Frailty in middle age is associated with race-specific changes to the transcriptome.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA531676 | ENA |
REPOSITORIES: ENA
Similar Datasets
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: Not available
| S-EPMC6710041 | biostudies-literature
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: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
Project description:The green algal Botryococcus braunii (Chlorophyte) is known for accumulating high levels of hydrocarbons that are a useful alternative to fossil fuels. B. braunii is categorized into three groups based on types of their accumulated hydrocarbons: alkadiene/triene in race A, botryococcenes in race B, and lycopadiene in race L. Transcriptomic studies in race A and race B have discovered tremendous information related to the genes encoding proteins involved in hydrocarbon biosynthesis. However, transcriptome of race L has not been reported. In this study, we report a transcriptome of race L B. braunii AC768 through the de novo assembly using Hiseq platform. Our analyses indicate that photosynthesis and protein biosynthesis are the most abundantly transcribed in actively growing race L B. braunii. We show that the transcriptome of race L shares similar amounts (~20%) of mutual best-hits with that of race A or race B. Sequence homologous analyses indicate that enzymes involved in squalene and phytoene biosynthesis are well separated into geranyl-diphosphate synthase, farnesyl-diphosphate synthase, geranylgeranyl-diphosphate synthase, phytoene synthase, and squalene synthase. Both B. braunii specific enzymes botryococcene synthase SSL3 and lycopaoctaene synthase LOS are found to form distinctive subgroups in the group of squalene synthase. One of the ESTs in AC768 transcriptome that falls into the subgroup with LOS and shares >88% identity with that of LOS. Together, our results show that SSL and LOS are unique to race B and race L B. braunii subspecies, respectively. We propose that phytoene synthase in race L shares higher homolog to squalene synthase than phytoene synthase in other algae.
2019-11-21 | GSE96585 | GEO
Project description:Risk factors for BPH/LUTS include sedentary lifestyle, anxiety/depression, obesity, and frailty. While physical exercise may reduce the progression and/or severity of BPH/LUTS, the mechanisms responsible remain unknown.
2024-02-07 | PXD044453 | Pride
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