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5 An Overview of Biomarker Research from Community and Population-Based Studies on Aging Jennifer R. Harris, Tara L. Gruenewald, and Teresa Seeman T he goal of this chapter is to provide an overview of findings from community-based studies that have profitably incorporated bio- markers along with more traditional interview data to address important questions regarding factors that affect health risks at older ages. The focus on older age stems from a series of activities (National Research Council, 1997, 2001a) funded by the National Institute on Aging that promoted a new era of population aging research predicated on the importance of integrating biomarkers into survey research. Prior efforts to include biomarkers in community and population studies have yielded a wealth of knowledge regarding the role of biologi- cal systems and processes in cognitive and physical functioning, mental and physical disease development, and mortality outcomes. The bio- marker initiative under the National Institute on Aging was particularly concerned with identifying biomarkers of physiological age (Butler et al., 2004). In contrast, biomarker research in the social and behavioral sciences has emphasized elucidating the interplay of biological systems with sociodemographic, behavioral, psychosocial, pharmacological, and genetic factors in health outcomes (Institute of Medicine, 2006; National Research Council, 2001b). This chapter highlights research contributions from a selected group of community and population studies that include various biomarker measurements in study assessments. It is not intended to review com- pletely, catalogue, or present in-depth results, but rather to provide an overview of the range of biomarker research conducted in these studies 96
JENNIFER R. HARRIS, TARA L. GRUENEWALD, AND TERESA SEEMAN 97 and highlight some key findings and research directions stemming from this integrative research. For the purposes of this review, we have limited our consideration of biomarkers mainly to DNA and physiological biomarkers collected from blood (e.g., glycosylated hemoglobin, cholesterol), saliva (cortisol) or urine (cortisol and catecholamines); not included are more functional parameters that are also considered to be biomarkers, such as hand grip strength, mea- sures of vision or hearing, and assessments of cognitive or physical func- tioning. This chapter highlights the types of questions that can be addressed when social and behavioral studies are supplemented with biomarker data, and therefore we also exclude descriptions of biomarker research derived from postmortem studies of brain tissue. It is important to note, however, the value of postmortem biomarkers for elucidating biological pathways and mechanisms, including those linking social and behavioral measures with disease outcomes. This is illustrated by research from, for example, the Nunâs Study (Snowdon, Kemper, Mortimer, Wekstein, and Markesbery, 1996), the Religious Order Study (Wilson, Bienias, and Evans, 2004), and the Memory and Aging Project (Bennett et al., 2005). Our decision to focus on physiological parameters and genes was driven in large part by a central goal of the current volume, namely, to help inform social scientists about the potential value of incorporating biomarkers into their projects through exposition of prior research in which analyses of such biomarkers or candidate genes have provided insights into processes and mechanisms affecting healthy aging. In that context, the focus taken herein seems warranted, as such biomarkers have generally not been included in social surveys (whereas assessments of functioning have), so that evidence based on physiological biomarkers is much less well known to the social science community. Much of the information presented in this chapter derives from the studies summarized in Table 5-1. These were selected to represent a sam- pling of ongoing community or population-based studies on aging that have collected DNA or other biological or physiological biomarkers and that are not reviewed elsewhere in this volume. We have organized the wide range of findings generated from the studies reviewed according to a number of critical thematic areas that emerged during our review. These include biomarkers and aging, genetic and environmental influences on risk factors for cardiovascular disease (CVD), social and psychological factors, behavior genetics, biomarkers of cognitive aging, biomarkers of physical function and aging, indices of cumulative biological risk, and the relationship between biomarkers and genetic pleiotropy.
