety of long-lived flies, and extends life span when overexpressed. Here, we investigate the mechanisms of takeout-dependent longevity. takeout overexpression specifically in the fat body is sufficient to increase fly longevity and is additive to the longevity effects of Dietary Restriction. takeout long-lived flies do not show phenotypes often associated with increased longevity, such as enhanced stress resistance or major metabolic abnormalities. However, males exhibit greatly diminished courtship behavior, leading to a reduction in fertility. Interestingly, takeout contains a binding domain for Juvenile Hormone, a fly hormone that plays a role in the regulation of developmental transitions. Importantly, the longevity and courtship phenotypes of takeout overexpressing flies are reversed by treatment with the Juvenile Hormone analog methoprene. These data suggest that takeout is a key player in the tradeoff-switch between fertility and longevity. takeout may control fertility via modulation of courtship behavior. This regulation may occur through Juvenile Hormone binding to takeout and a subsequent reduction in Juvenile Hormone signaling activity.

Development of diet-induced insulin resistance in adult Drosophila melanogaster.

The fruit fly Drosophila melanogaster is increasingly utilized as an alternative to costly rodent models to study human diseases. Fly models exist for a wide variety of human conditions, such as Alzheimer's and Parkinson's Disease, or cardiac function. Advantages of the fly system are its rapid generation time and its low cost. However, the greatest strength of the fly system are the powerful genetic tools that allow for rapid dissection of molecular disease mechanisms. Here, we describe the diet-dependent development of metabolic phenotypes in adult fruit flies. Depending on the specific type of nutrient, as well as its relative quantity in the diet, flies show weight gain and changes in the levels of storage macromolecules. Furthermore, the activity of insulin-signaling in the major metabolic organ of the fly, the fat body, decreases upon overfeeding. This decrease in insulin-signaling activity in overfed flies is moreover observed when flies are challenged with an acute food stimulus, suggesting that overfeeding leads to insulin resistance. Similar changes were observed in aging flies, with the development of the insulin resistance-like phenotype beginning at early middle ages. Taken together, these data demonstrate that imbalanced diet disrupts metabolic homeostasis in adult D. melanogaster and promotes insulin-resistant phenotypes. Therefore, the fly system may be a useful alternative tool in the investigation of molecular mechanisms of insulin resistance and the development of pharmacologic treatment options.

Dominant-negative Dmp53 extends life span through the dTOR pathway in D. melanogaster.

Expression of dominant-negative (DN) versions of the Drosophila ortholog of the tumor suppressor p53 extends fly life span in a Calorie Restriction (CR) dependent manner. DN-Dmp53 expression furthermore leads to reduction of Drosophila insulin-like peptide (dILP) 2 mRNA levels and a decrease in insulin/insulin-like growth factor-signaling activity (IIS) in the fly fat body. It is unclear by which mechanisms DN-Dmp53 extends longevity, and whether modulation of insulin-signaling activity plays a pivotal role in life span regulation by Dmp53. Here we show that life span extension due to DN-Dmp53 expression is likely due to reduction of Dmp53 activity and that decreased Dmp53 activity does not extend life span when dILP2 is concomitantly over expressed. Furthermore, extended longevity due to DN-Dmp53 expression does not further extend the life span of flies over expressing the IIS associated transcription factor dFoxO, indicating that DN-Dmp53-dependent life span extension may be related to IIS. However, reduction of dFoxO levels does not decrease DN-Dmp53-dependent longevity extension. Interestingly, when DN-Dmp53 is expressed in flies lacking the translation initiation controlling factor Thor/4E-BP, the downstream target of dTOR signaling, no increase in life span is observed. Taken together, these data suggest that Dmp53 may affect life span by differentially engaging the IIS and dTor pathways.

dSir2 and Dmp53 interact to mediate aspects of CR-dependent lifespan extension in D. melanogaster.

Calorie Restriction (CR) is a well established method of extending life span in a variety of organisms. In the fruit fly D. melanogaster, CR is mediated at least in part by activation of dSir2. In mammalian systems, one of the critical targets of Sir2 is the tumor suppressor p53. This deacetylation of p53 by Sir2 leads to inhibition of p53's transcriptional activity. We have recently shown that inhibition of Dmp53 activity in the fly brain through the use of dominant-negative (DN) constructs that inhibit DNA-binding can extend life span. This life span extension appears to be related to CR, as CR and DN-Dmp53 donot display additive effects on life span. Here we report that life span extension by DN-Dmp53 expression is highly dynamic and can be achieved even when DN-Dmp53 is expressed later in life. In addition, we demonstrate that life span extension by activation of dSir2 and DN-Dmp53 expression are not additive. Furthermore, we show that dSir2 physically interacts with Dmp53 and can deacetylate Dmp53-derived peptides. Taken together, our data demonstrate that Dmp53 is a down stream target of dSir2 enzymatic activity and mediates some aspects of the life span extending effects of CR.

Expression of dominant-negative Dmp53 in the adult fly brain inhibits insulin signaling.

In Drosophila melanogaster, p53 (Dmp53) is an important mediator of longevity. Expression of dominant-negative (DN) forms of Dmp53 in adult neurons, but not in muscle or fat body cells, extends lifespan. The lifespan of calorie-restricted flies is not further extended by simultaneously expressing DN-Dmp53 in the nervous system, indicating that a decrease in Dmp53 activity may be a part of the CR lifespan-extending pathway in flies. In this report, we show that selective expression of DN-Dmp53 in only the 14 insulin-producing cells (IPCs) in the brain extends lifespan to the same extent as expression in all neurons and this lifespan extension is not additive with CR. DN-Dmp53-dependent lifespan extension is accompanied by reduction of Drosophila insulin-like peptide 2 (dILP2) mRNA levels and reduced insulin signaling (IIS) in the fat body, which suggests that Dmp53 may affect lifespan by modulating insulin signaling in the fly.

New tricks of an old molecule: lifespan regulation by p53.

As guardian of the genome the tumor suppressor p53 controls a crucial point in protection from cellular damage and response to stressors. Activation of p53 can have beneficial (DNA repair) or detrimental (apoptosis) consequences for individual cells. In either case activation of p53 is thought to safeguard the organism at large from the deleterious effects of various stresses. Recent data suggest that the function of p53 might also play a role in the regulation of organismal lifespan. Increased p53 activity leads to lifespan shortening in mice, while apparent reduction of p53 activity in flies leads to lifespan extension. Although the mechanism by which p53 regulates lifespan remains to be determined, these findings highlight the possibility that careful manipulation of p53 activity during adult life may result in beneficial effects on healthy lifespan.

Neuronal expression of p53 dominant-negative proteins in adult Drosophila melanogaster extends life span.

Hyperactivation of p53 leads to a reduction in tumor formation and an unexpected shortening of life span in two different model systems . The decreased life span occurs with signs of accelerated aging, such as osteoporosis, reduction in body weight, atrophy of organs, decreased stress resistance, and depletion of hematopoietic stem cells. These observations suggest a role for p53 in the determination of life span and the speculation that decreasing p53 activity may result in positive effects on some aging phenotypes . In this report, we show that expression of dominant-negative versions of Drosophila melanogaster p53 in adult neurons extends life span and increases genotoxic stress resistance in the fly. Consistent with this, a naturally occurring allele with decreased p53 activity has been associated with extended survival in humans . Expression of the dominant-negative Drosophila melanogaster p53 constructs does not further increase the extended life span of flies that are calorie restricted, suggesting that a decrease in p53 activity may mediate a component of the calorie-restriction life span-extending pathway in flies.

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.