Dietary switch reveals fast coordinated gene expression changes in Drosophila melanogaster.
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ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE47631 | GEO | 2014/06/01
SECONDARY ACCESSION(S): PRJNA206856
REPOSITORIES: GEO
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Project description:Dietary restriction (DR) is one of the most studied interventions known to extend life span. The robustness of its effect across species suggests the existence of conserved mechanisms to reduce mortality rates and increase longevity. However, because DR elicits a large number of physiological changes, many of which are unrelated to the longevity response, it has been difficult to identify these specific mechanisms. Whole-genome gene expression studies have typically reported several hundreds to thousands of differentially expressed genes in response to DR. The fruit fly Drosophila melanogaster shows a remarkable response to a change in diet: after a switch to DR, food mortality rates drop within 2-4 days to the same level as cohorts continuously on DR. Based on this observation, we utilized a novel experimental design to enrich for genes directly associated with the longevity response. By profiling gene expression in a cohort of fruit flies that were switched from normal food to DR we were able to partition genes in several classes with distinct patterns of expression. Canton-S flies were kept at 25˚C in a temperature-controlled incubator at 50% humidity with a 12 hour on/off light cycle. The flies were sorted into vials at a density of 25 males and 25 females per vial, randomly divided into treatment groups and passed every day on either Control Food (CF, 150 g/L sucrose, 150 g/L autolysed yeast, and 20 g/L agar, all w/v) or Restricted Food (RF, 50 g/L sucrose, 50 g/L autolysed yeast, and 20 g/L agar, all w/v) and the number of dead flies recorded. On day 40, half of the flies on Control Food were switched to the Restricted Food. During the course of the experiment, age-specific instantaneous mortality rate was analyzed and the separation of mortality rate between the food conditions was verified before the switch. Flies were sorted under light CO2 and collected at fixed time intervals during (0 = time of switch), and after (2, 4, 6, 8, 12, 18, 24, 32, 40, 48, 56, 72 hours after) the switch time point via snap freezing in liquid nitrogen and were stored at −80°C. Heads and thorax of female flies were collected for microarray experiments.
2014-06-01 | E-GEOD-47631 | biostudies-arrayexpress
Project description:Dietary restriction (DR) extends lifespan in a wide variety of species, yet the underlying mechanisms are not well understood. Here we show that the Caenorhabditis elegans HNF4α-related nuclear hormone receptor NHR-62 is required for metabolic and physiologic responses associated with DR-induced longevity. nhr-62 mediates the longevity of eat-2 mutants, a genetic mimetic of dietary restriction, and blunts the longevity response of DR induced by bacterial food dilution at low nutrient levels. Metabolic changes associated with DR, including decreased Oil Red O staining, decreased triglyceride levels, and increased autophagy are partly reversed by mutation of nhr-62. Additionally, the DR fatty acid profile is altered in nhr-62mutants. Expression profiles reveal that several hundred genes induced by DR depend on the activity of NHR-62, including a putative lipase required for the DR response. This study provides critical evidence of nuclear hormone receptor regulation of the DR longevity response, suggesting hormonal and metabolic control of life span.
2014-03-19 | GSE55988 | GEO
Project description:Dietary restriction (DR) extends lifespan in a wide variety of species, yet the underlying mechanisms are not well understood. Here we show that the Caenorhabditis elegans HNF4α-related nuclear hormone receptor NHR-62 is required for metabolic and physiologic responses associated with DR-induced longevity. nhr-62 mediates the longevity of eat-2 mutants, a genetic mimetic of dietary restriction, and blunts the longevity response of DR induced by bacterial food dilution at low nutrient levels. Metabolic changes associated with DR, including decreased Oil Red O staining, decreased triglyceride levels, and increased autophagy are partly reversed by mutation of nhr-62. Additionally, the DR fatty acid profile is altered in nhr-62mutants. Expression profiles reveal that several hundred genes induced by DR depend on the activity of NHR-62, including a putative lipase required for the DR response. This study provides critical evidence of nuclear hormone receptor regulation of the DR longevity response, suggesting hormonal and metabolic control of life span. Young adult worms before bearing eggs inside were collected. N2 serves as the control of wild type. 3 biological replicates included in this experiment.
