ABSTRACT
Multiple studies characterizing the human ageing phenotype have been conducted for decades. However, there is no centralized resource in which data on multiple age-related changes are collated. Currently, researchers must consult several sources, including primary publications, in order to obtain age-related data at various levels. To address this and facilitate integrative, system-level studies of ageing we developed the Digital Ageing Atlas (DAA). The DAA is a one-stop collection of human age-related data covering different biological levels (molecular, cellular, physiological, psychological and pathological) that is freely available online (http://ageing-map.org/). Each of the >3000 age-related changes is associated with a specific tissue and has its own page displaying a variety of information, including at least one reference. Age-related changes can also be linked to each other in hierarchical trees to represent different types of relationships. In addition, we developed an intuitive and user-friendly interface that allows searching, browsing and retrieving information in an integrated and interactive fashion. Overall, the DAA offers a new approach to systemizing ageing resources, providing a manually-curated and readily accessible source of age-related changes.
Subject(s)
Aging , Databases, Factual , Aging/genetics , Aging/pathology , Aging/physiology , Aging/psychology , Humans , InternetABSTRACT
Muscle aging is closely related to unhealthy late-life and organismal aging. Recently, the state of differentiated cells was shown to be critical to tissue homeostasis. Thus, understanding how fully differentiated muscle cells age is required for ensuring healthy aging. Adult Drosophila muscle is a useful model for exploring the aging process of fully differentiated cells. In this study, we investigated age-related changes of γH2AX, an indicator of DNA strand breaks, in adult Drosophila muscle to document whether its changes are correlated with muscle degeneration and lifespan. The results demonstrate that γH2AX accumulation increases in adult Drosophila thoracic and leg muscles with age. Analyses of short-, normal-, and long-lived strains indicate that the age-related increase of γH2AX is closely associated with the extent of muscle degeneration, cleaved caspase-3 and poly-ubiquitin aggregates, and longevity. Further analysis of muscle-specific knockdown of heterochromatin protein 1a revealed that the excessive γH2AX accumulation in thoracic and leg muscles induces accelerated degeneration and decreases longevity. These data suggest a strong correlation between age-related muscle damage and lifespan in Drosophila. Our findings indicate that γH2AX may be a reliable biomarker for assessing muscle aging in Drosophila.
Subject(s)
Drosophila Proteins/metabolism , Drosophila melanogaster/metabolism , Histones/metabolism , Longevity , Muscles/metabolism , Age Factors , Animals , Biomarkers/metabolism , Caspase 3/metabolism , Chromobox Protein Homolog 5 , Chromosomal Proteins, Non-Histone/genetics , Chromosomal Proteins, Non-Histone/metabolism , DNA Breaks, Double-Stranded , Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Female , Genotype , Muscles/pathology , Phenotype , Phosphorylation , Polyubiquitin/metabolism , Protein AggregatesABSTRACT
Curcumin feeding of Drosophila larvae or young adults inhibits TOR and other known longevity genes and induces an extended health span in a normal-lived Ra strain adult. Combining larval curcumin feeding with an adult dietary restriction (DR) diet does not yield an additive effect. The age-specific mortality rate is decreased and is comparable with that of genetically selected long-lived La animals. Feeding Ra adults with the drug their whole life, or only during the senescent span, results in a weak negative effect on median longevity with no increase in maximum lifespan. The La strain shows no response to this DR mimetic. Thus, curcumin acts in a life stage-specific manner to extend the health span. Histone deacetylase inhibitors decrease the longevity of Ra animals if administered over the health span only or over the entire adult lifespan, but these inhibitors increase longevity when administered in the transition or senescent spans. Their major effect is a reduction in the mortality rate of older flies, raising the possibility of reducing frailty in older organisms. Their life stage-specific effects are complementary to that of curcumin. Use of stage-specific drugs may enable targeted increases in health or senescent spans, and thus selectively increase the quality of life.