98 TABLE 5-1 Description of Selected Community and Population-Based Studies Conducting Biomarker Research Specimen Type and Study Name Design and How (year started) Sample General Purpose Collected Biomarkers Ascertained MacArthur Study 1,189 men and Longitudinal Biomarker Total/HDL cholesterol, glycosylated of Successful Aging women, ages 70- cohort study to data were hemoglobin, albumin, IL-6, C-reactive (Berkman et al., 79 at baseline. elucidate the factors collected protein, fibrinogen, complete blood 1993) Selection criteria (sociodemographic, at baseline count (CBC), blood chemistry tests employed to behavior, and three- (SMAC-24), DHEAS, antioxidants, enroll a cohort psychosocial, year follow- homocysteine, vitamin B and folate, representing biological) up. Home urinary norepinephrine, epinephrine, the top third associated with more specimen cortisol and dopamine, resting and of this age successful aging collectionsâ postural blood pressure, waist/hip group in terms (i.e., maintenance phlebotomist ratio, peak flow rate (Mini-Wright of physical of higher cognitive collected meter), ApoE genotyping. and cognitive and physical blood and functioning. functioning). Data 12-hour collected at baseline (overnight) and 3- and 7-year urine sample. follow-up exams via in-person and phone assessments.
Normative Aging Sample of 2,280 Longitudinal Clinical CBC, creatinine, albumin, fasting Study (1963) (Bell, initially healthy cohort study to examinations glucose, insulin, 2-hour glucose Rose, and Damon, men, ages 21-80 examine biomedical every 3-5 tolerance test, lipid profiles 1972) at enrollment. and psychosocial years with (LDL, HDL, triglycerides), serum Study characteristics collection of glutamic-oxaloacetic transaminase conducted of aging and blood and 24- (SGOT), calcium, blood urea through development of hour urines. nitrogen (BUN), blood lead levels, Department of disease. urinary catecholamines, blood Veteran Affairs pressure, heart rate, EKG reading, in Boston (96% pulmonary function, anthropometry, of participants homocysteine, vitamin B and folate. are veterans). Cardiovascular Representative Longitudinal cohort Clinic-based Resting and postural blood pressure, Health Study (CHS, sample of 5,000 study of risk factors collection ankle-arm index, fasting glucose, 1989; Fried et al., adults, ages for coronary heart of blood for insulin, 2-hour oral glucose tolerance 2001) 65+, sampled disease and stroke wide array of test, lipid profile (LDL, HDL, from Medicare in older adults. biomarkers, triclycerides), albumin, CBC, left listings for 4 Assessments at EBCT, ventricular ejection fraction, markers communities baseline and one-, ultrasound, of inflammation and coagulation, (N = 1,250 two-, and three-year and MRI. ApoE, body fat (bioelectric each; Forsyth follow-ups. impedance), height, weight, waist/ County, ND; hip ratio, 12-lead ECGs (24-hour Sacramento, ambulatory ECGs on subset of CA; Washington 600), forced vital capacity, forced County, MD; expiratory volume, grip strength, Pittsburgh, PA). ultrasonography of carotid arteries, m- mode, Doppler echocardiography (for left ventricular mass, ejection fraction, stroke volume and end-systolic stress, regional and segmental wall motion, % fractional shortening). 99 Continued
TABLE 5-1 Continued 100 Specimen Type and Study Name Design and How (year started) Sample General Purpose Collected Biomarkers Ascertained Later Life Resilience 135 older All participants Biological Blood pressure, heart rate, urinary Study (Ryff, Singer, women, ages took part in a prior data collected norepinephrine, epinephrine, and and Dienberg Love, 61-91, recruited 4-wave longitudinal through cortisol, glycosylated hemoglobin, 2004) from a prior study of community overnight visit total/HDL cholesterol, DHEAS, longitudinal relocation. to General salivary cortisol, waist/hip ratio, BMI. investigation Participants in the Clinical of move to biomarker study Research an assisted participated in a Center, living facility fifth wave of data including from personal collection, including blood, 12 hour residence in assessment of (overnight) Madison or biomarkers. urines and Milwaukee, WI saliva. (approximately half of the larger sample participated in biomarker substudy).
