In this prospective study involving American adults, we found that a linear negative correlation was observed between the serum selenium concentration and cancer mortality, but there was a nonlinear relationship between the serum selenium concentration and all-cause, CVD-related, and non-CVD related mortality. Higher serum selenium levels (range ≤ 129.82 μg/L) were associated with lower rates of all-cause and non-CVD-related mortality. Similarly, in cases where the serum selenium concentration was ≤ 129.08 μg/L, higher levels were associated with lower CVD-related mortality. However, this association ceases to be significant when serum selenium concentration exceeds the specified threshold range. All the results remained consistent across the subgroup analyses. Notably, we observed significant interactions between the serum selenium concentration and smoking, PIR, history of hypertension, and high cholesterol in terms of all-cause mortality. Specifically, when the serum selenium concentration exceeded 129.82 μg/L, in the nonsmoking population, there was no association between the serum selenium concentration and cause-specific mortality rates, while higher serum selenium levels were associated with a greater risk of overall mortality in the group of current smokers.The complex biological functions of serum selenium have garnered significant interest among researchers. Elucidating its association with human health outcomes remains a formidable challenge. In studies of the general population, the relationship between serum selenium levels and cause-specific mortality is intricate15,25,26. This complexity highlights the necessity for a more comprehensive elucidation of the dose‒response relationship between these two factors. Simple linear correlations may not be sufficient to explain the aforementioned outcomes. In our study, it is noteworthy that the previously observed negative correlation between serum selenium concentration and specific mortality rates lost its statistical significance once the serum selenium concentration surpassed a particular threshold. In addition, serum selenium has a significant protective effect against cause-specific mortality within distinct populations, including subgroups with diabetes19, hypertension27, kidney disease20, and liver disease. However, we detected a positive correlation between the serum selenium concentration and overall mortality rate, specifically among the current smoking population, when the serum selenium concentration surpassed the established range. Consequently, it is imperative to investigate the relationships between serum selenium and both all-cause mortality and cause-specific mortality in the general population and to identify the populations that are most benefitted or at risk.In the present study, we observed a linear negative correlation between the serum selenium concentration and cancer mortality in the general population, despite a p trend of 0.056. This finding is consistent with a 9-year longitudinal epidemiological research on aging caused by vascular disease28. Furthermore, a prospective study conducted in Poland revealed that higher serum selenium levels significantly improved the ten-year survival rate for patients with breast cancer29. In the Cancer Nutrition Prevention Trial involving 1312 participants, it was also established that exogenous selenium supplementation could reduce cancer mortality by 52%30. Elevated oxidative stress and impaired immune function in cancer patients may partially account for this observation. Selenium inhibits the Nrf2/Prx1 pathway, reducing tumor cell detoxification capacity and thereby enhancing drug cytotoxicity31,32,33. Moreover, selenium helps maintain normal cellular redox balance, facilitating drug detoxification while minimizing damage to healthy tissues. Additionally, selenium enhances the expression of p53-dependent DNA repair proteins, aiding in the repair of DNA damage in normal cells33.A comprehensive cohort study involving the general population in the Netherlands revealed an association between elevated serum selenium concentrations and decreased all-cause mortality15. Similarly, a meta-analysis encompassing 25,667 subjects demonstrated that lower selenium levels were correlated with an elevated risk of all-cause mortality in the broader population34. In contrast, a 15-year follow-up study involving 1103 individuals in the Chinese population did not reveal any significant associations between total mortality and serum selenium levels25. The aforementioned studies included representative samples from the general population, and the disparities in their findings underscore the limitations of establishing a linear correlation between serum selenium levels and mortality within the general population. Given the varying selenium statuses worldwide, it is plausible that a nonlinear relationship may more accurately reflect the actual situation35. Our study revealed a correlation between elevated serum selenium concentrations and decreased all-cause mortality, non-CVD-related mortality (range ≤ 129.82 μg/L), and CVD-related mortality (range ≤ 129.08 μg/L), aligning with prior research36, in which the safety range of the serum selenium level is less than 130 μg/L. Appropriate selenium levels can enhance the proliferation of activated T cells, increase natural killer cell activity, and augment cytotoxicity mediated by lymphocytes2, thereby bolstering the body’s defense against external stressors. Additionally, adequate selenium levels can promote synthesis of selenoproteins involved in genomic maintenance. For instance, GPX1 inhibits DNA breaks induced by ultraviolet and ionizing radiation, while SELENOH shields cells from genotoxic agents that elevate oxidative stress37. However, this associations lost significance when serum selenium concentration surpassed the established limit, suggesting that excessively high serum selenium concentrations do not continue to reduce the risk of mortality. In the Selenium and Vitamin E Cancer Prevention Trial (SELECT), participants administered selenium supplements were tracked over 5.5 and 8 years38,39, and no notable improvement in all-cause mortality was found. Similarly, a 7.6-year follow-up in a cancer nutrition prevention study failed to establish a significant correlation between