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The Highs and Lows of Cholesterol: A Paradox of Healthy Aging?

To the Editor: One of the paradoxes of aging is the seeming reversal in the direction of risk factors. For example, higher body mass index (BMI) in later life may be protective as may elevated cholesterol levels. Conversely, the prevailing belief that older adults benefit from higher blood pressure has been debunked, although what a so-called normal blood pressure should be for the average 80-year-old remains controversial. Whether the associations seen with cholesterol or BMI are true or reflect a survival bias remains unknown. Those who survive to be included in studies of older adults are likely to have made healthy choices throughout their lives, and their longevity may be influenced by other factors such as genetics. A challenge to understanding the natural history of common cardiovascular (CV) biomarker risk factors in older adults, such as total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TGs), is the need for longitudinal follow-up. One approach has been to use data from clinical trials. However, until recently, only a very limited number of participants older than 80 years have been enrolled in cholesterol-lowering trials. Furthermore, cholesterol levels measured in the context of CV risk reduction trials, which often include healthier individuals relative to the general population and are impacted by treatment, are not the same as understanding the natural history of cholesterol over the life span. Nevertheless, a meta-analysis of 312 175 individuals (mean age = 62 y) enrolled in clinical trials of cholesterollowering medications demonstrated that reduction in LDL was associated with a linear reduction in the relative risk of major CV events including CV mortality. LDL has inflammatory effects beyond the buildup of plaque in blood vessels, and the prevailing belief is that lower cholesterol and a corresponding reduction in inflammation is associated with better outcomes for both CV events and mortality. These data contrast with a systematic review of 30 cohort studies that included a total of 68 094 adults older than 60 years and demonstrated that elevated LDL was inversely associated with mortality. One concern regarding low cholesterol in older adults is the importance of cholesterol for many body functions including nerve conduction, intracellular transport (eg, for the fat-soluble vitamins A, D, E, and K), as a precursor for important molecules (eg, sex and steroid hormones), and as a part of all cell membranes. With frailty and other catabolic states common in older adults, elevated cholesterol has been hypothesized to be protective in survivors to very old age, and this theory has remained conventional wisdom among many geriatricians. For these reasons, two studies in this month’s Journal of the American Geriatrics Society are particularly notable in their attempt to shed light on the relationship between cholesterol and mortality in older adults. Using the Helsinki Businessmen Study (HBS), Sittiwet and colleagues examined the relationship between cholesterol metabolism and mortality in two cohorts of older men: 660 men recruited in 2003, with an average age of 78 years, and 398 men recruited in 2011, with an average age of 83 years. Each group was followed for 3 years, and the younger group was additionally followed for 11 years. After standardizing for age and statin use, at baseline the 2003 cohort had higher LDL and lower HDL levels compared with the 2011 cohort. This finding may reflect secular changes in cholesterol levels that have been declining over time, in part due to public health campaigns related to lifestyle and diet. In both cohorts, no significant association was found between baseline cholesterol level (HDL, LDL, total cholesterol, or TGs) and mortality (all P > .05). Using concentrations of cholesterol precursors as markers of cholesterol absorption, the authors report a reduction in cholesterol synthesis and reduction in the efficiency of cholesterol absorption in the older cohort that correlated with an increased risk of mortality at 3 years of follow-up. The authors postulate it is this reduction in both cholesterol synthesis and absorption efficiency that leads to the epiphenomenon of reverse epidemiology whereby lower serum cholesterol may be associated with an increased risk in mortality. However, in this study, clinical measures of cholesterol did not differ between those who were alive or those who had died. This is an important descriptive study because data are limited on the natural history of cholesterol synthesis in older adults, and it adds to potential mechanisms as to why older adults may have lower levels of cholesterol. However, the clinical relevance is unclear because the LDL, HDL, and TG levels were all within normal ranges, no significant differences were found between those who were alive and who DOI: 10.1111/jgs.16302