Branched-chain amino acids play critical roles in cardiac physiology and diseases. Genetic deficiency in the valine catabolic enzyme ACAD8 is clinically associated with isobutyryl-CoA deregulation and cardiomyopathy in humans, but its roles in cardiac disease remain undefined. Here, we show that the levels of ACAD8 are reduced in humans and male mice with cardiac hypertrophy. Cardiomyocyte-specific Acad8 knockout in male mice exacerbates cardiac hypertrophy and cardiac dysfunction underwent pressure overload. Mechanistically, Acad8 deficiency leads to the accumulation of its substrate isobutyryl-CoA, which enhances histone isobutyrylation, chromatin accessibility and TEAD2 enrichment at promoter regions of hypertrophy-related genes, which increases the sensitivity to hypertrophic stress in mouse hearts and cardiomyocytes. Conversely, ACAD8 overexpression in cardiomyocytes suppresses isobutyryl-CoA accumulation and histone isobutyrylation, thereby attenuating cardiac hypertrophy and dysfunction. These results elucidate the roles of ACAD8 deficiency in cardiac diseases and reveal histone isobutyrylation in transcription regulation and cardiac pathology.

Despite growing evidence implicating cellular senescence in tumor progression, methodological challenges in objectively quantifying senescent cell burden across cancer types continue to limit mechanistic studies and clinical translation. To establish a robust quantification framework, we curated a comprehensive compendium of 888 transcriptomic profiles spanning diverse cell types and senescence-inducing conditions. Following rigorous normalization and batch-effect correction, the Boruta algorithm was employed to derive a stable consensus cellular senescence-related gene signature (CSGS). By benchmarking ten machine learning algorithms within a rigorous cross-validation framework, we developed the Predictive Cellular Senescence Model (PreCSenM), which integrates the CSGS to compute a continuous cellular senescence (CS) score as a standardized metric for senescence level. Benchmarking analyses demonstrated that PreCSenM achieves robust and consistent performance, providing more reliable prediction of senescent states than existing methods across both normal and cancer transcriptomic datasets. In lung adenocarcinoma (LUAD), PreCSenM identified the CS score as a robust predictor of clinical outcomes. Multi-omics analyses further revealed that higher CS levels correlate with greater genomic stability and enhanced immune-related features, aligning with clinical observations. Notably, drug discovery using PreCSenM identified histone deacetylase inhibitors (HDACis) as potent inducers of CS in LUAD. Transcriptional and epigenetic profiling of HDACi-treated cells pinpointed FOSB as a core transcription factor driving CS, and FOSB knockdown reduced HDACi-induced senescence. Our study establishes PreCSenM as a multidimensional senescence quantification tool, bridging computational prediction with clinical relevance and mechanistic validation to enable senescence-directed therapies in precision oncology. A user-accessible web portal for PreCSenM is available at http://precsenm.bmicc.org/.

Caloric restriction (CR) improves metabolic health and reduces the risk of aging-related vascular diseases. However, the systematic metabolic reprogramming associated with CR remains unclear. To address this, we performed multi-tissue metabolomic profiling (liver, heart, and serum) in apolipoprotein E-deficient (ApoE-/-) mice subjected to CR. Metabolomic analyses of the multiple tissues revealed that glycerophospholipid metabolism pathway was consistently modulated by CR. To explore its relevance in vascular diseases, we performed serum metabolomic profiling in an abdominal aortic aneurysm (AAA) model induced by angiotensin Ⅱ (AngⅡ) infusion in ApoE-/- mice. The level of lysophosphatidylethanolamine (LPE) (16:0/0:0), a metabolite in the glycerophospholipid metabolism pathway, was elevated during AAA progression and significantly reduced by CR intervention, suggesting its potential as a vascular disease risk factor. Notably, glycerophospholipid metabolism and LPE (16:0) were significantly associated with vascular diseases and aging-related indicators in human multi-omics data, including public transcriptomic and lipidomic, and our serum multi-omics profiling of 76 healthy aged individuals. Collectively, our findings establish glycerophospholipid metabolism and LPE (16:0) as systemic signatures of CR with diagnostic potential. They highlight a crucial link between systemic metabolism and vascular remodeling and remodeling-associated vascular diseases, while also functioning as indicators of systemic aging.

