Pulmonary fibrosis (PF) is a fatal disease associated with ageing. The senescence of alveolar epithelial type II cells (AECIIs) can drive PF. Therefore, reducing AECII senescence is a promising treatment to prevent PF. Mai-wei-yang-fei decoction (MWYF) has shown significant clinical efficacy in the treatment of patients with PF. However, its mechanism of action remains unclear.

To investigate the role and underlying mechanism of MWYF in protecting against PF.

The main chemical components of MWYF were identified using UPLC-MS. The mouse and in vitro cell models of PF were established using BLM. Micro-CT, H&E, and Masson staining were used to observe the protective effect of MWYF on mice with PF. Immunohistochemistry, β-galactosidase staining, and IF-FISH were used to observe the inhibitory effect of MWYF on senescence and telomere shortening in mouse lung tissue or A549 cells. The Transwell assay and cell co-culture method were used to observe the effect of MWYF on the migration and activation of lung fibroblasts by inhibiting AECII senescence. Finally, lentiviral vector was used to overexpress FBW7 gene in A549 cells in vitro to observe the mechanism pathway of MWYF inhibiting AECII senescence and telomere shortening.

MWYF was effective in protecting against bleomycin (BLM)-induced PF. Furthermore, MWYF alleviated cellular senescence by reducing the DNA damage response (DDR) and shortening of the telomere in AECⅡs in mouse lung tissues. Mechanistically, genes related to telomere disorders were detected in BLM-induced PF mouse models using q-PCR. MWYF mainly inhibited telomere shortening by regulating FBW7 and reducing the degradation of TPP1. In vitro, MWYF reduced BLM-induced senescence in A549 cells, as well as proliferation and migration of MRC5 cells, by inhibiting DDR and telomere shortening via regulation of the FBW7/TPP1 axis.

MWYF is a potential therapeutic agent against PF, as it inhibits telomere shortening and reduces AECII senescence by regulating FBW7/TPP1.

Xeroderma pigmentosum (XP) is an autosomal recessive condition resulting from defects in the nucleotide excision repair pathway, causing heightened ultraviolet radiation sensitivity and significantly elevated risks of dermatological malignancies. This case report details a young adult man in his early 20s diagnosed with XP type C, characterised by severe dermatological manifestations, such as pronounced freckle-like pigmentation and photosensitivity, but notably devoid of neurological symptoms, despite MRI findings of white matter lesions. Molecular genetic analysis confirmed a homozygous c.780-2AC mutation in the XPC gene. Clinical management emphasised stringent photoprotection, continuous thyroid hormone replacement following a prior thyroidectomy and interdisciplinary surveillance to address dermatological and potential neurological sequelae. The findings of this case underscore the critical role of early molecular diagnosis, targeted preventative care, and the necessity of a multidisciplinary approach to optimise patient outcomes and mitigate disease progression.

This review summarises some of the key features of interstitial lung diseases (ILDs) from a translational science point of view and brings insights into potential therapeutic options. Genetic predisposition and environmental factors like smoking, pollution and infections significantly impact the onset, progression and treatment response in ILDs, highlighting the need for personalised management. Fibroblasts are central to ILD pathology, influencing the tissue microenvironment, immune cell interactions and extracellular matrix (ECM) production, making them critical therapeutic targets. Monocyte-derived M2 macrophages drive fibrosis in idiopathic pulmonary fibrosis by secreting cytokines and remodelling the ECM. Understanding macrophage subtypes and their dynamics offers new therapeutic possibilities. Chronic type 2 immunity contributes to fibrosis, emphasising the need to enhance protective markers in order to even out the balance shift of pathological immune responses in ILD treatments. Serum biomarkers like Krebs von den Lungen-6 (KL-6), surfactant protein (SFTP) D, matrix metalloproteinase-7 (MMP-7), and C-C motif chemokine ligand (CCL)-18 are valuable for diagnosing and predicting ILD progression, although more research is needed for clinical application. Animal models, especially bleomycin-based models, offer insights into ILD pathology, but challenges like lung hyperinflation highlight the need for careful model selection and translational research to bridge preclinical and clinical findings.

Human telomere length is tightly regulated and associated with diseases at either extreme, but how these bounds are established remains incompletely understood. Here, we developed a rapid cell-based telomere synthesis assay and found that nucleoside salvage bidirectionally constrains human telomere length. Metabolism of deoxyguanosine (dG) or guanosine via purine nucleoside phosphorylase (PNP) and hypoxanthine-guanine phosphoribosyltransferase to form guanine ribonucleotides strongly inhibited telomerase and shortened telomeres. Conversely, salvage of dG to its nucleotide forms via deoxycytidine kinase drove potent telomerase activation, the extent of which was controlled by the dNTPase SAMHD1. Circumventing limits on salvage by expressing Drosophila melanogaster deoxynucleoside kinase or augmenting dG metabolism using the PNP inhibitor ulodesine robustly lengthened telomeres in human cells, including those from patients with lethal telomere diseases. Our results provide an updated paradigm for telomere length control, wherein telomerase reverse transcriptase activity is actively and bidirectionally constrained by the availability of its dNTP substrates, in a manner that may be therapeutically actionable.