selenium supplementation and any cardiovascular disease endpoint30. Notably, a randomized double-blind controlled trial conducted in the Danish population revealed that the administration of 300 μg/day selenium supplements for five consecutive years resulted in an increased 10-year all-cause mortality in regions characterized by low selenium levels26. The above studies provide further evidence of our discovery regarding the intricate relationship between the serum selenium concentration and cause-specific mortality. Adequate selenium concentrations are beneficial for human health; however, beyond a certain threshold (in this study, 130 μg/L), this beneficial effect diminishes. Studies have shown that high levels of selenium, after participating in the synthesis of various selenoproteins, may influence protein function through residual low-molecular-weight selenium compounds and active selenium intermediates40. These compounds can modulate oxidation-sensitive cysteine residues in proteins or disrupt selenoprotein-dependent antioxidant systems. For example, selenocysteine can metabolize into selenol/selenate, engaging in intracellular redox reactions that generate superoxide radicals and react with thiols/diseleides to form selenylsulfides/disulfides26. The latter processes can lead to protein aggregation, transcription factor inactivation, disruption of redox-regulated cellular signaling pathways, endoplasmic reticulum stress, and consequent cellular damage41. Selenium deficiency results in a marked reduction in glutathione peroxidase activity, consequently elevating oxidative stress42. Conversely, elevated selenium levels induce DNA damage and cytotoxicity by augmenting reactive oxygen species (ROS) production43. Furthermore, excessive selenium intake diminishes nitric oxide bioavailability and exacerbates ROS production, culminating in endothelial dysfunction44.In further exploration of the relationships between the serum selenium concentration and all-cause mortality, as well as cause-specific mortality, we identified no correlation between the serum selenium concentration and cause-specific mortality in nonsmokers. Notably, when the serum selenium concentration exceeded 129.82 μg/L, elevated levels were associated with an increased risk of all-cause mortality among current smokers. Consistent with prior research45,46,47, our study aligns with the observation that nonsmokers present significantly higher serum selenium concentrations than current smokers (nonsmokers vs. current smokers, 131.5 μg/L vs. 128.7 μg/L). This discrepancy might result in a swift attainment of a plateau in selenoprotein concentration among nonsmokers, potentially diminishing its effectiveness in mitigating the risk of mortality. Furthermore, a population-based study revealed higher levels of serum selenium glutathione peroxidase, glutathione reductase, and extracellular superoxide dismutase activities in nonsmokers than in current smokers. This disparity may partially counteract the antioxidant effect of serum selenium in vivo, resulting in an inconspicuous protective effect of serum selenium in this population. In the case of current smokers, research has indicated that cadmium in cigarettes not only diminishes the bioavailability of selenium48 but also hastens excretion selenium45. Elevated selenium levels in the body, under such circumstances, may lead to selenium excess and subsequent adverse events. Notably, smoking also increases the content of arsenic, an element known for its synergistic toxic effect with selenium49. This interaction amplifies the toxicity of methylated selenium by obstructing the detoxification process, thereby resulting in adverse outcomes.Our findings suggest the following strengths: First, in light of regional and dietary differences, we opted against using dietary selenium intake as the primary study indicator. Instead, we selected serum selenium as it is the most representative measure of internal selenium levels50. Additionally, this study employed ICPDRC-MS to measure serum selenium levels, facilitating cross-comparison with other studies and providing insights into its clinical significance. Furthermore, this study is the first to comprehensively elucidate the impact of smoking status on the association between serum selenium and cause-specific mortality, suggesting that selenium supplementation may not be universally applicable. However, our study has limitations that should be considered. Due to inherent constraints in the database design, we only collected information on baseline serum selenium, thus we were unable to assess the impact of changes in serum selenium during follow-up on cause-specific mortality, potentially resulting in survival bias. Moreover, self-reported data on health status and smoking and drinking status may be subject to memory bias.Overall, this study reveals an important threshold range exists for the protective effect of serum selenium concentration for cause-specific mortality. Elevated serum selenium levels were correlated with reduced all-cause mortality and non-cardiovascular disease-related mortality when serum selenium concentrations were ≤ 129.82 μg/L. Additionally, increased serum selenium levels were linked to decreased cardiovascular disease-related mortality when serum selenium concentrations were ≤ 129.08 μg/L. However, this correlation diminishes when serum selenium concentrations surpass the specified range. Moreover, the study further emphasizes the impact of smoking on this association, specifically highlighting the elevated mortality risk correlated with higher serum selenium levels in current smokers. Therefore, based on our observation, the narrow therapeutic window of selenium warrants careful consideration. It is recommended that selenium supplementation be approached with heightened caution, considering regional, ethnic, and individual variability. Individuals exhibiting low baseline selenium levels may derive benefits from supplementation, whereas those with elevated selenium levels could face potential health risks, particularly in smokers. Regular monitoring of serum selenium concentrations during supplementation is imperative. Determining the optimal serum selenium levels and establishing safe supplementation dosages remain critical issues that require prompt resolution.
