AginAging: a portrait from gene expression profile in blood cells: a portrait from gene expression profile in blood cells.
Ontology highlight
ABSTRACT: In almost every countries the proportion of people over 60 years is growing faster that any other age group. Increased life expectancy is leading to the characterization of specific aspects of aging for the various physiological systems. The study of healthy aging is important to design strategies capable to maximize the health and to prevent chronic diseases in older people. Immunosenscence reflects the age-related changes of the immune system and the reduced capacity of elderly people to cope with new infections. To elucidate changes in gene expression related to systemic aging and immunosenescence in an unbiased manner we performed comparative microarray analysis on whole blood cell from healthy middle-aged versus elderly men, and correlated results with functional measurements of aerobic capacity. Blood cells from elderly subjects showed age-related changes in the expression of several markers of immunosenescence, inflammation and oxidative stress, and showed impairments in metabolic and biosynthetic capacities.
Project description:In almost every countries the proportion of people over 60 years is growing faster that any other age group. Increased life expectancy is leading to the characterization of specific aspects of aging for the various physiological systems. The study of healthy aging is important to design strategies capable to maximize the health and to prevent chronic diseases in older people. Immunosenscence reflects the age-related changes of the immune system and the reduced capacity of elderly people to cope with new infections. To elucidate changes in gene expression related to systemic aging and immunosenescence in an unbiased manner we performed comparative microarray analysis on whole blood cell from healthy middle-aged versus elderly men, and correlated results with functional measurements of aerobic capacity. Blood cells from elderly subjects showed age-related changes in the expression of several markers of immunosenescence, inflammation and oxidative stress, and showed impairments in metabolic and biosynthetic capacities. Whole blood samples from twenty healthy men between the ages of 45-55 (n=11) and 65-75 (n=9) years old were analyzed for this study. For each subject blood was sampled in two different occasions, which were separated by at least 7 days. To preseve RNA quality and integrity 3 ml of blood have been collected intoTEMPUS Blood RNA tubes (ABI, Foster City, CA, USA). Total RNA has been depleted of globin mRNA using the GLOBINclearâ¢-Human kit (Ambion, Austin, TX). To reduce variations due to confounding events, such as spontaneous up- and down-regulation of genes, the two samples of clean RNA from each subject were pooled into one single sample (1ug+1ug RNA).
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.
Project description:This model is built by COPASI 4.24(Build197), based on paper:
A mathematical model of the effects of aging on naive T-cell population and diversity
Authors:
Stephanie Lewkiewicz, Yao-li Chuang, Tom Chou
Abstract:
The human adaptive immune response is known to weaken in advanced age, resulting in increased severity of pathogen-born illness, poor vaccine efficacy, and a higher prevalence of cancer in the elderly. Age-related erosion of the T cell compartment has been implicated as a likely cause, but the underlying mechanisms driving this immunosenescence have not been quantitatively modeled and systematically analyzed. T cell receptor diversity, or the extent of pathogen-derived antigen responsiveness of the T cell pool, is known to diminish with age, but inherent experimental difficulties preclude accurate analysis on the full organismal level. In this paper, we formulate a mechanistic mathematical model of T cell population dynamics on the immunoclonal subpopulation level, which provides quantitative estimates of diversity. We define different estimates for diversity that depend on the individual number of cells in a specific immunoclone. We show that diversity decreases with age primarily due to diminished thymic output of new T cells and the resulting overall loss of small immunoclones.
Project description:Cardiovascular diseases (CVD) are the leading cause of death among elderly people. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of cholesterol metabolism. Herein, we investigated the role of PCSK9 in age-related CVD. Both in humans and rats, sPCSK9 correlated positively with increasing age and the development of cardiovascular dysfunction. Network analysis identified PCSK9 as an important factor in age-associated lipid alterations and it correlated positively with intima media thickness, a clinical parameter of CVD risk. PCSK9 inhibition with alirocumab effectively reduced the CVD progression in aging rats suggesting that PCSK9 plays an important role in cardiovascular aging.
