Does a relationship exist between spontaneous locomotor activity,fitness and lifespan in Drosophila melanogaster?

Spontaneous locomotor activity (SLA), fecundity, fertility and lifespan were measured in a wild laboratory strain of Drosophila melanogaster in order to ascertain whether there is a genetic correlation between these traits. In females there is no correlation either between SLA and fecundity or between SLA and lifespan. It is concluded that, although a high level of SLA probably constitutes a favorable behavioral component of fitness, this does not mean that more active females have a larger number of offspring and live longer than less active ones.     

The effect of diet, sex and mating status on longevity in Mediterranean fruit flies (Ceratitis capitata), Diptera: Tephritidae

Dietary Restriction (DR) extends lifespan in a range of model organisms such as yeast, flies and worms suggesting it is a 'public' mechanism for longevity extension. Lifespan extension has also been reported in the Mediterranean fruit fly (medfly), Ceratitis capitata in response to various types of dietary manipulation, however, the responses can be complex. There are also reported differences in the responses of medfly and Drosophila melanogaster longevity to DR, but it is not clear to what extent these are due to differences in feeding protocols or to what extent they reflect real biological differences. In order to investigate this, we applied a DR feeding protocol similar to that used in many D. melanogaster studies and tested for effects on male and female virgin and mated medfly longevity. Our results show a clear effect of DR and a cost of reproduction for both sexes. Female flies lived significantly longer than male flies at all food levels, indicating minimal interactions between diet and sex in determining longevity.     

High carbohydrate–low protein consumption maximizes Drosophila lifespan

Dietary restriction extends lifespan in a variety of organisms, but the key nutritional components driving this process and how they interact remain uncertain. In Drosophila, while a substantial body of research suggests that protein is the major dietary component affecting longevity, recent studies claim that carbohydrates also play a central role. To clarify how nutritional factors influence longevity, nutrient consumption and lifespan were measured on a series of diets with varying yeast and sugar content. We show that optimal lifespan requires both high carbohydrate and low protein consumption, but neither nutrient by itself entirely predicts lifespan. Increased dietary carbohydrate or protein concentration does not always result in reduced feeding—the regulation of food consumption is best described by a constant daily caloric intake target. Moreover, due to differences in food intake, increased concentration of a nutrient within the diet does not necessarily result in increased consumption of that particular nutrient. Our results shed light on the issue of dietary effects on lifespan and highlight the need for accurate measures of nutrient intake in dietary manipulation studies.     

Increased lifespan in transgenic Caenorhabditis elegans overexpressing human alpha-synuclein

alpha-Synuclein is a short 14-kDa protein found in pathological lesions of age-related neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and multiple system atrophy. Its overexpression in transgenic mice, rats, Drosophila melanogaster, and Caenorhabditis elegans recapitulates many of the pathologic features observed in human Parkinson's disease including loss of dopaminergic neurons and motor deficits. Integrated transgenic C. elegans lines were generated that overexpress either human wildtype (WT) or mutant (A53T) forms. These transgenic lines demonstrated approximately 25% increase in lifespan (p<0.0001) compared to controls. When the transgenes were crossed into long-lived daf-2 (m577) or daf-2 (e1370) genetic backgrounds, the lifespan increase was also approximately 25% in comparison to the corresponding daf-2 strains (p<0.05). Pharyngeal pumping and egg laying were significantly decreased in the overexpressing transgenic lines, and lifespan increases were attenuated when lines were grown on thick bacterial lawns, suggesting that caloric restriction may explain some of the effects on lifespan. These studies provide initial evidence for a beneficial role of human alpha-synuclein in influencing lifespan.     

Adaptive evolution of a candidate gene for aging in Drosophila

Examination of the phenotypic effects of specific mutations has been extensively used to identify candidate genes affecting traits of interest. However, such analyses do not reveal anything about the evolutionary forces acting at these loci, or whether standing allelic variation contributes to phenotypic variance in natural populations. The Drosophila gene methuselah (mth) has been proposed as having major effects on organismal stress response and longevity phenotype. Here, we examine patterns of polymorphism and divergence at mth in population level samples of Drosophila melanogaster, D. simulans, and D. yakuba. Mth has experienced an unusually high level of adaptive amino acid divergence concentrated in the intra- and extracellular loop domains of the receptor protein, suggesting the historical action of positive selection on those regions of the molecule that modulate signal transduction. Further analysis of single nucleotide polymorphisms (SNPs) in D. melanogaster provided evidence for contemporary and spatially variable selection at the mth locus. In ten surveyed populations, the most common mth haplotype exhibited a 40% cline in frequency that coincided with population level differences in multiple life-history traits including lifespan. This clinal pattern was not associated with any particular SNP in the coding region, indicating that selection is operating at a closely linked site that may be involved in gene expression. Together, these consistently nonneutral patterns of inter- and intraspecific variation suggest adaptive evolution of a signal transduction pathway that may modulate lifespan in nature.     

