BIOMARKERS IN COMMUNITY- OR POPULATION-BASED STUDIES

Scientists have long been interested in obtaining measures of biomarkers to understand the role of biological systems in functioning and disease processes. Much of this work has been conducted via well-controlled experiments in the laboratory with nonhuman animals or in small-scale human studies focused on specific physiological processes in the lab (e.g., physiological responses to a specific challenge or interaction of specific physiological systems). More recently the value of collecting biomarker measurements in large-scale community and population studies has been recognized (National Research Council, 2001a) and greater emphasis is being placed, by researchers and by funding agencies, on banking biological samples.

The impetus for the collection of biomarkers is to gain a better understanding of the role of specific biological systems in health conditions, including an understanding of the role of biological systems in association with other sociodemographic, behavioral, pharmacological, psychosocial, and genetic contributions to health outcomes. There is a growing literature in the behavioral sciences literature linking social and behavioral factors (ranging from sociocultural and neighborhood influences to interpersonal relations) to biomarkers and health (Berkman and Kawachi, 2000; Cacioppo, Hughes, Waite, Hawkley and Thisted, 2006; Hawkley Masi, Berry, and Cacioppo, 2006; House, Landis, and Umberson, 1988; Kiecolt-Glaser et al., 2005; Ryff and Singer, 2001; Uchino, Cacioppo, and Kiecolt-Glaser, 1996; Wen, Hawkley, and Cacioppo, 2006). These findings, in conjunction with methodological advances, are fostering integrative lines of research to study health and pathways to disease. For example, the recent Institute of Medicine report Genes, Behavior, and the Social Environment (2006) focuses on social environments in the study of gene by environment interactions and health.

A wide variety of biomarkers have been assessed in community- or population-based studies. Biomarkers of cardiovascular, metabolic, endocrine, and immune systems or processes are most commonly assessed. However, other types of biomarker measurements have also been obtained, including exposure indices (e.g., bone and blood lead levels or pesticide blood levels to assess environmental exposure), measurements of vitamin or antioxidant levels, anthropometric measures (e.g., bone length, height, weight), bone density scans, measurements of brain activity (e.g., functional magnetic resonance imaging, fMRI, or electroencephalogram, EEG), as well as markers of the functional status of a bodily system (e.g., forced expiratory volume to assess lung function).

Biomarker values are typically assessed for biological systems at a resting state (e.g., resting blood pressure, blood levels of glucose), but values are also sometimes assessed under conditions of challenge to a system (e.g., blood pressure levels after standing, levels of glucose after a glucose challenge test). Blood, urine, and saliva samples are typical sources for biomarker assessments, although for some of the biomarkers described above, mechanical or electrical devices (e.g., MRI machine) are also used to obtain measurements. The measurement of biomarkers in community- or population-based studies presents a methodological challenge for researchers, as they must determine how and where to obtain biomarker measurements on a large number of people. Most studies have used home-based or clinic-based protocols for the collection of biological specimens, with some investigations utilizing both approaches.

The primary advantage of clinic-based specimen collection is the ability to implement protocols requiring greater temperature control (e.g., samples must be kept cold or iced) as well as meeting more restricted processing requirements (e.g., within minutes or several hours at most). However, sample representativeness can sometimes suffer as certain subgroups are less able or willing to come to a clinic for reasons related to health, transportation, or unfamiliarity with the location. Examples of studies that have used clinic-based protocols successfully include the Women's Health and Aging Studies I and II, the Cardiovascular Health Study, and the Health, Aging and Body Composition Study. Studies using home-based protocols include the MacArthur Study of Successful Aging (Berkman et al., 1993), the Later Life Resilience Study (Ryff, Singer, and Dienberg Love, 2004), and the Swedish Twin Studies (Lichtenstein et al., 2002).

BIOMARKERS AND AGING

Most established biomarkers indices reflect age norms in disease-free samples from which individuals with known risks and diseases are excluded from study. This poses a challenge for aging studies because these criteria make it difficult to define “normal” values among groups of elderly individuals for whom morbidity is common. Furthermore, this approach could mask age changes in many biomarkers and values of routine biochemical blood tests. A study of clinical biochemical values in a population-based sample of twins ages 82 and older from the Swedish study of Origins of Variance in the Oldest-Old: Octogenarian Twins (OCTO-Twin) found few participants without clinical diagnoses; therefore, subsequent survival for six years was used as a marker of overall health in late life. Results revealed an association between mortality and higher serum levels of urea, urate, gamma-glutamyltransferase (gamma-GT), free thyroxin, and plasma homocysteine. In women, increased mortality was associated with low serum values for albumin and total cholesterol. The authors propose that these results could provide guidelines for clinical practice and general health examinations (Nilsson et al., 2003a, 2003b).

Further study of the association of biochemical values with morbidity, drug therapy, and anthropometry was examined. In addition to expected findings showing that biochemical values deviate under disease states common among the elderly, a number of biological risk factors exhibit patterns of increasing risk with age, including blood pressure, glucose, and markers of inflammation and homocysteine, each of which is associated with risks for one or more common diseases of aging, such as cardiovascular disease, osteoporosis, hip fracture, depression, and dementia (Nilsson et al., 2003a, 2003b). These findings indicate that morbidity and health-related factors common in aging populations substantially influence routine biochemical values.

