Telomere Shortening in Formerly Abused and Never Abused Women

Recent studies suggest that chronic psychological stress may accelerate aging at the cellular level. Telomeres are protective components that stabilize the ends of chromosomes and modulate cellular aging. Women exposed to intimate partner violence (IPV) experience chronic stress and report worse health. The purpose of this exploratory study was to examine telomeric DNA length in women who have experienced chronic stress related to IPV. We hypothesized that IPV exposure would be associated with shorter telomere length. The investigation used a cross-sectional design to study telomere length in women with a history of IPV exposure and control women who reported no prior exposure to IPV. Advertisements and public notices were used to recruit a convenience sample of healthy women. Mean leukocyte telomere length was measured in DNA samples from peripheral blood mononuclear cells (PBMCs) by a quantitative polymerase chain reaction assay (qPCR). Telomere length was significantly shorter in the 61 formerly abused women compared to the 41 controls ( t = 2.4, p = .02). Length of time in the abusive relationship and having children were associated with telomere length after controlling for age and body mass index (BMI) ( F(2, 99) = 10.23, p < .001). Numerous studies suggest that women who experience IPV have poorer overall health. It is often presumed that the stress of IPV may be causing greater morbidity. Findings from this descriptive study suggest a link between IPV exposure, duration of IPV-related stress, and telomere length molecular mechanisms that regulate cellular aging.

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Identification of Molecular Mechanisms in Parkinson’s Disease Pathogenesis: Significance of Survival and Inflammation Pathways

10.21203/rs.3.rs-41609/v1 ◽

2020 ◽

Author(s):

Zerrin Karaaslan ◽

Ozlem Timirci Kahraman ◽

Elif Sanli ◽

Hayriye Arzu Ergen ◽

Basar Bilgic ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Functional Annotation ◽

Molecular Mechanisms ◽

Mononuclear Cells ◽

Neuronal Degeneration ◽

Expression Profiles ◽

Quantitative Polymerase Chain Reaction ◽

Rt Pcr ◽

Peripheral Blood Mononuclear

Abstract Background: Our aim was to identify the differentially expressed genes (DEGs) between Parkinson’s disease (PD) patients and controls by microarray technology and analysis of related molecular pathways by functional annotation. Methods: Thirty PD patients and 30 controls were enrolled. Agilent Human 8X60 K Oligo Microarray was used for gene level expression identification. Gene ontology and pathway enrichment analyses were used for functional annotation of DEGs. Protein-protein interaction analyses were performed with STRING. Expression levels of randomly selected 5 genes among DEGs were quantified by real time quantitative polymerase chain reaction (RT-PCR) for validation. Flow cytometry was done to determine frequency of regulatory T cells (Tregs) in peripheral blood mononuclear cells. Results: A total of 361 DEGs (143 upregulated and 218 downregulated) were identified after GeneSpring analysis. DEGs were involved in 28 biological processes, 12 cellular components and 26 molecular functions. Pathway analyses demonstrated that upregulated genes mainly enriched in p53 (CASP3, TSC2, ATR, MDM4, CCNG1) and PI3K/Akt (IL2RA, IL4R, TSC2, VEGFA, PKN2, PIK3CA, ITGA4, BCL2L11) signaling pathways. TP53 and PIK3CA were identified as most significant hub proteins. Expression profiles obtained by RT-PCR were consistent with microarray findings. PD patients showed increased proportions of CD49d+ Tregs, which correlated with disability scores. Discussion: Survival pathway genes were upregulated putatively to compensate neuronal degeneration. Bioinformatics analysis showed an association between survival and inflammation genes. Increased CD49d+ Treg ratios might signify the attempt of the immune system to suppress ongoing inflammation. Conclusion: Altered functions of Tregs might have an important role in PD pathogenesis and CD49d expression could be a prognostic biomarker of PD.

