Frailty in middle age is associated with race-specific changes to the transcriptome.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA531676 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8870770.fastq.gz | Fastqsanger.gz | |||
| SRR8870771.fastq.gz | Fastqsanger.gz | |||
| SRR8870772.fastq.gz | Fastqsanger.gz | |||
| SRR8870773.fastq.gz | Fastqsanger.gz | |||
| SRR8870764.fastq.gz | Fastqsanger.gz |
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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:Frailty is an aging-associated syndrome resulting from diminished capacity to respond to stressors and 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 blacks and whites. Next generation RNA sequencing was completed using total RNA from peripheral blood mononuclear cells (n = 16). We analyzed differential gene expression patterns and completed a parametric analysis of gene set enrichment (PAGE). Differential gene expression was validated using RT-qPCR (n = 52). We identified 5,082 genes differentially expressed with frailty. Frailty altered gene expression patterns and biological pathways differently in blacks and whites, including pathways related to inflammation and immunity. 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 in middle-aged adults.
| S-EPMC6710041 | biostudies-literature
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 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 a geriatric multi-dimensional syndrome which reflects multisystem physiological change and is a transversal measure of reduced resilience to negative events. It is characterized by weakness, frequent falls, cognitive decline, increased hospitalization and dead, and represents a risk factor for the development of Alzheimer’s disease (AD). The fact that frailty is recognized as a reversible condition, encourages the identification of earlier biomarkers to timely predict and prevent its occurrence. SAMP8 (Senescence-Accelerated Mouse Prone-8) mice represent the most appropriate preclinical model to this aim and were used in this study to carry transcriptional and metabolic analyses in the brain and plasma respectively, upon a characterization at cognitive, motor, structural and neuropathological level at 2.5, 6 and 9 months of age. At 2.5 months SAMP8 mice started displaying memory deficits, muscle weakness and motor impairment. Functional alterations were associated with a neurodevelopment deficiency associated with reduced neuronal density and glial cell loss. Through transcriptomics we identified specific genetic signatures well distinguishing SAMP8 mice at 6 months and correlating with motor and cognitive dysfunction, whereas plasma metabolomics allowed to segregate SAMP8 mice from SAMR1 already at 2.5 months of age by detecting constitutively lower levels of acylcarnitines and lipids in SAMP8 at all ages investigated. Our findings suggest that specific genetic alterations at central level, as well as metabolomic changes in plasma, might allow to early assess a frail condition leading to dementia development, which paves the foundation for future investigation in a clinical setting.
2024-11-05 | GSE270589 | GEO
Project description:This work describes for the first time a different circular RNA (circRNAs) expression pattern between frail and robust individuals. Moreover, the level of some circRNAs is modulated after a physical intervention. These results suggest that they could be used as minimally invasive biomarkers of frailty. Frailty is an intermediate and reversible geriatric syndrome that often precedes dependency. Therefore, its identification is essential to prevent dependency. Diverse molecules have been proposed as biomarkers of frailty, but none of them has reached clinical practice. Recently, circular RNAs have emerged as new non-coding RNAs. Their regulatory role together with their high stability in biofluids makes them good candidates as biomarkers for several processes, but, to date, no studies have characterized circRNA expression in frailty. We studied RNA from leukocytes of 35 frail and 35 robust individuals. After RNA-Sequencing, circRNA detection was performed by CIRI2 and Circexplorer2 and differential expression analysis by DESeq2. Validation was performed by Quantitative-PCR. A Linear Discriminant Analysis was performed to determine the best circRNA combination to discriminate frails from robusts. Besides, CircRNA candidates were studied in 13 additional elder donors before and after a 3-month physical intervention. We found 89 differentially expressed circRNAs (p-value<0.05, FC>|1.5|) with frailty. The upregulation of hsa_circ_0007817, hsa_circ_0101802 and hsa_circ_0060527 in frail individuals was validated. The combination of hsa_circ_0079284, hsa_circ_0007817 and hsa_circ_0075737 levels showed a great biomarker value with a 95.9% probability of correctly classifying frail and robust individuals. Moreover, hsa_circ_0079284 levels decreased after physical intervention in concordance with an improvement in frailty scores.
