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Longevity Briefs: ‘Remnant Cholesterol’ Could Be Linked To Age-Related Frailty

Posted on 18 August 2023

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: Cholesterol is a vital molecule with a bad reputation. Cholesterol is transported within lipoprotein particles such as low and high density lipoprotein (if you want to know more about the different types of lipoprotein and what sets them apart, check out this article from our fat tissue series). 

‘Remnant cholesterol’ refers to all cholesterol not transported within LDL and HDL. Recent research suggests that regardless of how much LDL, HDL or total cholesterol you have, having more remnant cholesterol puts you at greater risk of heart disease. Remnant cholesterol may also affect cellular ageing as it can induce senescence in various types of cells. Cellular senescence is a process that limits the ability of cells to divide and function properly and contributes to ageing and frailty.

What did the researchers do: In this study, researchers analysed data from the National Health and Nutrition Examination Survey (NHANES), which is a large representative survey of health and nutrition in the US. The study included 11,838 participants aged 40 years and above. The researchers measured remnant cholesterol levels and assessed frailty using two different methods – the frailty index and the Fried frailty phenotype.

The researchers also used a technique called Mendelian randomisation to look at data from nearly 400,000 entries in pre-existing datasets. Mendelian randomisation is where scientists analyse the relationship between genetic factors (in this case genetic predisposition to high remnant cholesterol) and an outcome (frailty). This is done because genes can be assumed to be randomly distributed throughout the population and not linked to lifestyle factors. This eliminates confounding factors and reverse causation. For example, if someone has low remnant cholesterol, it could be because they are already less frail and so are able to exercise more. However, if someone has a gene that raises their remnant cholesterol, we can generally assume that this gene doesn’t affect how much exercise they do.

Key takeaway(s) from this research:

  • Higher remnant cholesterol was associated with significantly increased risk of frailty
  • Remnant cholesterol was associated with frailty regardless of LDL-C or total cholesterol
  • This increased risk of frailty was not fully explained by an increased risk of heart disease
  • Possessing gene variants that increased remnant cholesterol levels was associated with increased frailty

The observational study found a significant association between high serum remnant cholesterol and both measures of frailty in both over-60s and under-60s, irrespective of the presence of cardiovascular disease or diabetes. The odds of being defined as frail remained relatively constant until around 0.55 mmol/L before increasing sharply. Someone with a remnant cholesterol level of 1.2 mmol/L was twice as likely to be defined as frail compared to someone with a level of 0.6 mmol/L.

These graphs show the odds ratio (OR) of being defined as frail according to remnant cholesterol (RC, left), normalised RC as a proportion of total cholesterol (RC to TC, middle), or normalised RC to LDL-C ratio (right). Odds ratio means the chance of being frail relative to the baseline odds ratio of 1.
Association of remnant cholesterol with frailty: findings from observational and Mendelian randomization analyses

This association remained significant when the ratio between remnant cholesterol and total cholesterol or LDL-C (the ‘bad’ form of cholesterol) were considered. In other words, remnant cholesterol itself was associated with frailty and wasn’t just a side-effect of having more cholesterol in total and more LDL-C. It should be noted, however, that LDL-C was estimated from other measurements and not measured directly, and some frailty indicators were self-reported, so there will be inaccuracies in this data.

In the Mendelian randomisation study, there was a causal relationship between gene variants that increased remnant cholesterol levels and frailty index, but not frailty phenotype. While this supports the notion that these gene variants can cause frailty, it does not prove how they are doing it –  they could be acting partly through mechanisms that have nothing to do with remnant cholesterol, though attempts were made to control for this possibility.

How we can apply this knowledge today:

This study suggests that increased remnant cholesterol might increase frailty in middle aged and older adults, not only by promoting heart disease but also through other mechanisms. It suggests that we should be paying more attention to our remnant cholesterol as a proportion of our total cholesterol. 

Lower remnant cholesterol can be achieved by:

  • Adopting a diet low in saturated and trans fats, high in fibre, fruits, vegetables, and whole grains
  • Regular exercise
  • Maintaining a healthy weight
  • Not smoking
  • Taking statins

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

    Title image by Freepik

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