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Differential impacts of TNFα inhibitors on the transcriptome of Th cells

Arthritis Research & Therapy ◽

10.1186/s13075-021-02558-z ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Ching-Huang Ho ◽

Andrea A. Silva ◽

Beverly Tomita ◽

Hui-Ying Weng ◽

I-Cheng Ho

Keyword(s):

Molecular Mechanisms ◽

Mononuclear Cells ◽

Quantitative Polymerase Chain Reaction ◽

Physical Interaction ◽

Peripheral Blood Mononuclear ◽

Th Cells ◽

Specific Effects ◽

Tnfα Inhibitors

Abstract Background Targeting TNFα is beneficial in many autoimmune and inflammatory diseases, including rheumatoid arthritis. However, the response to each of the existing TNFα inhibitors (TNFis) can be patient- and/or disease-dependent. In addition, TNFis can induce the production of type 1 interferons (IFNs), which contribute to their non-infection side effects, such as pustular psoriasis. Thus far, the molecular mechanisms mediating the drug-specific effects of TNFis and their induction of type 1 IFNs are not fully understood. Methods Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors and stimulated in vitro with anti-CD3 and anti-CD28 in the absence or presence of adalimumab, etanercept, or certolizumab. Th cells were isolated from the stimulated PBMCs, and their RNA was subjected to RNA-seq and quantitative polymerase chain reaction. Results Adalimumab and etanercept, which contain Fc, but not certolizumab, which does not contain Fc, inhibited the expression of several effector cytokines by Th cells within anti-CD3/anti-CD28-stimulated PBMCs. Transcriptomic analyses further showed that adalimumab, but not certolizumab, reciprocally induced type 1 IFN signals and the expression of CD96 and SIRPG in Th cells. The unique effects of adalimumab were not due to preferential neutralization of soluble TNFα but instead were mediated by several distinct mechanisms independent or dependent of Fc-facilitated physical interaction between Th cells and CD14+ monocytes. Conclusions TNFis can have drug-specific effects on the transcriptional profile of Th cells.

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Football and Team Handball Training Postpone Cellular Aging in Women

10.21203/rs.3.rs-275962/v1 ◽

2021 ◽

Author(s):

Marie Hagman ◽

Bjørn Fristrup ◽

Rémi Michelin ◽

Peter Krustrup ◽

Muhammad Asghar

Keyword(s):

Telomere Length ◽

Mitochondrial Function ◽

Copy Number ◽

Mononuclear Cells ◽

Quantitative Polymerase Chain Reaction ◽

Cellular Aging ◽

Elderly Subjects ◽

Mtdna Copy Number ◽

Cross Sectional ◽

Team Handball

Abstract Aims: Several hallmarks of aging have been identified and examined separately in previous exercise studies. For the first time, this study investigates the effect of lifelong regular exercise in humans on two of the central aging hallmarks combined. Methods: This cross-sectional study involved 129 healthy, non-smoking women, including young elite football players (YF, n=29), young untrained controls (YC, n=30), elderly team handball players (EH, n=35) and elderly untrained controls (EC, n=35). From a resting blood sample, mononuclear cells (MNCs) were isolated and sorted into monocytes and lymphocytes. Telomere length, mitochondrial (mtDNA) copy number and mitochondrial function (PGC-1α and PGC-1β expression) were measured using quantitative polymerase chain reaction (qPCR). Results: Overall, young women showed significantly longer telomeres and higher mitochondrial function, but lower mtDNA copy number compared to elderly subjects. A multivariate analysis showed that YF had 22–24% longer telomeres in lymphocytes and MNCs compared to YC. In addition, YF showed 19–20% higher mtDNA copy number in lymphocytes and MNCs compared to YC. The two young groups did not differ in PGC-1α and PGC-1β expression. EH showed 14% lower mtDNA copy number in lymphocytes compared to EC, but 3.4-fold higher lymphocyte PGC-1α expression compared to EC. In MNCs, EH also showed 1.4-1.6- fold higher mitochondrial function. The two elderly groups did not differ in telomere length.Conclusion: Elite football training and lifelong team handball training are associated with anti-aging mechanisms in leukocytes in women, including maintenance of telomere length and upregulation of mitochondrial function.