Preeclampsia (PE) and gestational diabetes mellitus (GDM) are common pregnancy disorders with shared pathophysiological mechanisms. This study examined the association between SIRT1 polymorphisms (rs12778366 and rs7895833) and relative telomere length (RTL) in women with PE and GDM. The DNA from pregnant women with GDM with and without PE was analyzed. The RTL and genotyping were measured using quantitative real-time PCR. The women with GDM and PE had significantly shorter telomeres. The rs12778366 TC genotype was associated with a 4.48-fold increased risk of PE (OR = 4.48; 95% CI 1.54-13.08; p = 0.003). The PE group had a higher prevalence of the heterozygous TC rs12778366 genotype with short telomeres. The SIRT1 variant rs12778366 is associated with shorter telomeres and an increased risk of developing preeclampsia, suggesting it may be a useful biomarker for preeclampsia risk assessment in GDM pregnancies.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related mortality worldwide. Genetic alterations play a critical role in hepatocarcinogenesis, with mutations in the telomerase reverse transcriptase promoter (TERTp) and CTNNB1 exon 3 representing two of the most frequently reported somatic events in HCC. However, the frequency and distribution of these mutations vary across geographic regions and viral etiologies, particularly hepatitis B virus (HBV) and hepatitis C virus (HCV). This study aimed to assess the global distribution and etiological associations of TERTp and CTNNB1 exon 3 mutations in HCC through a comprehensive literature review. Our analysis, encompassing over 4000 HCC cases, revealed that TERTp mutations were present in 49.2% of tumors, with C228T being the predominant variant (93.3% among mutated cases). A striking contrast was observed between viral etiologies: TERTp mutations were detected in 31.6% of HBV-related HCCs, compared to 66.2% in HCV-related cases. CTNNB1 exon 3 mutations were identified in 23.1% of HCCs, showing a similar association with viral etiology, being more common in HCV-related cases (30.7%) than in HBV-related tumors (12.8%). Geographically, both mutations exhibited comparable patterns, with higher frequencies in Europe, Japan, and the USA, while lower rates were observed in China, Taiwan, and South Korea. Our findings underscore the distinct molecular profiles of HCC according to viral etiology and geographic origin, highlighting the need for region- and etiology-specific approaches to HCC prevention, diagnosis, and targeted therapy.

Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer, with a survival approaching only 11% at 5 years after diagnosis. In the last 15 years, telomere length (TL) measured in leukocyte (LTL) has been studied in relation to PDAC risk. The majority of the studies reported an association between short LTL and increased PDAC risk, but the results are heterogeneous. Genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) in the telomerase reverse transcriptase (TERT) gene as susceptibility loci for PDAC. Polygenic risk scores computed using SNPs associated with LTL have been tested in relation to PDAC susceptibility with various methods and giving contrasting results. The aim of this review is to analyze all publications carried out specifically on LTL, considering LTL measured with qPCR and with genetic proxies, and PDAC risk. Additionally, we will give an overview of the most relevant associations between SNPs in telomere-associated genes and PDAC, to answer the question shorter or longer? Which one of the two is associated with PDAC risk?

This article reviews the multitude of factors contributing to immune dysfunction and pulmonary infection risk in solid organ transplant recipients and references relevant clinical scientific reports. The mechanisms of action of individual immunosuppressive agents are explained, and the clinical effects of these drugs are compared. In addition, specialized methods to assess the net state of immunosuppression in individual transplant recipients and their limitations are discussed.

To investigate the roles of oxidative stress-related differentially expressed genes (OSRDEGs) in keloid formation and explore their potential value in diagnosis and treatment.

Gene expression data from the GEO database, including GSE145725 and GSE44270 as training sets and GSE7890 as a validation set, were utilized. OSRDEGs were identified, followed by Weighted Gene Co-expression Network Analysis (WGCNA), GO/KEGG enrichment analysis, and Gene Set Enrichment Analysis (GSEA). Key genes were further screened through protein-protein interaction (PPI) network analysis and receiver operating characteristic (ROC) curve analysis. miRNA targets, transcription factors (TF), and potential drug targets of these genes were predicted. Immune cell infiltration analysis was performed to assess the association between OSRDEGs and immune cells, which was validated using GSE7890. Finally, the expression of key genes was experimentally validated using quantitative PCR (qPCR), immunohistochemistry (IHC), and hematoxylin-eosin (HE) staining.

A total of 13 OSRDEGs were identified. WGCNA and functional enrichment analyses revealed that these genes were primarily involved in fibrosis and inflammatory processes in keloids, such as the MAPK signaling pathway, lymphocyte and monocyte proliferation, and inflammatory pathways involving IL-18 and IL-23. PPI network analysis, ROC analysis, and immune infiltration results identified Endothelin-1 (EDN1) and Neurotrophin-3(NTF3) as key genes with high sensitivity and specificity. These genes were positively and negatively correlated with activated mast cells, respectively, suggesting their dual regulatory roles in fibrosis and inflammation. External dataset validation, qPCR, correlation analysis, HE staining, and IHC results demonstrated that EDN1 and NTF3 were highly expressed in keloid tissues and were associated with excessive collagen deposition and immune cell infiltration.

EDN1 and NTF3, as OSRDEGs, play critical roles in the pathogenesis and progression of keloids. They may contribute to fibrosis and inflammation through the regulation of oxidative stress, the MAPK signaling pathway, and mast cell activation. These findings highlight EDN1 and NTF3 as potential diagnostic biomarkers and therapeutic targets, providing novel insights into the pathogenesis and treatment strategies for keloids.