Analyses of community-based studies, such as the MacArthur Study of Successful Aging, also point to potentially important age-related reductions in risks associated with some biological factors (e.g., a reduction in the apparent risks associated with elevated total cholesterol—Karlamangla, Singer, Reuben, and Seeman, 2004), although other major risk factors continue to exhibit strong effects with respect to risks for major outcomes, such as physical function (Reuben et al., 2002), cognitive function (Weaver et al., 2002), and longevity (Hu et al., 2005). Analyses of biomarker data from the Cardiovascular Health Study (CHS) have confirmed that lipid profiles (specifically total and low-density lipoprotein [LDL], cholesterol) are not significant predictors of myocardial infarction (MI), stroke, or mortality among older adults (Psaty et al., 2004).

CHS data also point to the continued importance of such biomarkers as high blood pressure, fasted glucose, low albumin, elevated creatinine, and low forced vital capacity as significant, independent risk factors for mortality, along with additional measures of subclinical disease, including aortic stenosis, abnormal left ventricular ejection fraction, major electrocardiographic abnormalities, and stenosis of the internal carotid artery (Fried et al., 1998) and markers of inflammation (Jenny et al., 2006). Analyses from the Health, Aging and Body Composition Study (Health ABC) (another cohort study of adults ages 70 and older) suggest that the presence of metabolic syndrome (based on a complex of risk factors, including cholesterol, blood pressure, and glucose) in older adults does continue to predict subsequent coronary events, heart failure, myocardial infarctions, and cardiovascular-related mortality (Butler et al., 2006). Like the MacArthur and other studies of aging, Health ABC data indicate that inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α are associated cross-sectionally with the presence of subclinical or clinical cardiovascular disease (Cesari et al., 2003a), and the presence of peripheral artery disease (McDermott et al., 2005) and that high levels of IL-6, TNF-α, and C-reactive protein (CRP) also prospectively predict incident coronary events, including coronary heart disease, stroke, and congestive heart failure (Cesari et al., 2003b).

A recent analysis of time trends in biological markers of health risks in participants ages 65 and older from the National Health and Nutrition Examination Surveys (NHANES) III (1988-1994) and NHANES IV (1999-2000) found significant reductions in the levels of high-risk indices of total cholesterol and homocysteine. These findings are consistent with the hypothesis that lipid-lowering medications and folate supplementation, respectively, have been effective in reducing the prevalence of “high-risk” values for these biological parameters. However, other changes indicate an increased burden associated with obesity-related measures and high-risk levels of CRP (Crimmins et al., 2005).

Analyses based on available biomarker data in the Women's Health and Aging Studies (WHAS I and II) have yielded insights into relationships of novel and potentially modifiable biomarkers, such as serum selenium and carotenoids and mortality—low levels in each case predicting higher mortality risk (Ray et al., 2006). Analyses also confirmed mortality risks associated with gradations of diabetic hyperglycemia (Blaum et al., 2005a).

Another example of age effects is illustrated by studies of mortality and the apolipoprotein E (ApoE) genotype. The ApoE gene is a cholesterol transporter involved in brain repair mechanism and is among the most widely studied genes in aging research. It has three common alleles, ApoE-2, ApoE-3, and ApoE-4, with ApoE-4 conferring a higher risk for developing Alzheimer disease (AD). Demographic models investigating the association between ApoE genotype and mortality rates using data from several countries revealed diminishing risks with age and that the ApoE genotypes are associated with little variation in mortality among centenarians (Ewbank, 2002).

GENETIC AND ENVIRONMENTAL INFLUENCES ON RISK FACTORS FOR CARDIOVASCULAR DISEASE

In certain respects, the strategy behind biomarker research reflects an endophenotype (intermediary phenotype) approach, described in psychiatric genetics (Gottesman and Gould, 2003). In polygenic systems, in which environmental influences also figure prominently, biomarkers often represent “downstream” traits in the pathways between genes and a measured behavior or outcome. Endophenotype-based strategies are becoming more common in gene detection studies, and it is critically important to recognize that many biomarkers are themselves complexly determined. As illustrated by studies of CVD risk factors, genetic and environmental analyses of biomarkers can provide insights regarding biomarker effects in complex causal pathways.

CVD risk factors are among the most studied biomarkers. They are well known, easy to measure, and routinely assayed in clinical practice. Heritable and environmental factors have long been known to play an important role in cardiovascular disease, although quantification of these risks in the population at large is not straightforward. Twin and family studies provide ample evidence that biological risk factors (biomarkers) for cardiovascular disease, such as serum lipids and apolipoproteins, are also influenced by multiple genetic and environmental factors. Developmental trends in lipid and apolioproteins have been described (e.g., early life, adolescence, menopause in women, and older age) and age-sex differences emerge in lipid profiles.