2014-03-19 | E-GEOD-55988 | biostudies-arrayexpress
Project description:Key molecules that modulate the effect of dietary restriction (DR), a well-known laboratory intervention for longevity in organisms, remain elusive in mammals. We evaluated neuropeptide Y (Npy), which is involved in the physiological adaptation to energy deficits, for its role in the effects of DR. At 12 weeks of age, Npy-/- and WT mice were divided into the AL (ad libitum) and DR groups. The DR groups received a food allotment consisting of 70% of the mean daily food intake of the AL groups. Two replicates per genotype per feeding group.
2013-02-28 | E-GEOD-42761 | biostudies-arrayexpress
Project description:Dietary restriction (DR), the process of decreasing overall food consumption over an extended period of time, has been shown to increase longevity across evolutionarily diverse species and delay the onset of age-associated diseases in humans. In Caenorhabditis elegans, the Myc-family transcription factors (TFs) MXL-2 (Mlx) and MML-1 (MondoA/ChREBP), which function as obligate heterodimers, and the forkhead box transcription factor A ortholog (PHA-4) are both necessary for the full physiological benefits of DR. However, the adaptive transcriptional response to DR and the role of MML-1::MXL-2 and PHA-4 remains elusive. We identified the transcriptional signature of C. elegans DR, using the eat-2 genetic model, and demonstrate broad changes in metabolic gene expression in eat-2 DR animals, which requires both mxl-2 and pha-4. While the requirement for these factors in DR gene expression overlaps, we found many of the DR genes exhibit an opposing change in relative gene expression in eat-2;mxl-2 animals compared to wild-type, which was not observed in eat-2 animals with pha-4 loss. We further show functional deficiencies of the mxl-2 loss in DR outside of lifespan, as eat-2;mxl-2 animals exhibit substantially smaller brood sizes and lay a proportion of dead eggs, indicating that MML-1::MXL-2 has a role in maintaining the balance between resource allocation to the soma and to reproduction under conditions of chronic food scarcity. While eat-2 animals do not show a significantly different metabolic rate compared to wild-type, we also find that loss of mxl-2 in DR does not affect the rate of oxygen consumption in young animals. The gene expression signature of eat-2 mutant animals is consistent with optimization of energy utilization and resource allocation, rather than induction of canonical gene expression changes associated with acute metabolic stress -such as induction of autophagy after TORC1 inhibition. Consistently, eat-2 animals are not substantially resistant to stress, providing further support to the idea that chronic DR may benefit healthspan and lifespan through efficient use of limited resources rather than broad upregulation of stress responses, and also indicates that MML-1::MXL-2 and PHA-4 may have different roles in promotion of benefits in response to different pro-longevity stimuli.
2023-12-13 | GSE240821 | GEO
Project description:Dietary restriction (DR) during adulthood can greatly extend lifespan and improve metabolic health in diverse species. However, whether DR in mammals is still effective when applied for the first time at ¬old age remains elusive. Here, we conducted a late-life DR switch experiment employing 800 mice, by switching old animals from ad libitum (AL) to DR and vice versa. Strikingly, the switch from DR-to-AL acutely increased mortality, while the switch from AL-to-DR caused only a weak and gradual increase in survival, highlighting a memory of earlier nutrition. A significant association between fat preservation and survival response pointed to the adipose tissue as a potential memory source. Consistently, post-switch RNA-seq profiling in liver, brown (BAT) and white adipose tissue (WAT) demonstrated that the transcriptional and metabolic program of chronic DR remained largely refractory to the AL-to-DR switch in the two fat tissues, particularly in WAT. This loss of transcriptional flexibility coincides with a major proinflammatory signature in aged preadipocytes, which is prevented by chronic DR feeding. Integration of lipidomics confirmed impaired membrane lipogenesis and limited mitochondrial copy number increase under late-life DR as functional consequences of this memory effect. Together, our results provide evidence for a nutritional memory as a limiting factor for DR-induced longevity and metabolic remodeling of WAT in mammals.