Ageing leads to diurnal misalignment with a global reduction in physiological fitness, yet the mechanisms underlying such age-related diurnal reprogramming and its role in ageing remain poorly understood. Here we generate diurnal transcriptomes across eight peripheral tissues and reveal that disrupted redox oscillations are common diurnal alterations in organismal ageing. Restoring redox rhythms through the time-restricted application of antioxidants and pro-oxidants markedly improved glucose metabolism, motor performance and ageing-related characteristics of liver and skeletal muscle in male aged mice. Through multi-omics analyses we further reveal that restoring redox rhythms partially rejuvenates the hepatic transcriptome and chromatin accessibility in ageing-associated functional pathways and involves redox modification of CLOCK protein. Perturbing redox-sensitive cysteine 195 of CLOCK causes premature ageing phenotypes and hepatic reprogramming. Overall, our study reveals that redox rhythms ameliorate functional decline by modulating ageing-relevant reprogramming in liver and skeletal muscle and indicates that redox rhythm-based interventions might promote healthy ageing.

Ectopic triglyceride accumulation resulting from impaired fatty acid β-oxidation (FAO) plays a crucial role in metabolic dysfunction-associated steatotic liver disease. The PPARα activation can promote FAO, thus reducing hepatic lipid levels. HnRNP K is known to act as an enhancer or repressor to regulate gene transcription, yet the relevance of hnRNP K to lipid metabolism remains elusive. In this study, hnRNP K is upregulated in diet-induced obesity mice livers and mouse primary hepatocytes stimulated with fatty acids. Functionally, hnRNP K overexpression promotes lipid deposition induced by fatty acids at the cellular level and also drives the development of diet-induced hepatosteatosis in mice. Conversely, knockdown of hnRNP K confers protection against hepatic lipid deposition. Mechanistically, Ppara is identified as a candidate target through integrating CUT&Tag-Seq and RNA-Seq. Moreover, hnRNP K represses Ppara expression by binding to its promoter, thus reducing FAO enzymes. Etomoxir, an FAO inhibitor, counteracted the alleviation of lipid accumulation induced by hnRNP K knockdown. In summary, this study demonstrates hnRNP K has a crucial role in modulating the function of PPARα and hepatic lipid metabolism.

EDITORIAL article Front. Cell Dev. Biol., 31 January 2024Sec. Cell Growth and Division Volume 12 - 2024 | https://doi.org/10.3389/fcell.2024.1374424

LncRNAs are involved in modulating the individual risk and the severity of progression in metabolic dysfunction-associated fatty liver disease (MASLD), but their precise roles remain largely unknown. This study aimed to investigate the role of lncRNA Snhg3 in the development and progression of MASLD, along with the underlying mechanisms. In vitro and in vivo experiments revealed that Snhg3 is involved in lipid metabolism and steatosis. The result showed that Snhg3 was significantly downregulated in the liver of high-fat-induced obesity (DIO) mice. Notably, palmitic acid promoted the expression of Snhg3 and overexpression of Snhg3 increased lipid accumulation in primary hepatocytes. Furthermore, knock-in and knock-out models showed significant changes in body and liver weight, heat production, total oxygen consumption, and carbon dioxide production. Hepatocyte-specific Snhg3 deficiency alleviated hepatic steatosis in DIO mice, whereas overexpression induced the opposite effect. Mechanistically, Snhg3 promoted the expression, stability and nuclear localization of SND1 protein via interacting with SND1, thereby inducing K63-linked ubiquitination modification of SND1. Moreover, Snhg3 decreased the H3K27me3 level and induced SND1-mediated chromatin loose remodeling, thus reducing H3K27me3 enrichment at the Pparγ promoter and enhancing Pparγ expression. In addition, the administration of PPARγ inhibitor T0070907 improved Snhg3 -aggravated hepatic steatosis. Our study revealed a new signaling pathway, Snhg3 /SND1/H3K27me3/PPARγ, responsible for MASLD and indicates that lncRNA-mediated epigenetic modification has a crucial role in the pathology of MASLD.