A key question is how variation in these age and sex patterns is differentially influenced by genes and environment. Research on CVD risk factors from the Swedish Adoption Twin Study of Aging (SATSA) have helped to elucidate this. Genetic differences account for more than half the variation in plasma factor VII levels (Hong, Pedersen, Egberg, and deFaire, 1999). Analyses of total cholesterol, high-density lipoprotein (HDL), apolipoproteins A-I and B, and triglycerides revealed substantial heritabilities for these measures ranging from 0.63 to 0.78 in the younger group (ages 52-65) and from 0.28 to 0.55 in the older group (ages 66-86) for these measures. Heritabilities were consistently lower in the older age groups and significantly lower for apolipoprotein B and triglyceride levels (Heller, de Faire, Pedersen, Dahlen, and McClearn, 1993).

Furthermore, the unique design involving twins reared apart and reared together revealed that shared rearing environmental effects contributed to variation in total cholesterol levels. Most of the nongenetic variation for the other biomarkers was explained by unique environmental factors. This research was expanded on in a further twin study using augmented data that included SATSA, the Screening Across the Lifespan Twin (SALT) pilot study, and the Men and Women's Aging (GENDER) study. Sex and age differences in lipid and apolipoprotein levels were investigated in three age groups (17-49, 50-69, and 70-85). Heritabilities ranged from 35 to 74 percent and were consistently greater in women across all age groups. This age effect is almost entirely explained by greater variance associated with environmental factors (Iliadou, Lichtenstein, deFaire, and Pedersen, 2001). Age dependency in genetic effects for plasma lipids was also investigated in Dutch data, which showed some evidence for partially different sets of genes to influence lipid levels at different ages (Sneider, Van Doornen, and Boomsma, 1997).

Numerous other studies have confirmed the importance of genetic and environmental factors on cardiovascular risk factors in different countries (see Iliadou and Sneider, 2004, for a review), illustrating that genetic influences differentially affect various risk factors. For example, heritabilities for lipoprotein a Lp(a) levels are exceptionally high (.90) but may be affected by the use of sex hormones among women (Hong et al., 1995). Future research that incorporates measured environments into these models will help identify the nature of nonshared influences that impinge on CVD risk factors and become more important with age and, potentially, impact CVD outcomes.

SOCIAL AND PSYCHOLOGICAL FACTORS

A large and rapidly growing literature documents links among social, behavioral, and psychosocial measures with physiological, biological, and genetic factors (Harris, 2007; Ryff and Singer, 2005). A key goal of many of the studies reviewed here is to understand the nature of some of these links and to elucidate the interplay between these factors and their relationships to biology as these latter relationships affect healthy aging. This research has investigated an array of factors spanning different spheres of influence, including socioeconomic status, social engagement or social relationships, and various psychological factors.

BEHAVIOR GENETICS

Following the human genome project there has been a tremendous shift in the focus of behavioral genetic research that has moved this field more squarely into the realm of biomarker research. A large body of research unequivocally documents the importance of anonymous genetic influences for an array of behaviors that affect healthy aging, including symptoms of depression, physical functioning, personality, health-related behaviors, and cognition (see special issue of Behavior Genetics on Aging, 33(2), March 2003).

Candidate genes, and their protein products, represent biomarkers that are becoming more routinely catalogued and studied. For example, based on information regarding relevant biological pathways, projects from the Swedish twins (SATSA, OCTO-Twin, GENDER, HARMONY, and SALT) have identified a variety of candidate genes and gene markers to study in association with aging-related behaviors and health outcomes. An example finding from this approach and combining data from several studies (SATSA, OCTO-Twin, and GENDER) is the reported association between depressed mood in the elderly and the AA gene variant in the serotonin receptor gene (5-HTR2A) among men but not among women (Jansson et al., 2003). These results raise the question whether different genes or genetic mechanisms contribute to the development of depressed mood in the elderly.

Methodological advancements have added a new focus to behavior genetic research, and an increasing number of studies are interested in the localization and identification of functional genetic variants influencing individual differences in human behavior. For example, loneliness is common among the elderly and is central to a cluster of socioemotional states and affects behavior, psychological health (Cacioppo et al., 2006), and physical health (Tomaka, Thompson, and Palacios, 2006). Social isolation and loneliness are implicated in the pathogenesis of multiple diseases, responses to therapy, and mortality (Hawkley and Cacioppo, 2003). Putative disease pathways through which loneliness exerts an influence include health behaviors, excessive stress reactivity, and deficiencies in physiological repair and maintenance. Research indicates that genetic differences among people explain about half of the variation in loneliness among children (McGuire and Clifford, 2000) and adults (Boomsma, Willemsen, Dolan, Hawkley, and Cacioppo, 2005).

Data from the Netherlands Twin Registry (Boomsma et al., 2002) were analyzed to investigate the molecular-genetic basis for these findings. Genotypic marker (400 microsatellite markers) data were collected in 682 sibling pairs and their parents. Linkage and association analyses were conducted to elucidate candidate regions that may contain genes that influence variation in loneliness. Results pointed to a region on chromosome 12q23-24, and follow-up association tests showed significant association to two neighboring markers, D12S79 and D12S395. Linkage results in this region have been reported previously for a number of psychiatric disorders and neuroticism. Although the collective linkage results are not definitive or consistent, they provide enough evidence for the authors to postulate that this region on chromosome 12 may contain genes involved in affective and social regulation and dysregulation (Boomsma, Cacioppo, Slagbom, and Posthuma, 2006).

