Identification, expression and molecular polymorphism of T-cell receptors α and ß from the glacial relict Hucho bleekeri.

The T-cell receptor (TCR) is a specific molecule on the surface of all T cells that mediates cellular adaptive immune responses to antigens. Hucho bleekeri is a critically endangered species and is regarded as a glacial relict that has the lowest-latitude distribution compared with any Eurasian salmonid. In the present study, two TCR genes, namely, TCR α and ß, were identified and characterized in H. bleekeri. Both TCR α and TCR ß have typical TCR structures, including the IgV domain, IgC domain, connecting peptide, transmembrane and cytoplasmic domains. The two TCR genes were constitutionally expressed in various tissues, with the highest expression found in the spleen for TCR α and in the trunk kidney for TCR ß. Challenge of H. bleekeri with LPS or poly(I:C) resulted in significant upregulation of both TCR α and ß expression in headkidney and spleen primary cells, indicating their potential roles in the immune response. Molecular polymorphism analysis of the whole ORF regions of TCR α and ß in different individuals revealed high diversity of IgV domains of these two genes, especially in complementarity-determining region (CDR) 3. The ratio of nonsynonymous substitution occurred at a significantly higher frequency than synonymous substitution in the CDR of TCR α and ß, demonstrating the existence of positive selection. The results obtained in the present study enhance our understanding of TCR roles in regulating immune mechanisms and provide new information for the study of TCR lineage diversity in fish.

Enteric Dysbiosis in Children With Autism Spectrum Disorder and Associated Response to Stress.

Background Microbiome studies in humans, though limited, have facilitated the evaluation of the potential connection between the microbiome and brain function. Children with autism spectrum disorder (ASD) have several behavioral challenges and avoidant/restrictive food intake disorder, which may contribute to gut microbiome dysbiosis. Aim The aim of this study is to examine the extent to which the gut microbiome of children with ASD differs in comparison to children with neurotypical development (CWND) and to assess whether a probiotic intervention has the potential to influence the gut microbiome in mediating positive behavior change and stress regulation. Methods This pilot study collected data from three children with ASD and four CWND before and after a four-week probiotic intervention. Data collection included microbiome diversity screening from stool samples as well as the following biophysiological measures: salivary alpha-amylase (sAA) levels, response to simulated stressor and calming stimulus (behavior), including pulse rate, galvanic skin response, and pupil diameter (PD). In addition, telomere length was assessed. All measures, except for telomere length, were repeated after the four-week intervention on the ASD and CWND groups for pre-/post-comparison. Data analysis consisted of multivariate analyses, including ANOVA. Results While greater heterogeneity in the ASD group was evident in all measures, the gut microbiome of participants who received probiotic intervention differed from pretreatment results within and across the groups investigated. Further, the biophysiological parameter sAA displayed a significant increase between baseline and exposure to stress in both groups, whereas PD increased in both groups from baseline, F(11, 26615) = 123.43, p = 0.00. Conclusion Though gut microbiome diversity is diminished in children with ASD compared to CWND, the gap is narrowed following a brief probiotic intervention. The results suggest that probiotic interventions have the potential to rescue microbiome diversity and abundance, potentially supporting stress regulation in pediatric populations.

Circulating cell-free mitochondrial DNA levels and glucocorticoid sensitivity in a cohort of male veterans with and without combat-related PTSD.