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Levels of oxidative stress and telomeres in Lynch syndrome-associated malignancies.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.582 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 582-582

Author(s):

Grainne O'Kane ◽

Sarah A. McGarrigle ◽

Nadia Rehill ◽

Michael P. Farrell ◽

Jacintha O'Sullivan ◽

...

Keyword(s):

Oxidative Stress ◽

Colorectal Cancer ◽

Lynch Syndrome ◽

Telomere Length ◽

Mononuclear Cells ◽

Age Of Onset ◽

Quantitative Polymerase Chain Reaction ◽

Peripheral Blood Mononuclear ◽

Increased Risk ◽

The Mean

582 Background: Lynch Syndrome (LS) is caused by germline mutations in mismatch repair genes (MMR) genes which are critical in maintaining cellular integrity. Failure of the MMR pathway in LS culminates in the hypermutable phenotype of Microsatellite Instability. LS confers an increased risk of malignancy of which colorectal cancer (CRC) is most common. Carriers exhibit significant phenotypic variation in the age of onset of malignancy which cannot be predicted. Telomere length attrition is considered an early step in carcinogenesis and may be accelerated by oxidative stress. We investigated an association between relative telomere length (RTL) and levels of DNA oxidative damage in LS affected carriers (AC), unaffected carriers (UAC) and in patients with MMR- proficient colorectal cancer (MPC). Methods: Peripheral blood mononuclear cells were isolated from patients within each group. DNA was extracted and RTL measured by quantitative polymerase chain reaction (PCR). Real-Time PCR was used to quantitate expression levels of TERT, TERC and DKC1 (telomerase components) from RNA. Serum levels of 8-hydroxydeguanosine (8-OHdG) were measured from patients using the ELISA technique. Pearson’s correlation was used to compare mean RTL, telomerase levels and 8-OHdG between groups. Results: RTL and telomerase components were measured in 27 AC (median age 50yrs) 27 UAC (median age 40yrs) and 27 MPC (median age 66yrs). Corresponding RTLs were 0.89, 0.91 and 1.69 respectively. AC had significantly shorter RTL compared to UAC (p = 0.03) and MPC (p < 0.0001). There we no differences in the mean expression of TERT, TERC or DKC between groups. Younger age of tumour onset was associated with shorter telomere length in both AC (p = 0.0006) and MPC (p < 0.0001). 8-OHdG levels have been measured in 17 AC, 19 UAC and 14 MPC. The mean levels of AC and UAC were not statistically different. However the mean MPC level was significantly less than UAC (p = 0.03) and AC (p < 0.0001). Conclusions: Shortened telomere length is an important step in carcinogenesis. Affected LS patients have shorter telomeres and evidence of higher levels of DNA oxidative stress than patients with MMR-proficient CRC.

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Transcriptomics of Long-Term Meditation Practice: Evidence for Prevention or Reversal of Stress Effects Harmful to Health

Medicina ◽

10.3390/medicina57030218 ◽

2021 ◽

Vol 57 (3) ◽

pp. 218

Author(s):

Supaya Wenuganen ◽

Kenneth G. Walton ◽

Shilpa Katta ◽

Clifton L. Dalgard ◽

Gauthaman Sukumar ◽

...

Keyword(s):