Although linkage studies per se do not constitute strict biomarker research, the effort to identify biomarkers of complex behaviors is becoming more and more common, as illustrated by a recent special issue of Behavior Genetics, 36(1), January 2006, dedicated to genetic linkage studies for behavioral traits, including emotionality, depression, loneliness, cognition, addictive behaviors, health behaviors, and their endophenotypes. Such an approach may potentially generate numerous useful biomarkers that may become standard covariates in large cohort studies. Aided by publicly available databases, the value of these data for exploring complexly determined phenotypes could be greatly enhanced through cross-study comparisons and data pooling possibilities.

Recently, attention has focused on the importance of studying gene-environment interactions, including how behaviors may modify gene expression (Harris, 2007; Rutter, Moffit, and Caspi, 2006). One of the most extensively studied common genetic variants in human studies of social behavior is the 5′-promoter polymorphism of the serotonin transporter gene (5HTT). A wave of studies has explored interactions between functional polymorphisms of this gene with stressful life events and depression. Evidence supporting such an interaction effect is reported by some (Caspi et al., 2003; Eley et al., 2004; Grabe et al., 2005; Kaufman et al., 2004; Kendler, Kuhn, Vittum, Prescott, and Riley, 2005) but not confirmed by all (Gillespie, Whitfield, Williams, Heath, and Martin, 2005; Surtees et al., 2006) studies. Although these findings do not derive from aging studies per se, they generate important aging-related questions regarding the role of functional polymorphisms in the serotonin transporter gene and late life depression.

New findings from the Swedish SATSA study report evidence for genotype by environment interactions affecting change in a semantic memory task. This work investigated the role of several candidate genes including those coding for ApoE and estrogen receptor alpha (ESR1) and serotonin candidates (HTR2A and 5HTT). Further investigation aimed at identifying the nature of the environmental influences involved in this interaction examined social and stress factors, including social support, life events, and depressive symptoms. Results suggested that influences associated with depressive symptoms may moderate the gene-environment interaction observed for ESR1 and ApoE and longitudinal semantic memory change. The authors explain that noncarriers of putative risk alleles may be relatively more sensitive to depression-evoking environmental contexts than carriers of the risk allele. This suggests that the contexts that facilitate or reduce depressive symptoms could affect resiliency in semantic memory dependent on genotype (Reynolds, Gatz, Berg, and Pedersen, 2007).

BIOMARKERS OF COGNITIVE AGING

Cognition represents one of the two major domains of functioning, the other being physical functioning (see below). Among the biomarkers known to affect risks for cognitive decline, the ApoE genotype, more specifically the ApoE-4 allele, has received by far the most attention to date. After the initial discovery of the role of ApoE-4 for dementia, numerous works have examined the role of ApoE and the ApoE-4 variant in trajectories of normal aging as well as in the pathogenesis of other diseases. For example, analysis of stored samples in the MacArthur study confirmed that ApoE status is predictive of cognitive declines in this initially high-functioning cohort (Bretsky, Guralnik, Launer, Albert, and Seeman, 2003). Studies of diverse populations reveal that the risk conferred by the ApoE-4 allele does not pertain to all populations. Results from a study of healthy Medicare recipients in the Washington Heights–Inwood community of New York City (WHICAP) revealed that ApoE-4 conferred a greater risk for Alzheimer disease among non-Hispanic whites, but that blacks and Hispanics were at increased risk regardless of their ApoE genotype (Tang et al., 1998). These results indicate that other, unknown genetic or environmental risk factors contribute to the increased risk of Alzheimer disease in blacks and Hispanics.

A particularly exciting opportunity is offered by the growing availability of more population-based genetic information in studies that include a rich array of other information. These data offer extraordinary new possibilities to investigate the ways in which risks associated with genotype may be importantly modified by other characteristics (i.e., to test for interactions). Such research, particularly as it relates to potentially modifiable characteristics of individuals (or environments), may offer important insights regarding protective factors that can compensate for and reduce ultimate risks associated with particular genotypes—factors that could be the focus of interventions to reduce health risks. One such question has been whether acquisition of higher levels of education might provide a protective effect against the known risks for cognitive decline usually associated with the ApoE-4 allele. Results to date are mixed, although comparisons across studies are hampered by differences in study populations and, perhaps more importantly, by lack of comparability in measures used to assess cognitive aging. Findings are nonetheless illustrative of the potential for use of growing genotypic data in the context of population studies with information on other characteristics of the individual, the environment, or both. For example, analysis from the MacArthur Successful Aging Study revealed that the presence of the ApoE-4 allele was associated with greater declines in cognitive performance (based on detailed assessments of major domains of cognitive function, including naming, spatial recognition, praxis, and executive function) over a seven-year follow-up among the more educated but not among those with less than high school education; risks for cognitive decline were highest and comparable for those with and without the ApoE-4 allele (Seeman et al., 2005).