ABSTRACT
Age-related changes in long-lived tissue-resident stem cells may be tightly linked to aging and age-related diseases such as cancer. Centrosomes play key roles in cell proliferation, differentiation and migration. Supernumerary centrosomes are known to be an early event in tumorigenesis and senescence. However, the age-related changes of centrosome duplication in tissue-resident stem cells in vivo remain unknown. Here, using anti-γ-tubulin and anti-PH3, we analyzed mitotic intestinal stem cells with supernumerary centrosomes in the adult Drosophila midgut, which may be a versatile model system for stem cell biology. The results showed increased centrosome amplification in intestinal stem cells of aged and oxidatively stressed Drosophila midguts. Increased centrosome amplification was detected by overexpression of PVR, EGFR, and AKT in intestinal stem cells/enteroblasts, known to mimic age-related changes including hyperproliferation of intestinal stem cells and hyperplasia in the midgut. Our data show the first direct evidence for the age-related increase of centrosome amplification in intestinal stem cells and suggest that the Drosophila midgut is an excellent model for studying molecular mechanisms underlying centrosome amplification in aging adult stem cells in vivo.
Subject(s)
Centrosome/ultrastructure , Drosophila/cytology , Stem Cells/ultrastructure , Animals , Cellular Senescence , Drosophila/metabolism , Drosophila Proteins/metabolism , ErbB Receptors/metabolism , Intestines/cytology , Mitosis , Oxidative Stress , Proto-Oncogene Proteins c-akt/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Invertebrate Peptide/metabolismABSTRACT
Endurance exercise has received increasing attention as a broadly preventative measure against age-related disease and dysfunction. Improvement of mitochondrial quality by enhancement of mitochondrial turnover is thought to be among the important molecular mechanisms underpinning the benefits of exercise. Interactions between the mitochondrial and nuclear genomes are important components of the genetic basis for variation in longevity, fitness and the incidence of disease. Here, we examine the effects of replacing the mitochondrial genome (mtDNA) of several Drosophila strains with mtDNA from other strains, or from closely related species, on exercise performance. We find that mitochondria from flies selected for longevity increase the performance of flies from a parental strain. We also find evidence that mitochondria from other strains or species alter exercise performance, with examples of both beneficial and deleterious effects. These findings suggest that both the mitochondrial and nuclear genomes, as well as interactions between the two, contribute significantly to exercise capacity.
Subject(s)
Epistasis, Genetic , Genome, Insect , Genome, Mitochondrial , Mitochondria/genetics , Physical Conditioning, Animal , Animals , Drosophila melanogaster , Species SpecificityABSTRACT
Much has been learned about the genetics of aging from studies in model organisms, but still little is known about naturally occurring alleles that contribute to variation in longevity. For example, analysis of mutants and transgenes has identified insulin signaling as a major regulator of longevity, yet whether standing variation in this pathway underlies microevolutionary changes in lifespan and correlated fitness traits remains largely unclear. Here, we have analyzed the genomes of a set of Drosophila melanogaster lines that have been maintained under direct selection for postponed reproduction and indirect selection for longevity, relative to unselected control lines, for over 35 years. We identified many candidate loci shaped by selection for longevity and late-life fertility, but - contrary to expectation - we did not find overrepresentation of canonical longevity genes. Instead, we found an enrichment of immunity genes, particularly in the Toll pathway, suggesting that evolutionary changes in immune function might underpin - in part - the evolution of late-life fertility and longevity. To test whether this genomic signature is causative, we performed functional experiments. In contrast to control flies, long-lived flies tended to downregulate the expression of antimicrobial peptides upon infection with age yet survived fungal, bacterial, and viral infections significantly better, consistent with alleviated immunosenescence. To examine whether genes of the Toll pathway directly affect longevity, we employed conditional knockdown using in vivo RNAi. In adults, RNAi against the Toll receptor extended lifespan, whereas silencing the pathway antagonist cactus--causing immune hyperactivation - dramatically shortened lifespan. Together, our results suggest that genetic changes in the age-dependent regulation of immune homeostasis might contribute to the evolution of longer life.
