Mapping the evolving trend of research on leukocyte telomere length: a text-mining study

The annual number literature serves as indicators of the development speed and research progress in the field under study, as well as the level of research concentration [22, 23]. Our findings revealed that, over the past 23 years, a total of 1818 papers related to LTL were identified and incorporated into the final analysis. Overall, the count of publications exhibited a fluctuating upward trend from 2000 to 2022. The number of documents increased from 5 in 2000 to 165 in 2022, with an average growth rate of 17.2%. Similarly, the annual number of citations received by these publications also showed a significantly increasing trend. Overall, with a thorough understanding of telomeres and telomerase, the significance of LTL has increasingly captured scholarly interest, as evidenced by both the number of annual publications and citation volumes. As we all know that the Nobel Prize in Physiology or Medicine was awarded in 2009 to three scientists, including Elizabeth Blackburn, Carol Greider and Jack Szostak, for their remarkable contributions to the field of telomeres and telomerase research [24, 25]. This recognition was bestowed upon them for their discovery of the mechanisms by which telomeres and telomerase protect chromosomes. Since then, research on telomeres and telomerase has emerged as an important field in biomedical science. In addition, one study by Valera-Gran et al. [26] has investigated the research on telomere length in Children from 1991 to 2019 using bibliometric methods. Their findings indicated that since 2012, the number of publications on telomere length in children has markedly risen, with an overall trend showing consistent growth. This suggests that telomere length in children has become a significantly relevant research topic over the past decade. This result further proved the increasing attention of studies related to telomere length.

Over centuries, scholarly papers have remained crucial tools for researchers across all disciplines to communicate their findings. Disseminating research findings through international peer-reviewed journals is an indispensable aspect of establishing effective scientific communication [27]. By sharing their work through these platforms, researchers can disseminate their findings to a global audience, ensuring visibility and credibility within the scientific community. Thus, we have listed the 15 journals with the most publications related to LTL research in Fig. 3A. PLOS One published the most papers, followed by Scientific Reports and Aging US. This result shows that these journals are more willing to accept LTL-related research. At the same time, it can also provide a reference for scholars in this field to submit papers in the future. In addition to the quantity of publications, citation frequency is often regarded as a superior metric for assessing the influence of a journal. Thus, to gain a more comprehensive understanding, we further analyzed the co-citation network among journals using VOSviewer. The top five co-cited journals were PLOS One, Proceedings of the National Academy of Sciences of the United States of America, Lancet, Nucleic Acids Research as well as Aging Cell. This result revealed that these journals might have published several high-impact studies, which have garnered significant attention from researchers in this field.

Among the top 15 countries, the USA demonstrated a clear lead, as reflected by the highest number of research publications and the highest H-index value. Previous studies revealed that the discrepancies in publication quantity observed among different countries may be attributed more to economic factors rather than differences in population size [28]. National distribution of the top 10 funding agencies in this field further confirmed this. Among them, half of the funding organizations were from the USA and the U.S. Department of Health and Human Services has sponsored the highest number of research projects. Additionally, in terms of institutions in research regarding LTL, the institutions from the USA including University of California San Francisco, Harvard University, and National Institutes of Health occupied the top three positions based on number of publications. As for authors, among top 10 most prolific authors, 70% of them came from the USA. Specifically, Aviv A [29] from Rutgers State University published the most LTL articles in this study period, followed by Lin J [30] from University of California San Francisco, Kimura M [31] from Rutgers State University, and De Vivo I from Harvard University. The fact that these institutions and authors have published a large number of studies in this field is inseparable from the fact that they receive adequate financial support for research and advanced experimental conditions. Adequate financial support enables researchers to purchase advanced equipment, recruit high-quality research talents, and sustain high-level academic exchanges and cooperation. At the same time, advanced experimental conditions can provide reliable technical support and data security, making the research results more accurate and credible. More importantly, these research results not only reflect the leading position of the research institution in the field, but also provide valuable references for other scholars, and promote the sharing of knowledge and exchange of experience in the academic community. These research results can help other scholars identify potential partners and opportunities, promote cross-institutional and interdisciplinary collaborative research, and further promote the development of the field.

In addition, author co-citation analysis is a commonly employed method to unveil the prominent authors within a co-citation network of a specific field. Typically, authors who are frequently cited are considered to possess a greater influence and impact compared to their less-cited counterparts. We identified authors with high influence as those who obtained at least 100 citations. Among the 84 authors included, the top three authors including Cawthon RM, Blackburn EH, and Aviv A are all from the USA. Thus, these findings suggest that the consistent dominance of the United States in terms of both quantity and quality of publications in this field could be attributed, at least in part, to the contributions of these influential researchers and institutions.