Womenâs Health WHAS I: cohort Longitudinal Home-based Fasted glucose, markers of and Aging Studies of women (n cohorts, followed specimen inflammation, growth factors (IGF- (WHAS) I and II. = 1,002) ages to elucidate factors collection. 1), genetic information (e.g., IL-6 WHAS I (Simonsick 65+ sampled associated with haplotype), antioxidants, ambulatory et al., 1997); WHAS to represent trajectories of ECG, resting 12-lead ECG, BP (resting, II (Fried et al., 2000) the one-third functional decline or ankle-arm), height, weight, grip most disabled lack thereof. strength, spirometry. Medicare enrollees from the Baltimore, MD, area (based on 12 zip code areas in eastern Baltimore and parts of Baltimore County). WHAS II = cohort of women, age s65+, sampled to represent the remaining two-thirds least disabled women in that age range. Continued 101
TABLE 5-1 Continued 102 Specimen Type and Study Name Design and How (year started) Sample General Purpose Collected Biomarkers Ascertained Swedish Adoption Population- Longitudinal, Blood samples Serum lipoproteins: total cholesterol, Twin Study of based subset currently in 7th were drawn total triglycerides, HDL cholesterol, Aging (SATSA) of 958 twin wave, questionnaires during in- LDL cholesterol, apolipoproteins 1984-present pairs from the on all and in- person testing A-1 and B, MaoB H pylori, metals, (Pedersen et al., Swedish Twin person testing (12-hour creatinine, gamma-glutamyltransferase 1991) Registry. The on a subsample. fasting) drawn (gamma-GT), potassium, sodium, urea sample includes Combines twin and on subsample and uric acid, creatinine, electrolytes, twins reared adoption design of twins at telomere length. Whole blood for DNA apart and a to study genetic central testing bank. Plasma at in-person testing matched sample and environmental sites or in occasion 3 for evaluation of a variety of twins reared influences affecting home. of coagulation factors. together. variation in normal aging. Origins of Variance Swedish 5-wave longitudinal Blood samples Albumin, calcium, total cholesterol, in the Oldest-Old: twins ages study, measurements for clinical HDL cholesterol, creatinine, gamma- Octogenarian Twins 80 and older. conducted at 2-year assessment glutamyltransferase (gamma-GT), (OCTO-Twin) 1991- Original sample intervals, to explore and DNA potassium, sodium, urea and uric acid, 2002 (McClearn et identified 351 the origins of extraction for creatinine, electrolytes, cobalamin, free al., 1997) pairs for the individuality in the molecular thyroxin, folic acid, prostate-specific first wave of in- oldest-old. genetic antigen (PSA), and thyroid-stimulating person testing. analyses. hormone (TSH), homocysteine. Collected in home.
Screening Across Pilot included Computer-assisted Blood samples Biological samples only collected the Lifespan Study a random telephone interview. collected at in pilot project include clinical (SALT) 1998-2002 sample of 2,000 Multidimensional local clinics. biochemistries, zygosity plus blood twins ages health, demography, stored for future analyses. Through 5-85. Followed health behaviors, recent efforts, DNA, serum, TG, HDL, by full-scale disease identification LDL, apoliproteins, glucose, HbA1C, screening of diagnostic items. and DNA collected on all pairs alive all twins born (goal 16,000 individuals, current at 1958 or earlier, 12,000). population- based. Men and Womenâs 486 unlike- 3 wave longitudinal Collected Whole blood, serum, DNA, lipids, Aging (GENDER) sexed twins study with measures during in- clinical panel. born 1906-1925, 1995-1997, 1999-2001, person testing population- and 2001-2005. in home. based. Study of Dementia Twins born in Cross-sectional, Collected in Whole blood, serum, plasma, DNA, in Swedish Twins or before 1935, 1998-2001. Genetic home. lipids, clinical panel. (HARMONY) (Gatz population- and environmental et al., 1997) based. factors for Alzheimer disease and other dementias. Diagnostic assessments for dementia, cognitive testing, and risk factor information. Three-year follow up for small subsample. NOTES: HDL = high-density lipoprotein; IL-6 = interleukin 6; DHEAS = dehydroepiandrosterone sulfate; ApoE = apolipoprotein E; LDL = low- density lipoprotein; ECG or EKG = electrocardiogram; EBCT = electron beam computed tomography; MRI = magnetic resonance imaging. 103
104 BIOSOCIAL SURVEYS Biomarkers in Community- or Population-Based Studies Scientists have long been interested in obtaining measures of biomark- ers 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 bio- logical samples. The impetus for the collection of biomarkers is to gain a better under- standing of the role of specific biological systems in health conditions, including an understanding of the role of biological systems in associa- tion with other sociodemographic, behavioral, pharmacological, psycho- social, and genetic contributions to health outcomes. There is a growing literature in the behavioral sciences literature linking social and behav- ioral 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 Enviï¿½ ronment (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, endo- crine, 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., func- tional 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
