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While previous studies have demonstrated that prenatal exposure to environmental stressors is associated with mitochondrial DNA (mtDNA) methylation, more recent investigations are questioning the accuracy of the methylation assessment and its biological relevance. In this study, we investigated placental mtDNA methylation while accounting for methodological issues such as nuclear contamination, bisulphite conversion, and PCR bias. From the ENVIRONAGE birth cohort, we selected three groups of participants (n = 20/group). One group with mothers who smoked during pregnancy (average 13.2 cig/day), one group with high air pollutant exposure (PM2.5: 16.0 ± 1.4 µg/m3, black carbon: 1.8 ± 0.3 µg/m3) and one control group (non-smokers, PM2.5: 10.6 ± 1.7 µg/m3, black carbon: 0.9 ± 0.1 µg/m3) with low air pollutant exposure. DNA methylation levels were quantified in two regions of the displacement loop control region (D-loop and LDLR2) by bisulphite pyrosequencing. Additionally, we measured DNA methylation on nuclear genes involved in mitochondrial maintenance (PINK1, DNA2, and POLG1) and assessed mtDNA content using qPCR. Absolute D-loop methylation levels were higher for mothers that smoked extensively (+0.36%, 95% CI: 0.06% to 0.66%), and for mothers that were highly exposed to air pollutants (+0.47%, 95% CI: 0.20% to 0.73%). The relevance of our findings is further supported, as D-loop methylation levels were correlated with placental mtDNA content (r = −0.40, p = 0.002) and associated with birth weight (−106.98 g, 95% CI: −209.60 g to −4.36 g for an IQR increase in D-loop methylation). Most notably, our data demonstrates relevant levels of mtDNA methylation in placenta tissue, with significant associations between prenatal exposure to environmental stressors and D-loop methylation. [ABSTRACT FROM AUTHOR]

Simple Summary: Dairy cows are essential for milk production, but their productive lifespan—how long they stay healthy and productive—has not increased in recent years. This has led to concerns about animal welfare, environmental sustainability, and farm profitability. Scientists are searching for ways to predict which calves will have longer, healthier lives. One idea is to measure telomeres: tiny structures at the ends of chromosomes that shorten as animals age. In this study, we measured the telomere length of newborn dairy calves and investigated if it could predict their lifespan, milk production, or reproductive performance. We found that telomere length did not predict how long the cows lived or how much milk they produced. However, calves with the longest telomeres were less efficient at producing milk fat and protein. Interestingly, these calves also required fewer inseminations and had slightly longer intervals between calvings, suggesting a possible link to reproductive performance. While telomere length alone may not be a reliable predictor of lifespan or productivity, it could help us better understand the biology of aging and reproduction in dairy cows. Future research could provide more insights into how this information could improve animal welfare and farming efficiency. Telomere length (TL) has gained attention as a biomarker for longevity and productivity in dairy cattle. This study explored the association between neonatal TL in Holstein calves and lifetime parameters (lifespan, milk production, and reproduction). Blood samples were collected from 210 calves (≤10d old) across four dairy farms in Flanders, Belgium. Telomere length was measured using qPCR and analyzed as a continuous variable and across three groups: the 10% shortest, the 10% longest, and the remaining 80%. Survival analyses showed no association between TL and lifespan (p = 0.1) or TL groups (p = 0.8). Similarly, TL showed no significant association with production traits. However, categorical analyses revealed that calves with the longest TL had lower lifetime fat (p = 0.01) and protein yields (p = 0.01) than those with the shortest TL. Reproductive analyses showed cows in the long TL group required fewer inseminations per lactation (p = 0.02) and exhibited longer calving intervals (p = 0.05). These findings suggest that while neonatal TL may not predict productive lifespan, it may provide insight into reproductive efficiency. Future studies should prioritize longitudinal assessments of TL dynamics to better understand their interactions with management practices and application in herd improvement. [ABSTRACT FROM AUTHOR]

Telomere length is associated with longevity and survival in multiple species. In human population-based studies, multiple prenatal factors have been described to be associated with a newborn's telomere length. In the present study, we measured relative leukocyte telomere length in 210 Holstein Friesian heifers, within the first ten days of life. The dam's age, parity, and milk production parameters, as well as environmental factors during gestation were assessed for their potential effect on telomere length. We found that for both primi- and multiparous dams, the telomere length was 1.16% shorter for each day increase in the calf's age at sampling (P = 0.017). The dam's age at parturition (P = 0.045), and the median temperature-humidity index (THI) during the third trimester of gestation (P = 0.006) were also negatively associated with the calves' TL. Investigating multiparous dams separately, only the calf's age at sampling was significantly and negatively associated with the calves' TL (P = 0.025). Results of the present study support the hypothesis that in cattle, early life telomere length is influenced by prenatal factors. Furthermore, the results suggest that selecting heifers born in winter out of young dams might contribute to increased longevity in dairy cattle. [ABSTRACT FROM AUTHOR]

