Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Drug synergy slows ageing and improves healthspan through IGF and SREBP lipid signaling

ABSTRACT: Pharmacological interventions directly modulating ageing would extend human healthspan, resulting in dramatic medical and economic benefits. Such interventions should be efficacious in adults and ideally repurpose drugs known to be safe. Here we show that dramatic lifespan extension can be achieved by targeting multiple, evolutionarily conserved ageing pathways using drugs already used in humans. Using this approach in C. elegans, we were able to slow ageing, improve healthspan and minimize trade-offs. We show that daf-2, daf-7 and sbp-1 (mammalian SREBP-1c) interact upstream of changes in lipid metabolism, resulting in increased monounsaturated fatty acid content and lifespan extension. For one combination, we observed evolutionary conservation in fruit flies. To the best of our knowledge, this is the largest lifespan effect ever reported for any adult-onset drug treatment in C. elegans. Drug repurposing approaches, by leveraging drugs already approved for humans, could lead to rapid translation of experimental results to clinical applications.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE108263 | GEO | 2018/12/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity (RNA-seq)

Project description:Transcriptome-based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age-related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf-16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA-approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in C. elegans. This longevity is dependent on both daf-16 signaling and inhibition of the neuromuscular acetylcholine receptor. Other neuromuscular blockers tubocurarine and pancuronium caused similar healthspan benefits. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF-16 longevity pathway.

2021-07-06 | GSE149944 | GEO

RNA-seq data for: Anti-retroviral treatment with zidovudine alters pyrimidine metabolism, reduces translation, and extends healthy longevity via ATF-4

Project description:The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows for rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and healthspan in C. elegans, independent of electron transport chain impairment or ROS accumulation. Rather, zidovudine treatment modifies pyrimidine metabolism and transcripts related to proteostasis. Testing regulators of mitochondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, and specifically communication between mitochondrial and cytosolic translation. Translation is reduced in zidovudine-treated worms, also dependent on ATF-4. Finally, we show ATF-4-dependent lifespan extension induced by didanosine, another NRTI. Altogether, our work elucidates the geroprotective effects of NRTIs such as zidovudine in vivo, via reduction of translation and ATF-4.

2022-12-29 | GSE150108 | GEO

Anti-aging effects of Vicatia thibetica de Boiss root extract on Caenorhabditis elegans and doxorubicin-induced mice via promoting collagen and stress resistance

Project description:The root of Vicatia thibetica de Boiss is a Chinese herb medicine with homology of medicine and food. We first report that HLB01 (the extract of Vicatia thibetica de Boiss root) extends lifespan and promotes healthy parameters in Caenorhabditis elegans (C. elegans). In doxorubicin-induced senescent mice, HLB01 counteracts senescence associated biomarkers significantly, including AST, ALT, p21 and γH2AX. Interestingly, HLB01 promotes the level of collagen in C. elegans and mammalian cell systemically, which might be one of the essential factors to exert anti-aging effects of HLB01. In addition, HLB01 can scavenge free radical to perform antioxidant ability. Lifespan extension of HLB01 also dependent on DAF-16 and HSF-1 to perform oxidative stress resistance and heat stress resistance. Taken together, these data indicate that HLB01 extends lifespan and healthspan of C. elegans, resists doxorubicin‐induced senescence in mice via collagen promoting, antioxidant and stress resistance.

2021-03-06 | GSE168322 | GEO

Systemic lipolysis promotes healthspan in Drosophila melanogaster

Project description:Since healthspan-extending interventions such as caloric restriction or fasting robustly promote lipid catabolism, we investigated how lifespan and healthspan were affected by increased lipid catabolism via bmm (brummer, FBgn0036449), the major triglyceride hydrolase in Drosophila. Global overexpression of bmm strongly promoted lifespan extension as well as numerous markers of healthspan, including increased female fecundity, fertility maintenance, preserved locomotion activity, increased mitochondrial biogenesis and oxidative metabolism. Increased Bmm robustly upregulated the heat shock protein 70 (Hsp70) family of proteins, which equipped the flies with higher resistance to heat, cold, and ER stress via improved proteostasis. Overexpression of bmm recapitulated major physiological changes associated with dietary restriction (DR) and conveyed its effects through dSir2. Taken together, these data show that bmm overexpression has broad beneficial effects on healthspan, and implicate lipolysis as a key node underlying the beneficial effects of dietary interventions known to improve healthspan.

2022-09-27 | GSE178816 | GEO

Ginkgolide B increase healthspan and lifespan of female mice

Project description:Various anti-aging interventions exhibit potential in extending lifespan, yet most of these interventions are inefficacy or even have deleterious effects on healthspan. Ginkgolide B (GB) is a Ginkgo biloba-derived small molecule that reduces aging-related morbidities; however, the effects of GB on healthspan and longevity remain elusive. Here, we report that continuous oral GB administration in mice starting at 20 months extended their lifespan by 20% and reduced tumour incidence. Besides, GB administration significantly improved healthspan evidenced by enhancement in muscle quality, physical performance, grip strength, metabolism, frailty index, systemic inflammation, and senescence. Moreover, GB administration ameliorated aging-related pathologies without any apparent adverse effects. Single-nucleus RNA sequencing (snRNA-seq) revealed that GB improved aging-associated abnormal cell-type composition, intracellular signalling pathways, and cell-cell communication in skeletal muscles. GB also reduced the levels of aging-induced novel Runx1+ type 2B myonuclei, which are associated with apoptotic burden and aging-related signatures. Runx1 derived senescence, as shown by gain- and loss-of-function assays. Together, a new function of GB in extending the healthspan in aging is identified, which contributes to lifespan extension. The senomorphic effects of GB on the multifactorial aging process may provide new prospects for achieving healthy aging and longevity extension.