Biogenesis of human telomerase requires its RNA subunit (hTR) to fold into a multi-domain architecture that includes the template-pseudoknot (t/PK) and the three-way junction (CR4/5). These hTR domains bind the telomerase reverse transcriptase (hTERT) protein and are essential for telomerase activity. Here, we probe hTR structure in living cells using dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) and ensemble deconvolution analysis. Approximately 15% of the steady state population of hTR has a CR4/5 conformation lacking features required for hTERT binding. The proportion of hTR CR4/5 folded into the primary functional conformation is independent of hTERT expression levels. Mutations that stabilize the alternative CR4/5 conformation are detrimental to telomerase assembly and activity. Moreover, the alternative CR4/5 conformation is not found in purified telomerase RNP complexes, supporting the hypothesis that only the primary CR4/5 conformer is active. We propose that this misfolded portion of the cellular hTR pool is either slowly refolded or degraded, suggesting that kinetic RNA folding traps studied in vitro may also hinder ribonucleoprotein assembly in vivo.

As cells divide, telomeres shorten through a phenomenon known as telomere attrition, which leads to unavoidable senescence of cells. Unprotected DNA exponentially increases the odds of mutations, which can evolve into premature aging disorders and tumorigenesis. There has been growing academic and clinical interest in exploring this duality and developing optimal therapeutic strategies to combat telomere attrition in aging and cellular immortality in cancer. The purpose of this review is to provide an updated overview of telomere biology and therapeutic tactics to address aging and cancer.

We used the Rayyan platform to review the PubMed database and examined the ClinicalTrial.gov registry to gain insight into clinical trials and their results.

Cancer cells activate telomerase or utilize alternative lengthening of telomeres to escape telomere shortening, leading to near immortality. Contrarily, normal cells experience telomeric erosion, contributing to premature aging disorders, such as Werner syndrome and Hutchinson-Gilford Progeria, and (2) aging-related diseases, such as neurodegenerative and cardiovascular diseases.

The literature presents several promising therapeutic approaches to potentially balance telomere maintenance in aging and shortening in cancer. This review highlights gaps in knowledge and points to the potential of these optimal interventions in preclinical and clinical studies to inform future research in cancer and aging.

Telomere length is associated with chronic diseases and, in younger populations, may represent a biomarker of disease susceptibility. As growing evidence suggests that environmental factors, including metals, may impact telomere length. We investigated the association between 17 metals measured in toenail samples and leukocyte relative telomere length (RTL), among 472 5- to 7-year-old children enrolled in the Bangladesh Environmental Research in Children's Health (BiRCH) cohortIn single-exposure linear regression models, a doubling of arsenic (As) and mercury (Hg) (μg/g) were associated with a -0.21 (95% CI, -0.032 to -0.010; P = .0005) and -0.017 (95% CI, -0.029 to -0.004; P = .006) difference in RTL, respectively. In Bayesian Kernel Machine Regression (BKMR) mixture models, the overall metal mixture was inversely associated with RTL (P-for-trend < 0.001). Negative associations with RTL were observed with both log2-As and log2-Hg, while an inverted U-shaped association was observed for log2-zinc (Zn) with RTL. We found little evidence of interaction among metals. Sex-stratification identified stronger associations of the overall mixture and log2-As with RTL among females compared to males. Our study suggests that As and Hg may independently influence RTL in mid-childhood. Further studies are needed to investigate potential long-term impacts of metal-associated telomere shortening in childhood on health outcomes in adult life.

Leukocyte telomere length (LTL) shortening, a biomarker of telomere attrition, has been linked to multiple diseases. However, the relationship between LTL and digestive diseases remains uncertain. This study aimed to investigate the association between LTL and the risk of digestive diseases.

A cohort analysis of over 500,000 participants from the UK Biobank (UKB) between 2006 and 2021 was conducted to estimate the associations of LTL with more than 90 common digestive diseases. LTL was quantified using multiplex quantitative polymerase chain reaction, and cases of each disease were determined according to inpatient and primary care data. Multivariable Cox proportional hazards regression analysis was used to evaluate the associations of LTL with the risk of digestive diseases. Furthermore, such associations were also evaluated after stratification by sex and ethnicity.

After a mean follow-up time of 11.8 years, over 20 International Classification of Diseases, 10th Revision ( ICD-10 ) codes were showed to be associated with telomere attrition. LTL shortening is associated with an increased risk of several digestive diseases, including gastroesophageal reflux disease (K21: hazard ratio [HR] = 1.30, 95% confidence interval [95% CI]: 1.19-1.42), esophageal ulcer (K221: HR = 1.81, 95% CI: 1.22-2.71), Barrett's esophagus (K227: HR = 1.58, 95% CI: 1.14-2.17), gastritis (K29: HR = 1.39, 95% CI: 1.26-1.52), duodenal ulcer (K26: HR = 1.55, 95% CI: 1.14-2.12), functional dyspepsia (K30X: HR = 1.36, 95% CI: 1.06-1.69), non-alcoholic fatty liver disease (NAFLD) (K760: HR = 1.39, 95% CI: 1.09-1.78), liver cirrhosis (K74: HR = 4.73, 95% CI: 3.27-6.85), cholangitis (K830: HR = 2.55, 95% CI: 1.30-5.00), and hernia (K43: HR = 1.50, 95% CI: 1.17-1.94; K44: HR = 1.29, 95% CI: 1.17-1.42). The risk of rectal polyps (K621: HR = 0.77, 95% CI: 0.63-0.92) decreased per unit shortening of LTL.

This study suggests that LTL shortening is associated with an increased risk of most digestive diseases except for rectal polyps. These findings may provide some clues for understanding the pathogenesis of digestive diseases.