Circulating cell-free mitochondrial DNA (ccf-mtDNA) is a biomarker of cellular injury or cellular stress and is a potential novel biomarker of psychological stress and of various brain, somatic, and psychiatric disorders. No studies have yet analyzed ccf-mtDNA levels in post-traumatic stress disorder (PTSD), despite evidence of mitochondrial dysfunction in this condition. In the current study, we compared plasma ccf-mtDNA levels in combat trauma-exposed male veterans with PTSD (n = 111) with those who did not develop PTSD (n = 121) and also investigated the relationship between ccf mt-DNA levels and glucocorticoid sensitivity. In unadjusted analyses, ccf-mtDNA levels did not differ significantly between the PTSD and non-PTSD groups (t = 1.312, p = 0.191, Cohen's d = 0.172). In a sensitivity analysis excluding participants with diabetes and those using antidepressant medication and controlling for age, the PTSD group had lower ccf-mtDNA levels than did the non-PTSD group (F(1, 179) = 5.971, p = 0.016, partial η2 = 0.033). Across the entire sample, ccf-mtDNA levels were negatively correlated with post-dexamethasone adrenocorticotropic hormone (ACTH) decline (r = -0.171, p = 0.020) and cortisol decline (r = -0.149, p = 0.034) (viz., greater ACTH and cortisol suppression was associated with lower ccf-mtDNA levels) both with and without controlling for age, antidepressant status and diabetes status. Ccf-mtDNA levels were also significantly positively associated with IC50-DEX (the concentration of dexamethasone at which 50% of lysozyme activity is inhibited), a measure of lymphocyte glucocorticoid sensitivity, after controlling for age, antidepressant status, and diabetes status (ß = 0.142, p = 0.038), suggesting that increased lymphocyte glucocorticoid sensitivity is associated with lower ccf-mtDNA levels. Although no overall group differences were found in unadjusted analyses, excluding subjects with diabetes and those taking antidepressants, which may affect ccf-mtDNA levels, as well as controlling for age, revealed decreased ccf-mtDNA levels in PTSD. In both adjusted and unadjusted analyses, low ccf-mtDNA levels were associated with relatively increased glucocorticoid sensitivity, often reported in PTSD, suggesting a link between mitochondrial and glucocorticoid-related abnormalities in PTSD.

WITHDRAWN: Exposure to Ambient Particulate Matter during Pregnancy: Implications for Infant Telomere Length.

This manuscript has been withdrawn by the authors as it was submitted and made public without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. The authors have an approved version for citation that is peer reviewed. Ahlers, N.E.; Lin, J.; Weiss, S.J. Exposure to Ambient Particulate Matter during Pregnancy: Implications for Infant Telomere Length. Air 2024, 2, 24-37. https://doi.org/10.3390/air2010002.

Epigenetic age biomarkers and risk assessment in adult spinal deformity: a novel association of biological age with frailty and disability.

OBJECTIVE: Surgery for spinal deformity has the potential to improve pain, disability, function, self-image, and mental health. These surgical procedures carry significant risk and require careful selection, optimization, and risk assessment. Epigenetic clocks are age estimation tools derived by measuring the methylation patterns of specific DNA regions. The study of biological age in the adult deformity population has the potential to shed insight onto the molecular basis of frailty and to improve current risk assessment tools. METHODS: Adult patients who underwent deformity surgery were prospectively enrolled. Preoperative whole blood samples were used to assess epigenetic age and telomere length. DNA methylation patterns were quantified and processed to extract 4 principal component (PC)-based epigenetic age clocks (PC Horvath, PC Hannum, PC PhenoAge, and PC GrimAge) and the instantaneous pace of aging (DunedinPACE). Telomere length was assessed using both quantitative polymerase chain reaction (telomere to single gene [T/S] ratio) and a methylation-based telomere estimator (PC DNAmTL). Patient demographic and surgical data included age, BMI, American Society of Anesthesiologists Physical Status Classification System class, and scores on the Charlson Comorbidity Index, adult spinal deformity frailty index (ASD-FI), Edmonton Frail Scale (EFS), Oswestry Disability Index, and Scoliosis Research Society-22r questionnaire (SRS-22r). Medical or surgical complications within 90 days of surgery were collected. Spearman correlations and beta coefficients (ß) from linear regression, adjusted for BMI and sex, were calculated. RESULTS: Eighty-three patients were enrolled with a mean age of 65 years, and 45 were women (54%). All patients underwent posterior fusion with a mean of 11 levels fused and 33 (40%) 3-column osteotomies were performed. Among the epigenetic clocks adjusted for BMI and sex, DunedinPACE showed a significant association with ASD-FI (ß = 0.041, p = 0.002), EFS (ß = 0.696, p = 0.026), and SRS-22r (ß = 0.174, p = 0.013) scores. PC PhenoAge showed associations with ASD-FI (ß = 0.029, p = 0.028) and SRS-22r (ß = 0.159, p = 0.018) scores. PC GrimAge showed associations with ASD-FI (ß = 0.029, p = 0.037) and SRS-22r (ß = 0.161, p = 0.025) scores. Patients with postoperative complications were noted to have shorter telomere length (T/S 0.790 vs 0.858, p = 0.049), even when the analysis controlled for BMI and sex (OR = 1.71, 95% CI 1.07-2.87, p = 0.031). CONCLUSIONS: Epigenetic clocks showed significant associations with markers of frailty and disability, while patients with postoperative complications had shorter telomere length. These data suggest a potential role for aging biomarkers as components of surgical risk assessment. Integrating biological age into current risk calculators may improve their accuracy and provide valuable information for patients, surgeons, and payers.

