Ageing Intervention Study
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB43178 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Central longevity regulators have limited effects on age-dependent phenotypic changes assessed at scale
| PRJEB42917 | ENA
Project description:We aim to improve anti-ageing drug discovery, currently achieved through laborious and lengthy longevity analysis. Recent studies demonstrated that the most accurate molecular method to measure human age is based on CpG methylation profiles, as exemplified by several epigenetics clocks that can accurately predict an individual’s age. Here, we developed CellAge, a new epigenetic clock that measures subtle ageing changes in primary human cells in vitro. As such it provides a unique tool to measure effects of relatively short pharmacological treatments on ageing. We validated our CellAge clock against known longevity drugs such as rapamycin and trametinib. Moreover, we uncovered novel anti-ageing drugs, torin2 and Dactolisib (BEZ-235), demonstrating the value of our approach as a screening and discovery platform for anti-ageing strategies. CellAge outperforms other epigenetic clocks in measuring subtle ageing changes in primary human cells in culture. The tested drug treatments reduced senescence and other ageing markers, further consolidating our approach as a screening platform. Finally, we showed that the novel anti-ageing drugs we uncovered in vitro, indeed increased longevity in vivo. Our method expands the scope of CpG methylation profiling from measuring human chronological and biological age from human samples in years, to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, providing a novel accelerated discovery platform to test sought after geroprotectors.
2021-10-01 | E-MTAB-8327 | biostudies-arrayexpress
Project description:The aim of the study is to identify genetic mechanisms of longevity and to characterize their interaction with the environment. Using the results the future health of people without familial longevity can be improved in old age. Long-lived siblings of European descent were recruited together with their offspring and the partners of the offspring. Families were recruited if at least two long-lived siblings were alive and fulfilled the age criterion of 89 years or older for males and 91 years or older for females, representing less than 0.5% of the Dutch population in 2001.
2019-07-11 | MTBLS974 | MetaboLights
Project description:Neurons are central to lifelong learning and memory, but ageing disrupts their morphology and function, leading to cognitive decline. Although epigenetic mechanisms are known to play crucial roles in learning and memory, neuron-specific genome-wide epigenetic maps into old age remain scarce, often being limited to whole-brain homogenates and confounded by glial cells. Here, we mapped H3K4me3, H3K27ac, and H3K27me3 in mouse neurons across their lifespan. This revealed stable H3K4me3 and global losses of H3K27ac and H3K27me3 into old age. We observed patterns of synaptic function gene deactivation, regulated through the loss of the active mark H3K27ac, but not H3K4me3. Alongside this, embryonic development loci lost repressive H3K27me3 in old age. This suggests a loss of a highly refined neuronal cellular identity linked to global chromatin reconfigu-ration. Collectively, these findings indicate a key role for epigenetic regulation in neurons that is inextricably linked with ageing.
2024-08-21 | GSE190102 | GEO
Project description:The nutrient-sensing Target of Rapamycin complex 1 (TORC1) is an evolutionarily conserved regulator of longevity. S6 kinase (S6K) is an essential downstream mediator for the effect of TORC1 on longevity. However, mechanistic insights on how TORC1-S6K signalling promotes lifespan and healthspan are still limited. Here we show that activity of S6K in the Drosophila fat body is essential for rapamycin-mediated longevity. Fat-body-specific activation of S6K blocked lifespan extension upon rapamycin feeding and induced accumulation of multilamellar lysosomal enlargements. Besides, fat body-specific S6K knockdown extended lifespan in files. We performed proteomics for Drosophila fat body to explore the fat body-specific regulation of protein expression by two separate datasets: fat body-specific S6K activation (Lsp2GS>S6KCA) with rapamycin treatment; and fat body-specific S6K inhibition (Lsp2GS>S6KRNAi). To assess if the age-prolonging mechanisms of TORC1-S6K signalling are conserved between flies and mammals, we assessed the impact of rapamycin treatment in the proteome of liver from C3B6F1 mice (F1 hybrids of C3H/HeOuJ females and C57Bl/6N males).