刺玫果对果蝇寿命及大鼠LPO和SOD的影响

本文观察了刺玫果对果蝇寿命、大鼠血清脂质过氧化物(LPO)含量及超氧化物歧化酶(SOD)活性的影响。结果表明,刺玫果能显著延长果蝇的平均寿命和最高寿命,降低大鼠血清LPO含量;但对血SOD活性无明显作用。初步提示刺玫果有一定的抗衰老作用。     

Rhodiola: a promising anti-aging Chinese herb

Using the fruit fly, Drosophila melanogaster, we investigated the effects of Rhodiola on life-span. Rhodiola is a plant root used in traditional Chinese medicine that may increase an organism's resistance to stress. It has been proposed that Rhodiola can extend longevity and improve health span by alleviating oxidative stress. Rhodiola supplied every other day at 30 mg/mL significantly increased the lifespan of Drosophila melanogaster. When comparing the distribution of deaths between Rhodiola-supplemented and control flies, Rhodiola-fed flies exhibited decelerated aging. Although the observed extension in lifespan was associated with statistically insignificant reductions in fecundity, correcting for a possible dietary restriction effect still did not eliminate the difference between supplemented and control flies, nor does the effect of Rhodiola depend on dietary manipulation, strongly suggesting that Rhodiola is not a mere dietary restriction mimetic. Although this study does not reveal the causal mechanism behind the effect of Rhodiola, it does suggest that the supplement is worthy of continued investigation, unlike the other Chinese herbals, Lu Duo Wei (LDW), Bu Zhong Yi Qi Tang (BZYQT), San Zhi Pian (SZP, Three Imperial Mushrooms), Hong Jing Tian (Rhodiola) that were evaluated in this study.     

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.     

Why do life spans differ? Partitioning mean longevity differences in terms of age-specific mortality parameters

Populations typically differ in mean life spans because of genetic, environmental, or experimental factors. In this paper methods are presented that clarify the relationship between differences in the longevity of two populations and differences in their underlying age-specific patterns of mortality. Data are examined from rodent and fruit fly (Drosophila melanogaster) experiments that investigated the longevity effects of a variety of environmental and genetic manipulations, including temperature, dietary restriction, laboratory selection for increased longevity, and severe inbreeding. Analyses suggest that longevity differences mediated by temperature and dietary restriction result predominantly from differences in the rate of increase in mortality with age. Increases in longevity through laboratory selection result primarily from a reduction in baseline mortality and not a slowing of the rate of aging. Although the methods are applied primarily in the context of simple mathematical models of mortality (e.g., the Gompertz model), they are quite general and can be applied to mortality models of arbitrary complexity. Mathematica protocols ("notebooks") and computer software have been developed to perform all the analyses discussed and are available from the first author.     

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.     

Challenges in the manipulation, assessment and interpretation of craving relevant variables

The nature of drug craving and its role in the addictive process is a contentious issue in the addiction sciences. There are numerous disputes regarding the definition, assessment, manipulation and interpretation of craving, and progress toward resolving the enigmas of craving confronts numerous conceptual and methodological challenges. Greater attention to certain fundamental principles of measurement and manipulation should generate immediate and substantial improvements in efforts to understand and control alcohol craving. This paper provides suggestions for enhancing the measurement of self-reported alcohol craving and improving the manipulation of alcohol craving under controlled laboratory conditions. With regard to measurement, single-item scales commonly employed in craving research tend to be handicapped by limited reliability and validity. Multi-item craving scales are more likely to provide the accuracy required to accurately discriminate between different levels of craving across individuals or across different settings. Conceptual and practical considerations for the selection of multi-item craving instruments are discussed. With regard to the manipulation of alcohol craving in the laboratory, recent meta-analyses suggest that alcohol craving effects in such research may be relatively weaker than craving effects found in similar research with other addicts. Therefore, laboratory-based investigations into the nature of alcohol craving should utilize procedures and assessments that are particularly sensitive to the detection of alcohol craving. This paper offers methodological recommendations for enhancing the magnitude of alcohol craving effects generated in laboratory research.     

