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.