Hyperthyroidism, a prevalent endocrine disorder, affects 0.2-1.3% of the general population (1), with women more affected than men, and increases with age (2). Given the critical role of thyroid hormones in essential physiological processes like growth (3), maturation (4), and metabolism (5), many efforts have the positive association between thyroid function and cancer development (6, 7). Without treatment, hyperthyroidism can lead to serious complications including cardiac arrhythmias (8), congestive heart failure (9), osteoporosis (10), adverse obstetric outcomes (11), and metabolic imbalances (12), such as increased resting energy demand and gluconeogenesis (13). The intricate consequences of hyperthyroidism highlight the importance of understanding its prevalence and the diverse underlying mechanisms, emphasizing the need for effective control and prevention of associated disorders (14).

Hyperthyroidism, characterized by elevated thyroid hormone levels, plays a significant role in the aging process. Age-related changes in thyroid function have important implications for longevity (3). Studies suggest that longevity in vertebrates is positive associated with low metabolic rates and TH levels (15), and thyrotoxicosis in mice has been linked to aging traits like malnutrition and immune senescence (16). Telomeres are indispensable DNA-protein complexes at the ends of chromosomes, crucial for maintaining genomic stability by protecting repeated “TTAGGG” sequences (15). However, with each cell division, telomeres shorten, leading to replicative senescence, genetic instability, and ultimately cell death when critically short (16). Telomere length (TL) has been extensively studied as a biomarker for human aging across various tissues (17), with research linking TL to increased susceptibility to conditions such as cardiovascular disease (18), type 2 diabetes (19), cancers (20), Alzheimer’s disease (21), chronic kidney disease (22), chronic obstructive pulmonary disease (23), and alcohol consumption (24). However, the casual relationship between TL and hyperthyroidism remains underexplored.

Mendelian randomization (MR) as a statistical tool is used in epidemiology to examine causal associations between exposures, biomarkers, or risk factors and outcomes. MR is particularly useful in situations where conducting randomized controlled trials is not feasible or poses ethical dilemmas (17). MR is an excellent approach for mitigating the issues of residual confounding and reverse causality, which are sometimes encountered when studying observational data using alternative approaches (18). Recent research has explored the connections between depression (19), mortality (20), Graves’ diseases (21), multiple sclerosis (22), and TL. However, no MR analysis investigated the causal relationship between TL and hyperthyroidism.

Our study investigates the causal relationship between TL and hyperthyroidism using a two-sample bidirectional Mendelian randomization analysis. Using genome-wide association study (GWAS) data, we present casual evidence that genetically predicted longer TL decreases the risk of developing hyperthyroidism. Then, we validate these findings with an independent dataset from the Finne cohort. These findings underscore the potential of telomere length as a biomarker for hyperthyroidism, offering insights that could inform novel preventive and therapeutic strategies, including personalized treatments.

By two-sample bidirectional MR analyses, we firstly have explored that increased telomere length is associated with decreased risk of hyperthyroidism. An previous investigation (33) suggested an association between genetic variants governing TL and thyroid cancer risk. Our current study expands upon this assertion by leveraging data from larger cohorts than previously employed. Through a comprehensive and focused analysis, we establish a causal relationship between TL and hyperthyroidism. Our findings demonstrated robustness and consistency across various MR methods. Collectively, the result offers compelling evidence supporting a causal connection between shortened telomeres and hyperthyroidism, hinting at distinct underlying mechanisms for the disease. We further validated the causal link between hyperthyroidism and TL, we found no significant association in GWAS (IVW, OR = 0.999, p = 0.844, 95% CI: 0.987-1.011). In FinnGen, we found association between TL and hyperthyroidism (IVW, OR = 0.984, p = 0.009, 95% CI: 0.972-0.996). This suggests a specific correlation between TL and the progression of hyperthyroidism. In our MR study, we incorporated valid IVs from the latest and most extensive GWAS database of TL. Subsequently, we established stringent criteria for IV selection, opting only for TL variants significantly associated with TL measurements and meeting the three core assumptions of MR analysis. Additionally, to mitigate bias in causal estimation, we employed three MR methods, ensuring the validity and consistency of results in sensitivity analyses. Addressing heterogeneity, horizontal pleiotropy, and outliers, our findings suggest that hyperthyroidism may result from shortened TL and a senescent immune system. Conversely, hyperthyroidism appears to have no impact on TL.

