High Remnant Cholesterol Accelerates Biological Aging via Inflammation and Oxidative Stress

Remnant cholesterol (RC) — the cholesterol carried by triglyceride-rich lipoproteins such as VLDL and IDL remnants — has emerged as an independent cardiovascular risk factor, but its relationship to biological aging markers had been underexplored. The original study by Xing, Yu, and colleagues examined whether RC is associated with leukocyte telomere length (LTL) and serum α-Klotho, two well-established biomarkers of cellular and systemic aging, and whether inflammation and oxidative stress mediate these relationships.

Using a large cross-sectional dataset (NHANES or similar population-level data), the team performed multiple linear regression across four progressively adjusted models. Model 1 controlled for age and sex; Model 2 added metabolic and cardiometabolic covariates (BMI, WHR, liver enzymes, renal function, blood pressure, glycemic markers, lipid fractions, and uric acid); Model 3 further adjusted for total energy intake; and Model 4 additionally included inflammatory cytokines (TNF-α, IL-6, IL-1β) and oxidative stress markers (SOD, 8-OHdG). Outcomes were z-scored LTL and log-transformed α-Klotho.

The corrected Table 2 confirms that across all four models, each 1 mmol/L increment in RC was significantly and inversely associated with LTL (ranging from β = −0.162 to −0.184). Quartile analyses showed that Q3 and Q4 of RC consistently had significantly lower LTL compared to Q1 (reference), even after full covariate adjustment. For α-Klotho, Models 1–3 showed consistent inverse associations across quartiles, but in Model 4 — after adjusting for inflammatory and oxidative stress mediators — the continuous RC coefficient became non-significant (β = −0.017), while Q3 and Q4 quartile effects remained significant, suggesting partial mediation of the RC–α-Klotho pathway through inflammation and oxidative stress.

Mediation analyses (Figure 2) quantified the indirect effects of TNF-α, IL-6, IL-1β, SOD, and 8-OHdG on the RC–LTL relationship. Each mediator contributed meaningfully to the indirect pathway. The correction to Figure 2c adds a missing asterisk to the total effect of IL-1β, confirming statistical significance of the total RC→LTL effect through that mediator.

These findings suggest that elevated RC may accelerate cellular aging by promoting a pro-inflammatory and pro-oxidative environment that shortens telomeres and suppresses α-Klotho expression. Clinically, this positions RC reduction — through lifestyle modification or lipid-lowering therapies — as a potential strategy to slow biological aging. Caveats include the cross-sectional design (precluding causal inference), reliance on a single time-point measurement of biomarkers, and the correction itself highlighting the importance of scrutinizing published regression outputs.