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Open research questions in Telomeres, Telomerase, and Senescence

74 unresolved questions extracted from the limitations and future-work sections of 280 Telomeres, Telomerase, and Senescence papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Human umbilical cord-derived mesenchymal stem cells (HUC-MSCs) exhibit immunomodulatory properties; however, their mechanism of action in frail elderly populations remains unclear.

    Immunomodulatory effects of HUC-MSCs therapy: enhancing adaptive and innate immune responses in aging frailty · 2026 · DOI

  • While transcriptional regulation of senescence has been extensively studied, the contribution of post-translational modifications (PTM) to secretory pathway regulation remains poorly understood.

    Acetylation-dependent remodeling of the secretory pathway shapes the senescence-associated secretome · 2026 · DOI

  • Although resveratrol, as a multi-target inhibitor, provided evidence supporting the inhibitory effect of HY‑I on STAT3/NLRP3, a limitation of this study is the lack of specific STAT3 or NLRP3 inhibitors. Therefore, the specificity of the thera- peutic mechanism by which HY‑I targets STAT3/NLRP3 has not been fully established.

    Huyan-I formula attenuates renal senescence and fibrosis by inhibiting STAT3/NF-κB/NLRP3-driven SASP · 2026 · DOI

  • The tran- sient nature of AGS activity is further supported by phar- macokinetic considerations: although the formal half-life of AGS has not been determined in mice, data from other species indicate an approximate half-life of 3–4 h in rats.

    Improvement of fertility in female mice by treatment with novel telomerase-increasing compounds · 2026 · DOI

  • Markers of oxidative stress are widely used as indicators of physiological state, but their utility for ecological and evolutionary inference remains uncertain due to high intraindividual variation masking associations with environmental conditions, fitness, and other physiological indicators such as telomere length.

    Oxidative stress markers have low repeatability: A meta-analysis and simulation study with implications for measuring physiological condition and fitness · 2026 · DOI

  • Genetic variation at the TERC locus, encoding the telomerase RNA component, is associated with human diseases and lifespan, but a comprehensive functional annotation of this critical non-coding RNA is lacking.

    Saturating variant analysis of TERC redefines the human telomerase reverse transcription mechanism · 2026 · DOI

  • Background Acute myocardial infarction (AMI) incidence increases with population aging, alongside heightened cellular senescence; however, clinically useful senescence-related genes (SRGs) for AMI remain poorly defined.

    Identification and analysis of diagnostic senescence-related gene signatures for acute myocardial infarction based on multi-omics data and machine learning · 2026 · DOI

  • Leukocyte telomere length (LTL), a marker of cumulative cellular aging that shortens under chronic stress, may capture stress-related biological vulnerability, but has not been examined as a potential population-level contributor to PTB in Hispanic/Latina pregnancies.

    Mid-Pregnancy Maternal Leukocyte Telomere Length and Preterm Birth in a Population-Based Hispanic/Latina California Cohort · 2026 · DOI

  • The biochemical causes of long-term dormancy are still not fully understood, and conventional surveillance frequently lacks sufficient sensitivity to reliably predict relapse.

    “Immune senescence and dormant tumor cells: reconceptualizing breast cancer recurrence as an affliction of aging and chronic inflammation” · 2026 · DOI

  • However, the con- tribution of cellular senescence in ECs to coagulation remains unclear, and differential role of RS and SIPS in EC function remain insufficiently defined. Despite shared features, distinct functional roles remain unclear.

    Replicative and stress-induced premature senescence distinctively affect the endothelial anticoagulation capacity · 2026 · DOI

  • While preclinical evidence supporting SASP-targeted therapy is expanding rapidly, clinical translation remains challenging and is considered a key unresolved issue in this field. First, the SASP is highly heterogeneous across different tissues, disease stages, and senescent cell subtypes, making it difficult to select biomarkers and stratify patients (Kumar et al., 2021; Yang et al., 2026). Second, systemic senolysis may cause off-target toxicity or interfere with beneficial delivery strategies—though promising intervertebral discs—still need to overcome obstacles related to retention, penetration, dosing, and long-term safety (Zhang et al., 2026; Peilin et al., 2019).

    Senescence-associated secretory phenotype: the “pathogenic” factor driving orthopedic degenerative diseases and its regulation · 2026 · DOI

  • Future research should focus on developing targeted strate- gies to modulate these signaling pathways, thereby delaying or pre- venting endothelial cell senescence and its associated pathological consequences delineated. Furthermore, the upstream signaling and downstream effector networks of molecules such as TRPC5 in aging remain to be fully Histochemistry and Cell Biology (2026) 164:29 Page 13 of 17 29 Fig. Although noncoding RNAs, such as circular GNAQ (circGNAQ) and maternally expressed gene 3 (Meg3), have been shown to be crucial, their specific regulatory networks and functions in different vascular beds and tissue micro- environments are not yet fully understood.

    SASP-driven vascular aging: unraveling the transcriptional nexus in endothelial senescence and cardiovascular disease · 2026 · DOI

  • Third, the causal relationships among senescence activation, met- abolic rewiring and immune dysfunction remain to be resolved; integrated CRISPR-based gene editing, lineage-tracing and immune-cell co-culture models will be needed to dissect these pathways.

