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This work was supported by: the Spanish Association Against Cancer (Grant number PROYE18061FERN to M.F.F.), the Asturias Government (PCTI) cofounding 2018–2022/FEDER (Grant number IDI/2018/146 to M.F.F.), the Fundación General CSIC (Grant number 0348_CIE_6_E to M.F.F.), the Institute of Health Carlos III (Plan Nacional de I + D + I) cofounding FEDER (Grant numbers PI18/01527 and PI21/01067 to M.F.F. and A.F.F.; Grant numbers PI17/01517 and PI20/00269 to E.L.), and the Spanish Ministry of Science and Innovation (Grant number SGL2021-03-039/40 to M.F.F.) cofounding NextGenerationEU. J.R.T. is supported by a Juan de la Cierva fellowship from the Spanish Ministry of Science and Innovation (Grant number IJC2018-36825-I). J.J.A.L. is supported by the Spanish Association Against Cancer (Grant number PRDAS21642ALBA). R.F.P. and D.B.R. are supported by the Severo Ochoa program (Grant numbers BP17-114 and BP20-186). We also acknowledge support from the Institute of Oncology of Asturias (IUOPA, supported by Obra Social Cajastur Liberbank, Spain), the Health Research Institute of Asturias (ISPA-FINBA), the Health Research Institute INCLIVA and the Biomedical Research Networking Center on Rare Diseases (CIBERER-ISCIII).

Physical activity has been extensively associated with epigenetic modifications. However, the potential contribution of DNA methylation patterns to sports injury susceptibility remains largely unexplored, particularly among high-performance athletes. Since methylation regulates genes involved in inflammation, tissue repair, and musculoskeletal function, altered methylation profiles may influence injury risk. Moreover, epigenetic clocks are increasingly used to assess vulnerability to clinical phenotypes, as accelerated epigenetic aging has been linked to various diseases. Here, we studied the DNA methylome of peripheral blood cells in 74 elite female and male soccer players with extensive non-contact injury follow-up. We aimed to explore alterations associated with increased injury risk and to describe the dynamics of epigenetic age acceleration in this group. Although DNA methylomes between players with higher and lower injury risk were overall similar, we identified 1081 differentially methylated CpGs sites that partly affected genes involved in skeletal muscle functions. We also estimated epigenetic age using eight clocks but found no association with injuries. However, male athletes displayed higher epigenetic age acceleration than females. Comparing the methylome of age-accelerated versus decelerated individuals revealed widespread changes across five clocks, strongly biased towards hypomethylation in age-accelerated players. Differential CpGs targeted genes enriched in extracellular matrix, cytoskeletal and collagen-related functions. Overall, this study suggests a link between DNA methylation and non-contact injuries in elite soccer players and shows that epigenetic age acceleration, although unrelated to injuries, is associated with widespread hypomethylation.

Background Early life is a period of drastic epigenetic remodeling in which the epigenome is especially sensitive to extrinsic and intrinsic influence. However, the epigenome-wide dynamics of the DNA methylation changes that occur during this period have not been sufficiently characterized in longitudinal studies. Methods To this end, we studied the DNA methylation status of more than 750,000 CpG sites using Illumina MethylationEPIC arrays on 33 paired blood samples from 11 subjects at birth and at 5 and 10 years of age, then characterized the chromatin context associated with these loci by integrating our data with histone, chromatin-state and enhancer-element external datasets, and, finally, validated our results through bisulfite pyrosequencing in two independent longitudinal cohorts of 18 additional subjects. Results We found abundant DNA methylation changes (110,726 CpG sites) during the first lustrum of life, while far fewer alterations were observed in the subsequent 5 years (460 CpG sites). However, our analysis revealed persistent DNA methylation changes at 240 CpG sites, indicating that there are genomic locations of considerable epigenetic change beyond immediate birth. The chromatin context of hypermethylation changes was associated with repressive genomic locations and genes with developmental and cell signaling functions, while hypomethylation changes were linked to enhancer regions and genes with immunological and mRNA and protein metabolism functions. Significantly, our results show that genes that suffer simultaneous hyper- and hypomethylation are functionally distinct from exclusively hyper- or hypomethylated genes, and that enhancer-associated methylation is different in hyper- and hypomethylation scenarios, with hypomethylation being more associated to epigenetic changes at blood tissue-specific enhancer elements. Conclusions These data show that epigenetic remodeling is dramatically reduced after the first 5 years of life. However, there are certain loci which continue to manifest DNA methylation changes, pointing towards a possible functionality beyond early development. Furthermore, our results deepen the understanding of the genomic context associated to hyper- or hypomethylation alterations during time, suggesting that hypomethylation of blood tissue-specific enhancer elements could be of importance in the establishment of functional states in blood tissue during early-life.