Telomere length (TL) is a recognized biomarker for ageing in multiple species. In dairy cattle, the transition period is considered a very stressful period. We hypothesized that TL shortens during this period. Holstein cows (n = 61) were followed during the transition period. Blood and milk samples were collected at − 7, 3, 6, 9, 21d relative to calving to determine concentrations of oxidative, energetic metabolic, and inflammatory markers. Average relative leukocyte TL was measured by a modified qPCR protocol 7d before and 21d after parturition. We confirmed TL attrition during the transition period (P = 0.02), as TL was 1.05 ± 0.229 (mean ± SD) before, and 0.97 ± 0.191 (mean ± SD) after parturition. Univariable analyses assessed associations between blood markers and TL shortening. Greater plasma oxidative parameters, including oxidized glutathione and glutathione peroxidase, were positively and negatively (respectively) associated with TL attrition. Higher blood α- and β-globulin were all positively associated, while IGF-1, albumin-globulin ratio and albumin were negatively associated with TL attrition. Greater serum amyloid A and haptoglobin were linked with greater TL shortening. This study reveals significant TL shortening during the transition period in dairy cows and identifies significant associations with oxidative stress, metabolic stress, and inflammation. While these associations are observed, no causality can be established. Our findings suggest the need for further research to explore the effects of transition-related stress on TL dynamics. [ABSTRACT FROM AUTHOR]

Changes in NR3C1 and IGF2/H19 methylation patterns have been associated with behavioural and psychiatric outcomes. Maternal mental state has been associated with offspring NR3C1 promotor and IGF2/H19 imprinting control region (ICR) methylation patterns. However, there is a lack of prospective studies with long-term follow-up. 52 mother-offspring pairs were studied from 12 to 22 weeks of pregnancy and offspring was followed-up until 28–29 years-of-age. During pregnancy, mothers filled in a Life Event Scale and a Daily Hassles Scale measuring perceived stress; i.e., appraisal or subjectively experienced severity of impact of important life events and of daily hassles in several life domains during pregnancy, respectively. Green space was quantified around the residence, using high-resolution (1 m2) map data. Saliva and blood samples were obtained from the adult offspring. Absolute DNA methylation levels were determined in blood and saliva on four NR3C1 amplicons, and one IGF2/H19 ICR amplicon using a bisulfite PCR and sequencing method. Linear mixed effect models were used to test the associations between perceived stress and green spaces during pregnancy, and adult offspring methylation patterns. We found associations between maternal perceived stress during pregnancy and methylation patterns on two out of the four NR3C1 amplicons, measured in blood, from offspring in adulthood, but not with IGF2/H19 methylation. For an interquartile-range (IQR) increase in maternal perceived life event or daily hassles stress scores, absolute methylation levels on several NR3C1 CpG sites were significantly changed (-1.62 % to +5.89 %, p<0.05). Maternal perceived stress scores were not associated with IGF2/H19 methylation, neither in blood nor in saliva. Maternal exposure to green spaces surrounding the residence during the pregnancy was associated with IGF2/H19 ICR methylation (-0.80 % to −1.04 %, p<0.05) in saliva, but not with NR3C1 promotor methylation. We observed significant long-term effects of maternal perceived stress during pregnancy on the methylation patterns of the NR3C1 promotor in offspring well into adulthood. This may imply that maternal psychological distress during pregnancy may influence the regulation of the HPA-axis well into adulthood. Additionally, maternal proximity to green spaces was associated with IGF2/H19 ICR methylation patterns, which is a novel finding. • Maternal stress during pregnancy is associated with NR3C1 methylation in adult offspring. • Maternal proximity to green is associated with IGF2/H19 methylation in adult offspring. • Our results are in line with previous studies while adding long-term follow-up data. [ABSTRACT FROM AUTHOR]

Shortened telomere length (TL) has been associated with lower cognitive performance, different neurological diseases in adults, and certain neurodevelopmental disorders in children. However, the evidence about the association between TL and neuropsychological developmental outcomes in children from the general population is scarce. Therefore, this study aimed to explore the association between TL and neuropsychological function in children 4–5 years of age. We included 686 children from the INMA Project, a population-based birth cohort in Spain. Leucocyte TL was determined by quantitative PCR method, and neuropsychological outcomes were measured using the McCarthy Scales of Children's Abilities (MCSA). Multiple linear regression models were used to estimate associations adjusted for potential confounding variables. Main findings showed that a longer TL was associated with a higher mean working memory score (β = 4.55; 95% CI = 0.39, 8.71). In addition, longer TL was associated with a higher mean global quantitative score (β = 3.85; 95% CI = −0.19, 7.89), although the association was marginally significant. To our knowledge, this is the first study that shows a positive association between TL and better neuropsychological outcomes in children. Although further research is required to confirm these results, this study supports the hypothesis that TL is essential in protecting and maintaining a child's health, including cognitive functions such as working memory. [ABSTRACT FROM AUTHOR]

• MtDNAc at birth is a sensitive biomarker associated with prenatal temperature exposure. • Exposure to high ambient temperatures showed negative associations with cord blood mtDNAc. • Exposure to low ambient temperatures was positively associated with cord blood and placental mtDNAc. Mitochondrial DNA content (mtDNAc) at birth is a sensitive biomarker to environmental exposures that may play an important role in later life health. We investigated sensitive time windows for the association between prenatal ambient temperature exposure and newborn mtDNAc. In the ENVIR ON AGE birth cohort (Belgium), we measured cord blood and placental mtDNAc in 911 participants using a quantitative real-time polymerase chain reaction. We associated newborn mtDNAc with average weekly mean temperature during pregnancy using distributed lag nonlinear models (DLNMs). Double-threshold DLNMs were used to study the relationships between ambient temperature and mtDNAc below predefined low (5th, 10th, 15th percentile of the temperature distribution) and above predefined high temperature thresholds (95th, 90th, 85th percentile of the temperature distribution). Prenatal temperature exposure above the used high temperature thresholds was linked to lower cord blood mtDNAc, with the strongest effect in trimester 2 (cumulative estimates ranging from −21.4% to −25.6%). Placental mtDNAc showed positive and negative associations for high temperature exposure depending on the applied high temperature threshold. Negative associations were observed during trimester 1 using the 90th and 95th percentile threshold (−26.1% and –33.2% lower mtDNAc respectively), and a positive association in trimester 3 when applying the most stringent 95th percentile threshold (127.0%). Low temperature exposure was associated with higher mtDNAc for both cord blood and placenta. Cord blood mtDNAc showed a positive association in trimester 2 when using the 10th percentile threshold (11.3%), while placental mtDNAc showed positive associations during the whole gestation and for all applied thresholds (estimates ranging from 80.8% − 320.6%). Our study shows that in utero temperature exposure is associated with differences in newborn mtDNAc at birth, with stronger associations observed in the placenta. These findings highlight the impact of prenatal ambient temperature exposure on mtDNAc during pregnancy. [ABSTRACT FROM AUTHOR]