Fecal microbiota transplantation through transendoscopic enteral tubing for inflammatory bowel disease: High acceptance and high satisfaction.

BACKGROUND AND AIM: Fecal microbiota transplantation (FMT) has been shown to positively affect the treatment of inflammatory bowel disease (IBD). However, the safety and efficacy of FMT may depend on the route of microbiota delivery. This study investigates the acceptance, satisfaction, and selection preference of a new delivery route, transendoscopic enteral tubing (TET), for treating IBD. METHODS: A survey was conducted among patients with IBD from five medical centers across China. The objective was to assess their acceptance, subjective feelings, and major concerns regarding two types of TET: colonic TET and mid-gut TET. In addition, the survey also analyzed the factors affecting the selection of TET and TET types among these patients. RESULTS: The final analysis included 351 questionnaires. Up to 76.6% of patients were willing to accept TET and preferred to choose colonic TET when they first learned about TET. Patients with longer disease duration, history of enema therapy, or enteral nutrition were more open to considering TET among IBD patients. After treatment, 95.6% of patients were satisfied with TET, including colonic TET (95.9%) and mid-gut TET (95.1%). Patients with a history of enema therapy and ulcerative colitis preferred colonic TET. In contrast, those with a history of enteral nutrition and Crohn's disease were willing to choose mid-gut TET. However, some patients hesitated to accept TET due to concerns about efficacy, safety, and cost. CONCLUSIONS: TET was highly accepted and satisfied patients with IBD. Disease type and combination therapy influenced the choice of colonic or mid-gut TET.

Sub-optimal maternal gestational gain is associated with shorter leukocyte telomere length at birth in a predominantly Latinx cohort of newborns.

OBJECTIVE: To assess in utero exposures associated with leukocyte telomere length (LTL) at birth and maternal LTL in a primarily Latinx birth cohort. STUDY DESIGN: Mothers and newborns were recruited postnatally before 24 h of life. Newborn LTL was collected via heelstick at birth and maternal LTL was collected postnatally. LTL was determined by quantitative PCR. Using a longitudinal design, we evaluated associations between neonatal and maternal LTL and appropriate maternal gestational gain as indicated by the American College of Obstetrics and Gynecology (ACOG). RESULT: Mean infant LTL was 2.02 ± 0.30 T/S (n = 386) and maternal LTL was 1.54 ± 0.26 T/S (n = 58). Independent risk factors for shorter LTL at birth included longer gestational duration (Coeff:-0.03, 95%CI: -0.05-0.01;p < 0.01) and maternal gestational weight gain below ACOG recommendations (Coeff:-0.10, 95%CI: -0.18 - -0.02; p = 0.01). CONCLUSION: Gestational weight gain below ACOG recommendations may adversely impact neonatal health in Latinx infants as indicated by shorter LTL at birth.

Changes in leukocyte telomere length among children with obesity participating in a behavioural weight control program.