JENNIFER R. HARRIS, TARA L. GRUENEWALD, AND TERESA SEEMAN 105 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 chal- lenge 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 sub- groups 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 Womenâs 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 ânormalâ 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 bio- chemical blood tests. A study of clinical biochemical values in a popula- tion-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
106 BIOSOCIAL SURVEYS 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 associ- ated with risks for one or more common diseases of aging, such as car- diovascular 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 influ- ence routine biochemical values. Analyses of community-based studies, such as the MacArthur Study of Successful Aging, also point to potentially important age-related reduc- tions in risks associated with some biological factors (e.g., a reduction in the apparent risks associated with elevated total cholesterolâKarlamangla, 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 biomark- ers as high blood pressure, fasted glucose, low albumin, elevated creati- nine, and low forced vital capacity as significant, independent risk fac- tors 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)-Î± are associated cross-sectionally with the presence of sub- clinical or clinical cardiovascular disease (Cesari et al., 2003a), and the
JENNIFER R. HARRIS, TARA L. GRUENEWALD, AND TERESA SEEMAN 107 presence of peripheral artery disease (McDermott et al., 2005) and that high levels of IL-6, TNF-Î±, and C-reactive protein (CRP) also prospec- tively 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 âhigh-riskâ 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 Womenâs Health and Aging Studies (WHAS I and II) have yielded insights into relation- ships of novel and potentially modifiable biomarkers, such as serum sele- nium and carotenoids and mortalityâlow 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 choles- terol 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 psy- chiatric genetics (Gottesman and Gould, 2003). In polygenic systems, in which environmental influences also figure prominently, biomarkers often represent âdownstreamâ traits in the pathways between genes and a mea- sured behavior or outcome. Endophenotype-based strategies are becom- ing more common in gene detection studies, and it is critically important to recognize that many biomarkers are themselves complexly determined.
108 BIOSOCIAL SURVEYS 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. Develop- mental trends in lipid and apolioproteins have been described (e.g., early life, adolescence, menopause in women, and older age) and age-sex dif- ferences 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 contrib- uted to variation in total cholesterol levels. Most of the nongenetic varia- tion for the other biomarkers was explained by unique environmental factors. This research was expanded on in a further twin study using aug- mented data that included SATSA, the Screening Across the Lifespan Twin (SALT) pilot study, and the Men and Womenâs Aging (GENDER) study. Sex and age differences in lipid and apolipoprotein levels were investi- gated 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 vari- ance 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
JENNIFER R. HARRIS, TARA L. GRUENEWALD, AND TERESA SEEMAN 109 and environmental factors on cardiovascular risk factors in different coun- tries (see Iliadou and Sneider, 2004, for a review), illustrating that genetic influences differentially affect various risk factors. For example, heritabili- ties 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 mod- els 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 rela- tionships 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. Socioeconomic Status Although previous research has suggested that socioeconomic status (SES) is less strongly related to health outcomes at older ages (House et al., 1994), data from multiple population-based studies point to the con- tinued impact of lower SES on health risks in later life, including links to greater biological dysregulation in various major regulatory systems. Multiple studies based on data from the Health ABC Study have docu- mented relationships between indicators of SES and biomarkers and also provide evidence that lower SES confers a greater risk for poorer cogni- tive and physical functioning outcomes. Lower SES (assessed by levels of education, income, and assets) was associated with higher levels of CRP, TNF-Î±, and IL-6 (Koster et al., 2006). Behavioral factors, such as smoking, alcohol consumption, and obesity accounted for a greater proportion of these associations than prevalent disease (e.g., heart disease, diabetes). Lower SES participants were also at greater hazard of developing mobility disability (Koster et al., 2005a). Body mass index and an index of the number of inflammatory biomarkers (CRP, IL-6, TNF-Î±) for which participantsâ values were in the highest tertile were significant covariates in analyses, suggesting that these biomarkers may be important media- tors of relationships between SES and mobility disability.