Exposure to ambient air pollution is known to cause direct and indirect molecular expression changes in the placenta, on the DNA, mRNA, and protein levels. Ambient black carbon (BC) particles can be found in the human placenta already very early in gestation. However, the effect of in utero BC exposure on the entire placental proteome has never been studied to date. We explored whether placental proteome differs between mothers exposed to either high or low BC levels throughout the entire pregnancy. We used placental tissue samples from the ENVIR ON AGE birth cohort, of 20 non-smoking, maternal- and neonate characteristic-matched women exposed to high (n = 10) or low (n = 10) levels of ambient BC throughout pregnancy. We modeled prenatal BC exposure levels based on the mother's home address and measured BC levels in the fetal side of the placenta. The placental proteome was analyzed by nano-liquid chromatography Q-TOF mass spectrometry. PEAKS software was used for protein identification and label-free quantification. Protein-protein interaction and functional pathway enrichment analyses were performed with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) software. The accumulation of BC particles in placenta was 2.19 times higher in the high versus low exposure group (20943.4 vs 9542.7 particles/mm³; p = 0.007). Thirteen proteins showed a ≥2-fold expression difference between the two exposure groups, all overexpressed in the placentas of women prenatally exposed to high BC levels. Three protein-protein interactions were enriched within this group, namely between TIMP3 and COL4A2, SERPINE2 and COL4A2, and SERPINE2 and GP1BB. Functional pathway enrichment analysis put forward pathways involved in extracellular matrix-receptor interaction, fibrin clot formation, and sodium ion transport regulation. Prenatal BC exposure affects the placental proteome. Future research should focus on the potential consequences of these alterations on placental functioning, and health and disease during early childhood development. • Prenatal black carbon exposure affects the placental proteome. • 13 proteins are significantly upregulated in the highly exposed placentas. • Placental BC is associated with proteins of the extracellular matrix. • Affected pathways are nutrient transport, fibrin clotting, and hemostasis. [ABSTRACT FROM AUTHOR]

Telomere length (TL) and mitochondrial DNA (mtDNA) are central markers of vital biological mechanisms, including cellular aging. Prenatal air pollution exposure may impact molecular markers of aging leading to adverse health effects. To perform a systematic review on human population-based studies investigating the association between prenatal air pollution exposure and TL or mtDNA content at birth. Searches were undertaken on PubMed and Web of Science until July 2023. The framework of the review was based on the PRISMA-P guidelines. Nineteen studies studied prenatal air pollution and TL or mtDNA content at birth. Studies investigating TL or mtDNA content measured at any other time or did not evaluate prenatal air pollution were excluded. Twelve studies (including 4381 participants with study sample range: 97 to 743 participants) investigated newborn TL and eight studies (including 3081 participants with study sample range: 120 to 743 participants) investigated mtDNA content at birth. Seven studies focused on particulate matter (PM 2.5) exposure and newborn TL of which all, except two, showed an inverse association in at least one of the gestational trimesters. Of the eight studies on mtDNA content, four focused on PM 2.5 air pollution with two of them reporting an inverse association. For PM 2.5 exposure, observations on trimester-specific effects were inconsistent. Current literature showing associations with other prenatal air pollutants (including nitrogen oxides, sulfur dioxide, carbon monoxide and ozone) is inconsistent. This review provides initial evidence that prenatal PM 2.5 exposure impacts the telomere-mitochondrial axis of aging at birth. The current evidence did not reveal harmonious observations for trimester-specific associations nor showed consistent effects of other air pollutants. Future studies should elucidate the specific contribution of prenatal exposure to pollutants other than PM in relation to TL and mtDNA content at birth, and the potential later life health consequences. [ABSTRACT FROM AUTHOR]