2019-08-28 | GSE124772 | GEO
Project description:Dietary restriction (DR) has been shown to increase lifespan in organisms ranging from yeast to mammals. This suggests that the underlying mechanisms may be evolutionarily conserved. Indeed, upstream signalling pathways, such as TOR, are strongly linked to DR-induced longevity in various organisms. However, the downstream effector proteins that ultimately mediate lifespan extension are less clear. To shed light on this, we used a proteomic approach on budding yeast. Our reasoning was that analysis of proteome-wide changes in response to DR might enable the identification of proteins that mediate its physiological effects, including lifespan extension. Of over 2500 proteins we identified by liquid chromatography-mass spectrometry, 183 were significantly altered in expression by at least 3-fold in response to DR. Most of these proteins were mitochondrial and/or had clear links to respiration and metabolism. Indeed, direct analysis of oxygen consumption confirmed that mitochondrial respiration was increased several-fold in response to DR. In addition, several key proteins involved in mating, including Ste2 and Ste6, were downregulated by DR. Consistent with this, shmoo formation in response to α-factor pheromone was reduced by DR, thus confirming the inhibitory effect of DR on yeast mating. Finally, we found that Hsp26, a member of the conserved small heat shock protein (sHSP) family, was upregulated by DR and that overexpression of Hsp26 extends yeast replicative lifespan. As overexpression of sHSPs in C. elegans and Drosophila has previously been shown to extend lifespan, our data on yeast Hsp26 suggest that sHSPs may be universally conserved effectors of longevity.
2022-02-17 | PXD025004 | Pride
Project description:Sir2 is the most intensively discussed longevity gene in current aging research. Although the gene encoding for a NAD+-dependent histone deacetylase initially was found to extend lifespan of various organisms ranging from yeast to mammals, serious doubts regarding its role in longevity have been expressed recently. In this study, we tested whether tissue-specific overexpression of Sir2 in the adult fat body can extend lifespan when compared to genetically identical controls. We also wanted to elucidate the mechanisms by which fat body Sir2 promotes longevity by studying the phenotypic and transcriptional changes in the fat body. We found that moderate (3-fold) Sir2 overexpression in the fat body during adulthood only can promote longevity in both sexes by roughly 13 %. In addition, we obtained transcriptional profiles elicited by this overexpression and propose a role for Sir2 in lipid droplet biology especially under conditions of starvation. Furthermore, our data do not support the idea of Sir2 mediating the response to dietary restriction (DR) because transcriptional profiles of fat bodies after DR or Sir2 overexpression do not match. This study provides additional independent evidence for the concept of Sir2 as a longevity gene and as a promising pharmacological target to cure age-related diseases. 6 groups of sample types were included in the experiment: a) females overexpressing Sir2 in the fat body b) female controls c) males overexpressing Sir2 in the fat body d) male controls e) wildtype females subjected to DR f) wildtype females feeding on a normal diet. 3 biological replicates were included per group.
2013-05-01 | E-GEOD-45974 | biostudies-arrayexpress
Project description:Dietary restriction (DR), reduced food intake while avoiding malnutrition, profoundly extends lifespan in most model and non-model organisms. Both chronic (i.e. life-long) and acute (i.e. late-onset) DR have been shown to improve cognitive performance in aged mice compared to animals with an unrestricted access to food (ad libitium feeding; AL). Yet so far, quantitative analyses of the molecular dynamics in the brain of DR fed animals have been limited. Here we performed single-nuclei sequencing (Nuc-seq) of whole hippocampus isolated from young (5 months) and old (24 months) AL fed animals, as well as old chronic DR (DR started at 3 months) and acute DR (aDR) mice.
2023-04-17 | GSE227515 | GEO
Project description:Dietary restriction (DR) is a robust intervention to slow aging, but how individual tissues respond to DR is largely unknown. We developed a translating ribosome affinity purification method in Drosophila (Fly-TRAP) and investigated mRNA translational profiles of seven primary tissues upon DR. Here we demonstrate that DR alters the mRNA translation expression of proteins genes involved in tissue structural integrity, metabolism, and signal communication in a tissue-specific and coordinated manner. DR enhances the expression of mitochondrial genes in some tissues but decreases in others. Genes involved in mRNA translation were increased specifically in the gut and fat body. A key finding from the study was that DR upregulates several neuroendocrine factors and their corresponding receptors in specific peripheral tissues. Additionally, several a list of secreted factors was in non-neuronal tissues were increased upon changed in response to DR, some of which affected longevity. These results suggest that DR enhances tissue-tissue communication to leading to a longer lifespan and improved tissue homeostasis.
2018-05-20 | GSE81425 | GEO