Biology subjects

Shalev, I.

Publications and source records attributed to Shalev, I..

6 recordsLinked to original sources

bioRxiv2024

Cross-Tissue Comparison of Epigenetic Aging Clocks in Humans

Epigenetic clocks are a common group of tools used to measure biological aging - the progressive deterioration of cells, tissues and organs. Epigenetic clocks have been trained almost exclusively using blood-based tissues but there is growing interest in estimating epigenetic age using less-invasive oral-based tissues (i.e., buccal or saliva) in both research and commercial settings. However, differentiated cell types across body tissues exhibit unique DNA methylation landscapes and age-related alterations to the DNA methylome. Applying epigenetic clocks derived from blood-based tissues to estimate epigenetic age of oral-based tissues may introduce biases. We tested the within-person comparability of common epigenetic clocks across five tissue types: buccal epithelial, saliva, dry blood spots, buffy coat (i.e., leukocytes), and peripheral blood mononuclear cells. We tested 284 distinct tissue samples from 83 individuals aged 9-70 years. Overall, there were significant within-person differences in epigenetic clock estimates from oral-based versus blood-based tissues, with average differences of almost 30 years observed in some age clocks. In addition, most epigenetic clock estimates of blood-based tissues exhibited low correlation with estimates from oral-based tissues despite controlling for cellular proportions and other technical factors. Our findings indicate that application of blood-derived epigenetic clocks in oral-based tissues may not yield comparable estimates of epigenetic age, highlighting the need for careful consideration of tissue type when estimating epigenetic age.

genomics↗

bioRxiv2023

Cross-tissue comparison of telomere length and quality metrics of DNA among individuals aged 8 to 70 years

Telomere length (TL) is an important biomarker of cellular aging, yet its links with health outcomes may be complicated by use of different tissues. We evaluated within- and between-individual variability in TL and quality metrics of DNA across five tissues using a cross-sectional dataset ranging from 8 to 70 years (N=197). DNA was extracted from all tissue cells using the Gentra Puregene DNA Extraction Kit. Absolute TL (aTL) in kilobase pairs was measured in buccal epithelial cells, saliva, dried blood spots (DBS), buffy coat, and peripheral blood mononuclear cells (PBMCs) using qPCR. aTL significantly shortened with age for all tissues except saliva and buffy coat, although buffy coat was available for a restricted age range (8 to 15 years). aTL did not significantly differ across blood-based tissues (DBS, buffy coat, PBMC), which had significantly longer aTL than buccal cells and saliva. Additionally, aTL was significantly correlated for the majority of tissue pairs, with partial Spearmans correlations controlling for age and sex ranging from = 0.18 to 0.51. We also measured quality metrics of DNA including integrity, purity, and quantity of extracted DNA from all tissues and explored whether controlling for DNA metrics improved predictions of aTL. We found significant tissue variation: DNA from blood-based tissues had high DNA integrity, more acceptable A260/280 and A260/230 values, and greater extracted DNA concentrations compared to buccal cells and saliva. Longer aTL was associated with lower DNA integrity, higher extracted DNA concentrations, and higher A260/230, particularly for saliva. Model comparisons suggested that incorporation of quality DNA metrics improves models of TL, although relevant metrics vary by tissue. These findings highlight the merits of using blood-based tissues and suggest that incorporation of quality DNA metrics as control variables in population-based studies can improve TL predictions, especially for more variable tissues like buccal and saliva.

genomics↗

bioRxiv2022

Effects of DNA extraction, DNA integrity, and laboratory on the precision of qPCR-based telomere length measurement - a multi-lab impartial study

Measuring telomere length (TL) with high precision is challenging. Currently there is insufficient understanding of the causes of variation in measurement precision, particularly for qPCR-based measurement. To better understand how DNA extraction protocols and laboratory-specific analytical factors influence qPCR-based TL measurement precision, we conducted a multi-laboratory study involving four labs and six DNA extraction protocols assaying the same blinded human whole blood samples. DNA extraction protocols differed in underlying principles (magnetic beads, salting out, silica membrane) and commercial kits. A fifth lab performed Telomere Restriction Fragment (TRF) analysis using Southern Blot technique with one DNA extraction protocol. All labs performed TL measurement using their standard procedures on two sets of fifty double blinded samples. Data was sent to a central point for unblinding and statistical analyses. Precision was quantified using the Intraclass Correlation Coefficient (ICC). Correlations with TRF measurements were also calculated. Repeated qPCR-based measurements of the same DNA extraction yielded ICC values ranging from 0.24 to 0.94. ICC values calculated over measurements of repeated DNA extractions were on average 0.23 lower and ranged from 0.02 to 0.83. The latter ICC estimates more strongly predicted the association between qPCR- and Southern blot-based measurements across the protocol / lab combinations (R2=0.56 vs. R2=0.93). We conclude that ICC calculated over measurements on repeated DNA extractions reliably indicates measurement precision, while ICC calculated over multiple measurements of the same DNA extraction overestimates measurement precision. Variation in ICC was driven by variation between laboratories, with few consistent DNA extraction protocol effects. Values of DNA integrity and purity generally characterized as reflecting high sample quality, (e.g. OD 260/280 of 1.8 and OD 260/230 of 2.0) were associated with qPCR-based measurement precision, but did not always predict higher ICCs.