• PM 2.5 exposure during pregnancy is associated with the telomere-mitochondrial axis of aging at birth. • Telomere length is a mediator in the association between PM 2.5 and mitochondrial DNA content and p53 protein level. • This study provides insights in the air pollution induced core-axis of aging. • Follow-up studies are needed to investigate PM 2.5 -linked differences in the core-axis of aging in relation to health and disease later in life. Particulate matter (PM) is associated with aging markers at birth, including telomeres and mitochondria. It is unclear whether markers of the core-axis of aging, i.e. tumor suppressor p53 (p53) and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), are associated with prenatal air pollution and whether there are underlying mechanisms. 556 mother-newborn pairs from the ENVIR ON AGE birth cohort were recruited at the East Limburg Hospital in Genk (Belgium). In placenta and cord blood, telomere length (TL) and mitochondrial DNA content (mtDNAc) were measured using quantitative real-time polymerase chain reaction (qPCR). In cord plasma, p53 and PGC-1α protein levels were measured using ELISA. Daily ambient PM 2.5 concentrations during gestation were calculated using a spatial temporal interpolation model. Distributed lag models (DLMs) were applied to assess the association between prenatal PM 2.5 exposure and each molecular marker. Mediation analysis was performed to test for underlying mechanisms. A 5 µg/m3 increment in PM 2.5 exposure was associated with −11.23 % (95 % CI: −17.36 % to −4.65 %, p = 0.0012) and −7.34 % (95 % CI: −11.56 % to −2.92 %, p = 0.0014) lower placental TL during the entire pregnancy and second trimester respectively, and with −12.96 % (95 % CI: −18.84 % to −6.64 %, p < 0.001) lower placental mtDNAc during the third trimester. Furthermore, PM 2.5 exposure was associated with a 12.42 % (95 % CI: −1.07 % to 27.74 %, p = 0.059) higher cord plasma p53 protein level and a −3.69 % (95 % CI: −6.97 % to −0.31 %, p = 0.033) lower cord plasma PGC-1α protein level during the third trimester. Placental TL mediated 65 % of the negative and 17 % of the positive association between PM 2.5 and placental mtDNAc and cord plasma p53 protein levels, respectively. Ambient PM 2.5 exposure during pregnancy is associated with markers of the core-axis of aging, with TL as a mediating factor. This study strengthens the hypothesis of the air pollution induced core-axis of aging, and may unravel a possible underlying mediating mechanism in an early-life epidemiological context. [ABSTRACT FROM AUTHOR]

Mitochondria are known to respond to environmental stressors but whether green space is associated with mitochondrial abundance is unexplored. Furthermore, as exposures may affect health from early life onwards, we here evaluate if residential green space is associated with mitochondria DNA content (mtDNAc) in children. In primary schoolchildren (COGNAC study), between 2012 and 2014, buccal mtDNAc was repeatedly (three times) assessed using qPCR. Surrounding low (<3m), high (≥3m) and total (sum of low and high) green space within different radii (100m–1000m) from the residence and distance to the nearest large green space (>0.5ha) were estimated using a remote sensing derived map. Given the repeated measures design, we applied a mixed-effects model with school and subject as random effect while adjusting for a priori chosen fixed covariates. Results: mtDNAc was assessed in 246 children with a total of 436 measurements (mean age 10.3 years). Within a 1000m radius around the residential address, an IQR increment in low (11.0%), high (9.5%), and total (13.9%) green space was associated with a respectively 15.2% (95% CI: 7.2%–23.7%), 10.8% (95% CI: 4.5%–17.5%), and 13.4% (95% CI: 7.4%–19.7%) higher mtDNAc. Conversely, an IQR increment (11.6%) in agricultural area in the same radius was associated with a −3.4% (95% CI: 6.7% to −0.1%) lower mtDNAc. Finally, a doubling in distance to large green space was associated with a −5.2% (95% CI: 7.9 to −2.4%) lower mtDNAc. To our knowledge, this is the first study evaluating associations between residential surrounding green space and mtDNAc in children. Our results showed that green space was associated with a higher mtDNAc in children, which indicates the importance of the early life environment. To what extent these findings contribute to later life health effects should be further examined. [Display omitted] • Residential surrounding green space is associated with higher child mtDNA content. •Exposure to agriculture is associated with lower child mtDNA content. •Living closer to large green space is associated with higher mtDNA content. [ABSTRACT FROM AUTHOR]