110 BIOSOCIAL SURVEYS Lower SES has also been shown to predict the likelihood of cogni- tive decline in Health ABC participants (Koster et al., 2005b). Although a number of biomarkers were associated with both SES and cognitive decline in this investigation, biomarkers explained only a small portion of the relationship between SES and cognitive decline. Data from the MacArthur Study of Successful Aging document similar SES gradients in major biomarkers (lower SES being associated with increased prevalence of higher risk levels), with a significant, nega- tive gradient seen for a summary index of allostatic load (Seeman et al., 2004a). Analyses also indicate that these SES differences in allostatic load mediate 35 percent of the SES gradient in mortality (Seeman et al., 2004a). Parallel evidence for such SES gradients in cumulative biological risk has been reported from the Wisconsin Longitudinal Study (Singer and Ryff, 1999). And low levels of educational attainment were also shown to be associated with higher levels of allostatic load in the Normative Aging Study (NAS), with much of the association apparently mediated by higher levels of hostility (Kubzansky, Kawachi, and Sparrow, 1999). Recent anal- yses of NHANES III data also show consistent SES gradients in levels of biological risks with respect to blood pressure, cholesterol, metabolic profiles, and levels of inflammation (Seeman, Merkin, Crimmins, Koretz, and Karlamangla, no date). Social Engagement and Social Relationships A consistent body of evidence links greater social integration to bet- ter health and longevity (Seeman, 1996). A growing literature further indicates that health effects of social relationships persist importantly into older age, with evidence linking greater social integration or engagement to lower risks for cognitive decline (Bassuk, Glass, and Berkman, 1999; Seeman, Lusignolo, Albert, and Berkman, 2001a) and dementia (Frati- glioni, Wang, Ericsson, Maytan, and Winblad, 2000), as well as lower risks for physical disability (Seeman, Bruce, and McAvay, 1996) and greater longevity (Seeman, Kaplan, Knudsen, Cohen, and Guralnik, 1987; Seeman et al., 1993). More recently, attention has shifted to the identification of potential biological pathways through which social relationships affect health and aging. Greater social integration and higher levels of reported emotional support have been linked to lower levels of major stress hormones (e.g., cortisol, norepinephrine, epinephrine) among older men, with weaker and nonsignificant trends among women (Seeman, Berkman, Blazer, and Rowe, 1994), and similar findings have been reported more recently for patterns of association with IL-6 (Loucks, Berkman, Gruenewald, and Seeman, 2006). Examination of more cumulative measures of biological
JENNIFER R. HARRIS, TARA L. GRUENEWALD, AND TERESA SEEMAN 111 risk has yielded evidence of an inverse relationship between levels of positive social engagement and cumulative risk for both men and women (Seeman, Singer, Ryff, and Levy-Storms, 2002). Importantly, data on levels of social conflict point to the increased health risks associated with greater exposure to such interactions (see Burg and Seeman, 1994, for a review). Paralleling these earlier data, more recent data provide a growing body of evidence indicating that such negative social interactions are associated with heightened physiological activity and reactivity, resulting in significantly increased levels of biological risk (Seeman and McEwen, 1996; Taylor, Repetti, and Seeman, 1997; Seeman et al., 2002). These find- ings are consistent with the fact that man has evolved as a social animal. As such, it is not surprising that qualitative aspects of our social inter- actions should be associated with underlying and parallel patterns of physiological activation reflecting reduced versus heightened biological risk profiles. Psychological Factors The Later Life Resilience Study is another investigation that has focused on links between biomarkers and a number of social and psy- chological factors. Using a sample of women drawn from a larger study of the process of relocating to âsenior housing,â Ryff and colleagues (2006) examined biomarker correlates of positive and negative well-being in study participants to address the question of whether positive and nega- tive well-being are opposite sides of a single mental health continuum or whether these forms of well-being are separate and independent dimen- sions. They hypothesized that if positive and negative well-being are unique constructs, they should have distinct biomarker correlates, and this premise was largely supported by study findings. For example, salivary cortisol, norepinephrine, waist-hip ratio, HDL cholesterol, and total/HDL cholesterol showed significant associations with some measures of well-being (e.g., purpose in life, personal growth, perceived autonomy, positive affect, positive relations) but not with mea- sures of ill-being, while dehydroepiandrosterone sulfate (DHEAS) and systolic blood pressure showed significant associations with negative well-being (e.g., depressive symptoms, negative affect, trait anxiety, trait anger) but not positive well-being. Only two biomarkers, weight and glycosylated hemoglobin, showed significant associations with indicators of both positive and negative well-being. Other analyses have examined links between biomarkers and two dominant forms of positive well-being, eudaimonic (e.g., self-actualization, purpose in life) and hedonic (e.g., happiness, pleasure, satisfaction) well- being. A number of biomarkers, including salivary cortisol, urinary nor-