2023-01-31 | GSE206762 | GEO
Project description:Frailty is an intermediate status of human ageing process, associated with decompensated homeostasis and death. The immune phenotype of frailty and its underlying cellular and molecular processes remain poorly understood. Here we profiled 114,467 immune cells from cord blood, young adults, healthy and frail elderly using single-cell RNA and TCR V(D)J sequencing. An age-dependent accumulation of cell heterogeneity and transcriptome variability in defined immune cell types was observed. With the specific expression of gene sets, characteristic transcription factors were identified in given immune cell types of certain age group. Trajectory analysis revealed cells from non-frail and frail elderly often fall into distinct trajectories, despite similar chronological age. Numerous TCR clonotypes were shared among T cell subtypes in aged and frail samples, indicating differential pluripotency and resilience capability of aged T cells. Finally, a frailty-specific monocyte subset was identified with exclusively high expression of lncRNAs NEAT1 and MALAT1. Our results discover human frailty-specific immune cell characteristics based on the comprehensive dimensions in immune landscape of ageing and frailty.
2022-01-12 | GSE157007 | GEO
Project description:Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease (CVD) and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Here, we studied the association of abundance (flow cytometry) and gene expression profile (RNAseq) of stem/progenitor cells (HSPCs) and molecular markers of inflammaging (ELISA) with the cardiorespiratory phenotype and prospective adverse events of individuals classified according to levels of frailty. Two cohorts of older adults were enrolled in the study. In a cohort of pre-frail 35 individuals (average age: 75 years), a physical frailty score above the median identified subjects with initial alterations in cardiorespiratory function. RNA sequencing revealed S100A8/A9 upregulation in HSPCs from the bone marrow (>10-fold) and peripheral blood (>200-fold) of individuals with greater physical frailty. Moreover higher frailty was associated with increased alarmins S100A8/A9 and inflammatory cytokines in peripheral blood. We then studied a cohort of 104 more frail individuals (average age: 81 years) with multi-domain health deficits. Reduced levels of circulating HSPCs and increased S100A8/A9 concentrations were independently associated with the frailty index. Remarkably, low HSPCs and high S100A8/A9 simultaneously predicted major adverse cardiovascular events at 1-year follow-up after adjustment for age and frailty index. In conclusion, inflammaging characterized by alarmin and pro-inflammatory cytokines in pre-frail individuals is mirrored by the pauperization of HSPCs in frail older people with comorbidities. S100A8/A9 is upregulated within HSPCs, identifying a phenotype that associates with poor cardiovascular outcomes.
2022-03-23 | GSE190446 | GEO
Project description:Long-term hematopoietic stem cells (LT-HSCs) are responsible for lifelong maintenance and regeneration of the blood system. Loss of LT-HSC function is a major contributor to decline in hematopoietic function with aging, leading to increased rate of infection, poor vaccination response, and increased risk of hematologic malignancies. While cellular and molecular hallmarks of LT-HSC aging have been defined, a barrier to achieving the goal of extending healthy hematopoietic function into older age is the lack of understanding of the nature and timing of the initiating events that cause LT-HSC aging. Here we show that hallmarks of LT-HSC aging and decline in hematopoietic function accumulate by middle age in mice, and that the hematopoietic cell-extrinsic bone marrow (BM) microenvironment at middle age is necessary and sufficient to cause LT-HSC aging. Using unbiased transcriptome-based approaches, we identify decreased production of IGF1 by mesenchymal stromal cells (MSC) in the local middle-aged BM microenvironment as a factor causing LT-HSC aging and show that direct stimulation of middle-aged LT-HSCs with IGF1 rescues hallmarks of aging. Together, our study demonstrates that the initiating events causing LT-HSC and hematopoietic aging emerge by middle age and are caused by hematopoietic cell-extrinsic changes in the BM microenvironment. Declining IGF1 in the BM microenvironment at middle age represents a compelling target for intervention using prophylactic therapies to effectively extend healthspan and prevent decline in hematopoietic function during aging.
2021-01-12 | GSE164609 | GEO