molecular biology↗

bioRxiv2022

Data-driven dissection of the Fever Effect in Autism Spectrum Disorder

Some individuals with autism spectrum disorder (ASD) demonstrate marked behavioral improvements during febrile episodes, in what is perhaps the only present-day means of modulating the core ASD phenotype. Understanding the nature of this so-called fever effect is therefore essential for leveraging this natural temporary relief of symptoms to a sustained efficacious intervention. Towards this goal, we used machine learning to analyze the rich clinical data of the Simons Simplex Collection, in which 1 out of every 6 children with ASD was reported to improve during febrile episodes, across multiple ASD domains. Reported behavioral improvements during febrile episodes were associated with maternal infection in pregnancy (OR = 1.7, 95% CI = [1.42, 2.03], P = 4.24x10-4) and gastrointestinal (GI) dysfunction (OR=1.46, 95% CI = [1.15, 1.81], P = 1.94x10-3). Family members of children reported to improve when febrile have an increased prevalence of autoimmune disorders (OR=1.43, 95% CI = [1.23, 1.67], P = 3.0x10-6), language disorders (OR=1.63, 95% CI = [1.29, 2.04], P = 2.5x10-5), and neuropsychiatric disorders (OR=1.59, 95% CI = [1.34, 1.89], P < 1x10-6). Since both GI abnormalities and maternal immune activation have been linked to ASD via proinflammatory cytokines, these results might suggest a possible involvement of immune dysregulation in the fever effect, consistent with findings in mouse models. This work advances our understanding of the fever-responsive ASD subtype and motivates future studies to directly test the link between proinflammatory cytokines and behavioral modifications in individuals with ASD. Lay summarySome individuals with ASD demonstrate marked behavioral improvements when they have a fever. However, the magnitude, scope, nature, and underlying neurobiological basis of the so-called fever effect remain unknown. This large-scale biomedical data analysis found that children with ASD reported to improve when febrile tend to be those with worse gastrointestinal symptoms and whose mothers reported an infection during pregnancy. These and other findings point to the involvement of proinflammatory cytokines in this phenomenon.

neuroscience↗

bioRxiv2019

Internalizing Symptoms Associate with the Pace of Epigenetic Aging in Childhood

Childhood psychiatric symptoms may be associated with advanced biological aging. This study examined whether epigenetic age acceleration (EAA) associates with internalizing and externalizing symptoms across childhood in a longitudinal cohort study. At age 6 buccal epithelial cells from 148 children (69 girls) were collected to survey genome-wide DNA methylation. EAA was estimated using the Horvath clock. Internalizing symptoms at ages 2.5 and 4 years significantly predicted higher EAA at age 6, which in turn was significantly associated with internalizing symptoms from ages 6 to 10 years. Similar trends for externalizing symptoms did not reach significance. These findings indicate advanced biological aging in relation to child mental health and may help better identify those at risk for lasting impairments associated with internalizing disorders.

genetics↗

bioRxiv2019

Early-life adversity is associated with differential gene expression in response to acute psychological stress: preliminary findings

ObjectiveExposure to early-life adversity (ELA) can result in long-term changes to physiological systems, which predispose individuals to negative health outcomes. This biological embedding of stress-responsive systems may operate via dysregulation of physiological resources in response to common stressors. The present study used a novel experimental design to test how young adults exposure to ELA influence neuroendocrine and inflammatory responses to acute stress.\n\nMaterials and methodsParticipants were 12 males (mean age= 21.25), half of whom endorsed at least three significant adverse events up to age 18 years ( ELA group), and half who confirmed zero ( controls). Using a randomized within-subjects, between-groups experimental design, we induced acute psychosocial stress (Trier Social Stress Test, TSST), and included a no-stress control condition one week apart. During these sessions, we obtained repeated measurements of physiological reactivity, gene expression of NR3C1, FKBP5 and NFKB1, and plasma levels of pro-inflammatory cytokines (IL-1{beta}, IL-6, IL-8 and TNF) over a 4-hour window post-test.\n\nResultsThe ELA group evinced significantly higher cortisol response and lower NR3C1 gene expression in response to the TSST compared with controls, while no differences were observed in the no-stress condition. Cortisol and group status interacted such that increase in cortisol predicted increase in both NR3C1 and NFKB1 expression among controls, but decrease in the ELA group. For pro-inflammatory cytokines, only IL-6 increased significantly in response to the TSST, with no differences between the two groups.\n\nConclusionOverall, we provide preliminary findings for the biological embedding of stress via a dynamic and dysregulated pattern evidenced in response to acute psychosocial stress. ELA may program physiological systems in a maladaptive manner more likely to manifest during times of duress, predisposing individuals to the negative health consequences of everyday stressors. Future studies with larger sample size including both males and females are needed to replicate these findings.

molecular biology↗