Increasing neuronal glucose uptake attenuates brain aging and promotes life span under dietary restriction in Drosophila.
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ABSTRACT:
SUBMITTER: Oka M
PROVIDER: S-EPMC7806808 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Dietary restriction (DR) extends lifespan in diverse organisms and, in animal and cellular models, can delay a range of aging-related diseases including Alzheimer's disease (AD). A better understanding of the mechanisms mediating these interactions, however, may reveal novel pathways involved in AD pathogenesis, and potential targets for disease-modifying treatments and biomarkers for disease progression. Drosophila models of AD have recently been developed and, due to their short lifespan and susceptibility to genetic manipulation, we have used the fly to investigate the molecular connections among diet, aging and AD pathology. DR extended lifespan in both Arctic mutant A?42 and WT 4R tau over-expressing flies, but the underlying molecular pathology was not altered and neuronal dysfunction was not prevented by dietary manipulation. Our data suggest that DR may alter aging through generalised mechanisms independent of the specific pathways underlying AD pathogenesis in the fly, and hence that lifespan-extending manipulations may have varying effects on aging and functional declines in aging-related diseases. Alternatively, our analysis of the specific effects of DR on neuronal toxicity downstream of A? and tau pathologies with negative results may simply confirm that the neuro-protective effects of DR are upstream of the initiating events involved in the pathogenesis of AD.
| S-EPMC3176895 | biostudies-literature
Project description:Lifespan can be extended by reduction of dietary intake. This practice is referred to as dietary restriction (DR), and extension of lifespan by DR is evolutionarily conserved in taxonomically diverse organisms including yeast, invertebrates, and mammals. Although these two often-stated facts carry the implication that the mechanisms of DR are also evolutionarily conserved, extension of lifespan could be a case of evolutionary convergence, with different underlying mechanisms in different taxa. Furthermore, extension of lifespan by different methods of DR in the same organism may operate through different mechanisms. These topics remain unresolved because of the very fact that the mechanisms of DR are unknown. Given these uncertainties, it is essential that work on the mechanisms of DR is not clouded by imprecise descriptions of methods or by technical problems. Here we review the recent literature on DR in Drosophila to point out some methodological issues that can obscure mechanistic interpretations. We also indicate some experiments that could be performed to determine if DR in Drosophila operates through similar mechanisms to the process in rodents.
| S-EPMC1857724 | biostudies-literature
Project description:Dietary restriction is a powerful aging intervention that extends the life span of diverse biological species ranging from yeast to invertebrates to mammals, and it has been argued that the antiaging action of dietary restriction occurs through reduced oxidative stress/damage. Using Sod1(-/-) mice, which have previously been shown to have increased levels of oxidative stress associated with a shorter life span and a high incidence of neoplasia, we were able to test directly the ability of dietary restriction to reverse an aging phenotype due to increased oxidative stress/damage. We found that dietary restriction increased the life span of Sod1(-/-) mice 30%, returning it to that of wild-type, control mice fed ad libitum. Oxidative damage in Sod1(-/-) mice was markedly reduced by dietary restriction, as indicated by a reduction in liver and brain F2-isoprostanes, a marker of lipid peroxidation. Analysis of end of life pathology showed that dietary restriction significantly reduced the overall incidence of pathological lesions in the Sod1(-/-) mice fed the dietary-restricted diet compared to Sod1(-/-) mice fed ad libitum, including the incidence of lymphoma (27 vs 5%) and overall liver pathology. In addition to reduced incidence of overall and liver-specific pathology, the burden and severity of both neoplastic and nonneoplastic lesions was also significantly reduced in the Sod1(-/-) mice fed the dietary-restricted diet. These data demonstrate that dietary restriction can significantly attenuate the accelerated aging phenotype observed in Sod1(-/-) mice that arises from increased oxidative stress/damage.