Transcription of actively expressed genes is dampened for kilobases around DNA lesions via chromatin modifications. This is believed to favour repair and prevent genome instability. Nonetheless, mounting evidence suggests that transcription may be induced by DNA breakage, resulting in the local de novo synthesis of non-coding RNAs (ncRNAs). Such transcripts have been proposed to play important functions in both DNA damage signalling and repair. Here, we review the recently identified mechanistic details of transcriptional silencing at damaged chromatin, highlighting how post-translational histone modifications can also be modulated by the local synthesis of DNA damage-induced ncRNAs. Finally, we envision that these entangled transcriptional events at DNA breakages can be targeted to modulate DNA repair, with potential implications for locus-specific therapeutic strategies.

The interstitial lung diseases (ILDs) are a heterogeneous and complex group of diseases. The treatable trait (TT) model represents a shift in ILD management, away from traditional diagnostic labels towards a more individualised, trait-focused approach. This review explores the application of the TT paradigm to ILD, identifying key traits across the aetiological, pulmonary, extrapulmonary and behavioural domains. By addressing these traits, the TT model offers a framework to improve outcomes in ILD through multidisciplinary management with a precision medicine focus. Further research is necessary to evaluate the overall impact of this TT model on ILD care.

Shorter telomeres are associated with increased risk of cognitive decline and age-related diseases. Developing interventions to promote healthy aging by preserving telomere integrity is of paramount importance. Here, we investigated the effect of an 18-month meditation intervention on telomere length (TL) measures in older people without cognitive impairment.

A total of 137 adults age ≥65 years were randomized to one of the 3 groups (meditation training, non-native language training, or passive control). We evaluated the 50th and 20th percentile TL and the percentage of critically short telomeres (<3 kbp) in peripheral blood mononuclear cells.

Mixed model analysis showed a time effect indicating a general decrease on the 50th percentile TL (F = 80.72, p adjusted < .001), without a significant group effect or time × group interaction. No significant effect was detected in the 20th percentile TL or the percentage of critically short telomeres. Secondary analysis showed that only in the meditation training group 1) the 50th percentile TL positively correlated with class attendance time (r = 0.45, p adjusted < .011), 2) the 50th and 20th percentile TL positively correlated with responsiveness to the intervention, evaluated through a composite score (r = 0.46, p adjusted < .010 and r = 0.41, p adjusted = .029, respectively), and 3) lower scores on a measure of the personality trait "openness to experience" correlated with a lower percentage of critically short telomeres after the intervention (r = 0.44, p adjusted = .015).

In older adults, we found no evidence for a main effect of an 18-month meditation training program on TL compared with the control groups. Our findings highlight the importance of considering the impact of moderating factors when measuring the effectiveness of meditation-based trainings.

Zebrafish (Danio rerio) have emerged as a valuable model organism for investigating musculoskeletal development and the pathophysiology of associated diseases. Key genes and biological processes in zebrafish that closely mirror those in humans, rapid development, and transparent embryos make zebrafish ideal for the in vivo studies of bone and muscle formation, as well as the molecular mechanisms underlying musculoskeletal disorders. This review focuses on the utility of zebrafish in modeling various musculoskeletal conditions, with an emphasis on bone diseases such as osteoporosis and osteogenesis imperfecta, as well as muscle disorders like Duchenne muscular dystrophy. These models have provided significant insights into the molecular pathways involved in these diseases, helping to identify the key genetic and biochemical factors that contribute to their progression. These findings have also advanced our understanding of disease mechanisms and facilitated the development of potential therapeutic strategies for musculoskeletal disorders.

In order to elucidate novel actions of degalactosylated whey protein (D-WP) in comparison with intact whey protein (WP), the effects of oral intake of D-WP on peripheral blood telomere length and telomerase were examined in young and aged mice. In young mice, peripheral blood telomere length was significantly elongated following oral intake of D-WP for 4 weeks. mRNA expression of both telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) was significantly increased in the peripheral blood following oral intake of D-WP for 4 weeks. In aged mice, peripheral blood telomere length was significantly decreased as compared with that of young mice, and significantly restored to the level of young mice drinking water by the oral intake of D-WP for 4 weeks. The mRNA expression of peripheral blood TERT and TERC mRNA in aged mice significantly decreased as compared with the level in young mice drinking water, and was significantly restored to the level of expression of young mice drinking water by oral intake of D-WP for 4 weeks. These results suggest that D-WP, but not WP, potently increases peripheral blood telomere length accompanied by increased mRNA expression of TERT and TERC in both young and aged mice.

Accumulation of critically short telomeres (CST) is implicated in decreased tissular regenerative capacity and increased susceptibility to degenerative diseases such as Alzheimer's disease (AD). Telomere shortening has also been associated with age-related brain changes. However, it remains unclear whether CST accumulation is directly associated with AD markers or instead amplifies age-related effects, potentially increasing susceptibility of developing AD in cognitively healthy older adults.

This cross-sectional study used baseline data of 129 community-dwelling cognitively healthy older adults from the Age-Well trial (NCT02977819), aged 65 years and older enrolled between 2016 and 2018, in France. Using linear regressions, we analyzed the relationship between an innovative marker of telomere shortening, the percentage of CST (%CST), structural, functional and molecular neuroimaging outcomes, and multiple blood-based biomarkers related to AD pathophysiology. The effect of apolipoprotein E ε4 genotype (APOE4) was assessed on these relationships using interaction analysis.