112 BIOSOCIAL SURVEYS epinephrine, the soluble receptor for IL-6, weight, waist-hip ratio, HDL cholesterol, total/HDL cholesterol, glycosylated hemoglobin, and indica- tors of better sleep quality were found to relate to scores on measures of eudaimonic well-being, while only HDL cholesterol was associated with hedonic well-being (Ryff et al., 2004). Women with more positive social relations have also been found to have lower levels of IL-6 and better sleep efficiency (Friedman et al., 2005). Interestingly, social relations and sleep quality showed an interaction in their association with IL-6, such that those with both poor social relations and sleep efficiency had the highest levels of IL-6, while those women with poor scores on only one measure showed more moderate levels. This finding suggests that social relationships and sleep may act to buffer one another for deficits in one domain in terms of potential impacts on inflam- matory activity. Evidence that poor sleep may be related to CVD risk, particularly in older people under chronic stress, has also been reported. Poor sleep, as measured using polysomnography, was associated with higher plasma IL-6 and procoagulant marker fibrin D-dimer in a study of older community-dwelling caregiver and noncaregiver adults, and these effects were more pronounced in caregivers of patients with Alzheimer disease (von Kanel et al., 2006). Data from the Normative Aging Study also point to the potential importance of hostility as a factor affecting patterns of biological risk as well as major health outcomes. For example, high hostility has been linked to high levels of insulin and triglycerides and low HDL levels, with much of these associations mediated by links between higher hostility and higher body mass index and waist-hip ratio (Niaura et al., 2000). As indi- cated earlier, high levels of hostility have also been found to be associated with high scores on an allostatic load index, which represented a sum- mary score of high-risk values on a range of cardiovascular, endocrine, and metabolic biomarkers (Kubzansky, Kawachi, and Sparrow, 1999). Investigations of NAS participants have also examined the interaction of both biological and psychosocial risk factors in the development of disease. For example, one investigation found that high levels of hostility and the presence of metabolic syndrome (high-risk scores on measures of triglycerides, glucose, HDL cholesterol, blood pressure, and body mass index [BMI]) independently predicted the likelihood of myocardial infarc- tion over a 14-year follow-up period, but the concomitant presence of both high hostility and metabolic syndrome was associated with the greatest risk for subsequent myocardial infarction (Todaro et al., 2005). Chronic stress has also been linked to a myriad of effects, includ- ing poor health, reduced immune function, premature aging, less robust responses to treatment, and earlier age of disease onset. Epel and col- leagues (2004) analyzed peripheral blood mononuclear cells in pre-
JENNIFER R. HARRIS, TARA L. GRUENEWALD, AND TERESA SEEMAN 113 menopausal women to investigate the relationship between life stressors (chronic caretaking of an ill child) and cellular aging. Although there was no relationship between caregiver status and the indices of cellular aging, results revealed that perceived stress and duration of stress were associ- ated with higher oxidative stress, lower telomerase activity, and shorter telomere length (TL), even after controlling for age. This research provides insight into potential mechanisms that link psychological stress to biologi- cal aging and suggests that perceived or chronic stress may play a role in premature senescence. Longitudinal research that tracks changes in telomere length in association with other psychosocial and health indices is needed to provide further insights into the factors affecting telomere shortening across the lifespan. Although this research is not based upon a community sample, measures of telomere length and telomerase activ- ity are becoming more common biomarkers in larger cohort studies. For example, in the MacArthur Study of Successful Aging, stored DNA has been used to assess telomere length, and analyses now under way are examining both relationships to subsequent health risks and predictors of TL. 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