OBJECTIVE: To examine changes in leukocyte telomere length (LTL) during and after a behavioural weight control program for children with obesity. METHODS: We measured LTL among a cohort of 158 children 8-12 years of age with a body mass index greater than or equal to the 95th percentile for age and sex. Children were 55% female, 29% white, 52% Latinx, 8% Asian and 11% Pacific Islander, other or multiethnic. All children participated in a 6-month, family-based, group behavioural weight control program and were assessed before treatment, after treatment and 1 year after the end of treatment. To test the sample population slope of LTL over the intervention and maintenance time periods, we fit spline mixed-effect regression models. RESULTS: LTL increased an average of 0.09 T/S units per year (95% confidence interval [CI] 0.04 to 0.13; p = 0.0001) during the weight control program intervention period, followed by an average decline of -0.05 T/S units per year (95% CI -0.08 to -0.03; p < 0.0001) during the 1 year of follow-up after the completion of the intervention. Among 26 social, psychological, behavioural and physiological factors we examined, we did not find any predictors of these changes. CONCLUSIONS: LTL increased in response to a behavioural weight control program among children with obesity, suggesting an impact on biological health and cellular aging from participation in a behavioural weight control intervention. LTL may be a useful biomarker for assessing changes in response to behavioural interventions.

Working Status of First-Time Postpartum Mothers and Telomere Length-A 1-Year Prospective Study.

OBJECTIVE: Transitioning to motherhood can create work family conflicts affecting mothers' health. Although employment is generally associated with longer telomeres, this may diminish during the early years of child-rearing. This study aimed to assess the impact of work reentry on telomere length (TL) among first-time mothers. METHODS: In this 1-year prospective study, a total of 103 first-time postpartum mothers participated from two medical institutions in Northern Israel; they completed validated questionnaires, reported their current working status, and provided dried blood spots measuring TL. RESULTS: We found that working status significantly predicted change in TL and was negatively correlated with change in TL over time (ß = -0.245; 95% confidence interval, -0.169, -0.018; P = 0.016). CONCLUSIONS: Identifying ideal timing of work reentry is recommended for first-time postpartum mother's optimal health and TL.

Investigating the association of prenatal psychological adversities with mother and child telomere length and neurodevelopment.

BACKGROUND: Exposure to prenatal maternal psychological adversities can negatively affect the offspring's developing brain. Shortened telomere length (TL) has been implicated as a mechanism for the transgenerational effects of maternal psychological adversities on offspring. This study aimed to determine associations between prenatal psychological stressors and distress with maternal and early life TL, and associations between maternal, newborn and child TL with neurodevelopmental outcomes at 2 years of age. METHODS: Follow-up TL was measured in a subgroup of African mothers (n = 138) and their newborns (n = 142) and children (n = 96) at 2-years in the Drakenstein Child Health Study. Prenatal symptoms of depression, distress, intimate partner violence, posttraumatic stress-disorder and childhood trauma were measured at 27 weeks gestation. Neurodevelopment was assessed at 2 years using the Bayley Scales of Infant and Toddler Development III. TLs were measured in whole bloods from mothers and their children at 2-years, and cord bloods in newborns. RESULTS: Maternal prenatal stressors and distress were not significantly associated with TL in mothers or their children at birth or at 2-years. Furthermore, maternal psychological measures were not associated with early-life attrition of TL. Longer TL in children at 2-years was associated (p = 0.04) with higher motor functioning. LIMITATIONS: Limited numbers of participants and single time-point psychological measures. CONCLUSIONS: This study is the first to provide information on the association of early life TL with prenatal psychological adversities and neurodevelopmental outcomes in a population of low-income African mothers and their children.

Intraocular Pressure and Myopia Progression, Axial Length Elongation in Rural Chinese Children.