A higher %CST was associated with lower global kurtosis fractional anisotropy (β = -.230; P = .010), particularly in frontal and temporal regions. A higher %CST was also related to higher plasma levels of Neurofilament light chain (β = .195; P = .020) and a lower subiculum volume (β = -.206; P = .020), although these associations did not meet the threshold for multiple comparisons. %CST was not associated with AD-related neuroimaging markers, including the AD-sensitive gray matter pattern (β = -.060; P = .441), glucose metabolism pattern (β = -.099; P = .372), brain perfusion pattern (β = -.106; P = .694) or hippocampus volume (β = -.106; P = .194). In APOE4 carriers, higher %CST was associated with lower subiculum (β = -.423; P = 0.003), DG (β = -.410; P = 0.018) and CA1 volumes (β = -.373; P = 0.024), even though associations with DG and CA1 volumes did not survive multiple comparison.

Although an increase in %CST does not appear to be directly linked to the pathophysiology of AD in cognitively healthy older adults, it could heighten the susceptibility of APOE4 carriers to develop AD plausibly due to greater vulnerability to age-related effects. However, longitudinal studies would be necessary to determine whether %CST influences the development and progression of AD later in life.

Limited data exists concerning the post lung transplantation outcomes of patients diagnosed with myelodysplastic syndrome (MDS). We delineate the clinical trajectories and outcomes for 3 patients with MDS and Short Telomere Syndrome (STS) who underwent lung transplantation. Our findings suggest that patients with STS and low-risk MDS, especially those harboring the SF3B1 mutation, tolerated standard immunosuppression and antimicrobial prophylaxis well without significant deviation from a typical post-transplant course. Therefore, individuals with low-risk MDS should not be automatically excluded from lung transplantation consideration. Post-transplant monitoring is crucial to promptly detect and manage cytopenias. Conversely, our patient, diagnosed with high-risk MDS post-transplantation faced a poor prognosis, with severe cytopenias limiting immunosuppression treatment and resulting in rejection. Thus, abundance of caution is warranted when contemplating lung transplantation for individuals with high-risk MDS and STS. Further research is necessary to validate these findings.

Defective telomerase function or telomere maintenance causes genomic instability. Alterations in telomere length and/or attrition are the primary features of rare diseases known as telomere biology disorders or telomeropathies. Recent advances in the molecular basis of these disorders and cutting-edge methods assessing telomere length have increased our understanding of this topic. Multiorgan manifestations and different phenotypes have been reported even in carriers within the same family. In this context, apart from dyskeratosis congenita, disorders formerly considered idiopathic (i.e. pulmonary fibrosis, liver cirrhosis) frequently correlate with underlying defective telomere maintenance mechanisms. Moreover, these patients are prone to developing specific cancer types and exhibit exceptional sensitivity and toxicity in standard chemotherapy regimens. The current review describes the diverse spectrum of clinical manifestations of telomere biology disorders in pediatric and adult patients, their correlation with pathogenic variants, and considerations during their management to increase awareness and improve a multidisciplinary approach.

Senescent cells are characterized by replicative arrest and phenotypes that produce diverse pro-inflammatory and pro-oxidant mediators. The senescence of diverse hepatic cell types could constitute an unrecognized pathogenic mechanism and prognostic determinant in autoimmune hepatitis. The impact of cellular senescence in autoimmune hepatitis is unknown, and it may suggest adjunctive management strategies.

This review describes the molecular mechanisms of cellular senescence, indicates its diagnostic features, suggests its consequences, presents possible therapeutic interventions, and encourages investigations of its pathogenic role and management in autoimmune hepatitis. Treatment prospects include elimination or reversal of senescent cells, generation of ectopic telomerase, reactivation of dormant telomerase, neutralization of specific pro-inflammatory secretory products, and mitigation of the effects of mitochondrial dysfunction.

The occurrence, nature, and consequences of cellular senescence in autoimmune hepatitis must be determined. The senescence of diverse hepatic cell types could affect the outcome of autoimmune hepatitis by impairing hepatic regeneration, intensifying liver inflammation, and worsening hepatic fibrosis. Cellular senescence could contribute to suboptimal responses during conventional glucocorticoid-based therapy. Interventions that target specific pro-inflammatory products of the senescent phenotype or selectively promote apoptosis of senescent cells may be preferred adjunctive treatments for autoimmune hepatitis depending on the cancer risk.

A discrete mathematical model based on ordinary differential equations and the associated continuous model formed by a partial differential equation, which simulate the generational and temporal evolution of a stem cell population, are proposed. The model parameters are the maximum proliferation potential and the rates of mitosis, death events and telomerase activity. The mean proliferation potential at each point in time is suggested as an indicator of population aging. The model is applied on hematopoietic stem cells (HSCs), with different telomerase activity rates, in a range of variation of maximum proliferation potential in healthy individuals, to study the temporal evolution of aging. HSCs express telomerase, however not at levels that are sufficient for maintaining constant telomere length with aging [1,2]. Women with primary ovarian insufficiency (POI) are known to have low telomerase activity in granulosa cells and peripheral blood mononuclear cells [3]. Extrapolating this to hematopoietic stem cells, the mathematical model shows the differences in proliferation potential of the cell populations when telomerase expression is activated using sexual steroids, though the endogenous promoter or with gene therapy using exogenous, stronger promoters within the adeno-associated virus. In the first case, proliferation potential of cells from POI condition increases, but when adeno-associated viruses are used, the proliferation potential reaches the levels of healthy cell populations.