Objectives: Greater vulnerability of Black vs. White individuals to cardiovascular disease (CVD) and chronic kidney disease (CKD) is well charted in the United States, but studies involving sub-Saharan blacks are scarce., Methods: Baseline data (2021-2024) were collected in 168 sub-Saharan Blacks and 93 European Whites in an ongoing clinical trial (NCT04299529), using standardized patient selection criteria. Data included clinical and biochemical risk factors, ECG and echocardiographic traits, Framingham CVD risk, CKD grades (KDIGO 2024), self-assessed symptoms (WHO questionnaire), and urinary proteomic profiles predictive of left ventricular dysfunction (LVD) and CKD, HF1, and CKD273, respectively. Racial comparisons rested on unadjusted and multivariable-adjusted analyses., Results: Despite being younger (60.4 vs. 68.3 years), blacks had a worse risk profile, as evidenced by higher diabetes prevalence, higher BMI, faster heart rate, unfavourable serum cholesterol fractions, lower estimated glomerular filtration rate, microalbuminuria, and sedentary lifestyle. This resulted in blacks having higher 10-year CVD risk, higher heart age (index of vascular ageing with chronological age as reference), and a worse CKD grades. In both races, CKD273 increased with CKD grade, but CKD273 and HF1 were not different by race. These observations were robust in subgroup and adjusted analyses., Conclusion: This study did not differentiate host (genetic, molecular, and pathogenic) from environmental drivers of disease. Nonetheless, the findings call for a multipronged and comprehensive implementation of innovative health policies in sub-Saharan countries. Education, research, empowerment of stakeholders, and international learned societies connecting experts from a wide array of disciplines should vigorously sustain this effort., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Long-COVID is defined as the persistency or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation. Common persistent symptoms are fatigue, sleep disturbances, post-exertional malaise (PEM), pain, and cognitive problems. Long-COVID is estimated to be present in about 65 million people. We aimed to explore clinical and biological factors that might contribute to Long-COVID., Methods: Prospective longitudinal cohort study including patients infected with SARS-CoV-2 between March 2020 and March 2022. Patients were assessed between 4 and 12 months after infection at the COVID follow-up clinic at UZ Leuven. We performed a comprehensive clinical assessment (including questionnaires and the 6-min walking test) and biological measures (global DNA methylation, telomere length, mitochondrial DNA copy number, inflammatory cytokines, and serological markers such as C-reactive protein, D-dimer, troponin T)., Results: Of the 358 participants, 328 were hospitalised, of which 130 had severe symptoms requiring intensive care admission; 30 patients were ambulatory referrals. Based on their clinical presentation, we could identify 6 main clusters. One-hundred and twenty-seven patients (35.4%) belonged to at least one cluster. The bigger cluster included PEM, fatigue, sleep disturbances, and pain (n = 57). Troponin T and telomere shortening were the two main markers predicting Long-COVID and PEM-fatigue symptoms., Conclusions: Long-COVID is not just one entity. Different clinical presentations can be identified. Cardiac involvement (as measured by troponin T levels) and telomere shortening might be a relevant risk factor for developing PEM-fatigue symptoms and deserve further exploring., Competing Interests: Declarations. Ethics approval and consent to participate: The study was performed according to the Declaration of Helsinki and approved by the institutional ethics committees of KU/UZ Leuven (S64081 and amendment S65411). All participants agreed to participate and signed a written informed consent form. Consent for publication: No image, video, or other details of any participant are reported in the manuscript. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Telomere length is an important indicator of biological age and a complex multi-factor trait. To date, the telomere interactome for comprehending the high-dimensional biological aspects linked to telomere regulation during childhood remains unexplored. Here we describe the multi-omics signatures associated with childhood telomere length., Methods: This study included 1001 children aged 6 to 11 years from the Human Early-life Exposome (HELIX) project. Telomere length was quantified via qPCR in peripheral blood of the children. Blood DNA methylation, gene expression, miRNA expression, plasma proteins and serum and urinary metabolites were measured through microarrays or (semi-) targeted assays. The association between each individual omics feature and telomere length was assessed in omics-wide association analyses. In addition, a literature-guided, sparse supervised integration method was applied to multiple omics, and latent components were extracted as predictors of child telomere length. The association of these latent components with early-life aging risk factors (child lifestyle, body mass index (BMI), exposure to smoking, etc.), were interrogated., Results: After multiple-testing correction, only two CpGs (cg23686403 and cg16238918 at PARD6G gene) out of all the omics features were significantly associated with child telomere length. The supervised multi-omics integration approach revealed robust associations between latent components and child BMI, with metabolites and proteins emerging as the primary contributing features. In these latent components, the contributing molecular features were known as involved in metabolism and immune regulation-related pathways., Conclusions: Findings of this multi-omics study suggested an intricate interplay between telomere length, metabolism and immune responses, providing valuable insights into the molecular underpinnings of the early-life biological aging., Competing Interests: Declarations. Ethics approval and consent to participate: The HELIX study complies with the Declaration of Helsinki. All six cohorts existed for several years before HELIX started, and had undergone the required evaluation by national ethics committees: EDEN received approval from the ethics committee (CCPPRB) of Kremlin Bicêtre and from CNIL (Commission Nationale Informatique et Liberté), the French data privacy institution; BiB received ethics approval from the Bradford Research Ethics Committee; INMA obtained the approval of the ethics committee of each involved hospital or health center; the research protocol of KANC was approved by the Lithuanian Bioethics Committee; MoBa received approval from a Norwegian regional committee for medical and health research ethics; and the ethics committee of the university hospital at Heraklion approved the study protocols of RHEA. An informed consent has been signed by all participants at recruitment and at the follow-up visit for clinical examinations and biospecimen collection. Each cohort also confirmed that relevant informed consent and approval were in place for the secondary use of data from pre-existing data. The work in HELIX was covered by new ethics approvals in each country. The HELIX project received ethical approvals from the Comité Ético de investigación Clínica Parc de Salut MAR. At follow-up enrolment in the HELIX subcohort and panel studies, participants were asked to sign an informed consent for clinical examination and biospecimen collection and analysis. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Blacks are more prone to salt-sensitive hypertension than Whites. This cross-sectional analysis of a multi-ethnic cohort aimed to search for proteins potentially involved in the susceptibility to salt sensitivity, hypertension, and hypertension-related complications. The study included individuals enrolled in African Prospective Study on the Early Detection and Identification of Cardiovascular Disease and Hypertension (African-PREDICT), Flemish Study of the Environment, Genes and Health Outcomes (FLEMENGHO), Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers (PROVALID)-Austria, and Urinary Proteomics Combined with Home Blood Pressure Telemonitoring for Health Care Reform Trial (UPRIGHT-HTM). Sequenced urinary peptides detectable in 70% of participants allowed the identification of parental proteins and were compared between Blacks and Whites. Of 513 urinary peptides, 300 had significantly different levels among healthy Black (n = 476) and White (n = 483) South Africans sharing the same environment. Analyses contrasting 582 Blacks versus 1731 Whites, and Sub-Saharan Blacks versus European Whites replicated the findings. COL4A1, COL4A2, FGA, PROC, MGP, MYOCD, FYXD2, and UMOD were identified as the most likely candidates underlying the racially different susceptibility to salt sensitivity, hypertension, and related complications. Enriched pathways included hemostasis, platelet activity, collagens, biology of the extracellular matrix, and protein digestion and absorption. Our study suggests that MGP and MYOCD being involved in cardiovascular function, FGA and PROC in coagulation, FYXD2 and UMOD in salt homeostasis, and COL4A1 and COL4A2 as major components of the glomerular basement membrane are among the many proteins potentially incriminated in the higher susceptibility of Blacks compared to Whites to salt sensitivity, hypertension, and its complication. Nevertheless, these eight proteins and their associated pathways deserve further exploration in molecular and human studies as potential targets for intervention to reduce the excess risk of hypertension and cardiovascular complications in Blacks versus Whites., (© 2024 The Author(s). PROTEOMICS published by Wiley‐VCH GmbH.)