Glioblastoma (GBM) is one of the most aggressive types of cancer and exhibits profound genetic and epigenetic heterogeneity, making the development of an effective treatment a major challenge. The recent incorporation of molecular features into the diagnosis of patients with GBM has led to an improved categorization into various tumour subtypes with different prognoses and disease management. In this work, we have exploited the benefits of genome‐wide multi‐omic approaches to identify potential molecular vulnerabilities existing in patients with GBM. Integration of gene expression and DNA methylation data from both bulk GBM and patient‐derived GBM stem cell lines has revealed the presence of major sources of GBM variability, pinpointing subtype‐specific tumour vulnerabilities amenable to pharmacological interventions. In this sense, inhibition of the AP‐1, SMAD3 and RUNX1/RUNX2 pathways, in combination or not with the chemotherapeutic agent temozolomide, led to the subtype‐specific impairment of tumour growth, particularly in the context of the aggressive, mesenchymal‐like subtype. These results emphasize the involvement of these molecular pathways in the development of GBM and have potential implications for the development of personalized therapeutic approaches.

In older adults, the Mediterranean diet is associated with lower risk of chronic diseases, but its association with health-related quality of life (HRQL) is still uncertain. This study assessed the association between the Mediterranean diet and HRQL in 2 prospective cohorts of individuals aged ≥60 years in Spain. The UAM-cohort (n = 2376) was selected in 2000/2001 and followed-up through 2003. At baseline, diet was collected with a food frequency questionnaire, which was used to develop an 8-item index of Mediterranean diet (UAM-MDP). The Seniors-ENRICA cohort (n = 1911) was recruited in 2008/2010 and followed-up through 2012. At baseline, a diet history was used to obtain food consumption. Mediterranean diet adherence was measured with the PREDIMED score and the Trichopoulou's Mediterranean Diet Score (MSD). HRQL was assessed, at baseline and at the end of follow-up, with the physical and mental component summaries (PCS and MCS) of the SF-36 questionnaire in the UAM-cohort, and the SF-12v.2 questionnaire in the Seniors-ENRICA cohort. Analyses were conducted with linear regression, and adjusted for the main confounders including baseline HRQL. In the UAM-cohort, no significant associations between the UAM-MDP and the PCS or the MCS were found. In the Seniors-ENRICA cohort, a higher PREDIMED score was associated with a slightly better PCS; when compared with the lowest tertile of PREDIMED score, the beta coefficient (95% confidence interval) for PCS was 0.55 (-0.48 to 1.59) in the second tertile, and 1.34 (0.21 to 2.47) in the highest tertile. However, the PREDIMED score was non-significantly associated with a better MCS score. The MSD did not show an association with either the PCS or the MCS. No clinically relevant association was found between the Mediterranean diet and HRQL in older adults in Spain.

This work was supported by the Spanish Association Against Cancer (PROYE18061 FERN to M.F.F.), the Asturias Government (PCTI) cofunding 2018- 2022/FEDER (IDI/2018/146 to M.F.F.), Fundación General CSIC (0348_CIE_6_E to M.F.F.), and the Health Institute Carlos III (Plan Nacional de I þ DþI) cofunding FEDER (PI15/00892 and PI18/01527 to M.F.F and A.F.F.). They also acknowledge support from the Ramón Areces Foundation (CIVP18A3891 to P.J.F.M.), the AECC (SIRTBIO to P.J.F.M.), the MICINN (SAF2017-85766-R to P.J.F.M.), a Ramón y Cajal fellowship (MICINN, RYC-2017-22335 to P.J.F.M.), and the European Commission ATTRACT project (777222 to A.P.C.). J.R.T. is supported by a Juan de la Cierva fellowship from the Spanish Ministry of Science and Innovation (FJCI-2015-26965). R.F.P. and P.S.O. are supported by the Severo Ochoa program (BP17-114 and BP17-165, respectively). R.G.U. is supported by the Centro de Investigación Biomédica en Red de Enfermedades Raras (Health Institute Carlos III). L.V. was supported by the UAB Predoctoral training programme (PIF predoctoral fellowships). They also acknowledge support from the IMDEA Food Institute and IUOPA-ISPA-FINBA (the IUOPA is supported by the Obra Social Cajastur-Liberbank, Spain).