ABSTRACT
We tested the effects of dietary restriction (DR) on the standard w(1118) strain as well as on our previously described Ra and La strains and their reciprocal isogenic 'cybrid' lines containing heterologous nuclear-mitochondrial combinations. The w(1118) and Ra strains, but neither the La strains nor their 'cybrid' derivatives, are DR-inducible. The Ra and La animals are more robust than the w(1118) animals, and the Ra strain shows an upward shift in its DR threshold. The non-inducibility of the La strain suggests that it expresses a constituitive version of the inducible DR phenotype of its predecessor Ra strain. The difference in mitochondrial efficiency observed between the Ra and La mitochondria (Ross, 2000) has real effects on longevity in the adults: the presence of the more efficient La mitochondria enhances the longevity of an otherwise Ra animal; while the maximum longevity inherent in the La nuclear information cannot be fully expressed in the presence of the Ra mitochondria. Despite the absence of any demographic mathematical parameters robustly and uniquely associated with extended longevity, there are some common trends in that longer lived cohorts have a longer period of low and often constant early life mortality rates (comprising the "health span"), leading to a delayed onset of senescence as noted by the late life increase in age-specific mortality rates (comprising the "senescence span"). There is a genetic basis to this phenotype, but the context-dependence of the demographic data suggests that there is not likely to be only one mechanism or pathway involved in the DR response. In addition, the presence of live yeast had systemic strain specific effects such that it increased longevity in the w(1118) animals but decreased it in the Ra and derived lines. Higher density (4-10x) foods yielded a decreased longevity in all strains at the highest level, showing that malnutrition occurs at both low and high caloric levels.
Subject(s)
Animal Nutritional Physiological Phenomena , Caloric Restriction , Drosophila/metabolism , Energy Metabolism , Longevity , Mitochondria/metabolism , Animal Nutritional Physiological Phenomena/genetics , Animals , Drosophila/genetics , Energy Metabolism/genetics , Female , Genotype , Longevity/genetics , Male , Malnutrition/metabolism , Phenotype , Sex FactorsABSTRACT
The question has arisen in the literature as to whether dietary restriction (DR) will have a significant effect on human longevity. I initially use literature data to estimate the energy costs necessary to carry a human from conception to caloric self-sufficiency to be approximately 12.6 x 10(6)kcal, which amounts to approximately 25% of the the two parents' combined daily caloric intake for 20 years. Similar levels of financial costs are expended in developed societies. Thus, human reproductive costs are high enough to permit a DR response. I then review four different models relating diet and life span, three of which have been previously used to estimate the effects of DR on humans. A review of the pertinent literature suggests that these three models, while plausible, are not capable of making robust predictions that are consistent with human data not used in their development. Given this weakness, none of the predictions made by these theories should be relied on for policy development at this time. The fourth, or biocultural model, examined combines biologic and cultural factors. Human longevity is more complex than our model systems have led us to believe, and thus any solution will require the development of a new quantitative model. The outlines of a suggested quantitative biocultural model based on the prior model of Crews and the disposable soma model of Shanley and Kirkwood are presented and a prediction of the possible data outcomes is made. If the human cultural pro-longevity practices can be quantified in terms of their effect on energy allocation, then this model may serve in future as a realistic quantitative model capable of identifying pertinent pathways and making robust predictions.
Subject(s)
Caloric Restriction , Reproduction , Adolescent , Adult , Animals , Child , Child, Preschool , Costs and Cost Analysis , Energy Intake , Female , Humans , Infant , Longevity , Models, Economic , PregnancyABSTRACT
Three different longevity phenotypes exist in Drosophila and other model systems, but only two are known in humans. The "missing" phenotype is the delayed onset of senescence phenotype, which can be induced by various interventions, including pharmaceuticals. The lability of the onset of senescence indicates that the mechanisms involved are plastic and can be altered. Only interventions that involve the upregulation of stress resistance genes, probably via the JNK pathway and/or dFOXO3a transcription factor, seem capable of generating a delayed onset of senescence phenotype. The data suggest that the cellular mechanisms responsible for maintaining the cell in a healthy state are under constant attack by ROS and/or abnormal protein accumulation. A stochastic growth factor/signal transduction failure may be the proximal event responsible for the decreased efficiency of the cell's defenses, resulting in the onset of senescence, degradation of the gene interaction network, and continuing loss of function.
Subject(s)
Aging/physiology , Health , Longevity , Animals , Drosophila Proteins/metabolism , Forkhead Transcription Factors/metabolism , Humans , Life Expectancy , Phenotype , Survival RateABSTRACT
Evolutionary theory postulates that there should be a robust relationship between fecundity and longevity. Prior work has generally supported this concept, but has not shed much light on the mechanisms at play. In preceding work, we have developed and verified a mathematical model of Drosophila melanogaster female fecundity based on the analysis of empirical studies independently done by several different laboratories. Then we applied this technique to Mediterranean fruit fly (medfly) populations. In this article we analyze associations between individual longevity and the parameters of individual fecundity pattern in Drosophila and medfly. We cluster both Drosophila and medfly individuals by life span and discuss the differences. It allows us to demonstrate that only one fecundity-related parameter is associated with longevity in Drosophila, whereas two such parameters can be found in medflies. This difference demonstrates different ways of aging in various Diptera species. Finally, we discuss the possible implications of this finding.
