Conclusion

This analysis reveals a complex mediation pattern where cholesterol serves as a significant mediator of the age-sex relationship, but the indirect and direct effects operate in opposite directions, creating a suppression effect. This pattern has important implications for understanding sex differences in cardiovascular health and metabolic aging.

The positive indirect effect (RR_NIE = 1.1972) indicates that as age increases cholesterol levels, and higher cholesterol is paradoxically associated with a higher relative proportion of males in the sample. This counterintuitive finding may reflect several mechanisms. First, it may indicate differential survival patterns, where males with higher cholesterol survive to older ages in this cohort, while females with similar cholesterol levels may have different health outcomes. Second, it could reflect sex-specific cholesterol metabolism, where the relationship between age, cholesterol, and health outcomes differs fundamentally between males and females.

The negative direct effect (RR_NDE = 0.8870) suggests that age decreases the relative male proportion through pathways independent of cholesterol. This could reflect differential mortality rates, with males having higher mortality at younger ages due to factors unrelated to cholesterol (accidents, violence, occupational hazards), or it could indicate sampling or recruitment patterns in the study that vary by age and sex.

The highly significant interactions indicate that these relationships are not constant across the age range. The mediated interaction (p < 0.001) shows that the cholesterol-mediated pathway becomes stronger at older ages, while the reference interaction (p < 0.001) indicates that the direct pathway also varies with age. These age-dependent effects suggest that the mechanisms linking age, cholesterol, and sex distribution change across the lifespan.

This causal mediation analysis demonstrates that total cholesterol levels significantly mediate the relationship between age and sex distribution in the sample, but in a complex suppression pattern. The natural indirect effect is highly significant (RR_NIE = 1.1972, p < 0.001), indicating that age-related increases in cholesterol are associated with a 19.72% increase in the relative proportion of males. However, the natural direct effect operates in the opposite direction (RR_NDE = 0.8870, p = 0.026), showing an 11.30% decrease in male proportion through pathways independent of cholesterol. These opposing effects largely cancel out, resulting in a non-significant total effect (RR_TE = 1.0620, p = 0.185).

The findings reveal important sex differences in the relationships between age, cholesterol, and cardiovascular health. The strong negative association between cholesterol and male proportion (RR = 0.8897, p < 0.001) suggests that higher cholesterol levels are more common among females in this sample, consistent with known sex differences in lipid metabolism. The highly significant interactions (both mediated and reference interactions, p < 0.001) indicate that these relationships vary across the age range, highlighting the importance of age-specific and sex-specific approaches to cardiovascular risk assessment.