Combined exposure to several healthy behaviors (HB) is associated with reduced mortality in older adults but its impact on health-related quality of life (HRQL) is uncertain. This is a cohort study of 2,388 individuals aged ≥60 recruited in 2000-2001, whose data were updated in 2003 and 2009. At baseline, participants reported both traditional HB (non-smoking, being very or moderately active, healthy diet) and non-traditional HB (sleeping 7-8 h/d, being seated <8 h/d, and seeing friends every day). HRQL was measured with the SF-36 questionnaire at baseline, in 2003 (short-term) and in 2009 (long-term); a higher score on the SF-36 represents better HRQL. Linear regression models were used to assess the association between HB at baseline and HRQL in 2003 and 2009, with adjustment for the main confounders including baseline HRQL. In the short-term, being physically active, sleeping 7-8 h/d, and being seated <8 h/d was associated with better HRQL. Compared to having ≤1 of these HB, the β (95% confidence interval) for the score on the physical component summary of the SF-36 in 2003 was 1.42 (0.52-2.33) for 2 HB, and 2.06 (1.09-3.03) for 3 HB, p-trend <0.001. Corresponding figures for the mental component summary score were 1.89 (0.58-3.21) for 2 HB and 3.35 (1.95-4.76) for 3 HB, p-trend <0.001. Non-smoking, a healthy diet or seeing friends did not show an association with HRQL. In the long-term, being physically active was the only HB associated with better physical HRQL. As a conclusion, a greater number of HB, particularly more physical activity, adequate sleep duration, and sitting less, were associated with better short-term HRQL in older adults. However, in the long-term, being physically active was the only HB associated with better physical HRQL.

Information on the association between socioeconomic status (SES) throughout life and sarcopenic obesity is scarce, whereas no study has been focused on the association between SES and frail obesity. This analysis estimated the prevalence of sarcopenic obesity and frail obesity, and their associations with SES in older adults. Data were collected in 2012 from 1,765 non-institutionalized individuals aged ≥65 participating in the Seniors-ENRICA study in Spain, by using standardized techniques and equipment. SES throughout life was evaluated with the father’s occupation, participant’s educational level, former own occupation, and current poor housing condition. Overall, 17.2% of participants had sarcopenic obesity, and 4.0% frail obesity. No association was found between SES and sarcopenic obesity. In contrast, the prevalence of frail obesity was higher in those with lower education, having worked in manual job, and currently having poor housing condition. Having ≥1 social disadvantages throughout life was associated with higher prevalence of frail obesity. The prevalence of this disorder increased by 1.49 (95% CI: 1.21–1.85) times for each social disadvantage added. The OR (95% CI) of frail obesity was 3.13 (1.71–5.7) for those having 3 or 4 vs. 0 or 1 social disadvantages, implying a more complex process beginning early in life.

Autophagy is an essential protective mechanism that allows mammalian cells to cope with a variety of stressors and contributes to maintaining cellular and tissue homeostasis. Due to these crucial roles and also to the fact that autophagy malfunction has been described in a wide range of pathologies, an increasing number of in vivo studies involving animal models targeting autophagy genes have been developed. In mammals, total autophagy inactivation is lethal, and constitutive knockout models lacking effectors of this route are not viable, which has hindered so far the analysis of the consequences of a systemic autophagy decline. Here, we take advantage of atg4b−/− mice, an autophagy-deficient model with only partial disruption of the process, to assess the effects of systemic reduction of autophagy on the metabolome. We describe for the first time the metabolic footprint of systemic autophagy decline, showing that impaired autophagy results in highly tissue-dependent alterations that are more accentuated in the skeletal muscle and plasma. These changes, which include changes in the levels of amino-acids, lipids, or nucleosides, sometimes resemble those that are frequently described in conditions like aging, obesity, or cardiac damage. We also discuss different hypotheses on how impaired autophagy may affect the metabolism of several tissues in mammals.

Type 1 diabetes (T1D) is an autoimmune disease that leads to insulin deficiency and hyperglycemia. Little is known about how this metabolic dysfunction, which substantially alters the internal environment, forces cells to adapt through epigenetic mechanisms. Consequently, the purpose of this work was to study what changes occur in the epigenome of T1D patients after the onset of disease and in the context of poor metabolic control. We performed a genome-wide analysis of DNA methylation patterns in blood samples from 18 T1D patients with varying levels of metabolic control. We identified T1D-associated DNA methylation differences on more than 100 genes when compared with healthy controls. Interestingly, only T1D patients displaying poor glycemic control showed epigenetic age acceleration compared to healthy controls. The epigenetic alterations identified in this work make a valuable contribution to improving our understanding of T1D and to ensuring the appropriate management of the disease in relation to maintaining healthy aging.