Cholesterol and Health in Old Age: Risk Factor or Risk Marker?

Karlamangla et al., in their article, ‘‘Increases in serum non-high-density lipoprotein cholesterol may be beneficial in some high-functioning older adults: MacArthur Studies of Successful Aging,’’ have examined the association between cholesterol and health status in an epidemiological study nested in the MacArthur Studies of Successful Aging. Their principle finding is that, in high-functioning older persons, higher levels of cholesterol are associated with good health. This study joins a long series of articles over the past 30 years that have framed a debate about cholesterol and health, contributing to controversy over whether treatment for hypercholesterolemia could be detrimental to health in old age. The epidemiological method originated in the investigation of infectious disease. Description of symptoms and signs of infection, identification of infected persons, and the vector for infection provided a systematic framework to successfully contain infection. That host factors contribute to risk was later appreciated as also important, but in the setting of acute illness, these host factors were assumed to represent a ‘‘usual’’ health state. These principles formed the cornerstone of the epidemiological process. Application of this investigative process to conditions of old age has been problematic, especially because epidemiological principles were designed for acute health problems rather than chronic illnesses. In particular, chronic diseases have long preclinical phases that may change endogenous factors such as hormones or lipids or exogenous factors such as physical activity, smoking, or drinking. By the time the disease becomes clinically apparent, the process of insidious preclinical change may mask true risk associations, and risk factors associated with disease etiology may even appear protective. This pattern of ‘‘reverse causation,’’ where the onset of a disease modifies a risk factor so that the relationship at the time the disease is diagnosed is inverse or neutral, is common in diseases of old age and has obscured important health relationships. For instance, in cognitive decline, the insidious preclinical phase often includes weight loss, which, in turn, is associated with decreases in blood pressure and cholesterol. At the time the cognitive impairment is diagnosed, patients often have ‘‘normal’’ systolic blood pressure (SBP). First-generation risk factor studies of cognitive decline found an inverse association between SBP and cognitive function. As a result, it was hypothesized that low flow might exacerbate cognitive decline, and clinical reluctance to treat systolic hypertension grew. Later studies rebutted this hypothesis by demonstrating that midlife hypertension was associated with late-life cognitive decline regardless of the level of latelife blood pressure and that control of blood pressure might ameliorate the cognitive decline. Those studies also demonstrated that the lower SBP at the time of diagnosis was secondary to change in weight and health. Thus, in the general population, those with lower SBP will be a mix of persons with lifelong low blood pressure (primary low blood pressure) who for the most part function well and those with low blood pressure that reflects poor health status (secondary low blood pressure) and contributes to reverse causation. Cholesterol–health relationships in old age also have been controversial, with many of the same methodological problems discussed above. Because cholesterol, reflecting diet and genetics, has become a hallmark risk factor for cardiovascular disease, it is often forgotten that other factors, particularly diseases that alter liver function or factors that trigger the acute phase response, can affect serum cholesterol level. Thus, in old age, a period of life when diseases associated with the acute phase response are common, it is reasonable to assume that, although cholesterol may influence health, health may also influence cholesterol. Several examples of health factors influencing cholesterol are instructive. An acute illness episode can lower cholesterol. Comparison of cholesterol levels in healthy donors who were acutely ill with those without acute illness showed that cholesterol levels of those who reported an acute illness were systematically lower. It is also wellknown that cholesterol levels measured at the time of a major stress such as a myocardial infarction are an unreliable indicator of the patient’s usual level of lipids. Low cholesterol has also been associated with risk of cancer, findings that lead to concerns that population interventions to lower cholesterol could lead to an increased risk of cancer, but careful investigation revealed that the low cholesterol was a result of the preclinical presentation of the cancer. This preclinical decline in cholesterol with cancer was also reported in a patient with resistant hypercholesterolemia that dropped spontaneously before presentation with a gallbladder cancer. The cells from that cancer secreted a factor that altered cholesterol metabolism in cell culture. Selected cytokines, including granulocytemacrophage colony factor, can result in abrupt declines in serum cholesterol. A review of major factors that can affect cholesterol include smoking, alcohol intake, major and minor illnesses, hospitalization, acute myocardial infarction, acquired immune deficiency syndrome (AIDS), weight change, and selected medications. The relationship between cholesterol and mortality has also been problematic, with several studies reporting an