| S-EPMC3696984 | biostudies-literature
Project description:Dietary restriction (DR) extends life span in diverse organisms, including mammals, and common mechanisms may be at work. DR is often known as calorie restriction, because it has been suggested that reduction of calories, rather than of particular nutrients in the diet, mediates extension of life span in rodents. We here demonstrate that extension of life span by DR in Drosophila is not attributable to the reduction in calorie intake. Reduction of either dietary yeast or sugar can reduce mortality and extend life span, but by an amount that is unrelated to the calorie content of the food, and with yeast having a much greater effect per calorie than does sugar. Calorie intake is therefore not the key factor in the reduction of mortality rate by DR in this species.
| S-EPMC1140680 | biostudies-literature
Project description:ABSTRACT MAGWIRE, MICHAEL MAHLON. Mutations Increasing Drosophila melanogaster Life Span. (Under the direction of Trudy F. C. Mackay.) Better living conditions and advances in medicine have made it possible for humans to live considerably longer than before. This has uncovered many health problems associated with age. By identifying genes involved in the limitation of life span, we may better understand the processes that lead to aging. In model organisms, we can use mutagenesis to discover mutations that increase life span, and hence infer that the wild-type allele limits life span by some means. We have assessed longevity in a collection of 1332 co-isogenic gene-trap P-element insertion lines and determined changes in life span of each insert line relative to the corresponding control line. Significant lines were determined via two different methods of analysis: A 95% confidence interval was established based on deviations of the mutant life spans from the controls and Dunnett’s two tailed t-tests were used to examine differences between mutant and control in each individual block. Based on the 95% confidence interval, 139 inserts displayed an increase in life span and 194 inserts a decrease. Using Dunnett’s, 70 lines increased in life span, while 270 decreased in life span. An additional 48 increased longevity lines were close enough to meeting Dunnett’s criteria to be considered for additional investigation. Combining these two analyses, we chose 83 inserts associated with increased life span for a secondary screen using an additional twelve replicates. 58 of these lines remained significant. We have determined the P-element insertion site for 50 of these lines. Starvation resistance, chill coma recovery time and climbing activity were measured on the lines remaining significant after the the secondary screen to identify pleiotropic effects. A positive correlation was found for males between life span and starvation resistance as well as between life span and chill coma recovery. Females only displayed a correlation between life span and chill coma recovery, which was negative. None of the lines indicated increased fitness for all phenotypes, indicating there may be some type of trade-off. There also appears to be a lot of pleiotropic variation depending on background and sex. Ten of the lines, all with the same parental background, were chosen for a half-diallel cross to identify epistasis between the mutants. There were substantial epistatic interactions between all ten lines. Furthermore, males and females displayed vastly different patterns of epistasis, again indicating major differences in life span regulation between the sexes. Finally, a subset of seven of the lines used in the epistatic study, in addition to the corresponding parental control, were chosen for microarray analysis to look for possible pathways and novel genes involved in increasing life span. 1,996 probe sets were significant at a false discovery rate q-value threshold of q < 0.0001. Tukeys tests were carried out for these probe sets to determine how each of the seven mutant backgrounds differed compared to the control and each other. In addition, each mutant background was compared individually with the control to identify any changes in expression. Gene ontologies were determined for each of the lines to identify over-represented biological functions which would indicate possible longevity pathways. Dozens of pathways were suggested, including several novel pathways. Keywords: Genetic (P-element insertion) modification and comparison to control line
2008-08-01 | GSE8775 | GEO
Project description:Dietary restriction (DR) extends lifespan in many species which is a well-known phenomenon. Long non-coding RNAs (lncRNAs) play an important role in regulation of cell senescence and important age-related signaling pathways. Here, we profiled the lncRNA and mRNA transcriptome of fruit flies at 7 day and 42 day during DR and fully-fed conditions, respectively. In general, 102 differentially expressed lncRNAs and 1406 differentially expressed coding genes were identified. Most informatively we found a large number of differentially expressed lncRNAs and their targets enriched in GO and KEGG analysis. We discovered some new aging related signaling pathways during DR, such as hippo signaling pathway-fly, phototransduction-fly and protein processing in endoplasmic reticulum etc. Novel lncRNAs XLOC_092363 and XLOC_166557 are found to be located in 10 kb upstream sequences of hairy and ems promoters, respectively. Furthermore, tissue specificity of some novel lncRNAs had been analyzed at 7 day of DR in fly head, gut and fat body. Also the silencing of lncRNA XLOC_076307 resulted in altered expression level of its targets including Gadd45 (involved in FoxO signaling pathway). Together, the results implicated many lncRNAs closely associated with dietary restriction, which could provide a resource for lncRNA in aging and age-related disease field.
