Why is Low Blood Cholesterol Associated with Increased Late Life Mortality?
The conventional wisdom propagated by physicians and cardiovascular researchers is that it is good to reduce cholesterol in the bloodstream attached to low-density lipoprotein (LDL) particles. The lower the better. This is cholesterol transported outwards from its creation in the liver for use elsewhere in the body. When sustained over decades, higher LDL-cholesterol increases the pace of development of fatty atherosclerotic plaques in blood vessel walls, the cause of eventual heart attack and stroke. Human mutants with abnormally low LDL-cholesterol levels exhibit as much as a 50% reduction in risk of death due to rupture of a plaque and resulting heart attack or stroke.
Interestingly, however, low levels of total cholesterol in the bloodstream are associated with increased late life mortality. A measure of total cholesterol counts the cholesterol attached to all forms of transport particle - so not just LDL-cholesterol leaving the liver (along with VLDL and IDL cholesterol-bearing particles) but also the high-density lipoprotein (HDL) cholesterol that is carried back to the liver. It remains unclear as to exactly why low total cholesterol is associated with increased mortality, though there is no shortage of hypotheses.
One of those hypotheses is that low total cholesterol is a side-effect of a poor diet. Another is that forms of chronic age-related dysfunction independently produce both low total cholesterol and increased mortality. In today's open access paper, researchers analyze epidemiological data to suggest that the mortality effects of low total cholesterol are not associated with diet, though the database they are working from cannot provide much further insight into mechanisms. On a related note, it is entirely unclear as to whether pharmacological approaches such as PCKS9 inhibitors that can produce very low LDL-cholesterol will also trigger increased mortality in late life, the 80s and beyond, significantly older than the patients typically included in clinical trials for heart disease. These drugs are too new for meaningful amounts of long-term data to exist.
The present findings showed that a lower total cholesterol (TC) level was associated with elevated all-cause mortality risk in a population of oldest-old adults (aged ≥85 years). When TC level was used as a continuous variable, the mortality risk increased by 12% with each 1 mmol/L reduction in TC. This is consistent with findings from several previous studies, which demonstrated that a low TC level was a risk factor for all-cause mortality in older people. This could be explained by the increased risk of non-cardiovascular mortality (e.g., from cancers and infections). After identifying this inverse association, we further explored the lower limit of TC and found a continuous increment of all-cause mortality risks when TC levels fell below 3.40 mmol/L. This indicates that a TC level lower than 3.40 mmol/L is associated with higher mortality risk among oldest-old adults. To our knowledge, this is the first study to clarify the lower TC cutoff point in this population, and it has been suggested that lower TC levels are associated with frailty and chronic disease in seniors, which further increases mortality risk.
Some researchers suggest that higher TC levels are associated with better nutritional and chronic health status in the oldest old population; thus, individuals with elevated TC levels are more likely to live longer. In the present study, we attempted to exclude the potential effect of dietary or physiological factors by including these variables in the model. In our study, self-reported diabetes, heart disease, and stroke were not significantly associated with all-cause mortality, and thus not included as covariates in the final multivariable models. The predictive value of traditional risk factors for mortality may diminish in the oldest old compared to younger populations, as supported by some previous studies.
As for dietary factors, fresh fruit consumption and fish consumption were protective factors in the multivariable model, whereas daily consumption of eggs and sugar were risk factors for all-cause mortality, which is consistent with previous findings. Adjustment for dietary behaviors and chronic health conditions did not alter the protective effect of TC on all-cause mortality, indicating that the association between TC and all-cause mortality is independent of nutritional status.
Although the biological pathways that link TC to mortality are poorly understood, several mechanisms may explain this inverse association. For example, blood lipids, which are an important component of cell membranes, may affect cell electrophysiology by modulating the distribution and function of some ion channels. Low TC levels may contribute to the pathogenesis of some common diseases in older people, such as atrial fibrillation. Another potential mechanism is that TC may regulate inflammatory markers such as C-reactive protein and attenuate the biological response to inflammation. Therefore, individuals with low TC levels may be more vulnerable to physiological disorders because of enhanced inflammation.