Life course epidemiology studies the long-term effects on later health- or disease-risk of physical or social exposures during gestation, childhood, adolescence, young adulthood, and later adult life (Kuh et al., 2003). It allows the integration of biological, behavioral, clinical, psychological, and social processes that interact across a person's life (Ben-Shlomo et al., 2002). This is not a new concept in aging research. Over 50 years ago Nathan Shock wrote, ''In the broadest sense, problems of growth, development, and maturation are as much a part of gerontology as are those of atrophy, degeneration, and decline'' (Baker et al., 1992). He emphasized the need to examine aging over the entire life span.
The likelihood of developing certain chronic conditions (e.g., type 2 diabetes, ischemic heart disease) appears to depend in part on the early environment (Gluckman et al., 2004). A noxious stimulus at a critical, sensitive period earlier in life may lead to permanent structural, physiologic, and/or metabolic changes (Godfrey et al., 2001). These changes in the young organism might confer immediate survival advantages but at a subsequent cost, especially if there is a mismatch between the developmental and adult environments (e.g., constrained fetal growth followed by exposure to high-calorie foods after birth). This is not to deny the importance of adult risk factors—life course epidemiology allows the joint study of both early life and adult factors. Understanding the biological, clinical, psychological, lifestyle, and social factors that influence physical performance in midlife may provide clues to the origin of frailty in old age.
Whether frailty risk accumulates or there is a required chain of events is unknown (Kuh et al., 2003). It is also unknown whether there are critical or sensitive periods for the development of frailty; middle-age might be a critical period (Lu et al., 2004). Confounding, mediating, and modifying factors will require consideration. The very complexity of the life course approach in the study of frailty would be an attraction—it would allow the consideration of a mix of both early and late risk factors as well as biomedical and psychosocial influences.
The Alameda County Study looked at risk factors for frailty over the previous three decades in an older cohort (Strawbridge et al., 1998). It was found that (listed alphabetically) depression, fair or poor self-rated health, heavy drinking, physical inactivity, prevalence of chronic conditions, prevalence of chronic symptoms, and smoking were adult risk factors that predicted the occurrence of what they defined as frailty (i.e., problems in two or more of the following domains—physical functioning, nutritional status, cognition, sensation).
Although we have no direct evidence linking early life factors and frailty, suggestive data are becoming available. Muscle weakness typically is included as one of its characteristics. Grip strength is often used in epidemio-logical studies to measure this attribute. The Medical Research Council National Survey of Health and Development found a positive relationship between birth weight and grip strength at the age of 53 (Kuh et al., 2002). The Hertfordshire cohort study found that grip strength in the mid-60s was significantly associated with birth weight (Sayer et al., 2004). A suggested mechanism for the association is that birth weight is related to the number of muscle fibers at birth. Because of the loss of muscle fibers with aging, a deficit in the number at birth could predispose an individual to sarcopenia later in life.
Other early life factors that may be associated with the development of late-life frailty include exposure to infections and chronic stress. The induction of chronic inflammation might explain the relationship between early-life infections and late-life morbidity and mortality. The reduction in lifetime exposure to infectious diseases and other sources of inflammation may be contributing to the decline we've seen throughout the developed world in late-life mortality (Finch et al., 2004). As noted previously, activation of the immune system may play a role in the etiology of frailty. An interesting and potentially testable hypothesis is whether lifetime exposure to infectious diseases influences the incidence of frailty. A recent study found that chronic cytomegalo-virus infection was associated with the presence of frailty (Schmaltz et al., 2005). High IL-6 levels increased the strength of the association.
Challenging social conditions (e.g., having a relatively lower social standing) over the life course can be associated with chronic stress and increased susceptibility to various disease states (Brunner, 1997). When survivors of the Whitehall Study were resurveyed after a 29-year gap, men in clerical or manual jobs at middle age were four times more likely to report poor physical performance than senior administrators (Breeze et al., 2001). It was estimated that at most 20% of this could be explained by baseline differences in cardio-respiratory disease and risk factors. Chronic stress has been shown to be associated with a variety of biological effects including increases in IL-6 levels (Kiecolt-Glaser et al., 2003) and accelerated telomere shortening (Epel et al., 2004).
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