Another epidemiological study from Washington state has examined this question using a community-dwelling (n = 2,168) sample of nondemented elderly who were followed prospectively for six years using the cognitive abilities screening instrument. With their larger sample, analyses of gene-dose effect were possible and provided evidence for biological effects of the ApoE-4/ApoE-4 genotype compared with the heterozygous and other homozygous configurations. Analyses of a possible interaction with education yielded evidence for education modification of effects only among those with the ApoE-4/ApoE-4 genotype; cognitive decline was greater among those with less education (Shadlen et al., 2005). Differences in analytic approach and operationalization of ApoE status preclude direct comparisons to the MacArthur findings. However, the findings do appear to contrast with trends seen in the MacArthur study, in which greater overall declines were associated with the presence of the ApoE-4 allele among those with higher education (though they remained at higher levels of function than carriers of the ApoE-4 allele who had lower education throughout the follow-up). However, comparisons between these studies are hampered by noncomparability on outcome measures as well as study populations. Nonetheless, their findings suggest that further attention to the joint effects of ApoE and education with respect to cognitive aging are clearly merited.

Along similar lines to the foregoing studies are efforts to investigate the potential of early life socioeconomic environment to modify the relationship between ApoE status and risk for development of Alzheimer disease. Census data were used to index socioeconomic risk based on a number of parental and demographic measures. In addition to the increased risk conferred by genetic predisposition and early life environment, risk for AD was found to be greatly elevated (OR = 14.8; 95% CI, 4.9-46) when both the genetic and the environmental risk factors were present (Moceri et al., 2001). Other data from the CHS also point to possibly important interactions with dietary fatty fish consumption in relation to dementia risk: dietary intake had a significant effect only for those without the ApoE-4 allele (Huang et al., 2005).

Findings from community-based studies on the effect of ApoE on memory performance and memory change are mixed, with some finding deficits in performance or quicker rates of decline and others reporting no effect. However, ApoE-4 influences are more consistently reported for episodic versus working memory.

Two other genes with mixed support as genetic risk factors for Alzheimer disease, A2M (alpha-2-macroglobulin) and low-density LRP (lipoprotein receptor-related protein), have now been studied in relation to memory among nondemented adults. Variation in these three genes was analyzed in latent growth models measuring memory performance over a 13-year period in SATSA. Polymorphisms of ApoE and A2M (but not low-density LRP) were associated with memory performance and change in memory in this nondemented sample. Specifically, ApoE status affected ability levels of working and recall memory, the ApoE-4/ApoE-4 genotype was associated with worst performance across all ages. Furthermore, this study provided evidence of within-locus interactions (genetic dominance deviations) because memory performance among the heterozygotes was better than among the noncarriers of the ApoE-4 allele. Finally, the rare del/del genotype of A2M was associated with a more rapid rate of decline on figural recognition than the other two genotypes (Reynolds et al., 2006).

The role of other candidate genes has recently been explored in relation to cognitive aging. Age-related loss of serotonin receptors 2A (5-HT2A) is associated with a loss in brain regions including the hippocampus and posterior medial prefrontal cortex. A functional variant (H452Y) of the gene coding for the 5-HT2A serotonin receptor (HTR2A) has been associated with recall tests in young adults (de Quervain et al., 2003). This was further investigated using a new approach that explored allelic associations and trajectories of change in memory performance over a 13-year period in the SATSA data. Findings suggested that the 5-HT2A serotonin receptor is involved in the formation of episodic memories in older adults. Performance on figural memory at age 65 and change in figural memory were associated with the HTR2A genotype. Genotype-dependent effects comparing the AG, AA, and AG configurations revealed the steepest declines associated with AG heterozygotes. Performance over time was consistently worse among those with the AA compared with the GG genotypes, with trajectories differing by 2-6 percent per year (Reynolds, Jansson, Gatz, and Pedersen, 2006).

Other biomarkers also show an association with cognitive decline. Data from the OCTO-Twin study revealed lower homocysteine values among those with intact cognitive function, a finding that contrasts results regarding dementia. These findings overlap somewhat with those from the MacArthur Study of Successful Aging and the NAS, both of which found that high levels of homocysteine and low levels of vitamin B and folate were associated with cognitive decline (Kado et al., 2005; Tucker, Qiao, Scott, Rosenberg, and Spiro, 2005). Elevations in various stress hormones (i.e., urinary free cortisol and/or epinephrine) have also been shown to predict increased risks for cognitive decline (Seeman, McEwen, Singer, Albert, and Rowe, 1997a; Karlamangla, Singer, Chodosh, McEwen, and Seeman, 2005b; Karlamangla, Singer, Greendale, and Seeman, 2005a). Additional biomarkers found to predict cognitive and mental health status, independent of other standard sociodemographic and lifestyle risk factors, include low serum thyroxine (a marker of thyroid function) as a risk factor for cognitive decline (Volpato et al., 2002) and vitamin B12 deficiency as a risk factor for depression (Penninx et al., 2000). High levels of lead in bone and blood have also been shown to be associated with cognitive impairment (Payton, Riggs, Spiro, Weiss, and Hu, 1998). Greater vitamin E intake or vitamin E levels have also been associated with less cognitive impairment and dementia in the InChianti study (Cherubini et al., 2005).

