A longitudinal study of female and male mice to identify DNA methylation signatures of frailty beyond age
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE316651 | GEO | 2026/01/15
REPOSITORIES: GEO
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Project description:Frailty in aging is driven by the dysregulation of multiple biological pathways. Protectin DX (PDX) is a docosahexaenoic acid (DHA)-derived molecule that alleviates many chronic inflammatory disorders, but its potential effects on frailty remain unknown. Our goal is to identify age-related impairments in metabolic systems and to evaluate the therapeutic potential of PDX on frailty, physical performance, and health parameters. A set of 22-month-old C57BL/6 male and female mice were assigned to vehicle (Old) or PDX daily gavage treatment for 8 weeks, whereas 6-monthold (Adult) mice received only vehicle. Forelimb and hindlimb strength, endurance, voluntary wheel activity and walking speed determined physical performance and were combined with a frailty index score and body weight loss to determine frailty status. Our data shows that old vehicle-treated mice from both sexes had body weight loss paralleling visceromegaly, and old females also had impaired insulin clearance as compared to the Adult group. Aging was associated with physical performance decline together with higher odds of frailty development. There was also age-driven mesangial expansion and glomerular hypertrophy as well as bone mineral density loss. All of the in vivo and in vitro impairments observed with aging co-occurred with upregulation of inflammatory pathways and Myc signaling as well as downregulation of genes related to adipogenesis and oxidative phosphorylation in liver. PDX attenuated the age-driven physical performance (strength, exhaustion, walking speed) decline, promoted robustness, prevented bone losses and partially reversed changes in hepatic expression of Myc targets and metabolic genes. In conclusion, our data provides evidence of the beneficial therapeutic effect of PDX against features of frailty in mice. Further studies are warranted to investigate the mechanisms of action and the potential for human translation.
2023-04-05 | GSE228901 | GEO
Project description:Frailty is defined as a clinical syndrome. It reflects a decrease in physiological reserve capacities that alters the mechanisms of adaptation to stress. Its clinical expression is modulated by biological, physiological, social and environmental changes. Thus, the accumulation of declines in these multiple systems leads to vulnerability to adverse outcomes (Fried et al., 2001; Nourhashémi et al., 2001). Indeed, frailty increases the risk of disability, falls, hospitalization and death. Age is currently a major determinant of frailty but does not explain this syndrome alone. It has been estimated that the prevalence of frailty is 4% in people aged 65-69 years and increases to 26% in people aged over 85 years (Clegg et al., 2013). However, this parameter is not sufficient to understand why long-lived people can preserve their physical function even at extreme ages (Ayers et al., 2017). The characterization of frailty has therefore become a priority in order to put in place actions to reduce or delay its harmful consequences. Early diagnostic methods are needed to identify those at risk. The search for biomarkers is part of this approach. As a result, the search for biomarkers of frailty has led to the identification of several types of molecules linked to the inflammatory response (e.g. IL-6, CRP, TNF-α and homocysteine), to nutritional status (e.g. vitamin D, albumin) or even endocrine. metabolism (e.g. IGF-1 and testosterone) (Picca et al., 2022; Mailliez et al., 2020; Alvarez-Sanchez et al, 2020). The development of new analytical techniques now allows multiplexed analysis rather than an individual biomarker to characterize a biological profile of this complex and dynamic frailty syndrome (Picca et al., 2022). Proteomic analysis is the technique of choice for studying the complete protein content of a biological sample. This technique has already proven itself in the discovery of new biomarkers in age-related diseases such as Parkinson's disease (Raghunathan et al., 2022) and Alzheimer's disease (Bai et al., 2021). Several studies have already described the plasma proteomic profile of frailty (Shamsi et al., 2012; Lin et al., 2017; Landino et al., 2021; Sathyan et al., 2020; Verghese et al., 2021), highlighting the importance of biological pathways associated with frailty: immune response, coagulation pathway or lipid metabolism. On the other hand, the determination of the level of frailty of the patients thanks to a proteomic analysis could also make it possible to improve the prediction of this syndrome as well as its phenotyping. In a first work on plasma samples, Sathyan et al. constructed a frailty prediction model that was more strongly correlated with chronological age than observed clinical frailty (Sathyan et al., 2020). Cognitive impairment plays a key role in determining vulnerability to adverse outcomes (Cesari et al., 2013), leading to the proposal in 2013 of a concept and operational definition of “cognitive frailty”. (Sugimoto et al., 2022). Proteomic analysis of cerebrospinal fluid (CSF) is therefore an approach of choice for understanding brain responses to aging and frailty syndrome. Its analysis could allow the identification of new biomarkers linked to the frailty syndrome. Indeed, many of the CSF proteins are released by the various cells of the central nervous system (CNS). This biofluid thus reflects the molecular content of neuronal and glial cells. For this reason, any change in the composition of the CSF reflects the pathophysiological state of the brain (inflammation, infection, neurodegeneration...). CSF proteomics is therefore a technique of choice to comprehensively understand the cerebral pathogenic pathways linked to frailty. The PROLIPHYC cohort is composed of patients suspected of normal pressure hydrocephalus (NPH). We have previously shown that there is an association in these patients between an alteration of the biomechanical properties of the CNS and the frailty index, and that homocysteine is the only plasma macromolecule associated with these two clinical and biomechanical parameters (Vallet et al., 2020; Guillotin et al., 2022). In this new study, we sought to characterize the protein composition of CSF related to frailty by quantitative proteomic analysis. The second objective was to develop a model for predicting frailty from the abundance of CSF proteins. This model was then compared to the frailty estimated by the frailty index. Together, our results enabled us to highlight a possible link between inhibition of the expression of proteins involved in neurogenesis and the frailty index, then to propose a first proteomic profile of frailty in the CSF and a model for predicting frailty based on the biological signature of the CNS.