Gene Expression ◽

Energy Efficiency ◽

Differential Expression ◽

Molecular Mechanisms ◽

Mononuclear Cells ◽

Quantitative Polymerase Chain Reaction ◽

Control Group ◽

Post Traumatic Stress ◽

Peripheral Blood Mononuclear ◽

Early Results

Background and Objectives: Stress can overload adaptive mechanisms, leading to epigenetic effects harmful to health. Research on the reversal of these effects is in its infancy. Early results suggest some meditation techniques have health benefits that grow with repeated practice. This study focused on possible transcriptomic effects of 38 years of twice-daily Transcendental Meditation® (TM®) practice. Materials and Methods: First, using Illumina® BeadChip microarray technology, differences in global gene expression in peripheral blood mononuclear cells (PBMCs) were sought between healthy practitioners and tightly matched controls (n = 12, age 65). Second, these microarray results were verified on a subset of genes using quantitative polymerase chain reaction (qPCR) and were validated using qPCR in larger TM and control groups (n = 45, age 63). Bioinformatics investigation employed Ingenuity® Pathway Analysis (IPA®), DAVID, Genomatix, and R packages. Results: The 200 genes and loci found to meet strict criteria for differential expression in the microarray experiment showed contrasting patterns of expression that distinguished the two groups. Differential expression relating to immune function and energy efficiency were most apparent. In the TM group, relative to the control, all 49 genes associated with inflammation were downregulated, while genes associated with antiviral and antibody components of the defense response were upregulated. The largest expression differences were shown by six genes related to erythrocyte function that appeared to reflect a condition of lower energy efficiency in the control group. Results supporting these gene expression differences were obtained with qPCR-measured expression both in the well-matched microarray groups and in the larger, less well-matched groups. Conclusions: These findings are consistent with predictions based on results from earlier randomized trials of meditation and may provide evidence for stress-related molecular mechanisms underlying reductions in anxiety, post-traumatic stress disorder (PTSD), cardiovascular disease (CVD), and other chronic disorders and diseases.

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The Impacts of Short-Term NMN Supplementation on Serum Metabolism, Fecal Microbiota, and Telomere Length in Pre-Aging Phase

Frontiers in Nutrition ◽

10.3389/fnut.2021.756243 ◽

2021 ◽

Vol 8 ◽

Author(s):

Kai-Min Niu ◽

Tongtong Bao ◽

Lumin Gao ◽

Meng Ru ◽

Yumeng Li ◽

...

Keyword(s):

Telomere Length ◽

Molecular Mechanisms ◽

Mononuclear Cells ◽

Fecal Microbiota ◽

The Body ◽

Short Term ◽

Peripheral Blood Mononuclear ◽

Nicotinamide Mononucleotide ◽

Human Volunteers ◽

Term Administration

Aging is a natural process with concomitant changes in the gut microbiota and associate metabolomes. Beta-nicotinamide mononucleotide, an important NAD+ intermediate, has drawn increasing attention to retard the aging process. We probed the changes in the fecal microbiota and metabolomes of pre-aging male mice (C57BL/6, age: 16 months) following the oral short-term administration of nicotinamide mononucleotide (NMN). Considering the telomere length as a molecular gauge for aging, we measured this in the peripheral blood mononuclear cells (PBMC) of pre-aging mice and human volunteers (age: 45–60 years old). Notably, the NMN administration did not influence the body weight and feed intake significantly during the 40 days in pre-aging mice. Metabolomics suggested 266 upregulated and 58 downregulated serum metabolites. We identified 34 potential biomarkers linked with the nicotinamide, purine, and proline metabolism pathways. Nicotinamide mononucleotide significantly reduced the fecal bacterial diversity (p < 0.05) with the increased abundance of Helicobacter, Mucispirillum, and Faecalibacterium, and lowered Akkermansia abundance associated with nicotinamide metabolism. We propose that this reshaped microbiota considerably lowered the predicated functions of aging with improved immune and cofactors/vitamin metabolism. Most notably, the telomere length of PBMC was significantly elongated in the NMN-administered mice and humans. Taken together, these findings suggest that oral NMN supplementation in the pre-aging stage might be an effective strategy to retard aging. We recommend further studies to unravel the underlying molecular mechanisms and comprehensive clinical trials to validate the effects of NMN on aging.

