Raised Remnant Cholesterol Level Correlates with Frailty

Remnant cholesterol refers to circulating cholesterol in the bloodstream that is not attached to LDL transport particles coming from the liver or HDL transport particles going to the liver. The remnant is attached to some mix of VLDL and IDL particles that serve much the same purpose as LDL particles, or incorporated into much larger chylomicron transporters that carry dietary lipids from the intestines throughout the body.

Researchers have noted that remnant cholesterol appears to contribute to cardiovascular risk, speeding the progression of atherosclerosis and increasing the risk of stroke and heart attack. It is perhaps the case that remnant cholesterol increases risk to a greater degree than LDL-cholesterol levels. Certainly, remnant cholesterol is higher in people who are overweight or obese, as one might expect given that chylomicron-encapsulated dietary cholesterol contents make up a sizable fraction of remnant cholesterol.

One doesn't have to propose any great new understanding of how atherosclerotic lesions form to expect remnant cholesterol to contribute to risk. A lesion forms after a tipping point is reached at which localized excess cholesterol overwhelms the macrophage cells responsible for cleaning it up and handing it off to HDL particles. More cholesterol in circulation shifts that tipping point by stressing the cleanup capacity of these macrophages. Greater chronic inflammation shifts the tipping point by making macrophages less able to clean up cholesterol. Both of those points tend to be the case for those who are overweight or obese in addition to being old. We can also talk about the role of toxic oxidized cholesterol and oxidized transport particles such as LDL in disrupting macrophage function, but the generation of these oxidized molecules scales with the overall amount of cholesterol as well, all other factors being equal.

Today's open access paper notes an interesting correlation between remnant cholesterol and frailty. Here is becomes more speculative as to what the mechanism might be to link raised cholesterol and frailty syndrome. The contribution of inflammation arising from oxidized cholesterol and transport particles is one possibility. The researchers here focus on a high fat diet as a driving factor in increasing both frailty and remnant cholesterol (via chylomicrons), but the question still remains as to what exactly is going on as a consequence of increased dietary cholesterol that might lead to the signs of frailty, including loss of muscle mass and strength, impaired immunity, and so forth.

Association of remnant cholesterol with frailty: findings from observational and Mendelian randomization analyses

Recent insights suggest that remnant cholesterol (RC) plays a role in cellular senescence, yet its specific contribution to frailty remains indeterminate. Through the integration of observational and Mendelian randomization (MR) studies, this research explores the impact of elevated serum RC levels on frailty susceptibility. The observational study included 11,838 participants from the National Health and Nutrition Examination Survey. To circumvent observational study limitations, a two-sample MR analysis was conducted using the inverse-variance weighted method, leveraging genome-wide association studies (GWAS) data.

After adjusting for potential confounding variables, the observational study identified a significant association between high serum RC levels and frailty in middle-aged and older adults (odds ratio [OR] = 1.67), exhibiting a non-linear dose-response correlation. This association persisted after propensity score matching (OR = 1.53). The MR study echoed these results, demonstrating a causal association of RC with the frailty index (β = 0.059), consistent with the observational findings (β = 0.017).

Despite a lack of direct epidemiological evidence linking serum circulating RC levels to frailty, recent MR studies have spotlighted the influential role of elevated LDL-C levels in inducing frailty. Substantial increases in RC levels have been documented in adults consuming high-fat diets. The same diets administered to mice resulted in a heightened frailty level, while simultaneously diminishing the anti-frailty benefits of intermittent fasting. Consequently, this indirect evidence suggests a connection between higher RC levels and a heightened frailty risk, which this study substantiates.

Although increased serum RC levels are regarded as a potent independent risk factor for CVD, this analysis reveals that the association between serum RC levels and frailty persists, even after adjusting for CVD and T2DM. This suggests that the contribution of RC to frailty risk is not exclusively attributed to a higher susceptibility to CVD. Furthermore, the results from our epidemiological studies and multivariable MR confirm that this association remains significant, regardless of total cholesterol or LDL-cholesterol levels.

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