Average citations per item (ACI) is another metric that reflects the value and scientific contribution of a paper [32]. As shown in Table 1, China ranks second in terms of the quantity of publications. However, the ACI of China is relatively lower compared to certain European and American countries. Hence, there is a pressing need to focus not only on increasing the quantity but also on enhancing the quality of publications. Of note, the Chinese scientific management agencies have noticed this issue and has successively issued a series of policies to encourage high quality research [33]. Meanwhile, the value of ACI might be associated with the time factor. As depicted in Fig. 2C, the USA, UK and Netherlands are highlighted in purple or blue, indicating that researchers from these countries made early contributions to the field of LTL. That means their publications with more opportunities for citation. Nevertheless, it is important to note that this premise is based on the assumption of high-quality studies from these countries. Furthermore, Fig. 4B illustrates the international collaboration between different countries, with the thickness of the lines representing the strength of cooperation. It is evident that the USA has established close collaborations with China, UK and Canada. China has active cooperation with Canada and Sweden. Generally, collaborative relationships are concentrated mainly in European, American, and East Asian countries. Efforts should be made to further enhance cooperation with less developed nations.

Citation analysis is a crucial methodology in bibliometric studies. It is widely acknowledged that the number of citations can serve as an indicator of a publication’s impact. A higher frequency of citations typically signifies a greater academic influence and also considered a crucial knowledge source and key readings for researchers interested in this area [34, 35]. Figure 7 summarized top 10 most cited papers on LTL. Among them, the study with the highest number of citations is the one authored by Valdes AM and colleagues published in Lancet [36]. In this cross-sectional study, they have investigated 1122 white women aged 18–76 years. Their results revealed that LTL declined consistently with age at an average rate of 27 bp per year, and telomeres in obese women were 240 bp shorter compared to those in lean women. Furthermore, the results indicated that each pack-year of smoking was associated with an additional 5 bp decrease in telomere length compared to the overall cohort. This study emphasized the pro-ageing effects of obesity and cigarette smoking. The second-most cited study was a genome-wide meta-analysis with a large sample [37]. In this study, they identified seven loci, of which five are novel, that exhibit significant associations with mean LTL. Within two of these loci (TERC and TERT), lead single nucleotide polymorphisms are implicated in various cancers and this study also observed a significant association between alleles associated with shorter LTL and an increased risk of coronary artery disease. In additional to the aforementioned highly cited studies of LTL, several studies investigated the role of LTL in cardiovascular disease such as atherosclerosis, premature myocardial infarction and coronary heart disease have also received significant attention from many scholars [8, 38,39,40]. Multiple lines of evidence, including from recent large genetics-based analyses, indicated that short leukocyte telomeres were a risk factor mainly a contributory role for many cardiovascular diseases [41, 42]. Therefore, there has been a significant amount of work on unveiling the connection between LTL and cardiovascular diseases.

Although the top 10 most cited articles mentioned above hold significant value in their respective contributions, it is important to note that there exists a moderate correlation between the number of citations and the years since publication. It is commonly accepted that articles published earlier tend to accumulate a higher number of citations [13, 14]. Therefore, to monitor and comprehend the dynamic evolution of research hotspots, we employed the technique of document burst detection using CiteSpace. Generally, articles exhibiting citation bursts indicate that they have garnered notable attention from relevant academic circles during a specific time. As can be seen from Fig. 9, the lobal hotspot research at different time periods are also different. Among them, it is worth noting that while the burst in the majority of references has subsided, there are still ongoing bursts in two references, suggesting that these research topics continue to acquire attention in recent years [43, 44]. Of them, Factor-Litvak et al. [44], investigated the role of LTL in newborns. Their findings showed that substantial variation in LTL observed among newborns poses a challenge to the conventional telomeric clock model. Individuals may possess inherently short or long LTL since birth, potentially influencing the development of diseases in adulthood several decades later. Therefore, it is now being questioned by an increasing number of scholars about whether a single assessment of LTL could meaningfully serve as a personal biological aging clock [45].

Reference co-citation analysis is a widely used method to identify prominent research themes within a specific field. In this study, we utilized the publications and their corresponding references to generate homogeneous clusters. References that exhibited strong interconnections were grouped together, while those with weaker connections were assigned to different clusters. Our results revealed the presence of 13 distinct clusters within the co-citation network map. It is important to note that the Q value and S value are crucial parameters for evaluating the significance of the community structure. Specifically, a Q value greater than 0.3 and an S value greater than 0.7 indicate significant clustering. In this study, the Q value was determined to be 0.7668, indicating the reasonable nature of this network. The largest cluster was “framingham heart study” (#0) [46, 47]. Figure 8 presents the timeline view of the major clusters, providing insights into the temporal dynamics and evolutionary patterns of each cluster. The emergence of cluster 4, cluster 10, and cluster 11 could be traced back to earlier periods, indicating their early development and influence. Conversely, “longitudinal study (#1)” and “mendelian randomization study (#7)” represent more recent research topics in the field of LTL, reflecting a shift in research focus over time and both of these clusters received a lot of attention in recent years. Take mendelian randomization study as an example, it is a study design that utilizes genetic variants as instrumental variables to investigate causal relationships between an exposure of interest and an outcome [48]. This approach leverages the random assortment of genetic variants during meiosis, mimicking the randomization process in a randomized controlled trial. In recent years, it has been widely employed to investigate the causal relationship between LTL and various diseases. For example, multiple mendelian randomization studies have investigated the potential causal role of LTL in cardiovascular disease, cancer, neurodegenerative disease [49, 50]. These studies provide evidence supporting a causal relationship between shorter LTL and increased risk of certain diseases and mortality. Meanwhile, there are also several studies investigating the role of LTL in modulating the impact of risk factors such as smoking, obesity, and inflammation on disease outcome [51, 52]. By disentangling causality, it could help reveal the underlying biology and potential therapeutic targets associated with LTL.