114 BIOSOCIAL SURVEYS genetic research, and an increasing number of studies are interested in the localization and identification of functional genetic variants influenc- ing 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 iso- lation and loneliness are implicated in the pathogenesis of multiple dis- eases, 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 loneli- ness 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 chromo- some 12q23-24, and follow-up association tests showed significant asso- ciation 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 becom- ing 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, cog- nition, 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 com- plexly 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
JENNIFER R. HARRIS, TARA L. GRUENEWALD, AND TERESA SEEMAN 115 behavior is the 5â-promoter polymorphism of the serotonin transporter gene (5HTT). A wave of studies has explored interactions between func- tional polymorphisms of this gene with stressful life events and depres- sion. 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 sup- port, life events, and depressive symptoms. Results suggested that influ- ences 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 puta- tive 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 spe- cifically 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 trajec- tories 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 HeightsâInwood community of
116 BIOSOCIAL SURVEYS 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 environ- mental risk factors contribute to the increased risk of Alzheimer disease in blacks and Hispanics. A particularly exciting opportunity is offered by the growing avail- ability 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 poten- tially modifiable characteristics of individuals (or environments), may offer important insights regarding protective factors that can compensate for and reduce ultimate risks associated with particular genotypesâfac- tors 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 compa- rability in measures used to assess cognitive aging. Findings are nonethe- less 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 perfor- mance (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 nonde- mented elderly who were followed prospectively for six years using the cognitive abilities screening instrument. With their larger sample, analy- ses 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). Differ-
JENNIFER R. HARRIS, TARA L. GRUENEWALD, AND TERESA SEEMAN 117 ences 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 rela- tionship between ApoE status and risk for development of Alzheimer dis- ease. Census data were used to index socioeconomic risk based on a num- ber 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. Further- more, this study provided evidence of within-locus interactions (genetic dominance deviations) because memory performance among the het- erozygotes was better than among the noncarriers of the ApoE-4 allele. Finally, the rare del/del genotype of A2M was associated with a more
118 BIOSOCIAL SURVEYS 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 rela- tion to cognitive aging. Age-related loss of serotonin receptors 2A (5- HT2A) is associated with a loss in brain regions including the hippocam- pus 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 asso- ciations 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 sta- tus, 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 evi- dence linking early cognitive test performance to risks for Alzheimer
JENNIFER R. HARRIS, TARA L. GRUENEWALD, AND TERESA SEEMAN 119 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, peg- board, and putting-on-blouse tests for upper extremity function. Analy- ses 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 bio- logical processes thought to impact such performance, such as inflamma- tion or growth factors, has afforded important opportunities to examine the joint and independent contributions of performance abilities and bio- logical 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 nega- tive 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 lev- els of oxidized LDL (oxLDL) and IL-6 predict incident mobility disability, with those individuals with high levels of both biomarkers being at great- est 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 phys- ical activity and risks for functional decline. Data from the InChianti (Invecchiare in Chianti, meaning âaging in the Chianti areaâ) Study, a pro- spective investigation of over 1,000 community-dwelling French adults,