LncRNAs are involved in modulating the individual risk and the severity of progression in metabolic dysfunction-associated fatty liver disease (MASLD), but their precise roles remain largely unknown. This study aimed to investigate the role of lncRNA Snhg3 in the development and progression of MASLD, along with the underlying mechanisms. The result showed that Snhg3 was significantly downregulated in the liver of high-fat diet-induced obesity (DIO) mice. Notably, palmitic acid promoted the expression of Snhg3 and overexpression of Snhg3 increased lipid accumulation in primary hepatocytes. Furthermore, hepatocyte-specific Snhg3 deficiency decreased body and liver weight, alleviated hepatic steatosis and promoted hepatic fatty acid metabolism in DIO mice, whereas overexpression induced the opposite effect. Mechanistically, Snhg3 promoted the expression, stability and nuclear localization of SND1 protein via interacting with SND1, thereby inducing K63-linked ubiquitination modification of SND1. Moreover, Snhg3 decreased the H3K27me3 level and induced SND1-mediated chromatin loose remodeling, thus reducing H3K27me3 enrichment at the Pparg promoter and enhancing PPARγ expression. The administration of PPARγ antagonist T0070907 improved Snhg3-aggravated hepatic steatosis. Our study revealed a new signaling pathway, Snhg3/SND1/H3K27me3/PPARγ, responsible for mice MASLD and indicates that lncRNA-mediated epigenetic modification has a crucial role in the pathology of MASLD.

BACKGROUND:Numerous diseases are associated with the interplay of mitochondrial and macrophage polarization. However, the correlation of mitochondria-related genes (MRGs) and macrophage polarization-related genes (MPRGs) with the prognosis of glioma remains unclear. This study aimed to examine this relationship based on bioinformatic analysis. METHODS:Glioma-related datasets (TCGA-GBMLGG, mRNA-seq-325, mRNA-seq-693, GSE16011, GSE4290, and GSE138794) were included in this study. The intersection genes were obtained by overlapping differentially expressed genes (DEGs) from differential expression analysis in GSE16011, key module genes from WGCNA, and MRGs. Subsequently, the intersection genes were further screened to obtain prognostic genes. Following this, a risk model was developed and verified. After that, independent prognostic factors were identified, followed by the construction of a nomogram and subsequent evaluation of its predictive ability. Furthermore, immune microenvironment analysis and expression validation were implemented. The GSE138794 dataset was utilized to evaluate the expression of prognostic genes at a cellular level, followed by conducting an analysis on cell-to-cell communication. Finally, the results were validated in different datasets and tissue samples from patients. RESULTS:ECI2, MCCC2, OXCT1, SUCLG2, and CPT2 were identified as prognostic genes for glioma. The risk model constructed based on these genes in TCGA-GBMLGG demonstrated certain accuracy in predicting the occurrence of glioma. Additionally, the nomogram constructed based on risk score and grade exhibited strong performance in predicting patient survival. Significant differences were observed in the proportion of 27 immune cell types (e.g., activated B cells and macrophages) and the expression of 32 immune checkpoints (e.g., CD70, CD200, and CD48) between the two risk groups. Single-cell RNA sequencing showed that CPT2, ECI2, and SUCLG2 were highly expressed in oligodendrocytes, neural progenitor cells, and BMDMs, respectively. The results of cell-cell communication analysis revealed that both oligodendrocytes and BMDMs exhibited a substantial number of interactions with high strength. CONCLUSION:This study revealed five genes associated with the prognosis of glioma (ECI2, MCCC2, OXCT1, SUCLG2, and CPT2), providing novel insights into individualized treatment and prognosis.

Long noncoding RNAs (lncRNAs) are strongly associated with glucose homeostasis, but their roles remain largely unknown. In this study, the potential role of lncRNA-Snhg3 in glucose metabolism was evaluated both in vitro and in vivo. Here, we found a positive relationship between Snhg3 and hepatic glycogenesis. Glucose tolerance improved in hepatocyte-specific Snhg3 knock-in (Snhg3-HKI) mice, while it worsened in hepatocyte-specific Snhg3 knockout (Snhg3-HKO) mice. Furthermore, hepatic glycogenesis had shown remarkable increase in Snhg3-HKI mice and reduction in Snhg3-HKO mice, respectively. Mechanistically, Snhg3 increased mRNA and protein expression levels of PPP1R3B through inducing chromatin remodeling and promoting the phosphorylation of protein kinase B. Collectively, these results suggested that lncRNA-Snhg3 plays a critical role in hepatic glycogenesis.