Cystic fibrosis (CF) is characterized by chronic airway inflammation and premature aging. The link with leukocyte telomere length (LTL) as a marker of biological aging is unclear. We studied disease severity and LTL in 168 CF patients of which 85 patients had a second retrospective LTL assessment. A higher FEV 1 was associated with longer LTL, with a stronger effect in men (5.08% longer LTL) compared to women (0.41% longer LTL). A higher FEV 1 /FVC ratio was associated with 7.05% ( P =0.017) longer LTL in men. CF asthma, as defined by the treatment with inhaled corticosteroids, was associated with -6.65% shorter LTL ( P =0.028). Men homozygous for the ΔF508 genotype showed a -10.48% ( P =0.026) shorter LTL compared to heterozygotes. A genotype-specific non-linear association between LTL shortening and chronological age was observed. Stronger age-related LTL shortening was observed in patients homozygous for the ΔF508 genotype ( P -interaction= 0.044). This work showed that disease severity in CF patients negatively influences LTL, with slightly more pronounced effects in men. The homozygous genotype for ΔF508 may play a role in LTL attrition in CF patients. Understanding factors in CF patients that accelerate biological aging provides insights into mechanisms that can extend the overall life quality in CF-diseased.

Background: Mitochondrial heteroplasmy reflects genetic diversity within individuals due to the presence of varying mitochondrial DNA (mtDNA) sequences, possibly affecting mitochondrial function and energy production in cells. Rapid growth during early childhood is a critical development with long-term implications for health and well-being. In this study, we investigated if cord blood mtDNA heteroplasmy is associated with rapid growth at 6 and 12 months and overweight in childhood at 4-6 years., Methods: This study included 200 mother-child pairs of the ENVIRONAGE birth cohort. Whole mitochondrial genome sequencing was performed to determine mtDNA heteroplasmy levels (in variant allele frequency; VAF) in cord blood. Rapid growth was defined for each child as the difference between WHO-SD scores of predicted weight at either 6 or 12 months and birth weight. Logistic regression models were used to determine the association of mitochondrial heteroplasmy with rapid growth and childhood overweight. Determinants of relevant cord blood mitochondrial heteroplasmies were identified using multiple linear regression models., Results: One % increase in VAF of cord blood MT-D-Loop 16362T > C heteroplasmy was associated with rapid growth at 6 months (OR = 1.03; 95% CI: 1.01-1.05; p = 0.001) and 12 months (OR = 1.02; 95% CI: 1.00-1.03; p = 0.02). Furthermore, this variant was associated with childhood overweight at 4-6 years (OR = 1.01; 95% CI 1.00-1.02; p = 0.05). Additionally, rapid growth at 6 months (OR = 3.00; 95% CI: 1.49-6.14; p = 0.002) and 12 months (OR = 4.05; 95% CI: 2.06-8.49; p < 0.001) was also associated with childhood overweight at 4-6 years. Furthermore, we identified maternal age, pre-pregnancy BMI, maternal education, parity, and gestational age as determinants of cord blood MT-D-Loop 16362T > C heteroplasmy., Conclusions: Our findings, based on mitochondrial DNA genotyping, offer insights into the molecular machinery leading to rapid growth in early life, potentially explaining a working mechanism of the development toward childhood overweight., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Screening for and prevention of osteoporosis and osteoporotic fractures is imperative, given the high burden on individuals and society. This study constructed and validated an aging-related biomarker derived from the urinary proteomic profile (UPP) indicative of osteoporosis (UPPost-age). In a prospective population study done in northern Belgium (1985-2019), participants were invited for a follow-up examination in 2005-2010 and participants in the 2005-2010 examination again invited in 2009-2013. Participants in both the 2005-2010 and 2009-2013 examinations (n = 519) constituted the derivation (2005-2016 data) and time-shifted validation (2009-2013 data) datasets; 187 participants with only 2005-2010 data formed the synchronous validation dataset. The UPP was assessed by capillary electrophoresis coupled with mass spectrometry. Analyses focused on 2372 sequenced urinary peptides (101 proteins) with key roles in maintaining the integrity of bone tissue. In multivariable analyses with correction for multiple testing, chronological age was associated with 99 urinary peptides (16 proteins). Peptides derived from IGF2 and MGP were upregulated in women compared to men, whereas COL1A2, COL3A1, COL5A2, COL10A1 and COL18A1 were downregulated. Via application of a 1000-fold bootstrapped elastic regression procedure, finally, 29 peptides (10 proteins) constituted the UPPost-age biomarker, replicated across datasets. In cross-sectional analyses of 2009-2013 data (n = 706), the body-height-to-arm-span ratio, an osteoporosis marker, was negatively associated with UPPost-age (p&;lt0.0001). Over 4.89 years (median), the 10-year risk of osteoporosis associated with chronological age and UPPost-age (53 cases including 37 fractures in 706 individuals) increased by 21% and 36% (p ≤ 0.044). Among 357 women, the corresponding estimates were 55% and 60% for incident osteoporosis (37 cases; p ≤ 0.0003) and 42% and 44% for osteoporotic fractures (25 cases; p ≤ 0.017). In conclusion, an aging-related UPP signature with focus on peptide fragments derived from bone-related proteins is associated with osteoporosis risk and available for clinical and trial research.

