Testing three hypotheses about effects of sensitive-insensitive parenting on telomeres.

Telomeres are the protective DNA-protein sequences appearing at the ends of chromosomes; they shorten with each cell division and are considered a biomarker of aging. Shorter telomere length and greater erosion have been associated with compromised physical and mental health and are hypothesized to be affected by early life stress. In the latter case, most work has relied on retrospective measures of early life stressors. The Dutch research (n = 193) presented herein tested 3 hypotheses prospectively regarding effects of sensitive-insensitive parenting during the first 2.5 years on telomere length at age 6, when first measured, and change over the following 4 years. It was predicted that (1) less sensitive parenting would predict shorter telomeres and greater erosion and that such effects would be most pronounced in children (2) exposed to prenatal stress and/or (3) who were highly negatively emotional as infants. Results revealed, only, that prenatal stress amplified parenting effects on telomere change-in a differential-susceptibility-related manner: Prenatally stressed children displayed more erosion when they experienced insensitive parenting and less erosion when they experienced sensitive parenting. Mechanisms that might initiate greater postnatal plasticity as a result of prenatal stress are highlighted and future work outlined. (PsycINFO Database Record (c) 2020 APA, all rights reserved)

Translating Measures of Biological Aging to Test Effectiveness of Geroprotective Interventions: What Can We Learn from Research on Telomeres?

Intervention studies in animals suggest molecular changes underlying age-related disease and disability can be slowed or reversed. To speed translation of these so-called “geroprotective” therapies to prevent age-related disease and disability in humans, biomarkers are needed that can track changes in the rate of human aging over the course of intervention trials. Algorithm methods that measure biological processes of aging from combinations of DNA methylation marks or clinical biomarkers show promise. To identify next steps for establishing utility of these algorithm-based measures of biological aging for geroprotector trials, we considered the history a candidate biomarker of aging that has received substantial research attention, telomere length. Although telomere length possesses compelling biology to recommend it as a biomarker of aging, mixed research findings have impeded clinical and epidemiologic translation. Strengths of telomeres that should be established for algorithm biomarkers of aging are correlation with chronological age across the lifespan, prediction of disease, disability, and early death, and responsiveness to risk and protective exposures. Key challenges in telomere research that algorithm biomarkers of aging must address are measurement precision and reliability, establishing links between longitudinal rates of change across repeated measurements and aging outcomes, and clarity over whether the biomarker is a causal mechanism of aging. These strengths and challenges suggest a research agenda to advance translation of algorithm-based aging biomarkers: establish validity in young-adult and midlife individuals; test responsiveness to exposures that shorten or extend healthy lifespan; and conduct repeated-measures longitudinal studies to test differential rates of change

Testing three hypotheses about effects of sensitive-insensitive parenting on telomeres.

Telomeres are the protective DNA-protein sequences appearing at the ends of chromosomes; they shorten with each cell division and are considered a biomarker of aging. Shorter telomere length and greater erosion have been associated with compromised physical and mental health and are hypothesized to be affected by early life stress. In the latter case, most work has relied on retrospective measures of early life stressors. The Dutch research (n = 193) presented herein tested 3 hypotheses prospectively regarding effects of sensitive-insensitive parenting during the first 2.5 years on telomere length at age 6, when first measured, and change over the following 4 years. It was predicted that (1) less sensitive parenting would predict shorter telomeres and greater erosion and that such effects would be most pronounced in children (2) exposed to prenatal stress and/or (3) who were highly negatively emotional as infants. Results revealed, only, that prenatal stress amplified parenting effects on telomere change-in a differential-susceptibility-related manner: Prenatally stressed children displayed more erosion when they experienced insensitive parenting and less erosion when they experienced sensitive parenting. Mechanisms that might initiate greater postnatal plasticity as a result of prenatal stress are highlighted and future work outlined. (PsycINFO Database Record (c) 2020 APA, all rights reserved)

Biological stability of DNA methylation measurements over varying intervals of time and in the presence of acute stress