Subject(s)
Aging , Ceratitis capitata/physiology , Drosophila melanogaster/physiology , Animals , Female , Fertility , Longevity , Mathematics , Models, Biological , Species SpecificityABSTRACT
Endurance exercise has emerged as a powerful intervention that promotes healthy aging by maintaining the functional capacity of critical organ systems. In addition, long-term exercise reduces the incidence of age-related diseases in humans and in model organisms. Despite these evident benefits, the genetic pathways required for exercise interventions to achieve these effects are still relatively poorly understood. Here, we compare gene expression changes during endurance training in Drosophila melanogaster to gene expression changes during selective breeding for longevity. Microarrays indicate that 65% of gene expression changes found in flies selectively bred for longevity are also found in flies subjected to three weeks of exercise training. We find that both selective breeding and endurance training increase endurance, cardiac performance, running speed, flying height, and levels of autophagy in adipose tissue. Both interventions generally upregulate stress defense, folate metabolism, and lipase activity, while downregulating carbohydrate metabolism and odorant receptor expression. Several members of the methuselah-like (mthl) gene family are downregulated by both interventions. Knockdown of mthl-3 was sufficient to provide extension of negative geotaxis behavior, endurance and cardiac stress resistance. These results provide support for endurance exercise as a broadly acting anti-aging intervention and confirm that exercise training acts in part by targeting longevity assurance pathways.
Subject(s)
Drosophila melanogaster/physiology , Longevity/genetics , Physical Conditioning, Animal , Selective Breeding , Animals , Female , Flight, Animal/physiology , Gene Expression Profiling , Genes, Insect , Heart/physiology , MaleABSTRACT
We delineated the mechanism regulating the inhibition of centrosome amplification by metformin in Drosophila intestinal stem cells (ISCs). Age-related changes in tissue-resident stem cells may be closely associated with tissue aging and age-related diseases, such as cancer. Centrosome amplification is a hallmark of cancers. Our recent work showed that Drosophila ISCs are an excellent model for stem cell studies evaluating age-related increase in centrosome amplification. Here, we showed that metformin, a recognized anti-cancer drug, inhibits age- and oxidative stress-induced centrosome amplification in ISCs. Furthermore, we revealed that this effect is mediated via down-regulation of AKT/target of rapamycin (TOR) activity, suggesting that metformin prevents centrosome amplification by inhibiting the TOR signaling pathway. Additionally, AKT/TOR signaling hyperactivation and metformin treatment indicated a strong correlation between DNA damage accumulation and centrosome amplification in ISCs, suggesting that DNA damage might mediate centrosome amplification. Our study reveals the beneficial and protective effects of metformin on centrosome amplification via AKT/TOR signaling modulation. We identified a new target for the inhibition of age- and oxidative stress-induced centrosome amplification. We propose that the Drosophila ISCs may be an excellent model system for in vivo studies evaluating the effects of anti-cancer drugs on tissue-resident stem cell aging.
Subject(s)
Cellular Senescence , Centrosome/metabolism , Drosophila/metabolism , Metformin/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolism , Animals , Antineoplastic Agents/chemistry , Centrosome/ultrastructure , DNA Damage , Down-Regulation , Female , Green Fluorescent Proteins/metabolism , Hypoglycemic Agents/therapeutic use , Intestines/drug effects , Male , Oxidative Stress , Paraquat/chemistry , Signal TransductionABSTRACT
The antagonistic pleiotropy theory of the evolution of aging is shown to be too simple to fully apply to the situation in which Drosophila are selected directly for delayed female fecundity and indirectly for extended longevity. We re-evaluated our own previously reported selection experiments using previously unreported data, as well as new data from the literature. The facts that led to this re-evaluation were: (1) the recognition that there are at least three different extended longevity phenotypes; (2) the existence of metabolic and mitochondrial differences between normal- and long-lived organisms; and most importantly; (3) the observation that animals selected for extended longevity are both more fecund and longer-lived than their progenitor control animals. This latter observation appears to contradict the theory. A revised interpretation of the events underlying the selection process indicates that there is a two-step change in energy allocations leading to a complex phenotype. Initial selection first allows the up-regulation of the antioxidant defense system genes and a shift to the use of the pentose shunt. This is later followed by alterations in mitochondrial fatty acid composition and other changes necessary to reduce the leakage of H(2)O(2) from the mitochondria into the cytosol. The recaptured energy available from the latter step is diverted from somatic maintenance back into reproduction, resulting in animals that are both long-lived and fecund. Literature review suggests the involvement of mitochondrial and antioxidant changes are likely universal in the Type 1 extended longevity phenotype.
