A U-shaped relationship between TC and mortality was observed in each age-sex group. TC levels associated with the lowest mortality were 210–249 mg/dL in both sexes in all age groups, except for the youngest groups of men, aged 18–34 years (180–219 mg/dL), and women aged 18–34 years (160–199 mg/dL) and 35–44 years (180–219 mg/dL). At TC levels of 50–199 and 200–449 mg/dL, each 39 mg/dL (1 mmol/L) increase in TC was associated with 23% lower (95% CI = 23–24%) and 7% higher (6–7%) mortality, respectively. Inverse associations in the lower TC range were strongest at the ages for which the mean TC levels were highest (men aged 45–54 years and women aged 55–64 years), while positive associations in the upper TC range were strongest in the youngest ages (<45 years) in both sexes. Both the inverse associations in the lower TC range and the positive associations in the upper TC range weakened with advancing age beyond the ages with the strongest associations.

Previous cohort studies have reported inconsistent results on the shape of associations between TC and all-cause mortality, including positive linear, inverse, U-curve, and reverse-L-curve (or reverse-J-curve) associations3,8,9,10,11,13,14,17,22. Some previous studies suggested different shapes of associations by sex and age3,17. The associationbetween TC and mortality was substantially modified by age and, to a lesser degree, by sex, in our study. Our study clearly demonstrated that the shape of association is a U-curve in each sex and each age group, including those aged 75–99 years (mean age: 79.0 years), which constituted 154,321, 80,776, and 18,080 elderly people aged 75–79, 80–84, and ≥85 years, respectively. Considering the weaker effect size associated with high TC with advancing age in the elderly, it is no surprise that previous studies conducted mainly in elderly populations found generally inverse or reverse-L-curve associations13,14. Additionally, the previously reported positive associations in younger adults8, may be explained by the stronger positive associations and lower optimal range in younger ages observed in our study, combined with the higher TC concentrations and larger proportions of morbidity and mortality from heart diseases in Western populations.

The NCEP experts classified TC levels into 3 categories: <200, 200–239, and ≥240 mg/dL, as desirable, borderline high, and high levels, respectively, mainly based on the association between TC and IHD21. In the current study, however, TC levels of 210–249 mg/dL and approximately 200–240 mg/dL were associated with the lowest mortality in the categorical and spline analyses, respectively. Our study suggested that the optimal ranges for overall survival are higher than that those for IHD. Similarly, a higher optimal range for overall survival than for IHD mortality has also been reported for BMI23. In contrast, the optimal ranges for all-cause mortality and IHD mortality were similar for fasting glucose and blood pressure24,25,26,27. Cholesterol levels might be a marker of general health, rather than a marker specific for CVD28. Even within CVD subtypes, TC ranges associated with lowest risk have not been consistent. For example, for stroke, TC levels <200 mg/dL were not associated with the lowest mortality in prospective cohort studies29,30, and randomized trials have not provided clear evidence of whether lipid-lowering therapies, including statins, reduce stroke mortality6,31. Hemorrhagic stroke, respiratory diseases (especially chronic obstructive pulmonary disease), digestive diseases (especially liver disease), and several cancers have been suggested to be associated with lower TC levels10,30,32,33,34; thus, the ranges associated with lowest risk might be even higher for these diseases than those for all-cause mortality. However, we could not examine whether the associations differed by cause of death, due to data unavailability.

Reverse causality has been suggested as an explanation of higher mortality associated with low cholesterol levels. However, a long term follow-up study in a Japanese-American population showed that individuals with low cholesterol levels maintained over a 20-year period had the worst all-cause mortality, and concluded that reverse causality was unlikely to account for the higher mortality associated with low cholesterol entirely14.

Lower optimal ranges for survival at younger ages than at older ages have also been observed for BMI19, whereas consistent ranges have been found regardless of sex and age for blood pressure and fasting glucose26,27,29. Whether different proportions of cause-specific mortality by age lead to the lower optimal range at younger ages needs to be investigated.