| S-EPMC5076457 | biostudies-literature
Project description:A multiple comparison approach using whole genome transcriptional arrays was used to identify genes and pathways involved in calorie restriction/dietary restriction (DR) life span extension in Drosophila. Starting with a gene centric analysis comparing the changes in common between DR and two DR related molecular genetic life span extending manipulations, Sir2 and p53, lead to a molecular confirmation of Sir2 and p53's similarity with DR and the identification of a small set of commonly regulated genes. One of the identified upregulated genes, takeout, known to be involved in feeding and starvation behavior, and to have sequence homology with Juvenile Hormone (JH) binding protein, was shown to directly extend life span when specifically overexpressed. Here we show that a pathway centric approach can be used to identify shared physiological pathways between DR and Sir2, p53 and resveratrol life span extending interventions. The set of physiological pathways in common among these life span extending interventions provides an initial step toward defining molecular genetic and physiological changes important in life span extension. The large overlap in shared pathways between DR, Sir2, p53 and resveratrol provide strong molecular evidence supporting the genetic studies linking these specific life span extending interventions.
| S-EPMC3100872 | biostudies-other
Project description:Mutations Increasing Drosophila melanogaster; Life Span. (Under the direction of Trudy F. C. Mackay.); Better living conditions and advances in medicine have made it possible for; humans to live considerably longer than before. This has uncovered many; health problems associated with age. By identifying genes involved in the; limitation of life span, we may better understand the processes that lead to aging. In model organisms, we can use mutagenesis to discover mutations that; increase life span, and hence infer that the wild-type allele limits life span by some means. We have assessed longevity in a collection of 1332 co-isogenic gene-trap; P-element insertion lines and determined changes in life span of each insert line relative to the corresponding control line. Significant lines were determined via two different methods of analysis: A 95% confidence interval was established based on deviations of the mutant life spans from the controls and Dunnettâs two tailed t-tests were used to examine differences between mutant and control in each individual block. Based on the 95% confidence interval, 139 inserts displayed an increase in life span and 194 inserts a decrease. Using Dunnettâs, 70 lines increased in life span, while 270 decreased in life span. An additional 48 increased longevity lines were close enough to meeting Dunnettâs criteria to be considered for additional investigation. Combining these two analyses, we chose 83 inserts associated with increased life span for a secondary screen using an; additional twelve replicates. 58 of these lines remained significant. We have; determined the P-element insertion site for 50 of these lines. Starvation resistance, chill coma recovery time and climbing activity were; measured on the lines remaining significant after the the secondary screen to identify pleiotropic effects. A positive correlation was found for males between life span and starvation resistance as well as between life span and chill coma recovery. Females only displayed a correlation between life span and chill coma recovery, which was negative. None of the lines indicated increased fitness for all phenotypes, indicating there may be some type of trade-off. There also appears to be a lot of pleiotropic variation depending on background and sex. Ten of the lines, all with the same parental background, were chosen for a; half-diallel cross to identify epistasis between the mutants. There were; substantial epistatic interactions between all ten lines. Furthermore, males and females displayed vastly different patterns of epistasis, again indicating major differences in life span regulation between the sexes. Finally, a subset of seven of the lines used in the epistatic study, in; addition to the corresponding parental control, were chosen for microarray; analysis to look for possible pathways and novel genes involved in increasing life span. 1,996 probe sets were significant at a false discovery rate q-value; threshold of q < 0.0001. Tukeys tests were carried out for these probe sets to determine how each of the seven mutant backgrounds differed compared to the control and each other. In addition, each mutant background was compared individually with the control to identify any changes in expression. Gene ontologies were determined for each of the lines to identify over-represented biological functions which would indicate possible longevity pathways. Dozens of pathways were suggested, including several novel pathways. Experiment Overall Design: We used seven mutant lines homozygous for a P-element insertion and a control line. All lines were isogenic other than the P-element insert. Males and females were done separately with two replicates for a total of 32 arrays.