    Machine learning-driven multi-omics integration uncovers a senescence associated molecular axis in HCC · 2026 · DOI

  • With age, the cardiovascular system gradually degenerates, resulting in a series of pathophysiological changes. It may precede or even underlie body-wide, age-related health deterioration. In addition to the increase in time itself, we have innovatively summarized five major etiological factors as well as risk factors that have the potential to promote cardiovascular ageing (Fig. 2). On this basis, we propose several specific management strategies for cardiovascular ageing (Fig. 6). Tables 2 and 3 list FDA-approved drugs and clinical trials targeting cardiovascular ageing. However, it is important to note that categorization does not mean that the etiologies are independent of each other. A poor lifestyle (e.g., diet) can lead to obesity,486 which, as a metabolic syndrome, can accelerate cardiovascular ageing.25 Together, all the etiologies and risk factors form a complex ‘spider web’ of cardiovascular ageing. Obviously, focusing on only one aspect of the problem is limited and ineffective. Therefore, future research should take a holistic approach to propose a macroscopic framework for the etiology of cardiovascular ageing and correspond- ing therapeutic improvement methods. For the first time, we have grouped the twelve hallmarks of cardiovascular ageing into three broad categories, from the micro- to the macrolevel, which are the molecular, cellular and systemic levels (Fig. 4). These findings collectively reveal that cardiovascular ageing is a complex process driven by the accumulation of multiple factors. Importantly, these hallmark features do not act independently but are intricately intertwined and synergistically interact, collectively exerting profound effects on ageing-related diseases (Fig. 5). However, many issues remain to be resolved. For example, the search for more specific ageing biomarkers than p16 remains an important direction for future research. In addition, different cardiac cells undergo senescence, either in naturally senescent or drug-induced senescent hearts.487 It remains unknown whether they play the same role in cardiac function or in the development of CVD.208 Whether reciprocal feedback loops exist between vascular ageing and nondiabetic metabolic disorders represents a compelling hypothesis that warrants further mechanistic investigation.

    Cardiovascular ageing: hallmarks, signaling pathways, diseases and therapeutic targets · 2026 · DOI

  • The ARCH Domain of RTEL1 helicase is highlighted as functionally important in Hoyeraal-Hreidarsson syndrome (reference 91), but systematic structure-function studies defining which specific RTEL1 mutations disrupt helicase activity versus telomere maintenance versus genome instability remain incomplete.

    Clonal Signatures of Telomere Biology Disorders · 2026 · DOI

  • The role of POT1 mutations in telomere end fill-in and telomere truncations (Coats plus) and in idiopathic pulmonary fibrosis requires clarification of the mechanistic differences between rare constitutional POT1 variants and their contribution to different clinical presentations of telomere biology disorders.

    Clonal Signatures of Telomere Biology Disorders · 2026 · DOI

  • Gain-of-function mutations in RPA1 cause telomere shortening with somatic genetic rescue mechanisms, but the prevalence and phenotypic spectrum of RPA1 variants in telomere biology disorders remain poorly characterized compared to recessive RTEL1 founder mutations and other established causative genes.

    Clonal Signatures of Telomere Biology Disorders · 2026 · DOI

  • The shared genetic predisposition between rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis (reference 77) linked to telomere biology genes requires investigation into how telomerase-associated protein mutations (NHP2, NOP10) and poly(A)-specific ribonuclease deficiency contribute to autoimmune manifestations in addition to pulmonary fibrosis phenotypes.

    Clonal Signatures of Telomere Biology Disorders · 2026 · DOI

  • Telomere-related lung fibrosis demonstrates diagnostic heterogeneity despite uniform progressive phenotypes. The specific molecular mechanisms differentiating diagnostic presentations in patients with telomere biology disorders affecting the lungs—particularly those with PARN, RTEL1, and POT1 mutations—require systematic comparative analysis.

    Clonal Signatures of Telomere Biology Disorders · 2026 · DOI

  • The epigenetic inheritance of telomere length obscures identification of causative PARN locus mutations, as noted in reference 79. This phenomenon requires investigation into the mechanisms by which epigenetic modifications affect telomere biology disorder penetrance and expressivity in families with biallelic and monoallelic PARN pathogenic variants.

    Clonal Signatures of Telomere Biology Disorders · 2026 · DOI

  • The hierarchical regulatory network linking telomere dysfunction, mitochondrial metabolic disorders, DNA damage, loss of autophagy, metabolic reprogramming, and mechanical stress changes in cardiovascular aging has been conceptually identified but lacks experimental validation of causal relationships and regulatory dependencies between these hallmarks.

    Transcriptional regulation in cardiovascular aging · 2026 · DOI

  • Integration of multi-omics data with functional validation to analyze spatiotemporal and dynamic characteristics of transcriptional regulatory networks in cardiovascular aging is not systematically developed. The paper identifies this as necessary but does not specify analytical frameworks or integration methodologies.

    Transcriptional regulation in cardiovascular aging · 2026 · DOI

  • Combined intervention strategies targeting multiple core transcriptional regulatory nodes simultaneously—such as activating SIRT6, inhibiting GATA4, and supplementing NAD+—lack systematic evaluation for synergistic effects. The hierarchical interactions and optimal combination ratios remain unmapped.

    Transcriptional regulation in cardiovascular aging · 2026 · DOI

  • Lactic acid modification-related interventions targeting the TRAP1-HDAC3-H4K12la axis have only been validated in animal models using glycolysis inhibitors (2-DG) and lactate dehydrogenase inhibitors (oxamate, GNE-140). Clinical translation efficacy, optimal dosing strategies, and safety profiles in human cardiovascular aging remain unexplored.

    Transcriptional regulation in cardiovascular aging · 2026 · DOI

  • SIRT2 activators have not been systematically screened or developed for cardiovascular aging applications. The paper identifies SIRT2 as a key epigenetic modifier but lacks concrete chemical development pipelines or candidate compounds for clinical translation targeting age-related cardiovascular disease.

    Transcriptional regulation in cardiovascular aging · 2026 · DOI

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74 open questions have been extracted from the limitations and future-work passages of 280 Telomeres, Telomerase, and Senescence papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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