SIGNIFICANCE: This study reported the relationship between intraocular pressure (IOP) and myopia progression, which helps to understand more comprehensively whether IOP can be an important reference factor to intervene in the progression of myopia. PURPOSE: This study aimed to investigate the association between IOP and myopia progression as well as axial length elongation in rural Chinese children. METHODS: A total of 598 (598 of 878 [68.1%]) children (6 to 17 years) from the baseline Handan Offspring Myopia Study who completed a 3.5-year follow-up vision examination were included. Ocular examinations at both visits included cycloplegic autorefraction, IOP, and axial length measurements. RESULTS: Children with myopia had the highest baseline IOP of the three refractive groups (14.13 ± 1.31, 13.78 ± 1.71, and 13.59 ± 1.64 mmHg in myopes, emmetropes, and hyperopes, respectively, P = .002). However, IOPs showed no significant difference between eyes with or without newly developed myopia (13.63 ± 1.68 vs. 13.89 ± 1.68, P = .16), with or without faster myopia progression (13.75 ± 1.61 vs. 13.86 ± 1.63, P = .46), or with axial length elongation (13.80 ± 1.61 vs. 13.76 ± 1.64, P = .80). The multivariate regression analysis demonstrated that neither baseline refractive error ( ß = -0.082, P = .13) nor baseline axial length ( ß = -0.156, P = .08) was associated with baseline IOP. CONCLUSIONS: Myopic eyes have slightly higher IOP compared with emmetropic and hyperopic eyes, although it was not clinically significant. However, IOP was not found to be associated with either myopia progression or axial length elongation in this cohort sample of rural Chinese children.

Associations between klotho and telomere biology in high stress caregivers.

Aging biomarkers may be related to each other through direct co-regulation and/or through being regulated by common processes associated with chronological aging or stress. Klotho is an aging regulator that acts as a circulating hormone with critical involvement in regulating insulin signaling, phosphate homeostasis, oxidative stress, and age-related inflammatory functioning. Both klotho and telomere length are biomarkers of biological aging and decrease with age; however, the relationship between them is not well understood. Here we test the association between klotho levels and the telomere length of specific sorted immune cells among a healthy sample of mothers caregiving for a child with autism spectrum disorder (ASD; i.e., experiencing higher caregiving stress) or a child without ASD, covarying age and body mass index, in order to understand if high stress associated with caregiving for a child with an ASD may be involved in any association between these aging biomarkers. In 178 caregiving women (n = 90 high-stress mothers of children with ASD, n = 88 low-stress mothers of neurotypical children), we found that klotho levels were positively associated with telomere length in PBMCs (an effect driven by CD4+ and CD8+CD28- T cells) among high-stress mothers of children with an ASD but not among low-stress mothers of neurotypical children. There were no significant associations between klotho and telomerase activity in either group, across cell types assessed here. Our results suggest that klotho levels and telomere length may be associated through a coordinated downregulation of longevity factors occurring under higher stress caregiving conditions.

Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging.

Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by ∼60%, along with a metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load.

A Lens on Caregiver Stress in Cancer: Longitudinal Investigation of Cancer-Related Stress and Telomere Length Among Family Caregivers of Adult Patients With Cancer.

OBJECTIVE: Family members are typically the primary caregivers of patients with chronic illnesses. Family caregivers of adult relatives with cancer are a fast-growing population, yet the physical consequences of their stress due to the cancer in the family have been poorly understood. This study examined the bidirectional relations of the perceived stress of family caregivers of individuals recently diagnosed with cancer and leukocyte cellular aging indexed by telomere length for 2 years. METHODS: Family caregivers ( N = 168; mean age = 51 years, 70% female, 46% Hispanic, 36% spouse to the patient) of patients with colorectal cancer provided psychological data and peripheral blood samples approximately 4 (T1), 12 (T2), and 21 months (T3) after diagnosis. Time-lagged cross-panel modeling was used to test the associations of perceived cancer-related stress and telomere length, controlling for age, sex, and body mass index. RESULTS: Cancer-related stress was highest at T1 and decreased by 1 year. Greater cancer-related stress predicted longer telomere length at subsequent assessments for 2 years ( ß ≥ 0.911, p ≤ .019). However, telomere length did not change significantly for 2 years overall and did not prospectively predict cancer-related stress over this period. CONCLUSIONS: Findings suggest the need to better understand how the perceived stress of colorectal cancer caregivers, which tends to be intense for a relatively short period compared with dementia caregiving, may impact immune cell distributions and telomere length. These findings emphasize the need for further knowledge about psychobiological mechanisms of how cancer caregiving may impact cellular aging.

Early life adversity predicts an accelerated cellular aging phenotype through early timing of puberty.