Data on haematological features of telomere biology disorders (TBD) remain scarce. We describe haematological, extra-haematological characteristics and prognosis of 127 genetically confirmed TBD patients diagnosed after the age of 15. Ninety-three index cases and 34 affected relatives were included. At diagnosis of TBD, 76.3% of index cases had haematological features, half pulmonary features and a third liver features. At diagnosis, bone marrow failure (BMF) was present in 59 (46.5%), myelodysplastic syndrome (MDS) in 22 (17.3%) and acute myeloid leukaemia (AML) in 2 (1.6%) while 13 (10.2%) developed or worsened bone marrow involvement during follow-up. At diagnosis, compared to MDS/AML patients, BMF patients were younger (median 23.1 years vs. 43.8, p = 0.007), and had a better outcome (4-year overall survival 76.3% vs. 31.8%, p < 0.001). While frequencies and burden of cytogenetical and somatic mutations increased significantly in myeloid malignancies, some abnormalities were also observed in patients with normal blood counts and BMF, notably somatic spliceosome variants. Solid cancers developed in 8.7% patients, mainly human papillomavirus-related cancers and hepatocellular carcinomas. TBD is a multiorgan progressive disease. While BMF is the main haematological disorder, high-risk myeloid malignancies are common, and are, together with age, the only factors associated with a worse outcome.

The telomere has long been regarded as a dependable biomarker for cellular senescence. The lung function can reflect the function and status of the lungs. As individuals age beyond adulthood, there is a gradual decline in lung function. However, the existence of a associated between leukocyte telomere length (LTL) and lung function remains uncertain.

A two-sample Mendelian randomization (MR) analysis was used. The Single-nucleotide polymorphisms (SNPs) of LTL from the genome-wide association (GWAS) study were used as exposure instruments variable, and the lung function indicator including Forced expiratory volume in 1-s (FEV1), FEV1 Best measure, FEV1 predicted and Forced vital capacity (FVC) from the Neale Lab and MRC-IEU were used as outcomes. The associated between the exposures and outcomes was assessed using inverse-variance weighted (IVW), MR-Egger, and weighted median methods. Sensitivity analysis was conducted using Cochran's Q-test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and Steriger test.

Using the IVW method, a significant association was identified between genetically determined telomere length extension and enhanced lung function in FEV1, with ukb-a-336 (P = 0.127, OR = 1.028,95CI% = 1.003-1.042) and ukb-b-19657 (P = 7.26E-05, OR = 1.051,95CI% = 1.025-1.077),in FEV1 predicted, ukb-a-234 (P = 0.013, OR = 1.029,95CI% = 1.003-1.042), ukb-b-8428 (P = 0.001, OR = 1.032,95CI% = 1.012-1.052), in FEV1 best measure, ukb-a-231 (P = 7.24E-05, OR = 1.050,95CI% = 1.025-1.075), ukb-b-11141 (P = 1.40E-09, OR = 1.067,95CI% = 1.045-1.090).The sensitivity analysis did not reveal heterogeneity or horizontal pleiotropy.Meanwhile, the Steriger test results also indicate that the directionality between exposure and outcome is correct. Therefore, the results indicated robustness.

There is a correlation between longer LTL and better lung function in the European dataset.

Telomere length is a putative biomarker of aging and is associated with multiple age-related diseases. There are limited data on the landscape of rare genetic variations in telomere length. Here, we systematically characterize the rare variant associations with leukocyte telomere length (LTL) through exome-wide association study (ExWAS) among 390,231 individuals in the UK Biobank. We identified 18 robust rare-variant genes for LTL, most of which estimated effects on LTL were significant (> 0.2 standard deviation per allele). The biological functions of the rare-variant genes were associated with telomere maintenance and capping and several genes were specifically expressed in the testis. Three novel genes (ASXL1, CFAP58, and TET2) associated with LTL were identified. Phenotypic association analyses indicated significant associations of ASXL1 and TET2 with cancers, age-related diseases, blood assays, and cardiovascular traits. Survival analyses suggested that carriers of ASXL1 or TET2 variants were at increased risk for cancers; diseases of the circulatory, respiratory, and genitourinary systems; and all-cause and cause-specific deaths. The CFAP58 carriers were at elevated risk of deaths due to cancers. Collectively, the present whole exome sequencing study provides novel insights into the genetic landscape of LTL, identifying novel genes associated with LTL and their implications on human health and facilitating a better understanding of aging, thus pinpointing the genetic relevance of LTL with clonal hematopoiesis, biomedical traits, and health-related outcomes.

Healthy dietary patterns have been negatively associated with methylation-based measures of biological age, yet previous investigations have been unable to establish the relationship between them and biological aging assessed through blood chemistry-based clinical biomarkers. We sought to assess the associations of 4 dietary metrics with 4 measures of biological age.

Among 16,666 participants in NHANES 1999-2018, 4 dietary metrics [Dietary inflammatory index (DII), Dietary approaches to stop hypertension index (DASH), Alternate mediterranean diet score (aMED), and Healthy eating index-2015 (HEI-2015)] were calculated through the 'dietaryindex' R package. Twelve blood chemistry parameters were utilized to compute 4 indicators of biological age [homeostatic dysregulation (HD), allostatic load (AL), Klemera-Doubal method (KDM), and phenotypic age (PA)]. Binomial logistic regression models and restricted cubic spline (RCS) regression were employed to evaluate the associations.