2024-01-12 | PXD035293 | Pride
Project description:Modulation of histone levels is commonly seen during ageing in many species. However, any role for histone levels in longevity of multicellular organisms remains undiscovered. Here we show that inhibition of mTORC1 by rapamycin post-transcriptionally increases expression of histone proteins H3 and H4 in Drosophila intestine. Expression of H3/H4 in enterocytes alters chromatin organization, induces intestinal autophagy through transcriptional regulation, and prevents age-related structural and functional decline in the intestine. Increased H3/H4 expression in enterocytes is essential for rapamycin-dependent longevity and intestinal health. Histones H3/H4 regulate expression of a selective autophagy cargo adaptor Bchs (ALFY in mammals), increased expression of which in enterocytes is necessary and sufficient for increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and ALFY transcript, and alters chromatin organisation in small intestine, suggesting the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.
2021-05-01 | GSE148002 | GEO
Project description:Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process
| PRJNA705979 | ENA
Project description:Mitochondrial complex I, the largest enzyme complex of the mitochondrial oxidative phosphorylation machinery, has been proposed to contribute to variety of age-related pathological alterations as well as longevity. The enzyme complex-consisting proteins are encoded by both nuclear- (nDNA) and mitochondrial DNA (mtDNA). While some association studies of mtDNA-encoded complex I genes and lifespan in humans have been reported, experimental evidence and functional consequence of such variants are limited to studies using invertebrate models. Here, we present experimental evidence that a homoplasmic mutation in mitochondrially encoded complex I gene, mt-Nd2, modulates lifespan by altering cellular tryptophan levels and consequently ageing-related pathways in mice. A conplastic mouse strain carrying a mutation at m.4738C>A in mt-Nd2 lived significantly shorter than the controls. The same mutation led to higher susceptibility to glucose intolerance induced by high fat diet feeding. These phenotypes were not observed in mice carrying a mutation in another mtDNA-encoded complex I gene, mt-Nd5, suggesting functional relevance of particular mutations in complex I to ageing and age-related diseases.
2019-12-23 | GSE114256 | GEO
Project description:While much research has focussed on advanced stages (and mechanisms) of ageing, this fundamental process may commence at a relatively early age, impacting organ function and resilience throughout the adult lifespan. In male C57BL/6 mice, multiple phenotypic and transcriptional features of cardiovascular ageing were evident from 16 weeks of age, well in advance of 'middle age'. Phenotypic changes include declining cardiac and coronary reserves and resistance to ischaemic insult. Gene changes support early constitutive stress together with a plateau in transcriptome responsiveness to ischaemia, and declining induction of cardioprotective and quality control pathways vs. increasing induction of genes promoting signalling dysfunction, hypertrophy and cell death. These findings support cardiac ageing from early adulthood. Molecular changes reflect declining adaptive capacity/quality control, consistent with evolutionary theories of biological ageing.
2021-12-31 | GSE179286 | GEO
Project description:Most eukaryotic proteins are N-terminally acetylated, but the functional impact on a global scale has remained obscure. Using genome-wide CRISPR knockout screens in human cells, we reveal a strong genetic dependency between a major N-terminal acetyltransferase and specific ubiquitin ligases. Biochemical analyses uncover that both the ubiquitin ligase complex UBR4-KCMF1 and the acetyltransferase NatC recognize proteins bearing an unacetylated N-terminal methionine followed by a hydrophobic residue. NatC KO-induced protein degradation and phenotypes are reversed by UBR knockdown, demonstrating the central cellular role of this interplay. We reveal that loss of Drosophila NatC is associated with male sterility, reduced longevity, and age-dependent loss of motility due to developmental muscle defects. Remarkably, muscle-specific overexpression of UbcE2M, one of the proteins targeted for NatC KO mediated degradation, suppresses defects of NatC deletion. In conclusion, NatC-mediated N-terminal acetylation acts as a protective mechanism against protein degradation, which is relevant for increased longevity and motility.
2023-09-18 | GSE221447 | GEO