2008-10-18 | E-GEOD-8775 | biostudies-arrayexpress
Project description:Understanding the genetic and environmental factors that affect variation in life span and senescence is of major interest for human health and evolutionary biology. Multiple mechanisms affect longevity, many of which are conserved across species, but the genetic networks underlying each mechanism and cross-talk between networks are unknown. We report the results of a screen for mutations affecting Drosophila life span. One third of the 1,332 homozygous P-element insertion lines assessed had quantitative effects on life span; mutations reducing life span were twice as common as mutations increasing life span. We confirmed 58 mutations with increased longevity, only one of which is in a gene previously associated with life span. The effects of the mutations increasing life span were highly sex-specific, with a trend towards opposite effects in males and females. Mutations in the same gene were associated with both increased and decreased life span, depending on the location and orientation of the P-element insertion, and genetic background. We observed substantial--and sex-specific--epistasis among a sample of ten mutations with increased life span. All mutations increasing life span had at least one deleterious pleiotropic effect on stress resistance or general health, with different patterns of pleiotropy for males and females. Whole-genome transcript profiles of seven of the mutant lines and the wild type revealed 4,488 differentially expressed transcripts, 553 of which were common to four or more of the mutant lines, which include genes previously associated with life span and novel genes implicated by this study. Therefore longevity has a large mutational target size; genes affecting life span have variable allelic effects; alleles affecting life span exhibit antagonistic pleiotropy and form epistatic networks; and sex-specific mutational effects are ubiquitous. Comparison of transcript profiles of long-lived mutations and the control line reveals a transcriptional signature of increased life span.
| S-EPMC2912381 | biostudies-literature
Project description:The life span of model organisms can be modulated by environmental conditions that influence cellular metabolism, oxidation, or DNA integrity. The yeast nicotinamidase gene pnc1 was identified as a key transcriptional target and mediator of calorie restriction and stress-induced life span extension. PNC1 is thought to exert its effect on yeast life span by modulating cellular nicotinamide and NAD levels, resulting in increased activity of Sir2 family class III histone deacetylases. In Caenorhabditis elegans, knockdown of a pnc1 homolog was shown recently to shorten the worm life span, whereas its overexpression increased survival under conditions of oxidative stress. The function and regulation of nicotinamidases in higher organisms has not been determined. Here, we report the identification and biochemical characterization of the Drosophila nicotinamidase, D-NAAM, and demonstrate that its overexpression significantly increases median and maximal fly life span. The life span extension was reversed in Sir2 mutant flies, suggesting Sir2 dependence. Testing for physiological effectors of D-NAAM in Drosophila S2 cells, we identified oxidative stress as a primary regulator, both at the transcription level and protein activity. In contrast to the yeast model, stress factors such as high osmolarity and heat shock, calorie restriction, or inhibitors of TOR and phosphatidylinositol 3-kinase pathways do not appear to regulate D-NAAM in S2 cells. Interestingly, the expression of D-NAAM in human neuronal cells conferred protection from oxidative stress-induced cell death in a sirtuin-dependent manner. Together, our findings establish a life span extending the ability of nicotinamidase in flies and offer a role for nicotinamide-modulating genes in oxidative stress regulated pathways influencing longevity and neuronal cell survival.
| S-EPMC2562057 | biostudies-literature