Identifying factors that influence the stability of DNA methylation measurements across biological replicates is of critical importance in basic and clinical research. Using a within-person between-group experimental design (n = 31, number of observations = 192), we report the stability of biological replicates over a variety of unique temporal scenarios, both in the absence and presence of acute psychosocial stress, and between individuals who have experienced early life adversity (ELA) and non-exposed individuals. We found that varying time intervals, acute stress, and ELA exposure influenced the stability of repeated DNA methylation measurements. In the absence of acute stress, probes were less stable as time passed; however, stress exerted a stabilizing influence on probes over longer time intervals. Compared to non-exposed individuals, ELA-exposed individuals had significantly lower probe stability immediately following acute stress. Additionally, we found that across all scenarios, probes used in most epigenetic-based algorithms for estimating epigenetic age or immune cell proportions had average or below-average stability, except for the Principal Component and DunedinPACE epigenetic ageing clocks, which were enriched for more stable probes. Finally, using highly stable probes in the absence of stress, we identified multiple probes that were hypomethylated in the presence of acute stress, regardless of ELA status. Two hypomethylated probes are located near the transcription start site of the glutathione-disulfide reductase gene (GSR), which has previously been shown to be an integral part of the stress response to environmental toxins. We discuss implications for future studies concerning the reliability and reproducibility of DNA methylation measurements. Abbreviations: DNAm – DNA methylation, CpG − 5’-cytosine-phosphate-guanine-3,’ ICC – Interclass correlation coefficient, ELA – Early-life adversity, PBMCs – Peripheral blood mononuclear cells, mQTL – Methylation quantitative trait loci, TSS – Transcription start site, GSR – Glutathione-disulfide reductase gene, TSST – Trier social stress test, PC – Principal component

Immune cell dynamics in response to an acute laboratory stressor: a within-person between-group analysis of the biological impact of early life adversity

Early life adversity (ELA) is a risk factor for early onset morbidities and mortality, a relationship that may be driven in part by immune system dysregulation. One mechanism of dysregulation that has yet to be fully examined in the context of ELA is alterations to immune cell dynamics in response to acute stress. Using a within-person between-group experimental design, we investigated stress-induced changes in immune cell populations, and how these changes may be altered in individuals with a history of ELA. Participants were young adults (N = 34, aged 18–25 years, 53% female, 47% with a history of ELA). Complete immune cell counts were measured at four time-points over a 5-hour window across two sessions (Trier Social Stress Test [TSST] vs. no-stress) separated by a week. Across all participants, total white blood cells increased over time (F(3,84)=38.97, p b = 0.43±.19; t(179)=2.22, p = .027). This pattern was mirrored by neutrophil counts. Lymphocyte counts were initially depressed by TSST exposure (b =−205±.67; t(184)=−3.07, p = .002) but recovered above baseline. ELA status was associated with higher stress-induced immune cell counts, a difference likely driven by increases in neutrophils (F(1,22)=4.45, p = .046). Overall, these results indicate differential immune cell dynamics in response to acute stress in individuals with a history of ELA. This points to altered immune system functioning in the context of stress, a finding that may be driving increased morbidity and mortality risk for ELA-exposed individuals.</p

An Alternative Domain Near the ATP Binding Pocket of Drosophila Myosin Affects Muscle Fiber Kinetics

We examined the importance of alternative versions of a region near the ATP binding site of Drosophila myosin heavy chain for muscle mechanical properties. Previously, we exchanged two versions of this region (encoded by alternative exon 7s) between the indirect flight muscle myosin isoform (IFI) and an embryonic myosin isoform (EMB) and found, surprisingly, that in vitro solution actin-activated ATPase rates were increased (higher V(max)) by both exon exchanges. Here we examined the effect of increased ATPase rate on indirect flight muscle (IFM) fiber mechanics and Drosophila locomotion. IFM expressing EMB with the exon 7a domain replaced by the IFM specific exon 7d domain (EMB-7d) exhibited 3.2-fold greater maximum oscillatory power (P(max)) and 1.5-fold greater optimal frequency of power generation (f(max)) versus fibers expressing EMB. In contrast, IFM expressing IFI with the exon 7d region replaced by the EMB exon 7a region (IFI-7a), showed no change in P(max), f(max), step response, or isometric muscle properties compared to native IFI fibers. A slight decrement in IFI-7a flight ability was observed, suggesting a negative influence of the increased ATPase rate on Drosophila locomotion, perhaps due to energy supply constraints. Our results show that exon 7 plays a substantial role in establishing fiber speed and flight performance, and that the limiting step that sets ATPase rate in Drosophila myosin has little to no direct influence in setting f(max) for fast muscle fiber types