Thoracic aortic aneurysms (TAAs) develop asymptomatically and are characterized by dilatation of the aorta. This is considered a life-threating vascular disease due to the risk of aortic rupture and without effective treatments. The current understanding of the pathogenesis of TAA is still limited, especially for sporadic TAAs without known genetic mutation. Sirtuin 6 (SIRT6) expression was significantly decreased in the tunica media of sporadic human TAA tissues. Genetic knockout of Sirt6 in mouse vascular smooth muscle cells accelerated TAA formation and rupture, reduced survival, and increased vascular inflammation and senescence after angiotensin II infusion. Transcriptome analysis identified interleukin (IL)-1β as a pivotal target of SIRT6, and increased IL-1β levels correlated with vascular inflammation and senescence in human and mouse TAA samples. Chromatin immunoprecipitation revealed that SIRT6 bound to the Il1b promoter to repress expression partly by reducing the H3K9 and H3K56 acetylation. Genetic knockout of Il1b or pharmacological inhibition of IL-1β signaling with the receptor antagonist anakinra rescued Sirt6 deficiency mediated aggravation of vascular inflammation, senescence, TAA formation and survival in mice. The findings reveal that SIRT6 protects against TAA by epigenetically inhibiting vascular inflammation and senescence, providing insight into potential epigenetic strategies for TAA treatment.

Aims The mechanisms underlying ageing-induced vascular remodelling remain unclear. This study investigates the role and underlying mechanisms of the cytoplasmic deacetylase sirtuin 2 (SIRT2) in ageing-induced vascular remodelling. Methods and results Transcriptome and quantitative real-time PCR data were used to analyse sirtuin expression. Young and old wild-type and Sirt2 knockout mice were used to explore vascular function and pathological remodelling. RNA-seq, histochemical staining, and biochemical assays were used to evaluate the effects of Sirt2 knockout on the vascular transcriptome and pathological remodelling and explore the underlying biochemical mechanisms. Among the sirtuins, SIRT2 had the highest levels in human and mouse aortas. Sirtuin 2 activity was reduced in aged aortas, and loss of SIRT2 accelerated vascular ageing. In old mice, SIRT2 deficiency aggravated ageing-induced arterial stiffness and constriction-relaxation dysfunction, accompanied by aortic remodelling (thickened vascular medial layers, breakage of elastin fibres, collagen deposition, and inflammation). Transcriptome and biochemical analyses revealed that the ageing-controlling protein p66(Shc) and metabolism of mitochondrial reactive oxygen species (mROS) contributed to SIRT2 function in vascular ageing. Sirtuin 2 repressed p66(Shc) activation and mROS production by deacetylating p66(Shc) at lysine 81. Elimination of reactive oxygen species by MnTBAP repressed the SIRT2 deficiency-mediated aggravation of vascular remodelling and dysfunction in angiotensin II-challenged and aged mice. The SIRT2 coexpression module in aortas was reduced with ageing across species and was a significant predictor of age-related aortic diseases in humans. Conclusion The deacetylase SIRT2 is a response to ageing that delays vascular ageing, and the cytoplasm-mitochondria axis (SIRT2-p66(Shc)-mROS) is important for vascular ageing. Therefore, SIRT2 may serve as a potential therapeutic target for vascular rejuvenation.