2024-10-31 | GSE254739 | GEO

wt vs daf-2 C. elegans protein turnover

Project description:Most aging hypotheses revolve around the accumulation of some sort of damage resulting in gradual physiological decline and ultimately death. Avoiding protein damage accumulation by enhanced turnover should slow down the aging process and extend lifespan. However, lowering translational efficiency extends rather than shortens lifespan in C. elegans. We studied turnover of individual proteins in the conserved Insulin/Insulin-like Growth Factor (IGF-1) receptor mutant daf-2 by combining Stable Isotope Labeling by Nitrogen-15 in Caenorhabditis elegans and LC-MS/MS. Intriguingly, the majority of proteins displayed prolonged half-lives in daf-2, while others remained unchanged, signifying that longevity is not supported by high protein turnover. This slow-down of protein turnover was most prominent for components of the translation machinery and mitochondria. In contrast, the high turnover of lysosomal hydrolases and very low turnover of cytoskeletal proteins remained largely unchanged in daf-2. The slow-down of protein dynamics and decreased abundance of the translational machinery may point at the importance of anabolic attenuation in lifespan extension as suggested by the hyperfunction theory.

2016-09-27 | PXD002317 | Pride

Transcriptomics of C. chinensis and E. ulmoides treated aged C. elegans

Project description:The nematode Caenorhabditis elegans was treated with extracts of the Traditional Chinese Medicine plants Cuscuta chinensis and Eucommia ulmoides from the L4 stage. In aged worms (on the 7th and 12th day of adulthood) different health parameters were determined. Besides the prolongation of lifespan, we found that C. chinensis improved the swimming behavior, pharyngeal pumping rate, stress resistance, mechanosensation and memory of aged C. elegans. Furthermore, the extract treatment reduced the autofluorescence, which is a known biomarker of ageing. Thus, we concluded that C. chinensis is an overall healthspan enhancer. In contrast, the E. ulmoides extract specifically enhanced the lifespan and stress resistance of aged C. elegans, but did not improve any other health aspect. To reveal the mechanism behind the healthspan enhancing effects of C. chinensis, the transcriptome of treated and untreated C. elegans on the 12th day of adulthood was analysed. For comparison purposes, E. ulmoides treated nematodes were included in the analysis.

2024-10-30 | GSE274478 | GEO

Effect of methione restriction in the liver of WT and Lmna G609G KI mice

Project description:Dietary intervention constitutes a feasible approach for modulating metabolism and improving healthspan and lifespan. Methionine restriction (MR) delays the appearance of age-related diseases and increases longevity in normal mice. However, the effect of MR on premature aging remains to be elucidated. Here, we describe that MR extends lifespan in two different mouse models of Hutchinson-Gilford progeria syndrome (HGPS) by reversing the transcriptome alterations in inflammation and DNA-damage response genes present in this condition. Further, MR improves the lipid profile and alters the levels of bile acids, both in wild-type and in progeroid mice. Notably, treatment with the bile acid cholic acid improves healthspan and lifespan in vivo. These results suggest the existence of a metabolic pathway involved in the longevity extension achieved by MR and support the possibility of dietary interventions for treating progeria.

2018-08-27 | GSE117188 | GEO

Loss of miR-83 extends lifespan and affects target gene expression in an age-dependent manner in Caenorhabditis elegans

Project description:We have identified a role of the C. elegans miR-83 in regulating lifespan. mir-83 mutants exhibit an extended lifespan, and its overexpression is sufficient to decrease the prolonged lifespan of the mutants. We observed an upregulation in the expression of sets of miR-83 targets in young mir-83 mutant adults. However, in older mir-83 mutant adults, a different set of genes are upregulated. In vivo assays show that miR-83 regulates expression of a number of targets, including din-1, spp-9 and col-178. We show that daf-16 and din-1 are required for the lifespan extension of mir-83 mutants. The regulation of din-1 by miR-83 during aging results in the differential expression of din-1 targets, such as gst-4 and gst-10. In daf-2 mutants, the expression levels of miR-83 are significantly reduced, as compared to wildtype animals. Our results identify a role of miR-83 in modulating lifespan in C. elegans, and provide molecular insights into its functional mechanism.

2018-12-15 | GSE123862 | GEO

Activation of DAF-16/FOXO by reactive oxygen species promotes longevity in long- lived mitochondrial mutants in C. elegans

Project description:Mild deficits in mitochondrial function have been shown to increase lifespan in multiple species including worms, flies and mice. Here, we study three C. elegans mitochondrial mutants (clk-1, isp-1 and nuo-6) to identify overlapping genetic pathways that contribute to their longevity. We find that genes regulated by the FOXO transcription factor DAF-16 are upregulated in all three strains, and that the transcriptional changes present in these worms overlap significantly with the long-lived insulin-IGF1 signaling pathway mutant daf-2. We show that DAF-16 and multiple DAF-16 interacting proteins (MATH-33, IMB-2, CST-1/2, BAR-1) are required for the longevity of all three mitochondrial mutants. Our results suggest that the activation of DAF-16 in these mutants results from elevated levels of reactive oxygen species. Overall, this work reveals an overlapping genetic pathway required for longevity in three mitochondrial mutants, and, combined with previous work, demonstrates that DAF-16 is a downstream mediator of lifespan extension in multiple pathways of longevity.

2018-02-26 | GSE93724 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data