Discussion
With the advancement of medical technology, the average life expectancy of humans has been increasing, and the issue of aging has gradually drawn attention from the medical community. A range of diseases associated with aging, including malignancies, cardiovascular diseases, metabolic disorders, and degenerative diseases, have become essential research topics. The aging of the immune system plays a crucial role in these conditions(12, 22). Telomere length, which typically shortens with physiological aging, is considered an important hallmark of aging(2). It is generally believed that shorter telomeres can lead to chromosomal instability, thus contributing to aging and the development of cancer(6). However, a recent study from the Johns Hopkins University School of Medicine has overturned our previous understanding by revealing that T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to some cancers(7). Simultaneously, previous studies have suggested that telomerase activity and telomere length may be altered in various systemic immunomediated diseases and appear to be associated with premature immune aging(5).
However, the causal relationship between telomere length and immune cells remains uncertain due to the common confounding and biases present in observational studies. Mendelian randomization (MR) is a novel approach that utilizes genetic variations as instrumental variables to determine the impact of certain exposures on outcomes. Since genetics are essentially unaffected by environmental factors, MR has the potential to overcome the limitations of traditional observational studies and produce reliable research findings(9, 10). In this study, we employed a two-sample MR method to assess the causal effect between telomere length and the quantity of immune cells.
Our results demonstrate that shorter telomere length does indeed lead to alterations in the percentage within lymphocytes of immune cells, resulting in impaired immune function. The most significant change observed is a lower percentage of T cells, particularly Natural Killer T cells, in lymphocytes with shorter telomere length. Meanwhile, the efficiencies of T lymphocytes and Natural Killer T cells may potentially interfere with the immune recognition of cancer cells(23, 24). In fact, senescent cells are typically eliminated by Natural Killer T cells, which implies the existence of selective pressure for immune evasion. During the process of eliminating these senescent cells, which are prone to carcinogenesis and malignant transformation, the resulting cancer cells may have been pre-selected to evade immune recognition(6, 25). Additionally, higher percentages of CD4 regulatory T cells and Effector Memory CD8+ T cells also indicate increased immune incompetence and immune suppression, which often contribute to a higher incidence and recurrence of viral infections and tumors(26, 27). Telomere length appears to have no causal relationship with the proportion of B cells in lymphocytes. However, further subgroup analysis reveals that shorter telomere length typically leads to an increase in the percentages of Transitional B cells and Naive-mature B cells, suggesting a differentiation blockade and an accumulation of B cells in an immature stage(28). Meanwhile, the decrease in the percentage of Memory B cells indicates a reduced occurrence and intensity of secondary immune responses upon re-exposure to antigens, consequently leading to the development of chronic inflammation. Previous studies showed that age-related chronic inflammation not only promotes tumor development by increasing cell turnover but also facilitates tumor initiation by weakening immune surveillance(29). This may be due to the age-driven accumulation of immunosuppressive cell types within the tumor micro-environment, similar to our finding of an elevated percentage of CD4 regulatory T cells associated with shorter telomere.
The strength of our study lies in the utilization of the latest genetic data on telomere length and immune cell counts derived from GWAS databases for conducting a two-sample Mendelian randomization analysis(12, 13). Moreover, we employed stringent criteria to select instrumental variables (IV) and employed multiple MR methods for causal assessment. Additionally, in sensitivity analyses no significant heterogeneity or horizontal pleiotropy was observed, indicating the validity and robustness of our findings. Our study establishes a causal relationship between genetically determined telomere length and the quantity and differentiation of immune cells.
Despite the validity and stability of our MR results, there are several limitations in the current study. Firstly, our study data predominantly comprise individuals of European descent, and therefore, the generalizability of our findings to other populations may be limited. Secondly, in our MR analysis, only summary-level statistics were available, and individual-level data relevant to specific factors were lacking, which restricted stratified analyses. Thirdly, telomere length is determined by genetics as well as environmental, lifestyle, and epigenetic modifications. It should be noted that our results can only partially explain the causal effect of telomere length on the quantity and differentiation of immune cells.