HomeHypertensionVol. 80, No. 8Epigenetic Clock: Future of Hypertension Prediction? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBEpigenetic Clock: Future of Hypertension Prediction? Xiao-Man Wang, He-Ping Wang, Hou-Zao Chen and De-Pei Liu Xiao-Man WangXiao-Man Wang https://orcid.org/0000-0002-7833-6108 State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (X.-M.W., H.-P.W., H.-Z.C., D.-P.L.). , He-Ping WangHe-Ping Wang State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (X.-M.W., H.-P.W., H.-Z.C., D.-P.L.). , Hou-Zao ChenHou-Zao Chen Correspondence to: De-Pei Liu, State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing, China 100005, Email E-mail Address: [email protected] https://orcid.org/0000-0001-6805-3182 State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (X.-M.W., H.-P.W., H.-Z.C., D.-P.L.). Medical Epigenetics Research Center, Chinese Academy of Medical Sciences, Beijing, China (H.-Z.C., D.-P.L.). and De-Pei LiuDe-Pei Liu Hou-Zao Chen, State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing, China 100005, Email E-mail Address: [email protected] https://orcid.org/0000-0002-2636-4297 State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China (X.-M.W., H.-P.W., H.-Z.C., D.-P.L.). Medical Epigenetics Research Center, Chinese Academy of Medical Sciences, Beijing, China (H.-Z.C., D.-P.L.). Haihe Laboratory of Cell Ecosystem, Tianjin, China (D.-P.L.). Originally published20 Jul 2023https://doi.org/10.1161/HYPERTENSIONAHA.123.21197Hypertension. 2023;80:1569–1571In the current issue of Hypertension, Jacob et al1 revealed the intriguing associations between hypertension and blood DNA methylation, advancing our understanding of the epigenetic clock in capturing essential features of age-related physiological changes and disease risk (Figure). They present a racially diverse, prospective cohort of nearly 4500 women who were aged between 35 and 74 years from 2003 to 2009. At the baseline, women were categorized as hypertensive if they had elevated blood pressure (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) or were taking antihypertensive medication. New cases of hypertension throughout follow-up were detected via self-report on annual health questionnaires. Three biological age metrics, including an estimator of aging rates (DunedinPACE) and 2 estimators of epigenetic age acceleration (PhenoAgeAccel, GrimAgeAccel), were defined based on previously published epigenetic clocks,2–4 and were measured using DNA methylation information derived from whole blood samples at the baseline. The authors conclude that DNA methylation-based biological age metrics significantly increased before hypertension diagnosis and remain persistently elevated in the years following clinical diagnosis and therapy.Download figureDownload PowerPointFigure. Omics strategies for hypertension prediction. DNA methylation-based epigenetic ages in the study showed strong statistical power to predict the incidence of hypertension in a large cohort of women (upper). Integrated age metrics using multi-omics data may have considerable potential to improve the accuracy and precision of hypertension prediction in the future (bottom).The study examines the direct relationships between epigenetic clocks and incident hypertension by conducting prospective cohorts, filling the lack of prospective evidence, particularly in the field of hypertension in women. Two interesting findings were highlighted. On the one hand, women with higher biological age at baseline are more prone to develop incident hypertension in the following years. The findings suggest that biological age could be a potential risk factor for hypertension, aiding in early intervention and prevention. Personalized prevention strategies for hypertension could also be developed based on an individual’s biological age. On the other hand, methylation-based biological age metrics remain elevated even after effective medication. The persistently increasing epigenetic age metrics even in the context of successful treatment and under-controlled blood pressure reflect the fact that epigenetic alterations may profile the comprehensive status of hypertension-induced molecular alterations. Thus, preventing harmful epigenetic changes caused by unhealthy lifestyles and damaging environmental factors5 may be more critical for hypertension treatment than just controlling blood pressure.Hypertension is typically diagnosed through the measurements of blood pressure, while well-established risk factors for the early prediction of hypertension remain complicated and unclear. Accumulating research has emerged to investigate various targets, including proteins,6 circular RNAs,7 and metabolites,8 which could potentially be used in the new prognosis, diagnosis, and therapy of hypertension. Jacob et al revealed that DNA methylation-based biological age metrics are prominently associated with hypertension, providing a new door for the discovery of hypertensive targets from the epigenetic perspective. Additionally, they have reported that biological age metrics have stronger associations with risk factors of cardiovascular diseases than with blood pressure alone. Specifically, significant positive correlations were observed between systolic blood pressure and biological age metrics (PhenoAgeAccel and GrimAgeAccel) when using minimally adjusted models, but these correlations were absent when adjusting for well-known risk factors of cardiovascular diseases. The independent relationships between biological age metrics and blood pressure further suggested that biological age metrics with the combination of blood pressure measurements could construct more effective predictive tools for hypertension events.Hypertension is the primary hazard factor for cardiovascular illness and premature death among females worldwide.9 Nevertheless, there is a crucial insufficiency of understanding regarding the gender-specific mechanisms of the disease. Additionally, risk factors for hypertension and cardiovascular illness that are