Subject(s)
Aging/genetics , Energy Metabolism/genetics , Longevity/genetics , Animals , Drosophila , Genome , PhenotypeABSTRACT
Evolutionary theories suggest that the expression of extended longevity depends on the organism's ability to shift energy from reproduction to somatic maintenance. New data led us to reexamine our older data and integrate the two into a larger picture of the genetic and metabolic alterations required if the animal is to live long. Our Ra normal-lived control strain can express any one of three different extended longevity phenotypes, only one of which involves significant and proportional increases in both mean and maximum longevity and thus a delayed onset of senescence. This phenotype is dependent on the up-regulation of the antioxidant defense system (ADS) genes and enzymes. Animals that express this phenotype typically have a pattern of altered specific activities in metabolically important enzymes, suggesting they are necessary to support the NAD+/NADP+ reducing system required for the continued high ADS enzyme activities. Fecundity data suggests that the energy required for this higher level of somatic maintenance initially came from a reduced egg production. This was only transient, however, for the females significantly increased their fecundity in later generations while still maintaining their longevity. The energy required for this enhanced fecundity was probably obtained from an increased metabolic efficiency, for the mitochondria of the La long-lived strain are metabolically more efficient and have a lower leakage of reactive oxygen species (ROS) to the cytosol. Selection pressures that do not lead to these shifts in energy allocations result in extended longevity phenotypes characterized by increased early survival or increased late survival but not by a delayed onset of senescence.
Subject(s)
Drosophila melanogaster/genetics , Energy Metabolism , Gene Expression Regulation , Longevity/genetics , Animals , Drosophila melanogaster/physiology , Female , Fertility , Genes, Insect , Mitochondria/metabolism , Models, Biological , PhenotypeABSTRACT
There is an ongoing debate as to whether or not human longevity is approaching its limits. The debate and its outcome are important since they might affect public policy. We review the evidence presented by both schools. We add our empirical observation that there exist multiple longevity phenotypes, each of which arises from the alteration of fundamental aging processes. The current debate only considers two of the three known mammalian longevity phenotypes. The overlooked phenotype is the delayed onset of senescence phenotype, which can be induced by various interventions, including pharmaceuticals. The existence of multiple phenotypes means that an overview of potential life expectancy outcomes for a species should be based on the analysis of all longevity phenotypes likely to occur in that species.
Subject(s)
Longevity/genetics , Animals , Humans , Models, Theoretical , PhenotypeABSTRACT
We review the empirical data obtained with our normal-lived Ra control strain of Drosophila and show that this one genome is capable of invoking at least three different responses to external stimuli that induce the animal to express one of three different extended longevity phenotypes, each of which arises from one of three different antagonistic molecular mechanisms of stress resistance. The phenotypes are distinguished by different age-specific mortality patterns. Depending on the selected mechanism, the genome may respond by expressing a delayed onset of senescence (type 1), an increased early survival (type 2), or an increased late survival (type 3) phenotype, suggesting their different demographic effects. We suggest that the different demographic effects stem in part from the differential ability of each selection regime to reallocate the organism's energy from reproduction to somatic maintenance. These data document the complexity of the aging process and argue for a relationship between molecular mechanisms and longevity phenotypes.