Background: Appetite hormones are considered a promising target in fighting obesity as impaired appetite hormone levels have already been associated with obesity. However, further insights in the drivers of appetite hormone levels are needed., Objectives: In this study, we investigated the associations of fasting appetite hormone levels with lifestyle and environmental exposures in children and adolescents., Methods: A total of 534 fasting blood samples were collected from children and adolescents (4-16y,50% boys) and appetite hormone levels (glucagon-like peptide-1 (GLP-1), peptide YY (PYY), pancreatic polypeptide (PP), leptin and ghrelin) were measured. Exposures included dietary quality (fiber-rich food intake, sugar propensity, fat propensity), psychosocial stress (happiness, negative emotions, negative life events and emotional problems), sleep duration, physical activity and environmental quality (long term black carbon (BC), particulate matter <2.5 μM (PM 2.5 ), nitrogen dioxide (NO 2 ) exposure, and green space in a 100 m and 2000 m radius around the residence). A multi-exposure score was calculated to combine all the exposures at study in one measure. Associations of individual exposures and multi-exposure score with appetite hormone levels were evaluated using linear mixed regression models adjusting for sex, age, socioeconomic status, waist-to-height ratio and multiple testing., Results: GLP-1 was associated with air pollution exposure (NO 2 β* = -0.13, BC β* = -0.15, PM 2.5 β* = -0.16, all p < 0.001). Leptin was associated with green space in a 100 m radius around the residence (β* = -0.11; p = 0.002). Ghrelin was associated with negative emotions (active ghrelin β* = -0.16; p = 0.04, total ghrelin β* = -0.23; p = 0.0051) and happiness (active ghrelin β* = 0.25; p < 0.001, total ghrelin β* = 0.26; p < 0.001). Furthermore, total ghrelin levels were associated with the multi-exposure score, reflecting unhealthy exposures and lifestyle (β* = -0.22; p = 0.036)., Discussion: Our findings provide new insights into the associations of exposures with appetite hormone levels, which are of high interest for preventive obesity research. Further research is crucial to reveal the underlying mechanisms of the observed associations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B 12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health., (© 2023. The Author(s).)

Background: Immunosuppressive treatment in heart transplant (HTx) recipient causes osteoporosis. The urinary proteomic profile (UPP) includes peptide fragments derived from the bone extracellular matrix. Study aims were to develop and validate a multidimensional UPP biomarker for osteoporosis in HTx patients from single sequenced urinary peptides identifying the parent proteins., Methods: A single-center HTx cohort was analyzed. Urine samples were measured by capillary electrophoresis coupled with mass spectrometry. Cases with osteoporosis and matching controls were randomly selected from all available 389 patients. In derivation case-control dataset, 1576 sequenced peptides detectable in ≥30 % of patients. Applying statistical analysis on these, an 18-peptide multidimensional osteoporosis UPP biomarker (OSTEO18) was generated by support vector modeling. The 2 replication datasets included 118 and 94 patients. For further validation, the whole cohort was analyzed. Statistical methods included logistic regression and receiver operating characteristic curve (ROC) analysis., Results: In derivation dataset, the AUC, sensitivity and specificity of OSTEO18 were 0.83 (95 % CI: 0.76-0.90), 74.3 % and 87.1 %, respectively. In replication datasets, results were confirmatory. In the whole cohort (154 osteoporotic patients [39.6 %]), the ORs for osteoporosis increased ( p  < 0.0001) across OSTEO18 quartiles from 0.39 (95 % CI: 0.25-0.61) to 3.14 (2.08-4.75). With full adjustment for known osteoporosis risk factors, OSTEO18 improved AUC from 0.708 to 0.786 ( p  = 0.0003) for OSTEO18 categorized (optimized threshold: 0.095) and to 0.784 ( p  = 0.0004) for OSTEO18 as continuously distributed classifier., Conclusion: OSTEO18 is a clinically meaningful novel biomarker indicative of osteoporosis in HTx recipients and is being certified as in-vitro diagnostic., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: uPROPHET was supported by the European Research Council (Advanced Researcher Grant-2011-294713-EPLORE and Proof-of-Concept Grant-713601-uPROPHET awarded to JAS). OMRON Healthcare, Co., Ltd., Kyoto, Japan provided a non-binding grant to the Non-Profit Research Association Alliance for the Promotion of Preventive Medicine (APPREMED), Mechelen, Belgium. Dries S. Martens holds a postdoctoral grant by the Research Foundations Flanders (FWO grants 12X9623N)., (© 2024 The Author(s).)