exceptional to women are inadequately recognized in clinical recommendations.10 The study is based on a large cohort of 4419 women, and female-specific risk factors (ie, menopause status) were included in the model testing. This assessment may contribute to the limited gender-specific clinical diagnosis and treatment.The main strengths of the study by Jacob et al, include the use of a large cohort of women, the application of multiple DNA methylation-based biological age metrics, and the combination of both prospective and case-control analyses. These comprehensive designs provide strong statistical power and allow to adjustment of multiple confounding factors to draw meaningful conclusions. The study is limited by the mere use of baseline DNA methylation data to calculate biological age metrics. It would be interesting to investigate how changes in DNA methylation over time relate to hypertension incidence and progression. Given that multi-omics evaluations of aging have the potential to enhance the resolution of exploring aging-related diseases,11,12 multi-omics studies are strongly recommended to systematically understand the associations between hypertension and age (Figure).In conclusion, the findings of Jacob and colleagues provide new insights into the cross-sectional and prospective links between DNA methylation-based biological age and hypertension in a large cohort of women, indicating that biological age as one of risk factors may assist in early intervention and prevention. The success of epigenetic ages in predicting incident hypertension emphasizes the importance of elucidating epigenetic molecular pathways in hypertension. Moreover, deciphering the associations between biological ages and hypertension suggested other illnesses with abnormal blood pressure should consider the potential role of epigenetic ages in clinical diagnosis. While epigenetic clocks in blood represent a small step towards the application of biological ages for improving early prevention of hypertension, there is still much to learn and refine regarding the potential applications of biological ages through more comprehensive omics methods.ARTICLE INFORMATIONSources of FundingThis work was supported by grants from the National Key Research and Development Project of China (2020YFC2008003), the National Natural Science Foundation of China (grant numbers: 92149305 and 82225007, 82030017), and National High Level Hospital Clinical Research Funding (grant numbers: 2022-PUMCH-C-008 and 2022-PUMCH-C-014).Disclosures None.Footnotes*X.-M. Wang and H.-P. Wang contributed equally.For Sources of Funding and Disclosures, see page 1571.The opinions expressed in this article are not necessarily those of the editors nor the American Heart Association.Correspondence to: De-Pei Liu, State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing, China 100005, Email liudp@pumc.edu.cnHou-Zao Chen, State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing, China 100005, Email chenhouzao@ibms.cams.cnREFERENCES1. Kresovich JK, Sandler DP, Taylor JA. Methylation-based biological age and hypertension prevalence and incidence.Hypertension. 2006; 26:645–649. doi: 10.1089/jir.2006.26.645CrossrefGoogle Scholar2. Lu AT, Quach A, Wilson JG, Reiner AP, Aviv A, Raj K, Hou L, Baccarelli AA, Li Y, Stewart JD, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan.Aging (Albany NY). 2019; 11:303–327. doi: 10.18632/aging.101684CrossrefMedlineGoogle Scholar3. Levine ME, Lu AT, Quach A, Chen BH, Assimes TL, Bandinelli S, Hou L, Baccarelli AA, Stewart JD, Li Y, et al. An epigenetic biomarker of aging for lifespan and healthspan.Aging (Albany NY). 2018; 10:573–591. doi: 10.18632/aging.101414CrossrefMedlineGoogle Scholar4. Belsky DW, Caspi A, Corcoran DL, Sugden K, Poulton R, Arseneault L, Baccarelli A, Chamarti K, Gao X, Hannon E, et al. DunedinPACE, a DNA methylation biomarker of the pace of aging.Elife. 2022; 11:e73420. doi: 10.7554/eLife.73420CrossrefMedlineGoogle Scholar5. Gharipour M, Mani A, Amini Baghbahadorani M, de Souza Cardoso CK, Jahanfar S, Sarrafzadegan N, de Oliveira C, Silveira EA. How are epigenetic modifications related to cardiovascular disease in older adults?Int J Mol Sci. 2021; 22:9949. doi: 10.3390/ijms22189949CrossrefMedlineGoogle Scholar6. Xu T, Zhong C, Wang A, Guo Z, Bu X, Zhou Y, Tian Y, HuangFu X, Zhu Z, Zhang Y. YKL-40 level and hypertension incidence: a population-based nested case-control study in China.J Am Heart Assoc. 2016; 5:e004534. doi: 10.1161/JAHA.116.004534LinkGoogle Scholar7. Sekar D. Circular RNA: a new biomarker for different types of hypertension.Hypertens Res. 2019; 42:1824–1825. doi: 10.1038/s41440-019-0302-yCrossrefMedlineGoogle Scholar8. Nikolic SB, Sharman JE, Adams MJ, Edwards LM. Metabolomics in hypertension.J Hypertens. 2014; 32:1159–1169. doi: 10.1097/HJH.0000000000000168CrossrefMedlineGoogle Scholar9. Gholizadeh L, Davidson P. More similarities than differences: an international comparison of CVD mortality and risk factors in women.Health Care Women Int. 2008; 29:3–22. doi: 10.1080/07399330701723756CrossrefMedlineGoogle Scholar10. Gerdts E, Sudano I, Brouwers S, Borghi C, Bruno RM, Ceconi C, Cornelissen V, Dievart F, Ferrini M, Kahan T, et al. Sex differences in arterial hypertension.Eur Heart J. 2022; 43:4777–4788. doi: 10.1093/eurheartj/ehac470CrossrefMedlineGoogle Scholar11. Wang X, Ma L, Pei X, Wang H, Tang X, Pei JF, Ding YN, Qu S, Wei ZY, Wang HY, et al. Comprehensive assessment of cellular senescence in the tumor microenvironment.Brief Bioinform. 2022; 23:bbac118. doi: 10.1093/bib/bbac118CrossrefMedlineGoogle Scholar12. Rutledge J, Oh H, Wyss-Coray T. Measuring biological age using omics data.Nat Rev Genet. 2022; 23:715–727. doi: 10.1038/s41576-022-00511-7CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails August 2023Vol 80, Issue 8 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.123.21197PMID: 37470774 Originally publishedJuly 20, 2023 PDF download Advertisement SubjectsCardiovascular DiseaseHypertensionWomen, Sex, and Gender