More detailed neuropsychological protocols have also provided evidence linking early cognitive test performance to risks for Alzheimer disease (Saxton et al., 2004), and more detailed MRI data show that levels of inflammation (e.g., fibrinogen) and forced vital capacity are positively and significantly related to white matter disease (Ding et al., 2003).

BIOMARKERS OF PHYSICAL FUNCTION AND AGING

Physical functioning represents the second major functional domain and has been a focus of considerable research attention. Among the most detailed of this work has been that by Fried and colleagues as part of the WHAS. A particular strength of the WHAS I and II studies is their detailed evaluation of both lower and upper extremity function, including various assessments of balance, walking speed, timed chair stands and knee extension force for lower extremity function and hand grip, pegboard, and putting-on-blouse tests for upper extremity function. Analyses based on these data have documented the significant contribution of muscle weakness to risks for disability (Rantanen et al., 1999) and the more general contributions of physical performance across the various domains of upper and lower extremity functioning to both progressive and catastrophic disability (Onder et al., 2005). In the WHAS I and II, availability of detailed performance measures, plus information on biological processes thought to impact such performance, such as inflammation or growth factors, has afforded important opportunities to examine the joint and independent contributions of performance abilities and biological processes to actual levels of functional disability.

Several analyses have highlighted the significant, negative impact of higher burdens of inflammation in terms of reduced muscle strength and declines in physical function (Ferrucci et al., 2002) as well as parallel negative associations between low insulin-like growth factor-1 (IGF-1) and declining IGF-1 with slower walking speed and reported difficulty with mobility tasks, respectively (Cappola, Bandeen-Roche, Wand, Volpato, and Fried, 2001). These findings on the relationship between muscle strength and inflammation mirror results from Health ABC showing that high levels of oxidized LDL (oxLDL) and IL-6 predict incident mobility disability, with those individuals with high levels of both biomarkers being at greatest risk. Loss of muscle strength and muscle mass may be one pathway involved in relationships between inflammation and physical disability, as high circulating levels of inflammatory biomarkers are associated with low muscle strength and muscle mass in study participants (Visser et al., 2002; Yende et al., 2006).

Inflammatory markers have also been linked to both levels of physical activity and risks for functional decline. Data from the InChianti (Invecchiare in Chianti, meaning “aging in the Chianti area”) Study, a prospective investigation of over 1,000 community-dwelling French adults, indicate that compared with sedentary individuals, physically active men have lower fibrinogen, CRP, IL-6, and TNF-α, as well as lower uric acid and a lower erythrocyte sedimentation rate, while physically active women have lower CRP, IL-6, and uric acid (Cherubini et al., 2005; Elosua et al., 2005). Similar findings have been reported from the MacArthur Study of Successful Aging in the United States (Reuben, Judd-Hamilton, Harris, and Seeman, 2003). Greater inflammatory burden has also been associated with increased risks for physical disability (Reuben et al., 2002) and with poorer physical performance (Cesari et al., 2005).

A number of investigations in InChianti have also examined biomarker correlates of anemia and links between anemia and indicators of physical health or functioning. Anemia is typically defined by low levels of blood hemoglobin (< 12 g/dL in women, < 13 g/dL in men). Hemoglobin is found in red blood cells, which contain iron and are responsible for carrying oxygen to bodily tissues. Anemia or low blood hemoglobin levels are associated with low muscle density, low skeletal muscle strength, a low muscle/total area ratio, and low bone mass and density (Cesari et al., 2005). Consistent with these bone and muscle correlates of anemia, anemic persons have also been found to be more likely to have physical disabilities, poor physical performance, lower hand grip strength, and lower knee extensor strength, compared with nonanemic individuals (Penninx et al., 2005).

Data from the InChianti study also point to the importance of additional biomarkers, including antioxidants such as vitamin E (alpha-tocopherol), which has been associated with a number of indicators of health and functioning in study participants. Those with lower vitamin E levels were less likely to be frail (as assessed by an index of weight loss, low energy, slow gait, low grip strength, and low physical activity; Ble et al., 2006), had higher conduction velocity in peripheral nerves (a slowing of conduction velocity is thought to contribute to decline in muscle strength; Di Iorio et al., 2006), and were less likely to have peripheral arterial disease (Antonelli-Incalzi et al., 2006).

The concept of frailty has become the focus of a growing body of research, stimulated in good measure by Linda Fried, a leader in developing and testing of an operational definition of the concept (Fried et al., 2001). Using data from the WHAS I and II studies, Fried and colleagues have provided confirmation of the internal validity of the component measures, which include poor extremity strength (low grip strength), slow gait, low levels of physical activity, exhaustion and weight loss, and the independent risks for functional disability, institutionalization, and mortality associated with such frailty (Bandeen-Roche et al., 2006). WHAS I and II data have also contributed to understanding of the various physiological processes that appear to contribute to frailty, including documenting the contribution of anemia (Chaves et al., 2005) and, perhaps most surprisingly, of obesity, which was found to be associated with prefrailty and frailty despite the fact that a defining characteristic of frailty is weight loss (Blaum, Xue, Michelon, Semba, and Fried, 2005b). This obesity-frailty association remained significant even with adjustments for multiple conditions associated with frailty (e.g., inflammation burden). Data from the CHS provide parallel evidence linking increased burdens of inflammation to risks for frailty (Walston et al., 2002). Research is needed to determine whether frailty represents an important pathway that underlies known links between a number of the biomarker correlates of frailty (e.g., inflammation, anemia, vitamin E) and disability, morbidity, and mortality outcomes (see review above).

