Aging is characterized by systemic dysregulation of intercellular communication, with extracellular vesicles (EVs) serving as key mediators that transport bioactive molecules, including long non-coding RNAs (lncRNAs), to modulate tissue homeostasis and aging processes. In this review, we summarize how EVs selectively package and deliver lncRNAs between cells, thereby transmitting senescence-related signals. These EV-associated lncRNAs regulate core aging-related signaling pathways such as p53, mammalian target of rapamycin (mTOR), and sirtuins, influencing cellular senescence, stress adaptation, and systemic aging. In age-related diseases, including neurodegenerative, cardiovascular, and metabolic disorders, as well as osteoarthritis, EV-lncRNAs play significant pathophysiological roles by mediating inflammation, metabolic dysregulation, and tissue repair. Owing to the protection provided by the vesicular membrane and the selectivity of their loading, EV-lncRNAs exhibit exceptional stability and cell-type specificity in biofluids, positioning them as candidate biomarkers for aging clocks and disease risk stratification. Furthermore, they also hold potential as vehicles for therapeutic delivery. However, progress in this field is constrained by methodological heterogeneity in EV isolation and characterization, a lack of causal in vivo validation, and an incomplete understanding of lncRNA sorting mechanisms. Emerging advances in experimental and analytical technologies are expected to overcome these bottlenecks and facilitate the translation of EV-lncRNA regulatory networks into precision diagnostics and aging-targeted therapeutic strategies.

The family of Nectin and Nectin-like molecules (Necls) and their immunoreceptors are essential in the immune response against cancer. While primarily involved in cell adhesion, motility, and proliferation, some Nectin members also serve as ligands for both stimulatory and inhibitory immune receptors, influencing immune responses. The Nectin/Necls and their receptors form a complex regulatory axis crucial for natural killer (NK) and T cell activity. The most relevant ligands in this axis are the Nectin CD112 and the Nectin-like molecule CD155. Both are ligands for the activating receptor DNAX accessory molecule-1 (DNAM-1) and the inhibitory receptor T cell immunoreceptor with Ig and ITIM domains (TIGIT). Additionally, CD155 is a ligand for T cell activation induced late expression (TACTILE), and CD112 for poliovirus receptor related immunoglobulin domain containing (PVRIG), both inhibitory receptors. These ligands bind with higher affinity to their inhibitory receptors than to the activating receptor DNAM-1. Recent advances in cancer immunotherapy have focused on identifying new targets to overcome tumor resistance. Antibody-mediated blockade of inhibitory receptors such as TIGIT, TACTILE, and PVRIG on NK and T cells has shown promising results in animal models and clinical trials, helping to break immune tolerance. Aging significantly increases cancer risk and contributes to the deterioration of the immune response, impairing cancer immune surveillance. Aging is also associated with an altered tumor microenvironment, reducing immune cell infiltration and promoting tumor progression. In elderly cancer patients, both immunosenescence and cancer-related immunosuppression contribute to a defective immune response against tumor cells. Thus, cancer immunotherapy strategies should be personalized to overcome the dysfunctional immune responses in elderly cancer patients. Understanding these interactions, including ligand-receptor binding mechanisms, is vital for developing effective immunotherapies. Since cancer predominantly affects older adults, further research is needed to explore how aging impacts Nectin-receptor interactions and to tailor immunotherapy strategies for elderly patients.

Aims: Recurrent and uncontrolled inflammation of the colon may cause inflammatory bowel diseases (IBD), which are strongly associated with the onset of colitis-associated cancer (CAC). However, the molecular mechanisms linking inflammation, dysregulated growth, and tumorigenesis remain unclear. This study aims to determine the role of the N⁶-methyladenosine (m⁶A) reader YTH m⁶A RNA binding protein 1 (Ythdf1) in regulating colitis severity and CAC development.

Methods: Ythdf1-deficient and wild-type mice were subjected to dextran sodium sulfate (DSS)-induced colitis to evaluate disease severity, epithelial survival, goblet cell and mucus preservation, and inflammatory signaling. m⁶A-dependent regulation of Jak1 mRNA and the Il6-Jak1-Stat3 pathway activation was assessed through molecular analyses. Additionally, an azoxymethane (AOM)/DSS model was used to determine the impact of Ythdf1 loss on CAC development.

Results: Ythdf1 deficiency significantly worsened DSS-induced colitis, with increased epithelial damage, loss of goblet cells and mucus, impaired epithelial survival, and reduced Stat3 activation. Mechanistically, Ythdf1 recognized m⁶A-modified Jak1 mRNA and enhanced Jak1 protein expression, thereby maintaining the Il6-Jak1-Stat3 signaling during inflammatory stress. Despite aggravating colitis, Ythdf1 loss markedly suppressed CAC progression and reduced tumor burden.