Aging leads to the global reduction of physiological fitness with circadian misalignment, yet the comprehensive view of aging-dependent circadian alterations in mammalian peripheral tissues and its underlying driving force remain unrevealed. By portraying the peripheral circadian landscape of 12 tissues from young and aged mice, we discovered the attenuated temporal coherence across tissues and heterogeneous circadian reprogramming in various tissues upon aging. Comprehensive and unbiased analyses recognized redox signaling as a tissue-sharing link between aging and rhythmic pathways. Importantly, perturbations of H2O2-CLOCK redox rhythm were observed in aged peripheral tissues, and significantly reduced the fitness of mice as revealed by rhythmic reprogramming similar to aging, impaired glucose metabolism, longer circadian period, and even premature phenotypes. Overall, our study unveiled the previously unappreciated role of redox signaling rhythms to drive aging-associated circadian transcriptome reprogramming across mammalian peripheral tissues, highlighting the therapeutic potential of redox rhythms for aging-related diseases.

Behçet’s disease (BD) is a chronic vasculitis characterized by systemic immune aberrations. However, a comprehensive understanding of immune disturbances in BD and how they contribute to BD pathogenesis is lacking. Here, we performed single-cell and bulk RNA sequencing to profile peripheral blood mononuclear cells (PBMCs) and isolated monocytes from BD patients and healthy donors. We observed prominent expansion and transcriptional changes in monocytes in PBMCs from BD patients. Deciphering the monocyte heterogeneity revealed the accumulation of C1q-high (C1qhi) monocytes in BD. Pseudotime inference indicated that BD monocytes markedly shifted their differentiation toward inflammation-accompanied and C1qhimonocyte–ended trajectory. Further experiments showed that C1qhimonocytes enhanced phagocytosis and proinflammatory cytokine secretion, and multiplatform analyses revealed the significant clinical relevance of this subtype. Mechanistically, C1qhimonocytes were induced by activated interferon-γ (IFN-γ) signaling in BD patients and were decreased by tofacitinib treatment. Our study illustrates the BD immune landscape and the unrecognized contribution of C1qhimonocytes to BD hyperinflammation, showing their potential as therapeutic targets and clinical assessment indexes.

Abstract Cellular senescence (CS), a state of permanent growth arrest, is intertwined with tumorigenesis. Due to the absence of specific markers, characterizing senescence levels and senescence-related phenotypes across cancer types remain unexplored. Here, we defined computational metrics of senescence levels as CS scores to delineate CS landscape across 33 cancer types and 29 normal tissues and explored CS-associated phenotypes by integrating multiplatform data from ~20 000 patients and ~212 000 single-cell profiles. CS scores showed cancer type-specific associations with genomic and immune characteristics and significantly predicted immunotherapy responses and patient prognosis in multiple cancers. Single-cell CS quantification revealed intra-tumor heterogeneity and activated immune microenvironment in senescent prostate cancer. Using machine learning algorithms, we identified three CS genes as potential prognostic predictors in prostate cancer and verified them by immunohistochemical assays in 72 patients. Our study provides a comprehensive framework for evaluating senescence levels and clinical relevance, gaining insights into CS roles in cancer- and senescence-related biomarker discovery.