INDICES OF CUMULATIVE BIOLOGICAL RISK

Using available biomarker data, investigators associated with the MacArthur study have been among the leaders in efforts to develop operational indices of allostatic load (AL)—that is, a multisystems measure of physiological dysregulation. Beginning with initial work using a simple count of the number of available biomarkers for which an individual had a value placing them in the top risk quartile, Seeman, McEwen, Singer, Albert, and Rowe (1997b) examined health risks associated with differences in such cumulative AL and demonstrated that higher levels of baseline AL were associated with significantly increased risks for cardiovascular disease, cognitive and physical decline, as well as mortality (Seeman, Singer, Horwitz, and McEwen, 1997b; Seeman Singer, Rowe, and McEwen, 2001). Subsequent work by Karlamangla, Singer, McEwen, Rowe, and Seeman (2002) using canonical correlation techniques demonstrated improved prediction of cognitive and physical decline when the full range of scores was used for each biomarker, and unequal weighting of the different biomarkers was incorporated into the scoring of overall AL. Recent work has also documented that measured change in AL predicts subsequent mortality risk (Karlamangla, Singer, and Seeman, 2006). Stimulated by Singer's work on recursive partitioning (Zhang and Singer, 1999; Singer, Ryff, and Seeman, 2004), recent analyses by Gruenewald, Seeman, Ryff, Karlamangla, and Singer (no date) have demonstrated that particular combinations of these biomarkers (e.g., inflammation and neuroendocrine biomarkers) predict higher versus lower mortality risks over a 12-year period.

A common thread seen in all of the work on AL has been the confirmation of contributions to cumulative health risks from multiple biological systems and the value of taking account of this range of contributions in understanding population variations in burdens of morbidity, disability, and mortality. As illustrated in Seeman et al. (2004a), analyses of AL as a mediator of education effects on mortality risk, the more comprehensive AL index accounted for the largest percentage reduction in the education effect on mortality, with subsets of biomarkers representing cardiovascular, inflammatory, and sympathetic nervous system/hypothalamic-pituitary-adrenal activity, each contributing to this overall effect (Seeman et al., 2004a).

As noted earlier, data from the Wisconsin Longitudinal Study (a cohort of men and women, ages 58-62, approximately a decade younger than the MacArthur study cohort) have provided evidence for relationships between SES and levels of positive social engagement and a similar “count” index of allostatic load (Singer and Ryff, 1999; Seeman et al., 2002). Using the MacArthur Study of Successful Aging protocols, the Social Environment and Biomarkers of Aging Study (SEBAS) (see Chapter 3) collected parallel biological data and provides another comparison to the MacArthur study. Analyses of SEBAS data have yielded intriguing similarities and differences with respect to relationships and allostatic load (weaker in Taiwan; Hu, Wagle, Goldman, Weinstein, and Seeman, 2006), and between social integration and allostatic load (nonsignificant in Taiwan; Seeman, Glei, Goldman, Weinstein, Singer, and Lin, 2004b). The possible importance of sociocultural differences between Asia and the United States represents one area of potentially fruitful future research to better understand how aspects of the social environment impact health.

RELATIONSHIP BETWEEN BIOMARKERS AND GENETIC PLEIOTROPY

Two other recent areas of interest in WHAS I and II include examination of possible interactions among biomarkers, with initial work showing cross-sectional relationships between higher serum levels of antioxidants and lower levels of IL-6 (as a marker of inflammation) and longitudinal relationships between initially low antioxidant levels and subsequent increases in IL-6 levels (Walston et al., 2006). A second area of investigation has been to incorporate consideration of genetic information in tracking the factors contributing to observed profiles of biological activity. Initial analyses focused on IL-6 alleles and their relationship to serum IL-6 levels and to decreased muscle strength and frailty. No significant relationships were found for any of these outcomes with any single IL-6 single nucleotide polymorphism (SNP) or any IL-6 haplotype (Walston et al., 2005).