BACKGROUND: The current study examined if early adversity was associated with accelerated biological aging, and if effects were mediated by the timing of puberty. METHODS: In early mid-life, 187 Black and 198 White (Mage = 39.4, s.d.age = 1.2) women reported on early abuse and age at first menstruation (menarche). Women provided saliva and blood to assess epigenetic aging, telomere length, and C-reactive protein. Using structural equation modeling, we created a latent variable of biological aging using epigenetic aging, telomere length, and C-reactive protein as indicators, and a latent variable of early abuse using indicators of abuse/threat events before age 13, physical abuse, and sexual abuse. We estimated the indirect effects of early abuse and of race on accelerated aging through age at menarche. Race was used as a proxy for adversity in the form of systemic racism. RESULTS: There was an indirect effect of early adversity on accelerated aging through age at menarche (b = 0.19, 95% CI 0.03-0.44), in that women who experienced more adversity were younger at menarche, which was associated with greater accelerated aging. There was also an indirect effect of race on accelerated aging through age at menarche (b = 0.25, 95% CI 0.04-0.52), in that Black women were younger at menarche, which led to greater accelerated aging. CONCLUSIONS: Early abuse and being Black in the USA may both induce a phenotype of accelerated aging. Early adversity may begin to accelerate aging during childhood, in the form of early pubertal timing.

Shorter telomere length predicts poor antidepressant response and poorer cardiometabolic indices in major depression.

Telomere length (TL) is a marker of biological aging, and shorter telomeres have been associated with several medical and psychiatric disorders, including cardiometabolic dysregulation and Major Depressive Disorder (MDD). In addition, studies have shown shorter TL to be associated with poorer response to certain psychotropic medications, and our previous work suggested shorter TL and higher telomerase activity (TA) predicts poorer response to Selective Serotonin Reuptake Inhibitor (SSRI) treatment. Using a new group of unmedicated medically healthy individuals with MDD (n = 48), we sought to replicate our prior findings demonstrating that peripheral blood mononuclear cell (PBMC) TL and TA predict response to SSRI treatment and to identify associations between TL and TA with biological stress mediators and cardiometabolic risk indices. Our results demonstrate that longer pre-treatment TL was associated with better response to SSRI treatment (ß = .407 p = .007). Additionally, we observed that TL had a negative relationship with allostatic load (ß = - .320 p = .017) and a cardiometabolic risk score (ß = - .300 p = .025). Our results suggest that PBMC TL reflects, in part, the cumulative effects of physiological stress and cardiovascular risk in MDD and may be a biomarker for predicting SSRI response.

Predictors of long-term neutralizing antibody titers following COVID-19 vaccination by three vaccine types: the BOOST study.

As concerns related to the COVID-19 pandemic continue, it is critical to understand the impact of vaccination type on neutralizing antibody response durability as well as to identify individual difference factors related to decline in neutralization. This was a head-to-head comparison study following 498 healthy, community volunteers who received the BNT162b2 (n = 287), mRNA-1273 (n = 149), and Ad26.COV2.S (n = 62). Participants completed questionnaires and underwent blood draws prior to vaccination, 1 month, and 6 months after the vaccination series, and neutralizing antibody (nAB) titers at 1- and 6-months post vaccination were quantified using a high-throughput pseudovirus assay. Over 6 months of follow-up, nABs declined in recipients of BNT162b2 and mRNA-1273, while nABs in recipients of Ad26.COV2.S showed a significant increase. At the 6-month time point, nABs to Ad26.COV2.S were significantly higher than nABs to BNT162b2 and equivalent to mRNA-1273. Irrespective of follow-up timing, being older was associated with lower nAB for participants who received BNT162b2 and Ad26.COV2.S but not for those who received mRNA-1273. A higher baseline BMI was associated with a lower nAB for Ad26.COV2.S recipients but not for recipients of other vaccines. Women and non-smokers showed higher nAB compared to men and current smokers, respectively. The durability of neutralizing antibody responses differed by vaccine type and several sociodemographic factors that predicted response. These findings may inform booster recommendations in the future.