Conclusion: Ythdf1 is a key regulator of intestinal homeostasis, maintaining the Il6-Jak1-Stat3 signaling to protect against colitis while paradoxically promoting CAC progression. These findings identify Ythdf1 as a context-dependent modulator of intestinal inflammation and tumorigenesis, highlighting its therapeutic potential in IBD and CAC.

Immunosenescence is a biological process accompanying ageing, characterized by increased susceptibility to infections, reduced vaccine efficacy, and the development of chronic low-grade inflammation. Although immunosenescence is systemic, the relative contribution and compensability of each organ in the adaptive immune axis remain debated. We consolidate current evidence supporting a thymus-centric model of immune ageing. In this model, early and progressive thymic involution, marked by thymic epithelial cell attrition, FOXN1 decline, and architectural disruption, emerges as the principal constraint on de novo naive T‑cell production and T-cell receptor (TCR) repertoire renewal. In contrast, age‑related changes in bone marrow and spleen often exhibit partial compensability through peripheral redistribution and clinical interventions, sustaining counts but not restoring de novo diversity. We evaluate mechanisms of thymic involution, inter-organ communication, and cross-species parallels, identifying shared features across animal models. Quantitative readouts, including age-associated declines in sjTRECs and TCR-β repertoire diversity, further support the thymus-centricity. Clinically, constrained thymopoiesis may undercut vaccine responsiveness and reduce the efficacy of cancer immunotherapies (chimeric antigen receptor T-cell and immune checkpoint inhibitors) in older adults. We assess genetic, pharmacological, and bioengineering strategies to preserve or restore thymic function and outline translational paths and endpoints for future trials.

Background: DNA methylation patterns are established during development and are propagated in a cell type specific manner, but these patterns may become aberrant during aging and cancer. Regions of alternating high and moderate to low levels of DNA methylation exist along all chromosomes in human cells. It is unclear how these distinct DNA methylation blocks are established. Most of the prior work in this area has been performed with mouse embryonic stem cells.

Methods: Using whole genome bisulfite sequencing and chromatin-immunoprecipitation sequencing, we have profiled DNA methylation at single base resolution and various histone modifications in human bronchial epithelial cells.

Results: We found that many regions of lower DNA methylation (< 50%) are characterized by presence of the Polycomb repressive complex 2 (PRC2) mark, histone H3K27 trimethylation, but less so by the PRC1 mark histone H2AK119 monoubiquitylation. These same PRC2-marked regions also showed a depletion of histone H3K36 di- and tri-methylation.

Conclusion: Since H3K36me2 and H3K36me3 are recognized by the reader domains of the DNA methyltransferases DNMT3A and DNMT3B, and H3K36 methylation is a block to the PRC2 methyltransferases, these two types of crosstalk may explain the stable maintenance and antagonism between H3K27me3 and broad DNA methylation domains. However, methylated CpG islands are depleted of H3K36me2 and show a different relationship between DNA methylation and H3K36me2 deposition compared to non-CpG island regions. The data give insight into how DNA methylation patterns are established in human cells. We discuss these findings and their potential relevance for altered DNA methylation patterns seen in aging tissues and in cancer cells.

Background: The outcomes of older adults with cancer are usually worse than those of their younger counterparts. Several randomised trials have demonstrated benefits of a comprehensive geriatric assessment (CGA) in older patients undergoing systemic cancer therapy. Despite that, CGA is not implemented into routine care in Germany and data on its efficacy and feasibility within the German healthcare system are missing.

Methods: This prospective, bicentric cohort study will assess the feasibility of CGA implementation into routine care for older adults with cancer in Germany. Patients ≥ 65 years with a positive geriatric screening (G8) and newly diagnosed cancer or progressive disease prior to a new treatment line undergo a CGA as part of their routine care. Patients who consent to participate in the study receive a follow-up call after three months to assess functional measures, and their (routine) CGA data are analyzed thereafter. CGA results are presented during the multidisciplinary team meeting to inform treatment recommendations provided by primary healthcare providers (pHCP; e.g., oncologists, gynecologists, urologists). pHCP are further evaluated for their satisfaction with CGA implementation and whether its results have influenced their recommendations. The primary endpoint is to estimate the patients’ willingness to participate with an accuracy of ± 7.5%. Secondary endpoints focus on additional feasibility measures and patient preferences.

Conclusion: This study will assess the feasibility of CGA implementation into routine care for older cancer patients. Its results will provide the framework to design a larger subsequent trial to assess the efficacy and cost effectiveness of CGA implementation in Germany.

Clinical trial registration number: DRKS00035569