120 BIOSOCIAL SURVEYS indicate that compared with sedentary individuals, physically active men have lower fibrinogen, CRP, IL-6, and TNF-Î±, 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 bio- marker 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). Hemoglo- bin is found in red blood cells, which contain iron and are responsible for carrying oxygen to bodily tissues. Anemia or low blood hemoglobin lev- els 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 physi- cal 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 addi- tional 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 slow- ing 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 devel- oping 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 vari- ous physiological processes that appear to contribute to frailty, includ-
JENNIFER R. HARRIS, TARA L. GRUENEWALD, AND TERESA SEEMAN 121 ing 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 adjust- ments 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 oper- ational indices of allostatic load (AL)âthat 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 car- diovascular 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 demon- strated 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 pre- dicts subsequent mortality risk (Karlamangla, Singer, and Seeman, 2006). Stimulated by Singerâs 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 confirma- tion 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,
122 BIOSOCIAL SURVEYS 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 cardiovas- cular, 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 relation- ships between SES and levels of positive social engagement and a similar âcountâ 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 Chap- ter 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 examina- tion 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 investi- gation has been to incorporate consideration of genetic information in tracking the factors contributing to observed profiles of biological activ- ity. 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 mul- tiple traits) could explain the association between biomarkers. A series of studies from the Swedish twin projects have investigated the variance
JENNIFER R. HARRIS, TARA L. GRUENEWALD, AND TERESA SEEMAN 123 architecture explaining the clustering between biomarkers for cardiovas- cular disease. Genetic and environmental correlations among the follow- ing five serum lipid measuresâtotal cholesterol, HDL cholesterol, triglyc- erides, and apolipoproteins A-I and Bâwere 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 fac- tors 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 componentsâtriglycerides, insulin resistance, and HDL cholesterolâcould be explained by shared sources of individual environmental influences. These findings demon- strating 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 trajecto- ries 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
124 BIOSOCIAL SURVEYS for use in elucidating the complex pathways through which individualsâ life experiences and situations affect their health and aging and the bio- logical 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 trajec- tories. 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 bio- logical 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 col- laboration, 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 bio- markers for inclusion in these studies. These factors include at least three common and critical considerationsâtwo scientific and one logistical or financial. First, from a scientific standpoint, biomarkers were selected to include those needed to address primary substantive, scientific ques- tions 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 inves- tigators) 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 consider- ations that relate to issues of feasibility both with respect to require- ments for implementation of protocols to collect and process needed biospecimens and with financial considerations. Perhaps foremost are
JENNIFER R. HARRIS, TARA L. GRUENEWALD, AND TERESA SEEMAN 125 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 can- not 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 selec- tion 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. REFERENCES Antonelli-Incalzi, R., Pedone, C., McDermott, M.M., Bandinelli, S., Miniati, B., Lova, R.M., Lauretani, F., and Ferrucci, L. (2006). Association between nutrient intake and peripher- al artery disease: Results from the InCHIANTI study. Atherosclerosis, 186(1), 200-206. Bandeen-Roche, K., Xue, Q.L., Ferrucci, L., Walston, J., Guralnik, J.M., Chaves, P., Zeger, S.L., and Fried, L.P. (2006). Phenotype of frailty: Characterization in the Womenâs Health and Aging Studies. Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 61(3), 262-266. Bassuk, S.S., Glass, T.A., and Berkman, L.F. (1999). Social disengagement and incident cogni- tive decline in community-dwelling elderly persons. Annals of Internal Medicine, 131, 165-173. Bell, B., Rose, C.L., and Damon, A. (1972). The normative aging study: An interdisciplinary and longitudinal study of health and aging. Aging and Human Development, 3(1), 5-17.
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