Genetic pleiotropy (in which a gene or set of genes influences multiple traits) could explain the association between biomarkers. A series of studies from the Swedish twin projects have investigated the variance architecture explaining the clustering between biomarkers for cardiovascular disease. Genetic and environmental correlations among the following five serum lipid measures—total cholesterol, HDL cholesterol, triglycerides, and apolipoproteins A-I and B—were analyzed in two different age groups from SATSA. Substantial genetic correlations were found in each age group, although there is no evidence for a single genetic factor common to all five lipids. There were significant age differences in the heritabilities for the various serum lipid levels, and genetic factors seemed to be more important for explaining the covariation between the lipid levels in the younger compared with the older group (Heller, Pedersen, de Faire U, and McClearn, 1994). Further research focused on the sources of clustering among five principal components (BMI, insulin resistance, triglycerides, HDL cholesterol, and systolic blood pressure) of the insulin resistance syndrome (IRS). Results suggest a single set of genetic factors is common to all five components; of particular note was the strong genetic association between BMI and insulin resistance. In contrast, the relationship between only three of the IRS components—triglycerides, insulin resistance, and HDL cholesterol—could be explained by shared sources of individual environmental influences. These findings demonstrating a strong genetic correlation between BMI and insulin resistance raises the question whether behavioral factors that affect both of these phenotypes, such as overeating, act through genetic pathways, perhaps related to control and sensations of satiation, rather than through such environmental factors as availability of food (Hong, Pedersen, Brismar, and deFaire, 1997).

SUMMARY AND FUTURE DIRECTION

Recent growth in the number of studies incorporating biomarkers into larger population-based surveys has yielded a rapidly growing body of evidence linking various aspects of biological functioning not only to major health outcomes, including cognitive and physical functioning and longevity, but also importantly to individual differences in socioeconomic and other social, psychological, and behavioral characteristics. Findings linking aspects of life situations to major biological risk factors provides important evidence on two fronts. First, it provides validation for various biopsychosocial models of aging and helps elucidate biological pathways through which social, psychological, and behavioral factors affect trajectories of aging and risks for various health outcomes. Second, such evidence provides further support for the potential value of interventions targeting such social, psychological, and behavioral factors as a means of altering underlying biological risk profiles.

A number of ongoing studies will soon provide even richer databases for use in elucidating the complex pathways through which individuals' life experiences and situations affect their health and aging and the biological pathways through which these effects are mediated. For example, current data collection for the MIDUS (Midlife Development in the United States) study will result in a rich set of data on life experiences, including longitudinal data covering the past decade, along with detailed biomarker data and daily diary data for subsets of some 1,500 MIDUS participants. These data will offer significantly improved opportunities to examine a wide variety of hypotheses regarding the role of life experiences (both current and past) in shaping patterns of biological risk and health trajectories. As also outlined in other chapters, data collection for other studies, such as the Health and Retirement Study and the reassessments currently under way for the Taiwan SEBAS study, will offer yet additional national and cross-national data, including socioeconomic, psychosocial, and biological data, that can be used to replicate and extend findings outlined here.

The data and research potential generated from these studies will be greatly enhanced by coordinating efforts such as those undertaken by the Chicago Core on Biomarkers in Population-Based Aging Research (CCBAR) at the University of Chicago-NORC Center on Aging. Through a number of activities, CCBAR provides a central resource to help foster collaboration, exchange information, and promote interdisciplinary research related to biomarker collections in population-based health research and aging, including an interactive website, http://biomarkers.health-studies.org/studydemo.php.

It is instructive to consider the factors that affect the selection of biomarkers for inclusion in these studies. These factors include at least three common and critical considerations—two scientific and one logistical or financial. First, from a scientific standpoint, biomarkers were selected to include those needed to address primary substantive, scientific questions of interest to the study investigators. Second, also from a scientific standpoint, in cases in which there is a presumption from the beginning that the wider community of health researchers will ultimately use these databases to address other, as yet unspecified, questions, there is clearly the additional question of whether additional biomarkers (i.e., other than those already selected based on the substantive interests of study investigators) should be included. Here, considerations generally relate to whether there are major biological systems or processes that are likely to affect health for which data would otherwise be missing.

Perhaps most challenging are a third set of nonscientific considerations that relate to issues of feasibility both with respect to requirements for implementation of protocols to collect and process needed biospecimens and with financial considerations. Perhaps foremost are the logistical constraints imposed by time and handling requirements for obtaining many biological measurements. Examples include (1) the need for phlebotomy to collect venous blood (e.g., when dried blood spots cannot be used), (2) the need for fasted blood samples, which can constrain collection to morning hours, (3) the need for sample collection at specific times due to diurnal rhythms of parameters such as cortisol, necessitating collection at the same time of day for everyone and collection of multiple samples over time, (4) the need for blood or urine samples to be processed within a limited time frame (usually within a couple of hours). The selection of biomarkers for inclusion in a given study will thus necessarily be heavily influenced by what is possible in the context of specific study designs and logistical parameters. For example, the national scope of the HRS study precludes collection of venous blood so dried blood spots are being collected. Selection of biomarkers is thus restricted to those for which assays are available that can use dried blood spots rather than venous blood. By contrast, the MIDUS study is collecting a wide array of biomarkers because participants are being brought to regional clinical research centers (each in a hospital setting) where venous blood can be drawn first thing in the morning (allowing for fasted samples) and where these samples can be processed immediately.

Thus, the final set of biomarkers included in any studies will reflect both the underlying scientific questions investigators seek to address and what is possible given their logistical and financial constraints. Despite the demands and challenges inherent in incorporating biomarkers into social science surveys, continued research development and efforts in the directions presented herein are critical to understanding better the factors that affect patterns of biological aging and trajectories of health at older ages.

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