Subject(s)
Drosophila/genetics , Longevity/genetics , Phenotype , Aging/genetics , Animals , Antioxidants/metabolism , Drug Resistance/genetics , Fertility/genetics , Hot Temperature , Paraquat/toxicityABSTRACT
Coordinate control of gene activity is critical for fitness and longevity of an organism. The SIN3 histone deacetylase (HDAC) complex functions as a transcriptional repressor of many genes. SIN3-regulated genes include those that encode proteins affecting multiple aspects of mitochondrial function, such as energy production and stress responsiveness, important for health maintenance. Here we used Drosophila melanogaster as a model organism to examine the role of SIN3 in the regulation of fitness and longevity. Adult flies with RNA interference (RNAi) induced knockdown expression of Sin3A have reduced climbing ability; an activity that likely requires fully functional mitochondria. Additionally, compared to wild type, adult Sin3A knockdown flies were more sensitive to oxidative stress. Interestingly, media supplementation with the antioxidant glutathione largely restored fly tolerance to oxidative stress. Although Sin3A knockdown flies exhibited decreased longevity compared to wild type, no significant changes in expression of many well-categorized aging genes were observed. We found, however, that Sin3A knockdown corresponded to a significant reduction in expression of genes encoding proteins involved in the de novo synthesis of glutathione. Taken together, the data support a model whereby SIN3 regulates a gene expression program required for proper mitochondrial function and effective stress response during adulthood.
Subject(s)
Drosophila Proteins/metabolism , Longevity/physiology , Oxidative Stress/physiology , Sin3 Histone Deacetylase and Corepressor Complex/metabolism , Stress, Physiological/physiology , Animals , Behavior, Animal/physiology , Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Motor Activity/physiology , RNA Interference , Sin3 Histone Deacetylase and Corepressor Complex/geneticsABSTRACT
We tested the effects of a Class I histone deacetylase inhibitor (HDAcI), sodium butyrate (NaBu), on the longevity of normal- and long-lived strains of Drosophila melanogaster. This HDAcI has mixed effects in the normal-lived Ra strain as it decreases mortality rates and increases longevity when administered in the transition or senescent spans, but decreases longevity when administered over the health span only or over the entire adult lifespan. Mostly deleterious effects are noted when administered by either method to the long-lived La strain. Thus "mid- to late-life" drugs may have different stage-specific effects on different genomes of a model organism. A different HDAcI (suberoylanilide hydroxamic acid, SAHA) administered to the normal-lived strain showed similar late-life extending effects, suggesting that this is not an isolated effect of one drug. These data also show that the use of an HDAcI can significantly alter the mortality rate of the senescent span by decreasing its vulnerability, or short-term risk of death, in a manner similar to that of dietary restriction. These studies may help to shed light on the frailty syndrome affecting some aging organisms.
Subject(s)
Butyrates/pharmacology , Drosophila Proteins/antagonists & inhibitors , Drosophila melanogaster/drug effects , Histone Deacetylase 1/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Longevity/drug effects , Age Factors , Animals , Butyrates/toxicity , Caloric Restriction , Dose-Response Relationship, Drug , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/embryology , Drosophila melanogaster/enzymology , Drosophila melanogaster/genetics , Gene Expression Regulation, Developmental/drug effects , Genotype , Histone Deacetylase 1/genetics , Histone Deacetylase 1/metabolism , Histone Deacetylase Inhibitors/toxicity , Hydroxamic Acids/toxicity , Kinetics , Larva/drug effects , Larva/enzymology , Longevity/genetics , Phenotype , VorinostatABSTRACT
Larval feeding with curcumin induces an extended health span with significantly increased median and maximum longevities in the adult fly. This phenotype is diet insensitive and shows no additive effect on longevity when combined with an adult dietary restriction (DR) diet, suggesting that curcumin and DR operate via the same or overlapping pathways for this trait. This treatment significantly slows the aging rate so that it is comparable with that of genetically selected long lived animals. The larval treatment also enhances the adult animal's geotactic activity in an additive manner with DR, suggesting that curcumin and DR may use different pathways for different traits. Feeding the drug to adults during only the health span also results in a significantly extended health span with increased median and maximum life span. This extended longevity phenotype is induced only during these stage-specific periods. Feeding adults with the drug over their whole life results in a weakly negative effect on median longevity with no increase in maximum life span. There are no negative effects on reproduction, although larval curcumin feeding increases development time, and also apparently accelerates the normal late-life neuromuscular degeneration seen in the legs. Gene expression data from curcumin-fed larvae shows that the TOR pathway is inhibited in the larvae and the young to midlife adults, although several other genes involved in longevity extension are also affected. These data support the hypothesis that curcumin acts as if it is a DR mimetic nutraceutical. These data also suggest that the search for DR mimetics may be enhanced by the use of stage-specific screening of candidate molecules.