Shorter leukocyte telomere length protects against NAFLD progression in children.

Leukocyte telomere length (LTL) gets shorter with each cell division and is also sensitive to reactive oxygen species damage and inflammatory processes. Studies in adults with non-alcoholic fatty liver disease (NAFLD) have found that increased fibrosis but not ALT levels are associated with shorter LTL. Few pediatric studies have been conducted; as such, we sought to evaluate potential associations between LTL and liver disease and liver disease progression in pediatric patients. Using data from the Treatment of NAFLD in Children (TONIC) randomized controlled trial, we assessed the potential predictive relationship between LTL and liver disease progression based on two successive liver biopsies over 96 weeks. We assessed the potential relationship between LTL and child age, sex, and race/ethnicity and features of liver disease including components of histology. We subsequently evaluated predictors for improvement in non-alcoholic steatohepatitis (NASH) at 96 weeks including LTL. We also assessed predictors of lobular inflammation improvement at 96 weeks using multivariable models. Mean LTL at baseline was 1.33 ± 0.23 T/S. Increasing lobular and portal inflammation were associated with longer LTL. In multivariable models, greater lobular inflammation at baseline was associated with longer LTL (Coeff 0.03, 95% CI 0.006-0.13; p = 0.03). Longer LTL at baseline was associated with worsening lobular inflammation at 96 weeks (Coeff 2.41, 95% CI 0.78-4.04; p < 0.01). There was no association between liver fibrosis and LTL. The association between LTL and pediatric NASH does not parallel adults with no association between fibrosis stage and NASH. Conversely, longer LTL was associated with more lobular inflammation at baseline and increased lobular inflammation over the 96-week period. Longer LTL in children may indicate greater risk for future complications from NASH.

Liver Transcriptome Analysis Reveals Energy Regulation and Functional Impairment of Onychostoma sima During Starvation.

Releasing juvenile fish into resource-depleted waters is regarded as an effective way to restore fishery resources. However, during this stage, released fish are most vulnerable to long-term food deprivation due to environmental changes and low adaptability. Therefore, research regarding the energy regulation of fish under starvation stress is crucial to the optimization of release strategies. In this study, we performed a transcriptome analysis of the liver of Onychostoma sima subjected to starvation for 14 days. The results showed that, under long-term starvation, the liver regulated glucose homeostasis by activating the gluconeogenesis pathway. Meanwhile, the fatty acid metabolism pathway was activated to supply acetyl-coA to the TCA cycle, thus increasing mitochondrial ATP production and maintaining the balance of energy metabolism. Nevertheless, the activation of energy metabolism could not completely compensate for the role of exogenous nutrients, as evidenced by the downregulation of many genes involved in antioxidant defenses (e.g., cat, gpx3, mgst1, and mgst2) and immune response (e.g., c3, cd22, trnfrsf14, and a2ml). In summary, our data reveal the effects of long-term starvation on the energy metabolism and defensive regulation of starved juvenile fish, and these findings will provide important reference for the optimization of artificial release.

OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases.

Patients with primary mitochondrial oxidative phosphorylation (OxPhos) defects present with fatigue and multi-system disorders, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. By integrating data from 17 cohorts of patients with mitochondrial diseases (n = 690) we find evidence that these disorders increase resting energy expenditure, a state termed hypermetabolism. We examine this phenomenon longitudinally in patient-derived fibroblasts from multiple donors. Genetically or pharmacologically disrupting OxPhos approximately doubles cellular energy expenditure. This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiency, excluding uncoupling as a general mechanism. Instead, hypermetabolism is associated with mitochondrial DNA instability, activation of the integrated stress response (ISR), and increased extracellular secretion of age-related cytokines and metabokines including GDF15. In parallel, OxPhos defects accelerate telomere erosion and epigenetic aging per cell division, consistent with evidence that excess energy expenditure accelerates biological aging. To explore potential mechanisms for these effects, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations. Taken together, these findings highlight the need to understand how OxPhos defects influence the energetic cost of living, and the link between hypermetabolism and aging in cells and patients with mitochondrial diseases.