High blood pressure (BP) and type-2 diabetes (T2DM) are forerunners of chronic kidney disease and left ventricular dysfunction. Home BP telemonitoring (HTM) and urinary peptidomic profiling (UPP) are technologies enabling risk stratification and personalized prevention. UPRIGHT-HTM (NCT04299529) is an investigator-initiated, multicenter, open-label, randomized trial with blinded endpoint evaluation designed to assess the efficacy of HTM plus UPP (experimental group) over HTM alone (control group) in guiding treatment in asymptomatic patients, aged 55-75 years, with ≥5 cardiovascular risk factors. From screening onwards, HTM data can be freely accessed by all patients and their caregivers; UPP results are communicated early during follow-up to patients and caregivers in the intervention group, but at trial closure in the control group. From May 2021 until January 2023, 235 patients were screened, of whom 53 were still progressing through the run-in period and 144 were randomized. Both groups had similar characteristics, including average age (62.0 years) and the proportions of African Blacks (81.9%), White Europeans (16.7%), women 56.2%, home (31.2%), and office (50.0%) hypertension, T2DM (36.4%), micro-albuminuria (29.4%), and ECG (9.7%) and echocardiographic (11.5%) left ventricular hypertrophy. Home and office BP were 128.8/79.2 mm Hg and 137.1/82.7 mm Hg, respectively, resulting in a prevalence of white-coat, masked and sustained hypertension of 40.3%, 11.1%, and 25.7%. HTM persisted after randomization (48 681 readings up to 15 January 2023). In conclusion, results predominantly from low-resource sub-Saharan centers proved the feasibility of this multi-ethnic trial. The COVID-19 pandemic caused delays and differential recruitment rates across centers., (© 2023 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: Inadequate sleep duration has been suggested as a chronic stressor associated with changes in telomere length (TL). This study aimed to explore the association between sleep duration and TL using the INMA birth cohort study data., Methods: A total of 1014 children were included in this study (cross-sectional: 686; longitudinal: 872). Sleep duration (h/day) was reported by caregivers at 4 years and classified into tertiles (7-10 h/day; >10-11 h/day; >11-14 h/day). Leucocyte TL at 4 and 7-9 years were measured using quantitative PCR methods. Multiple robust linear regression models, through log-level regression models, were used to report the % of difference among tertiles of sleep duration., Results: In comparison to children who slept between >10 and 11 h/day, those in the highest category (more than 11 h/day) had 8.5% (95% CI: 3.56-13.6) longer telomeres at 4 years. Longitudinal analysis showed no significant association between sleep duration at 4 years and TL at 7-9 years., Conclusion: Children who slept more hours per day had longer TL at 4 years independently of a wide range of confounder factors. Environmental conditions, such as sleep duration, might have a major impact on TL during the first years of life., Impact: Telomere length was longer in children with longer sleep duration (>11 h/day) independently of a wide range of confounder factors at age 4 and remained consistent by sex. Sleep routines are encouraged to promote positive child development, like the number of hours of sleep duration. Considering the complex biology of telomere length, future studies still need to elucidate which biological pathways might explain the association between sleep duration and telomere length., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Telomeres are vulnerable to various environmental exposures and lifestyle factors, encompassed in the exposome. Recent research shows that telomere length is substantially determined early in life and that exposures in childhood may have important consequences in setting later life telomere length., Objectives: We explore in a child population the associations of 17 exposures with telomere length and longitudinal telomere change., Methods: Children (2.8-10.3y at baseline, 51.3% boys) were followed-up for five to seven years. Relative telomere length was measured at baseline and follow-up using quantitative real-time PCR. Exposures and lifestyle factors included: body composition (body mass index and waist circumference), dietary habits (sugar- and fat-rich food intake, vegetables and fruit intake), psychosocial stress (events, emotions, behaviour), sleep duration, physical activity, and residential environmental quality (longterm black carbon, particulate matter exposure, and residential green space). Cross-sectional (n=182) and longitudinal (n=150) analyses were assessed using linear regression models, adjusting for age, sex, socioeconomic status and multiple testing., Results: Our longitudinal analyses showed that higher residential green space at baseline was associated with (β=0.261, p=0.002) lower telomere attrition and that children with a higher waist circumference at baseline showed a higher telomere attrition (β=-0.287, p=0.001). These two predictors were confirmed via LASSO variable selection and correction for multiple testing. In addition, children with more unhealthy exposures at baseline had a significantly higher telomere attrition over the follow-up period compared to children with more healthy exposures (β=-0.200, p=0.017)., Discussion: Waist circumference and residential green space were identified as predictors associated with telomere attrition in childhood. These results further support the advantages of a healthy lifestyle from early age onwards and the importance of a green environment to promote molecular longevity from childhood onwards., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Exposure to ambient NO 2 and benzene, toluene ethyl-benzene and m+p- and o-xylenes (BTEX) is associated with adverse cardiovascular effects, but limited information is available on the effects of personal exposure to these compounds in South African populations. This 6-month follow-up study aims to determine 7-day personal ambient NO 2 and BTEX exposure levels via compact passive diffusion samplers in female participants from Cape Town, and investigate whether exposure levels are associated with cardiovascular risk markers. Overall, the measured air pollutant exposure levels were lower compared to international standards. NO 2 was positively associated with systolic and diastolic blood pressure (SBP and DBP), and inversely associated with the central retinal venular equivalent (CRVE) and mean baseline brachial artery diameter. o-xylene was associated with DBP and benzene was strongly associated with carotid intima media thickness (cIMT). Our findings showed that personal air pollution exposure, even at relatively low levels, was associated with several markers of cardiovascular risk in women residing in the Cape Town region.