Abstract and Introduction

Introduction

Twenty-one years ago, Fran Kaiser and I published an editorial in this journal entitled "Cholesterol can be lowered in older persons. Should we care?"^[1] This editorial was written in response to a series of epidemiological articles suggesting that, in old persons, low cholesterol was associated with greater total mortality. In this issue of the Journal, Newson and colleagues^[2] found that higher total cholesterol and non-high-density lipoprotein cholesterol (HDL-C) in older persons was associated with a lower risk of noncardiovascular and total mortality. In part, this was attributable to a lower risk of cancer deaths.

One reason for the association between low cholesterol and mortality is that low cholesterol is associated with weight loss. Epidemiological studies have found that intentional or unintentional weight loss is associated with greater mortality.^[3] Although the authors adjusted their analysis for body mass index (BMI), many overweight persons lose weight while their BMI remains high. Many reasons have been suggested for why weight loss may increase mortality, including occult or mild disease, loss of bone and muscle mass, loss of adipose stem cells, inappropriate medication dosing, and release of fat-soluble toxins into the circulation.

Another possibility is that some components of non-HDL-C may be protective against disease and that persons who survive into old age are more likely to be enriched for these protective elements. Low-density lipoprotein cholesterol LDL-C consists of a triglyceride-enriched, small, dense LDL that the arteries preferentially take up and is readily oxidized and a large, buoyant LDL.^[4] This large LDL is nonatherogenic and is one of the factors associated with exceptional longevity.[5, 6] Increases in large LDL are associated with lower levels of the cholestryl ester transfer protein (CETP) and greater frequency in the homozygosity of the 1405 valine allele of CETP (VV genotype).

The correlation between low cholesterol and frailty may further explain the relationship with cholesterol reverse epidemiology in older persons.^[7] Frailty is strongly associated with subsequent mortality^[8] and with high cytokine levels and weight loss, both of which would lower cholesterol.

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