Project description:Immune system aging contributes significantly to declining health with age. It is unknown to what extent human and mice immune systems go through similar age-related changes and whether there are conserved biomarkers of aging. We characterized age-related changes in the immune system of long (C57BL/6J) and short-lived (NZO/HILtJ) strains and compared them with blood-driven human aging signatures. Peripheral blood lymphocytes (PBL), spleen cells and spleen-driven naive and memory CD8+ T cells were profiled using flow cytometry, RNA-seq and ATAC-seq from young (3 months) and old (18 months) mice. Pro-inflammatory myeloid genes were activated with age across strains and tissues, echoing human 'inflammaging' signatures. ATAC-seq footprinting analyses uncovered increased binding of pro-inflammatory transcription factors with age (e.g., AP1 complex, NFKB signaling pathway). Machine learning models identified inflammation, cytotoxic, and naive T cell derived genes to be strong signatures of immunosenescence. These data are publicly shared as a resource for immune aging (https://immune-aging.jax.org/mice).
Project description:Immune system aging contributes significantly to declining health with age. It is unknown to what extent human and mice immune systems go through similar age-related changes and whether there are conserved biomarkers of aging. We characterized age-related changes in the immune system of long (C57BL/6J) and short-lived (NZO/HILtJ) strains and compared them with blood-driven human aging signatures. Peripheral blood lymphocytes (PBL), spleen cells and spleen-driven naive and memory CD8+ T cells were profiled using flow cytometry, RNA-seq and ATAC-seq from young (3 months) and old (18 months) mice. Pro-inflammatory myeloid genes were activated with age across strains and tissues, echoing human 'inflammaging' signatures. ATAC-seq footprinting analyses uncovered increased binding of pro-inflammatory transcription factors with age (e.g., AP1 complex, NFKB signaling pathway). Machine learning models identified inflammation, cytotoxic, and naive T cell derived genes to be strong signatures of immunosenescence. These data are publicly shared as a resource for immune aging (https://immune-aging.jax.org/mice).
Project description:Immunosenescence, the age-related decline in immune system function, is a general hallmark of aging. While much is known about the cellular and physiological changes that accompany immunosenescence, we know very little about the genetic influences on this phenomenon. We used microarrays to determine genome-wide expression profiles in twelve inbred D. melanogaster lines that varied in their ability to to clear an E. coli infection at one and four weeks of age.
Project description:It has been observed that immune cell deterioration occurs in the elderly, as well as a chronic low-grade inflammation called inflammaging. These cellular changes must be driven by numerous changes in gene expression and in fact, both protein-coding and non-coding RNA expression alterations have been observed in peripheral blood mononuclear cells from elder people. In the present work we have studied the expression of small non-coding RNA (microRNA and small nucleolar RNA -snoRNA-) from healthy individuals from 24 to 79 years old. We have observed that the expression of 69 non-coding RNAs (56 microRNAs and 13 snoRNAs) changes progressively with chronological age. According to our results, the age range from 47 to 54 is critical given that is the period when the expression trend (increasing or decreasing) of age-related small non-coding RNAs is more pronounced. Furthermore, age-related miRNAs regulate genes that are involved in immune, cell cycle and cancer-related processes, which had already been associated to human aging. Therefore, human aging could be studied as a result of progressive molecular changes, and different age ranges should be analysed to cover the whole aging process.
Project description:Rheumatoid arthritis (RA) usually begins in females in their 4th-5th decade, suggesting that the aging of the immune system (immunosenescence) has a major impact on this disease. In the present microarray study, we set out to identify age- and arthritis-related gene expression pattern changes in proteoglycan (aggrecan)-induced arthritis (PGIA) model. Keywords: disease state analysis
Project description:Studies on immunometabolism have indicated that metabolism and the immunological state are inherently interconnected . Recent research has highlighted the impacts of metabolic syndrome on innate and adaptive immune function, which are linked to overall negative effects on the progression of related diseases . Notably, aging of immune system can be potentiated by dysmetabolism, culminating in chronic inflammation and immune fitness loss . Several age-related immune changes such as progressive loss of naive T cells, an increase in memory cells, and increased percentages of cells with immunosenescence markers, were identified in patients with T2DM . Dysfunction of both innate and adaptive immune responses in T2DM manifests similarly to aging, including poor control of infection and reduced vaccination response, along with elevated inflammatory activity.Hence, we sought to investigate the mechanism of accelerated immunosenescence during T2DM.