The sex- and age- specific levels of TC in the current study of Koreans were lower than those reported in other high-income countries, including Japan, England, and the US15,16,17,35,36. The distribution of TC levels by sex and age, however, were generally similar to those of other regional and ethnic populations, although detailed information is not always available. TC levels peaked at 50–51 years in men and at 56–57 years in women, and after the peak age, the levels decreased more rapidly in men than in women. The crossover point of the mean TC levels between sexes occurred at the age of 50–51 years, exactly at the median age of menopause37. The steep decline in estrogen corresponds well to the sharp increase in TC in women that was observed around the time of menopause in the current study.

Randomized trials have provided evidence that statin therapy may lower the overall mortality risk in persons with increased cardiovascular risk, mostly due to the reduction of mortality from heart disease5,6. The evidence, however, may not be definitive enough to claim that “the lower the cholesterol, the better” for all-cause mortality reduction in the general population with relatively low heart disease risk38.

The current cholesterol guidelines are heavily based on heart disease risk and recommend a TC range of <200 mg/dL as desirable. TC range <200 mg/dL, however, may not be necessarily a sign of good health when other diseases are considered. The diseases associated with lower TC levels and potential mechanisms have not been conclusively identified. Since the inverse associations in lower TC range were stronger than the positive associations in upper TC range, identification of diseases associated with lower TC levels and further understanding of the mechanisms of such associations may help improve health outcomes in the general population. Pending more research for clarification, careful evaluation and management might increase the chance of preventing and diagnosing potentially life-threatening diseases at an earlier stage in adults with low TC levels.

A very large number of participants, the prospective nature of the study, and complete follow-up for death are clear strengths of this study. Another major strength is that the study participants were ethnically homogeneous and lived in a similar environment covered by the same health care system. Another strength is that this study estimated mortality risk associated with TC levels down to below 120 mg/dL. However, there are limitations. First, the use of lipid-lowering medication was unaccounted for. The risk associated with high cholesterol might have been underestimated. However, in Korea, IHD mortality accounted for only approximately 5% of all-cause mortality, and only 10% of people with hypercholesterolemia received lipid-lowering therapy39. Therefore, the impact of not considering medication use is likely to be modest, and the TC levels in this study generally reflect levels without lipid-lowering medications. Additionally, this study could not determine whether statin-induced low cholesterol increases mortality. Second, other lipid measures, such as low-density lipoprotein and high-density lipoprotein cholesterol levels, were unavailable. Recent dyslipidemia management guidelines are more closely focused on these sub-fractions of cholesterol, so the direct application of our findings to individual patient care might be somewhat limited. Further study is needed to determine the sex- and age-specific associations of cholesterol fractions. Third, information on cause-specific mortality was not available. Fourth, the generalizability of our findings may be affected by the fact that the study participants were homogeneously Korean. The U-curve associations may be generalized to other ethnic populations, since the shape of the associations was generally the same for each sex and each age group, despite their varying cardiometabolic risk profiles. However, some results, such as the magnitude of relative risk associated with TC and the TC range associated with the lowest mortality, may vary by ethnic groups with different distributions of cause-specific mortality and dyslipidemia-related healthcare utilization.

In conclusion, U-curve relationships between TC and mortality were found, regardless of sex and age. TC ranges associated with the lowest mortality were 210–249 mg/dL in each sex-age subgroup, except for the youngest groups of men, aged 18–34 years (180–219 mg/dL), and women aged 18–34 years (160–199 mg/dL) and 35–44 years (180–219 mg/dL). Inverse associations in the range <200 mg/dL were more than 3-fold stronger than positive associations for cholesterol levels ≥200 mg/dL, except for the youngest adults. Positive associations in the upper TC range were strongest for youngest adults and weakened with advancing age. TC levels <200 mg/dL may not necessarily be a sign of good health. Identification and proper management of diseases associated with lower TC levels might improve survival.