All 4 dietary metrics were significantly associated with biological age acceleration or deceleration. In comparison to the lowest DII, the odds ratios (ORs) for accelerated HD, AL, KDM, and PA were 1.25 (1.08,1.45), 1.29 (1.11,1.50), 1.34 (1.08,1.65), and 1.61 (1.39,1.87) for the highest. The multivariable-adjusted ORs of the highest quartile of DASH, aMED, and HEI-2015 were 0.85 (0.73,0.97), 0.88 (0.74,1.04), and 0.84 (0.74,0.96) for HD, 0.64 (0.54,0.75), 0.61 (0.52,0.72), and 0.70 (0.59,0.82) for AL, 0.68 (0.54,0.85), 0.62 (0.50,0.76), and 0.71 (0.58,0.87) for KDM, and 0.50 (0.42,0.59), 0.64 (0.54,0.76), and 0.51 (0.44,0.58) for PA when compared with the lowest level. The findings were validated by the best-fitting dose-response curves for the associations. Among participants consuming dietary supplements (Pinteraction < 0.05), the positive effects of a healthy dietary pattern on biological aging were more pronounced. Systemic immune inflammation index (SII) and atherogenic index of plasma (AIP) were identified as being involved in and mediating the associations.

Biological aging assessed through blood chemistry-based clinical biomarkers is negatively associated with diet quality. The anti-aging benefits of improving the diet may be due to its ability to reduce inflammation and lower blood lipids.

T cell exhaustion refers to a progressive state in which T cells become functionally impaired due to sustained antigenic stimulation, which is characterized by increased expression of immune inhibitory receptors, but weakened effector functions, reduced self-renewal capacity, altered epigenetics, transcriptional programme and metabolism. T cell exhaustion is one of the major causes leading to immune escape of cancer, creating an environment that supports tumor development and metastatic spread. In addition, T cell exhaustion plays a pivotal role to the efficacy of current immunotherapies for cancer. This review aims to provide a comprehensive view of roles of T cell exhaustion in cancer development and progression. We summerized the regulatory mechanisms that involved in T cell exhaustion, including transcription factors, epigenetic and metabolic reprogramming events, and various microenvironmental factors such as cytokines, microorganisms, and tumor autocrine substances. The paper also discussed the challenges posed by T cell exhaustion to cancer immunotherapies, including immune checkpoint blockade (ICB) therapies and chimeric antigen receptor T cell (CAR-T) therapy, highlightsing the obstacles encountered in ICB therapies and CAR-T therapies due to T cell exhaustion. Finally, the article provides an overview of current therapeutic options aimed to reversing or alleviating T cell exhaustion in ICB and CAR-T therapies. These therapeutic approaches seek to overcome T cell exhaustion and enhance the effectiveness of immunotherapies in treating tumors.

Telomerase is a specialized reverse transcriptase that uses an intrinsic RNA subunit as the template for telomeric DNA synthesis. Biogenesis of human telomerase requires its RNA subunit (hTR) to fold into a multi-domain architecture that includes the template-containing pseudoknot (t/PK) and the three-way junction (CR4/5). These two hTR domains bind the telomerase reverse transcriptase (hTERT) protein and are thus essential for telomerase catalytic activity. Here, we probe the structure of hTR in living cells using dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) and ensemble deconvolution analysis. Unexpectedly, approximately 15% of the steady state population of hTR has a CR4/5 conformation lacking features thought to be required for hTERT binding. The proportion of hTR CR4/5 that is folded into the primary functional conformation does not require hTERT expression and the fraction of hTR that assumes a misfolded CR4/5 domain is not refolded by overexpression of its hTERT binding partner. This result suggests a functional role for an RNA folding cofactor other than hTERT during telomerase biogenesis. Mutagenesis demonstrates that stabilization of the alternative CR4/5 conformation is detrimental to telomerase assembly and activity. Moreover, the alternative CR4/5 conformation is not found in telomerase RNP complexes purified from cells via an epitope tag on hTERT, supporting the hypothesis that only the major CR4/5 conformer is active. We propose that this misfolded portion of the cellular hTR pool is either slowly refolded or degraded. Thus, kinetic traps for RNA folding that have been so well-studied in vitro may also present barriers for assembly of ribonucleoprotein complexes in vivo.

Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.

Telomeres prevent damage to coding DNA as end-nucleotides are lost during mitosis. Mutations in telomere maintenance genes cause excessive telomere shortening, a condition known as short telomere syndrome (STS). One hepatic manifestation documented in STS is porto-sinusoidal vascular disorder (PSVD).

As the etiology of many cases of PSVD remains unknown, this study explored the extent to which short telomeres are present in patients with idiopathic PSVD.

This monocentric cross-sectional study included patients with histologically defined idiopathic PSVD. Telomere length in 6 peripheral blood leukocyte subpopulations was assessed using fluorescent in situ hybridization and flow cytometry. Variants of telomere-related genes were identified using high-throughput exome sequencing. In total, 22 patients were included, of whom 16 (73%) had short (9/22) or very short (7/22) telomeres according to age-adjusted reference ranges. Fourteen patients (64%) had clinically significant portal hypertension. Shorter telomeres were more frequent in males (p = 0.005) and patients with concomitant interstitial lung disease (p < 0.001), chronic kidney disease (p < 0.001), and erythrocyte macrocytosis (p = 0.007). Portal hypertension (p = 0.021), low serum albumin level (p < 0.001), low platelet count (p = 0.007), and hyperbilirubinemia (p = 0.053) were also associated with shorter telomeres. Variants in known STS-related genes were identified in 4 patients with VSTel and 1 with STel.

Short and very short telomeres were highly prevalent in patients with idiopathic PSVD, with 31% presenting with variants in telomere-related genes. Telomere biology may play an important role in vascular liver disease development. Clinicians should consider measuring telomeres in any patient presenting with PSVD.