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.     

Decreased expression of Cu-Zn superoxide dismutase 1 in ants with extreme lifespan

Reactive oxygen species, the by-products of oxidative energy metabolism, are considered a main proximate cause of aging. Accordingly, overexpression of the enzyme Cu-Zn superoxide dismutase 1 (SOD1) can lengthen lifespan of Drosophila melanogaster in the laboratory. However, the role of SOD1 as a main determinant of lifespan has been challenged on the grounds that overexpression might be effective only in compromised genetic backgrounds. Moreover, interspecific comparisons show lower levels of antioxidant activities in longer-lived species, suggesting that life-span extension may evolve through less reactive oxygen species generation from the mitochondria rather than higher expression of SOD1. The tremendous variation in lifespan between ant castes, ranging over 2 orders of magnitude, coupled with the fact that all individuals share the same genome, provides a system to investigate the role of SOD1 in the wild. We used the ant Lasius niger as a model system, because queens can reach the extreme age of 28 years, whereas workers and males live only 1-2 years and a few weeks, respectively. We cloned SOD1 and found that long-lived queens have a lower level of expression than workers and males. Specific enzyme-activity assays also showed higher SOD1 activity levels in males and workers compared with queens, which had SOD1 activity levels similar to that of D. melanogaster. Altogether, these data show that increased expression of SOD1 is not required for the evolution of extreme lifespan, even in a system in which differential gene expression is the only way to express phenotypes with great lifespan differences.     

Selection on stress resistance increases longevity in Drosophila melanogaster.

Tests for the causal involvement of specific physiological mechanisms in the control of aging require evidence that these mechanisms can be used to increase longevity or reproductive lifespan. Selection for later reproduction in Drosophila has been shown to lead to increased longevity, as well as increased resistance to starvation and desiccation stresses. Selection for increased resistance to starvation and desiccation in Drosophila melanogaster is here shown to lead to increased longevity, indicating that alleles that increase stress resistance also may increase longevity. The responses of desiccation and starvation resistance to selection are partly independent of each other, indicating a multiplicity of physiological mechanisms involved in selectively postponed aging, and thus aging in general.     

Targeted neuronal gene expression and longevity in Drosophila

Earlier studies from this laboratory have shown that in the insect, Drosophila melanogaster, the motorneuron is an important cellular nexus between the metabolism of reactive oxygen species (ROS) and adult lifespan. This was demonstrated by experiments in which expression of CuZn SOD (SOD1) specifically in motorneurons was shown to extend the mean and maximum adult lifespans to 140% of normal, and to rescue the majority of deliterious phenotypes displayed by SOD1-null mutants. We have interpreted these results to mean either that the lifespan of the organism is normally limited by the functional lifespan of this post-mitotic cell type, or that ROS metabolism in motorneurons affects organismic lifespan via a systemic, perhaps neuroendocrine, signaling mechanism.

We have now extended these studies to ask: (i) whether expression of catalase (CAT) or of the mitochondrially-localized Mn SOD (SOD2) in motorneurons, either singly or in combination with SOD1, have similar effects on lifespan; (ii) if expression of SOD2 can rescue SOD1-null mutant phenotypes; and (iii) if ROS metabolism in cell types other than motorneurons has significant impact on aging and lifespan determination.     

Targeted neuronal gene expression and longevity in Drosophila

Earlier studies from this laboratory have shown that in the insect, Drosophila melanogaster, the motorneuron is an important cellular nexus between the metabolism of reactive oxygen species (ROS) and adult lifespan. This was demonstrated by experiments in which expression of CuZn SOD (SOD1) specifically in motorneurons was shown to extend the mean and maximum adult lifespans to 140% of normal, and to rescue the majority of deliterious phenotypes displayed by SOD1-null mutants. We have interpreted these results to mean either that the lifespan of the organism is normally limited by the functional lifespan of this post-mitotic cell type, or that ROS metabolism in motorneurons affects organismic lifespan via a systemic, perhaps neuroendocrine, signaling mechanism.We have now extended these studies to ask: (i) whether expression of catalase (CAT) or of the mitochondrially-localized Mn SOD (SOD2) in motorneurons, either singly or in combination with SOD1, have similar effects on lifespan; (ii) if expression of SOD2 can rescue SOD1-null mutant phenotypes; and (iii) if ROS metabolism in cell types other than motorneurons has significant impact on aging and lifespan determination.     