2024-08-10 | PXD043497 | Pride
Project description:Frailty is an aging-associated syndrome resulting from diminished capacity to respond to stressors, disrupted homeostasis. It is a significant risk factor for disability and mortality. Although frailty is usually studied in old age, it is present in mid-life. Given the increases in mortality statistics among middle-aged Americans, understanding molecular drivers of frailty in a younger, diverse cohort may facilitate identifying pathways for early intervention. We analyzed frailty-associated, genome-wide transcriptional changes in middle-aged African Americans (AAs) and whites. Next generation RNA sequencing was completed using total RNA from peripheral blood mononuclear cells. We analyzed differential gene expression patterns and completed a parametric analysis of gene set enrichment (PAGE). Differential gene expression was validated using RT-qPCR. We identified 5,082 genes differentially expressed with frailty. Frailty altered gene expression patterns and biological pathways differently in AAs and whites, including inflammatory and immune response pathways. The validation study showed a significant two-way interaction between frailty, race, and expression of the cytokine IL1B and the transcription factor EGR1. The glucose transporter, SLC2A6, the neutrophil receptor, FCGR3B, and the accessory protein, C17orf56, were decreased with frailty. These results suggest that there may be demographic dependent, divergent biological pathways underlying frailty diagnosis in middle-aged adults.
2019-08-21 | GSE129534 | GEO
Project description:The impact of healthy aging on molecular programming of immune cells is poorly understood. Here, we report comprehensive characterization of healthy aging in human classical monocytes, with a focus on epigenomic, transcriptomic, and proteomic alterations, as well as the corresponding proteomic and metabolomic data for plasma, using healthy cohorts of 20 young and 20 older males (~27 and ~64 years old on average). For each individual, we performed eRRBS-based DNA methylation profiling, which allowed us to identify a set of age-associated differentially methylated regions (DMRs) – a novel, cell-type specific signature of aging in DNA methylome. Hypermethylation events were associated with H3K27me3 in the CpG islands near promoters of lowly-expressed genes, while hypomethylated DMRs were enriched in H3K4me1 marked regions and associated with age-related increase of expression of the corresponding genes, providing a link between DNA methylation and age-associated transcriptional changes in primary human cells.
2022-02-16 | PXD021821 | Pride
Project description:<p>Due to global aging, frailty and sarcopenia are increasing. Sarcopenia is defined as loss of volume and strength of skeletal muscle in elderlies, while frailty involves multiple domains of aging-related dysfunction, impaired cognition, hypomobility and decreased social activity. However, little is known about the metabolic basis of sarcopenia, either shared with or discrete from frailty. Here we analyzed comprehensive metabolomic data of human blood in relation to sarcopenia, previously collected from 19 elderly participants in our frailty study. Among 131 metabolites, we identified 22 sarcopenia markers, distinct from 15 frailty markers, mainly including antioxidants, although sarcopenia overlaps clinically with physical frailty. Notably, 21 metabolites that decline in sarcopenia or low SMI are uremic compounds that increase in kidney dysfunction. These comprise TCA cycle, urea cycle, nitrogen and methylated metabolites. Sarcopenia markers imply a close link between muscle and kidney function, while frailty markers define a state vulnerable to oxidative stress.</p>
2022-10-19 | MTBLS3341 | MetaboLights
Project description:As human society ages globally, age-related disorders are becoming increasingly common. Due to decreasing physiological reserves and increasing organ system dysfunction associated with age, frailty affects many elderly people, compromising their ability to cope with acute stressors. Frail elderly people commonly manifest complex clinical symptoms, including cognitive dysfunction, hypomobility, and impaired daily activity, the metabolic basis of which has been little understood. We applied untargeted, comprehensive, LC-MS metabolomic analysis to human blood from 19 frail and non-frail elderly patients, who were clinically evaluated using the Edmonton Frail Scale, the MoCA-J for cognition, and the TUG for mobility. Among 131 metabolites assayed, we identified 22 markers for frailty, cognition, and hypomobility, most of which were abundant in blood. Frailty markers included 5 of 6 markers specifically related to cognition and 6 of 12 associated with hypomobility. These overlapping sets of markers include metabolites related to antioxidation, muscle or nitrogen metabolism, and amino acids, most of which decrease in frail elderly people. Five frailty-related metabolites that decreased (1,5-anhydroglucitol, acetyl-carnosine, ophthalmic acid, leucine, and isoleucine) have been previously reported as markers of aging, providing a metabolic link between human aging and frailty. Our findings clearly indicate that metabolite profiles efficiently distinguish frailty from non-frailty. Importantly, the antioxidant, ergothioneine, which decreases in frailty, is neuroprotective. Oxidative stress resulting from diminished antioxidant levels, could be a key vulnerability for pathogenesis of frailty, exacerbating illnesses related to human aging.