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Football and team handball training postpone cellular aging in women

Scientific Reports ◽

10.1038/s41598-021-91255-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Marie Hagman ◽

Bjørn Fristrup ◽

Rémi Michelin ◽

Peter Krustrup ◽

Muhammad Asghar

Keyword(s):

Telomere Length ◽

Copy Number ◽

Mononuclear Cells ◽

Quantitative Polymerase Chain Reaction ◽

Cross Sectional Study ◽

Cellular Aging ◽

Elderly Subjects ◽

Mtdna Copy Number ◽

Cross Sectional ◽

Team Handball

AbstractSeveral hallmarks of aging have been identified and examined separately in previous exercise studies. For the first time, this study investigates the effect of lifelong regular exercise in humans on two of the central aging hallmarks combined. This cross-sectional study involved 129 healthy, non-smoking women, including young elite football players (YF, n = 29), young untrained controls (YC, n = 30), elderly team handball players (EH, n = 35) and elderly untrained controls (EC, n = 35). From a resting blood sample, mononuclear cells (MNCs) were isolated and sorted into monocytes and lymphocytes. Telomere length, mitochondrial (mtDNA) copy number and key regulators of mitochondrial biogenesis and function (PGC-1α and PGC-1β expression) were measured using quantitative polymerase chain reaction (qPCR). Overall, young women showed significantly longer telomeres and higher PGC-1α and PGC-1β expression, but lower mtDNA copy number compared to elderly subjects. A multivariate analysis showed that YF had 22–24% longer telomeres in lymphocytes and MNCs compared to YC. In addition, YF showed 19–20% higher mtDNA copy number in lymphocytes and MNCs compared to YC. The two young groups did not differ in PGC-1α and PGC-1β expression. EH showed 14% lower mtDNA copy number in lymphocytes compared to EC, but 3.4-fold higher lymphocyte PGC-1α expression compared to EC. In MNCs, EH also showed 1.4–1.6-fold higher PGC-1α and PGC-1β expression. The two elderly groups did not differ in telomere length. Elite football training and lifelong team handball training are associated with anti-aging mechanisms in leukocytes in women, including maintenance of telomere length and superior mitochondrial characteristics.

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Impact of Delaying Antiretroviral Treatment during Primary HIV Infection on Telomere Length

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab186 ◽

2021 ◽

Author(s):

Marieke Raffenberg ◽

Tanja Engel ◽

Isabella C Schoepf ◽

Neeltje A Kootstra ◽

Peter Reiss ◽

...

Keyword(s):

Hiv Infection ◽

Telomere Length ◽

Antiretroviral Treatment ◽

Mononuclear Cells ◽

Multivariable Analysis ◽

Limited Effect ◽

Peripheral Blood Mononuclear ◽

Primary Hiv Infection ◽

Hiv Seroconversion ◽

Chronic Hiv Infection

Abstract Background Telomere length (TL) shortens during aging, HIV-seroconversion and untreated chronic HIV infection. It is unknown whether early antiretroviral therapy (ART) start is associated with less TL shortening during primary HIV infection (PHI). Methods We measured TL in peripheral blood mononuclear cells by quantitative PCR in participants of the Zurich PHI Study with samples available for >6 years. We obtained uni-/multivariable estimates from mixed-effects models and evaluated the association of delaying ART start or interrupting ART with baseline and longitudinal TL. Results In 105 participants with PHI (median age 36 years, 9% women), median ART delay was 25, 42, and 60 days, respectively, in the 1 st (shortest), 2 nd, and 3 rd (longest) ART delay tertile. First ART delay tertile was associated with longer baseline TL (p for trend=0.034), and longer TL over 6 years, but only with continuous ART (p<0.001), not if ART was interrupted >12 months (p=0.408). In multivariable analysis, participants in the 2 nd and 3 rd ART delay tertile had 17.6% (5.4-29.7%; p=0.004) and 21.5% (9.4-33.5%; p<0.001) shorter TL, after adjustment for age, with limited effect modification by clinical variables. Discussion In PHI, delaying ART start for even a matter of weeks was associated with significant and sustained TL shortening.