Targeting telomere maintenance has emerged as a promising strategy for hepatocellular carcinoma (HCC) treatment. However, given the duality of the telomere-telomerase axis in telomere maintenance, a comprehensive strategy is urgently needed. Herein, we develop a poly(amino acid) (D-PAAs)-based strategy for spatiotemporal codelivery of telomerase inhibitor, BIBR1523, and AKT inhibitor, isobavachalcone. By leveraging D-PAAs' modifiability, we synthesize polymer-inhibitor conjugates (PB and PI) and a folic acid-decorated tumor-targeting vector (PF). These building blocks undergo micellization to fabricate a codelivery nanomedicine (P-BI@P-FA) by exploiting D-PAAs' noncovalent assembly. P-BI@P-FA improves the pharmacokinetics, tumor selectivity, and bioavailability of small molecule inhibitors and initiates a dual telomere-specific inhibition by combining telomerase deactivation with telomere disruption. Furthermore, a hybrid tumor-targeting magnetic nanosystem is designed using D-PAAs and manganese dioxide to showcase magnetic resonance imaging capacities. Our D-PAAs-based strategy addresses the pressing need for telomere-specific HCC treatment while allowing for diagnostic application, presenting a promising avenue for nanomedicine design.

Telomere Length (TL) and integrity is significantly associated with age-related disease, multiple genetic and environmental factors. We observe mouse genomic DNA (gDNA) isolation methods to have a significant impact on average TL estimates. The canonical qPCR method does not measure TL directly but via the ratio of telomere repeats to a single copy gene (SCG) generating a T/S ratio. We use a monochromatic-multiplex-qPCR (mmqPCR) method which multiplexes the PCR and enables quantification of the target and the single copy gene within the same qPCR reaction. We demonstrate that TL measurements, from murine gDNA, isolated via Spin Columns (SC) and Magnetic Beads (MB), generate significantly smaller T/S ratios compared to gDNA isolated via traditional phenol/chloroform methods. The former methods may impede correct TL estimation by producing non representative fragment sets and reducing qPCR efficacy. This work highlights discrepancies in TL measurements due to different extraction techniques. We recommend the use of gDNA isolation methods that are shown to preserve DNA length and integrity, such as phenol/chloroform isolation. We propose that widely used high throughput DNA isolation methodologies can create spurious associations within a sample set, thus creating misleading data. We suggest that published TL associations should be revisited in the light of these data.

Insufficient numbers of peripheral blood stem cells (PBSC) after granulocyte colony-stimulating factor (G-CSF) mobilization occurs in a significant proportion of PBSC collections, often from older age donors. Telomere length (TL) is often used as an indicator of an individual's biological age. This study aimed to investigate the relationship between donors' leukocyte TL and the outcome of G-CSF-induced PBSC mobilization in healthy unrelated donors.

Donors' leukocyte TLs and the outcome of G-CSF-induced PBSC mobilization, as assessed by pre-harvest CD34+ cell counts, were analyzed in 39 healthy PBSC donors. TL in a non-mobilized general population (n = 90) was included as a control group. G-CSF mobilization effect was categorized into three groups according to pre-harvest CD34+ cell count: poor (≤25/μL, PMD), intermediate (between 25 and 180/μL), and good (≥180/μl, GMD).

Leukocyte TL of PBSC donors correlated well with pre-harvest CD34+ cell counts (r = 0.645, p < 0.001). Leukocyte TLs of PMDs (n = 8) were significantly shorter than those of GMDs (n = 9) and non-mobilization controls (p < 0.05). Moreover, all PMD TLs were below the 50th percentile, and 62.5% of PMDs had TLs below the 10th percentile of age-matched control participants. In contrast, no GMD TLs were below the 10th percentile; in fact, 33.3% (3/9) of them were above the 90th percentile.

Our results indicate that shorter donor leukocyte TL is associated with poor G-CSF-induced PBSC mobilization. TL, which represents a donor's biological age, could be a potential predictor for mobilization outcome.

Encounters with pathogens and other molecules can imprint long-lasting effects on our immune system, influencing future physiological outcomes. Given the wide range of microbes to which humans are exposed, their collective impact on health is not fully understood. To explore relations between exposures and biological aging and inflammation, we profiled an antibody-binding repertoire against 2,815 microbial, viral, and environmental peptides in a population cohort of 1,443 participants. Utilizing antibody-binding as a proxy for past exposures, we investigated their impact on biological aging, cell composition, and inflammation. Immune response against cytomegalovirus (CMV), rhinovirus, and gut bacteria relates with telomere length. Single-cell expression measurements identified an effect of CMV infection on the transcriptional landscape of subpopulations of CD8 and CD4 T-cells. This examination of the relationship between microbial exposures and biological aging and inflammation highlights a role for chronic infections (CMV and Epstein-Barr virus) and common pathogens (rhinoviruses and adenovirus C).

Idiopathic pulmonary fibrosis (IPF) has traditionally been considered the archetype of progressive fibrotic interstitial lung diseases (f-ILDs), but several other f-ILDs can also manifest a progressive phenotype. Integrating genomic signatures into clinical practice for f-ILD patients may help to identify patients predisposed to a progressive phenotype. In addition to the risk of progressive pulmonary fibrosis, there is a growing body of literature examining how pharmacogenomics influences treatment response, particularly regarding the efficacy and safety profiles of antifibrotic and immunomodulatory agents. In this narrative review, we discuss current studies in IPF and other forms of pulmonary fibrosis, including systemic autoimmune disorders associated ILDs, sarcoidosis and hypersensitivity pneumonitis. We also provide insights into the future direction of research in this complex field.

Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases.

Retrospective multicenter analysis of liver disease (transaminases > 30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n = 1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological, and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease in 48% and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and HCC occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥ 3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group [80/396, (20%)], OR 12.9 (CI 95%: 7.8-21.3, p < 0.001).