The effects of the epidermal and fibroblast growth factors on the replicative lifespan of cultured bovine granulosa cells.

The effects of fibroblast growth factor (FGF) and epidermal growth factor (EGF) on the lifespan of cultured bovine granulosa cell cultures have been investigated. Granulosa cell cultures from small follicles (4-7 mm) had a lifespan of 11-12 generations, whereas the lifespan of cultures originating from large follicles did not exceed seven generations. The addition of either EGF or FGF to the medium of cultures originating from small follicles greatly increased the lifetime of the cultures, which can then exceed 60 generations. A similar, although less pronounced, effect was observed with cultures originating from large follicles. The lifespan of granulosa cell cultures depends upon the presence of FGF or EGF in the medium, as the deletion of the mitogens resulted in rapid terminal differentiation and a shortened replicative lifespan. As either FGF or EGF can prolong the replicative lifespan of granulosa cell cultures, it is suggested that limited replicative lifespan when maintained in the absence of mitogens is not so much determined by a fixed rate of mutation as it is by the culture conditions in which the cells are maintained.     

Lifespan extension by dietary restriction in female Drosophila melanogaster is not caused by a reduction in vitellogenesis or ovarian activity

Dietary restriction (DR) extends lifespan in a wide range of organisms. DR also reduces daily and lifetime fecundity. The latter may be an evolutionary adaptation to survive periods of food shortage. Reproductive rate is often negatively correlated with lifespan, and a reduced cost of reproduction could be the mechanism by which DR extends lifespan. We tested this hypothesis in Drosophila melanogaster females, by directly suppressing different aspects of reproduction and measuring the effect on the response of lifespan and age-specific mortality to DR. DR resulted in lifespan extension in females kept with males, in females kept without males, in females with vitellogenesis blocked by the mutant ovoD1 and in females with no germline as a result of X-irradiation. Moreover, rapid (48 h) changes in age-specific mortality, previously seen in fertile females switched between full feeding and DR, were also seen in ovoD1 females. Furthermore, these rapid changes in age-specific mortality in cohorts of fertile wild type females were not accompanied by concurrent changes in egg-production. These results indicate either that reduced reproduction is not necessary for lifespan extension by DR in Drosophila females, or that the relevant aspects of reproduction act upstream of our interventions and were therefore not blocked in our experiments.     

Metabolic rate is not reduced by dietary-restriction or by lowered insulin/IGF-1 signalling and is not correlated with individual lifespan in Drosophila melanogaster

The link between resting metabolic rate and aging, measured as adult lifespan, was investigated in Drosophila melanogaster by (i) comparing lifespan and metabolic rate of individual flies, (ii) examining the effect of dietary-restriction on the metabolic rate of adult flies, and (iii) comparing the metabolic rate of wild-type and insulin/IGF-1 signalling mutant chico1 flies. The resting oxygen consumption of 65 individually housed and fully fed Drosophila was measured weekly throughout their lifetime. There was no significant difference in the mass-specific rate of oxygen consumption between cohorts that differed in lifespan. Nor was there any statistical correlation between mass-specific oxygen consumption and lifespan of individual Drosophila. The average mass-specific rate of oxygen consumption at 25 degrees C was 3.52+/-0.07 microl O2 mg(-1) h(-1). Variation in mass-specific metabolic rate explained only 4% of variation in individual life span in these flies. Contrary to predictions from the 'rate of living' theory of aging lifetime oxygen consumption was not constant and the lifespan of individual flies accounted for 91% of their lifetime oxygen consumption. An average Drosophila consumes about 3 ml O2 during its adult life. Dietary-restriction had no effect on mass-specific resting metabolic rate both when measured as oxygen consumption by respirometry and when measured as heat production by microcalorimetry. The mass-specific resting heat production of fully fed adult flies at 25 degrees C averaged 17.3+/-0.3 microW mg(-1). Similarly there was no difference in mass-specific metabolic rate of wild-type flies and longliving chico1 insulin/IGF-1 signalling mutant flies, either when measured as oxygen consumption or heat production. Thus, individual variation in lifespan in wild-type flies, and life extension by dietary-restriction and reduced insulin/IGF-1 signalling is not attributable to differences in metabolic rate.