2020-05-01 | MTBLS1540 | MetaboLights
Project description:Frailty is a geriatric syndrome that represents a state of vulnerability with increased risk of negative health outcomes. In the last years, independent studies attempted to identify biomarkers of frailty at biological level, but no consensus has been reached to date. In this work, we performed a transcriptomic analysis of 25 robust and frail community-dwelling individuals based on Timed Up and Go, Gait Speed and Tilburg Frailty Indicator scales. The comparison between individuals classified as frail or robust by the three tools revealed the expression of 35 transcripts associated with frailty status. These include genes linked to inflammation- and hypoxia-related pathways, immune response or microRNAs. Among them, additional analyses showed that the expression of a 3-gene pattern, increased EGR1 and reduced DDX11L1 and miR454, was able to identify frail individuals with an area under the curve (AUC) of 0.86
2020-07-31 | GSE140358 | GEO
Project description:Aging-associated functional decline and disease susceptibility are believed to be mediated, at least in part, through alterations in the epigenome. To explore epigenetic changes that might influence visual function with advanced age, we performed whole genome bisulfite sequencing of purified mouse rod photoreceptors at four different ages and identified 2054 genomic regions that gain or lose DNA methylation. Differentially methylated regions (DMRs) clustered at chromosomal hotspots, especially on Chromosome 10 that included a longevity interactome. DMRs were preferentially detected at an early stage of aging in long neuronal genes and in rod-specific regulatory regions containing open chromatin domains and H3K27 acetylation. Integration of methylome to age-related transcriptome changes, chromatin signatures and first order protein-protein interactions uncovered an enrichment of DMRs in pathways associated with aging, longevity, synaptic function, and energy homeostasis. In concordance, we detected reduced mitochondrial maximum reserve capacity with retinal age in ex vivo assays. Our study reveals age-dependent genomic and chromatin features susceptible to DNA methylation changes in rod photoreceptors and identifies associations with established and cell type-specific pathways altered in aging.
2020-03-10 | GSE134872 | GEO
Project description:Aging-associated functional decline and disease susceptibility are believed to be mediated, at least in part, through alterations in the epigenome. To explore epigenetic changes that might influence visual function with advanced age, we performed whole genome bisulfite sequencing of purified mouse rod photoreceptors at four different ages and identified 2054 genomic regions that gain or lose DNA methylation. Differentially methylated regions (DMRs) clustered at chromosomal hotspots, especially on Chromosome 10 that included a longevity interactome. DMRs were preferentially detected at an early stage of aging in long neuronal genes and in rod-specific regulatory regions containing open chromatin domains and H3K27 acetylation. Integration of methylome to age-related transcriptome changes, chromatin signatures and first order protein-protein interactions uncovered an enrichment of DMRs in pathways associated with aging, longevity, synaptic function, and energy homeostasis. In concordance, we detected reduced mitochondrial maximum reserve capacity with retinal age in ex vivo assays. Our study reveals age-dependent genomic and chromatin features susceptible to DNA methylation changes in rod photoreceptors and identifies associations with established and cell type-specific pathways altered in aging.
2020-03-10 | GSE134871 | GEO
Project description:Aging-associated functional decline and disease susceptibility are believed to be mediated, at least in part, through alterations in the epigenome. To explore epigenetic changes that might influence visual function with advanced age, we performed whole genome bisulfite sequencing of purified mouse rod photoreceptors at four different ages and identified 2054 genomic regions that gain or lose DNA methylation. Differentially methylated regions (DMRs) clustered at chromosomal hotspots, especially on Chromosome 10 that included a longevity interactome. DMRs were preferentially detected at an early stage of aging in long neuronal genes and in rod-specific regulatory regions containing open chromatin domains and H3K27 acetylation. Integration of methylome to age-related transcriptome changes, chromatin signatures and first order protein-protein interactions uncovered an enrichment of DMRs in pathways associated with aging, longevity, synaptic function, and energy homeostasis. In concordance, we detected reduced mitochondrial maximum reserve capacity with retinal age in ex vivo assays. Our study reveals age-dependent genomic and chromatin features susceptible to DNA methylation changes in rod photoreceptors and identifies associations with established and cell type-specific pathways altered in aging.
2020-03-10 | GSE137935 | GEO