Keywords play a vital role in accurately capturing core content of scientific articles. In the domains of bibliometric analysis and data visualization, keyword co-occurrence analysis has emerged as a valuable approach for identifying development trends and research hotspots within specific fields. In our study, we performed an extensive keyword co-occurrence analysis to identify the key research directions and focal areas within the field of LTL. From the results of keyword co-occurrence network visualization analysis, apart from the keywords “leukocyte telomere length”, the other most common keywords were “aging”, “telomerase”, “oxidative stress”, “biomarker”, as well as “inflammation”. In addition, Fig. 11 presented Top 15 diseases related keywords with the most occurrences. It can be seen that the most concerned diseases in LTL fields were aging [2, 3], inflammation [53, 54], cardiovascular diseases such as atherosclerosis, coronary artery disease, and myocardial infarction [41, 42], endocrine diseases including obesity and type 2 diabetes [52, 55], neurological and psychiatric diseases including depression, stress, Alzheimer’s disease and schizophrenia [56,57,58], and cancers especially breast cancer [59]. This result was consistent with the analysis of most popular research areas. As can be seen from the top 10 most active research areas presented in Fig. 3C, Geriatrics Gerontology, Science Technology Other Topics, Oncology, Neurosciences Neurology, Cell Biology, and Psychiatry yielded the largest number of studies, suggesting these areas have received the most attention.

Moreover, all the keywords were also marked with different colors based on the AAY by VOSviewer. Earlier appearing keywords were represented in blue, while more recent keywords were depicted in red [12]. Through this analysis, we identified key topics that were prominent during the early stages of research, such as “hypertension”, “blood pressure”, “gender”, and “atherosclerosis”. On the other hand, keywords such as “COPD”, “mendelian randomization”, “adiposity”, “colorectal cancer”, “National Health and Nutrition Examination Survey (NHNES)”, “telomerase reverse transcriptase”, “pregnancy” displayed a relatively recent appearance, suggesting a growing interest in these areas and their potential as future research hotspots. Take telomerase reverse transcriptase as an example, telomerase is also believed to have a close relationship with various diseases especially tumors [60]. The study of LTL and telomerase has gained increasing attention in the field of cancer, particularly with regard to targeting the mechanisms of telomere elongation and exploring telomerase inhibitors as potential novel therapeutic targets for anti-tumor treatments. Strategies aimed at disrupting telomere elongation, such as telomerase inhibitors or telomere-targeting agents, have shown promising results in preclinical and clinical studies [61,62,63]. These interventions aim to induce telomere shortening, which leads to telomere dysfunction and cellular senescence or apoptosis in cancer cells. However, due to differences in the design and methodology of analytical studies, including studies in cell culture and humans, it is still difficult to translate into actual clinical practice. Further investigation of the mechanisms underlying telomere maintenance and telomerase regulation may pave the way for the development of innovative therapies that can effectively inhibit tumor growth and improve patient outcomes. In addition, the NHANES database is an invaluable resource for studying all aspects of health and disease in the U.S. population. This database provides a large and representative sample of the U.S. population, making it an invaluable resource for studying the relationship between LTL and various health factors such as age, sex, race/ethnicity, socioeconomic status, lifestyle behaviors (smoking, physical activity), and the presence of chronic diseases [64]. Moreover, the NHANES database allows for longitudinal analysis, enabling researchers to examine changes in leukocyte telomere length over time and to investigate the effects of interventions or lifestyle changes on telomere dynamics [65]. Encouragingly, the NHANES database is seeing increased adoption in LTL research.

Strengths and limitations

This study offers several notable advantages. Firstly, it presents the first comprehensive analysis of LTL through bibliometrics, providing an important reference for researchers in this field. Secondly, compared to traditional reviews, bibliometric analysis provides a more comprehensive understanding of research trend, main contributors, hotspots and frontiers in this field. Lastly, the use of three bibliometric tools, including the widely used VOSviewer and CiteSpace, enhances the objectivity of our data analysis process. Nevertheless, there are still shortcomings in the present study. Firstly, the data solely relies on the WoSCC database, potentially overlooking relevant studies from other databases. Secondly, the exclusion of non-English publications may result in underestimating the presence of non-English research papers. Additionally, since the study from 2023 is incomplete, this study does not include publications after December 2022. As a result, some important studies may have been missed.

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