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Peripheral Blood Gene Expression and IgG Glycosylation Profiles as Markers of Tocilizumab Treatment in Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.110961 ◽

2012 ◽

Vol 39 (5) ◽

pp. 916-928 ◽

Cited By ~ 20

Author(s):

BERTALAN MESKO ◽

SZILARD POLISKA ◽

SZILVIA SZAMOSI ◽

ZOLTAN SZEKANECZ ◽

JANOS PODANI ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Gene Expression ◽

Peripheral Blood ◽

Multiple Testing ◽

Mononuclear Cells ◽

Expression Profiles ◽

Quantitative Polymerase Chain Reaction ◽

Response To Treatment ◽

Peripheral Blood Mononuclear ◽

Gene Sets

Objective.Tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, has recently been approved as a biological therapy for rheumatoid arthritis (RA) and other diseases. It is not known if there are characteristic changes in gene expression and immunoglobulin G glycosylation during therapy or in response to treatment.Methods.Global gene expression profiles from peripheral blood mononuclear cells of 13 patients with RA and active disease at Week 0 (baseline) and Week 4 following treatment were obtained together with clinical measures, serum cytokine levels using ELISA, and the degree of galactosylation of the IgG N-glycan chains. Gene sets separating responders and nonresponders were tested using canonical variates analysis. This approach also revealed important gene groups and pathways that differentiate responders from nonresponders.Results.Fifty-nine genes showed significant differences between baseline and Week 4 and thus correlated with treatment. Significantly, 4 genes determined responders after correction for multiple testing. Ten of the 12 genes with the most significant changes were validated using real-time quantitative polymerase chain reaction. An increase in the terminal galactose content of N-linked glycans of IgG was observed in responders versus nonresponders, as well as in treated samples versus samples obtained at baseline.Conclusion.As a preliminary report, gene expression changes as a result of tocilizumab therapy in RA were examined, and gene sets discriminating between responders and nonresponders were found and validated. A significant increase in the degree of galactosylation of IgG N-glycans in patients with RA treated with tocilizumab was documented.

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Decreased levels of miR-28-5p and miR-361-3p and increased levels of insulin-like growth factor 1 mRNA in mononuclear cells from patients with hereditary hemorrhagic telangiectasia

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2018-0508 ◽

2019 ◽

Vol 97 (6) ◽

pp. 562-569 ◽

Cited By ~ 4

Author(s):

Anthony Cannavicci ◽

Qiuwang Zhang ◽

Si-Cheng Dai ◽

Marie E. Faughnan ◽

Michael J.B. Kutryk

Keyword(s):

Growth Factor ◽

Peripheral Blood ◽

Hereditary Hemorrhagic Telangiectasia ◽

Mononuclear Cells ◽

Quantitative Polymerase Chain Reaction ◽

Clinical Manifestations ◽

Mrna Levels ◽

Insulin Like Growth Factor ◽

Peripheral Blood Mononuclear ◽

Micro Rnas

Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disorder inherited in an autosomal dominant manner. Patients with HHT can develop vascular dysplasias called telangiectasias and arteriovenous malformations (AVMs). Our objective was to profile and characterize micro-RNAs (miRNAs), short noncoding RNAs that regulate gene expression posttranscriptionally, in HHT patient-derived peripheral blood mononuclear cells (PBMCs). PBMCs, comprised mostly of lymphocytes and monocytes, have been reported to be dysfunctional in HHT. A total of 40 clinically confirmed HHT patients and 22 controls were enrolled in this study. PBMCs were isolated from 16 mL of peripheral blood and purified for total RNA. MiRNA expression profiling was conducted with a human miRNA array analysis. Select dysregulated miRNAs and miRNA targets were validated with reverse transcription–quantitative polymerase chain reaction. Of the 377 miRNAs screened, 41 dysregulated miRNAs were identified. Both miR-28-5p and miR-361-3p, known to target insulin-like growth factor 1 (IGF1), a potent angiogenic growth factor, were found to be significantly downregulated in HHT patients. Consequently, IGF1 mRNA levels were found to be significantly elevated. Our research successfully identified miRNA dysregulation and elevated IGF1 mRNA levels in PBMCs from HHT patients. This novel discovery represents a potential pathogenic mechanism that could be targeted to alleviate clinical manifestations of HHT.

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