Epigenetic Aging Associations With Psychoneurological Symptoms and Social Functioning in Adults With Sickle Cell Disease.

Objective: Sickle cell disease (SCD), the most common inherited blood disorder in the United States, is associated with severe psychoneurological symptoms. While epigenetic age acceleration has been linked to psychoneurological symptom burden in other diseases, this connection is unexplored in SCD. This study aimed to assess the association between epigenetic age acceleration and psychoneurological symptom burden in SCD. Methods: In this cross-sectional study, emotional impact, pain impact, sleep impact, social functioning, and cognitive function were assessed in 87 adults living with SCD. DNA methylation data were generated from blood specimens and used to calculate epigenetic age using five clocks (Horvath, Hannum, PhenoAge, GrimAge, & DunedinPACE). Associations between epigenetic age acceleration and symptoms were assessed. Results: The sample (N = 87) had a mean (SD) chronologic age was 30.6 (8.1) years. Epigenetic age acceleration was associated with several symptom outcomes. GrimAge age acceleration (ß = -0.49, p = .03) and increased DunedinPACE (ß = -2.23, p = .004) were associated with worse emotional impact scores. PhenoAge (ß = -0.32, p = .04) and the GrimAge (ß = -0.48, p = .05) age acceleration were associated with worse pain impact scores. Increased DunedinPACE (ß = -2.07 p = .04) were associated with worse sleep impact scores. Increased DunedinPACE (ß = -2.87, p = .005) was associated with worse social functioning scores. We did not find associations between epigenetic age acceleration and cognitive function in this sample. Conclusion: Epigenetic age acceleration was associated with worse symptom experiences, suggesting the potential for epigenetic age acceleration as a biomarker to aid in risk stratification or targets for intervention to mitigate symptom burden in SCD.

Characterizing epigenetic aging in an adult sickle cell disease cohort.

ABSTRACT: Sickle cell disease (SCD) affects ∼100 000 predominantly African American individuals in the United States, causing significant cellular damage, increased disease complications, and premature death. However, the contribution of epigenetic factors to SCD pathophysiology remains relatively unexplored. DNA methylation (DNAm), a primary epigenetic mechanism for regulating gene expression in response to the environment, is an important driver of normal cellular aging. Several DNAm epigenetic clocks have been developed to serve as a proxy for cellular aging. We calculated the epigenetic ages of 89 adults with SCD (mean age, 30.64 years; 60.64% female) using 5 published epigenetic clocks: Horvath, Hannum, PhenoAge, GrimAge, and DunedinPACE. We hypothesized that in chronic disease, such as SCD, individuals would demonstrate epigenetic age acceleration, but the results differed depending on the clock used. Recently developed clocks more consistently demonstrated acceleration (GrimAge, DunedinPACE). Additional demographic and clinical phenotypes were analyzed to explore their association with epigenetic age estimates. Chronological age was significantly correlated with epigenetic age in all clocks (Horvath, r = 0.88; Hannum, r = 0.89; PhenoAge, r = 0.85; GrimAge, r = 0.88; DunedinPACE, r = 0.34). The SCD genotype was associated with 2 clocks (PhenoAge, P = .02; DunedinPACE, P < .001). Genetic ancestry, biological sex, ß-globin haplotypes, BCL11A rs11886868, and SCD severity were not associated. These findings, among the first to interrogate epigenetic aging in adults with SCD, demonstrate epigenetic age acceleration with recently developed epigenetic clocks but not older-generation clocks. Further development of epigenetic clocks may improve their predictive ability and utility for chronic diseases such as SCD.

Lysyl oxidase-like 1-antisense 1 (LOXL1-AS1) lncRNA differentially regulates gene and protein expression, signaling and morphology of human ocular cells.

Pseudoexfoliation glaucoma (PEXG) is characterized by dysregulated extracellular matrix (ECM) homeostasis that disrupts conventional outflow function and increases intraocular pressure (IOP). Prolonged IOP elevation results in optic nerve head damage and vision loss. Uniquely, PEXG is a form of open angle glaucoma that has variable penetrance, is difficult to treat and does not respond well to common IOP-lowering pharmaceuticals. Therefore, understanding modulators of disease severity will aid in targeted therapies for PEXG. Genome-wide association studies have identified polymorphisms in the long non-coding RNA lysyl oxidase-like 1-antisense 1 (LOXL1-AS1) as a risk factor for PEXG. Risk alleles, oxidative stress and mechanical stretch all alter LOXL1-AS1 expression. As a long non-coding RNA, LOXL1-AS1 binds hnRNPL and regulates global gene expression. In this study, we focus on the role of LOXL1-AS1 in the ocular cells (trabecular meshwork and Schlemm's canal) that regulate IOP. We show that selective knockdown of LOXL1-AS1 leads to cell-type-specific changes in gene expression, ECM homeostasis, signaling and morphology. These results implicate LOXL1-AS1 as a modulator of cellular homeostasis, altering cell contractility and ECM turnover, both of which are well-known contributors to PEXG. These findings support LOXL1-AS1 as a key target for modifying the disease.

A partial genome assembly of the miniature parasitoid wasp, Megaphragma amalphitanum.

Body size reduction, also known as miniaturization, is an important evolutionary process that affects a number of physiological and phenotypic traits and helps animals conquer new ecological niches. However, this process is poorly understood at the molecular level. Here, we report genomic and transcriptomic features of arguably the smallest known insect-the parasitoid wasp, Megaphragma amalphitanum (Hymenoptera: Trichogrammatidae). In contrast to expectations, we find that the genome and transcriptome sizes of this parasitoid wasp are comparable to other members of the Chalcidoidea superfamily. Moreover, compared to other chalcid wasps the gene content of M. amalphitanum is remarkably conserved. Intriguingly, we observed significant changes in M. amalphitanum transposable element dynamics over time, in which an initial burst was followed by suppression of activity, possibly due to a recent reinforcement of the genome defense machinery. Overall, while the M. amalphitanum genomic data reveal certain features that may be linked to the unusual biological properties of this organism, miniaturization is not associated with a large decrease in genome complexity.