Hyperthyroidism itself is not typically considered an age-related disease, but the risk factors and underlying causes can be influenced by age-related factors (34). This is an intricate biological process that may be roughly categorized into replicative senescence, caused by inherent cellular mechanisms such as telomere shortening, and cellular senescence, which can be induced by different stressors such oxidative stress and DNA damage (35). Based on our research, we hypothesize that the process of telomere shortening may play a significant role in causing cellular senescence in hyperthyroidism. This is similar to how telomere-associated driver mutations are linked to rheumatoid arthritis (36), systemic sclerosis (37), and systemic lupus erythematosus (38). Shorter TL could also result from immune senescence (39). Currently, there is a growing recognition of the correlation between telomere and hyperthyroidism. The process of telomere length shortening is accelerated by age (40), and this is likely a component of the modified immune response seen in individuals with hyperthyroidism. To reduce the role of confounding factors, we excluded TL variations in our MR analysis that are related with features that might independently affect the risk of hyperthyroidism. prior research consistently indicates that a shorter TL is associated with an increased risk of developing immune-mediated inflammatory diseases (41, 42). Our results align with these prior studies.

The result indicating a cause-and-effect relationship between premature telomere erosion and hyperthyroidism offers many possibilities. Possible therapeutic strategies may include interventions targeting inadequate telomere maintenance, either on a broad scale or specifically in cells that play a significant role in the development of the illness (43). Replenishing telomere length is a complex process that cannot be easily achieved, since just enhancing the activity of telomerase may raise the likelihood of developing cancer (44). Current clinical studies, such as NCT04110964 (45), are examining this method in different medical diseases. Safe telomerase activation treatment is being investigated in other medical disciplines, such as cardiology, to mitigate the possible danger of increasing endogenous telomerase activity (46). This therapy involves temporarily delivering modified TERT RNA to prevent sustained elevation of telomerase activity (47). Despite encountering difficulties in achieving in vivo targeted distribution, the use of this method in hyperthyroidism may become possible in the future due to potential advancements. Androgens may also normalize telomerase levels in cells from individuals with telomere illness who have heterozygous mutations in the TERT gene (48).

Approaches that enhance general well-being while positively influencing TL promotion exist. Speculatively, these approaches could be further integrated into the clinical management of hyperthyroidism patients (49), incorporating strategies such as exercise (50), stress reduction (51), and mindfulness (52). Our findings indicate that individuals with hyperthyroidism tend to engage in reduced physical activity, likely exacerbated by poor physical health. Thoughtfully increasing exercise could yield multiple benefits, promoting chromosomal telomere length while enhancing fitness and mental health (50). Similarly, stress resulting from challenging life circumstances, like social deprivation, may be alleviated through mindfulness practices (51). Relatively straightforward measures that enhance patient well-being could fundamentally contribute to reducing telomere attrition.

Our research has many limitations. The major investigations of TL and hyperthyroidism GWAS solely involved individuals of European ethnicity. As a result, the generalizability of our findings to other populations is uncertain, emphasizing the need for stratification by various racial groups. Secondly, our MR analysis was confined to summary-level statistics, with individual-level data remaining inaccessible. This limitation restricts our ability to conduct stratified analyses based on specific factors. Thirdly, information on the subtype and severity of hyperthyroidism was not available, preventing the estimation of the relationship between TL and different hyperthyroidism subtypes and severity levels. Fourthly, there may be unidentified confounders influencing the associations between TL and hyperthyroidism that require further investigation. Lastly, it is essential to recognize that telomere length is determined by a combination of genetics, environmental factors, lifestyles, and epigenetic modifications. Hence, it is essential to acknowledge that our findings only partly clarify the causative impact of TL on hyperthyroidism.

The finding that longer telomeres reduce hyperthyroidism risk highlights the need to validate hyperthyroidism’s impact on telomere length, offering valuable insights for prevention and treatment.