Arun S. Karlamangla

Allostatic load as a predictor of functional decline: MacArthur studies of successful aging

Allostatic load has been proposed as a cumulative measure of dysregulation across multiple physiological systems, and has been postulated to impact health risks. In the allostatic load model, increased risk is hypothesized to result not only from large and clinically significant dysregulation in individual systems, but also from more modest dysregulation, if present in multiple systems. Our objective was to construct an allostatic load score by optimally combining several physiologic measurements, and to examine its association with future functional decline. We analyzed data from a 7-year longitudinal study of a community-based cohort, whose age at baseline was between 70 and 79 years. Canonical correlation analysis was used to study the association of 10 biological measurements representing allostatic load with declines in scores on five tests each of physical and cognitive function over two follow-up periods: 1998-1991 and 1991-1995. We used bootstrapping to evaluate the stability of the canonical correlation and canonical weights. The canonical correlation between allostatic load and the 20 decline scores was 0.43 (P =.03) and the [25th, 75th] percentile interval of its distribution over 200 bootstrapped subsamples of the cohort was [0.48, 0.53]. These findings were not substantially affected by adjusting for covariates and cardiovascular disease. We conclude that a summary measure of physiologic dysregulation, such as allostatic load, is an independent predictor of functional decline in elderly men and women.

Socio-economic differentials in peripheral biology: cumulative allostatic load.

This chapter focuses on evidence linking socio‐economic status (SES) to “downstream” peripheral biology. Drawing on the concept of allostatic load, we examine evidence linking lower SES with greater cumulative physiological toll on multiple major biological regulatory systems over the life course. We begin by reviewing evidence linking lower SES to poorer trajectories of aging in multiple, individual physiological systems, followed by evidence of the resulting cumulative, overall burdens of physiological dysregulation seen among those of lower SES. The role of cumulative physiological dysregulation in mediating SES gradients in morbidity and mortality is then examined. We conclude with discussion of the question of interactions between SES (and other such environmental factors) and genetic endowment, and their potential consequences for patterns of physiological activity—an area of research that appears poised to contribute significantly to our understanding of how social conditions “get under the skin” to affect health and aging.

Relative Muscle Mass Is Inversely Associated with Insulin Resistance and Prediabetes. Findings from The Third National Health and Nutrition Examination Survey

CONTEXT Insulin resistance, the basis of type 2 diabetes, is rapidly increasing in prevalence; very low muscle mass is a risk factor for insulin resistance. OBJECTIVE The aim was to determine whether increases in muscle mass at average and above average levels are associated with improved glucose regulation. DESIGN We conducted a cross-sectional analysis of National Health and Nutrition Examination Survey III data. PARTICIPANTS Data from 13,644 subjects in a national study were evaluated. OUTCOME MEASUREMENTS We measured homeostasis model assessment of insulin resistance (HOMA-IR), blood glycosylated hemoglobin level, prevalence of transitional/pre- or overt diabetes (PDM), and prevalence of overt diabetes mellitus. RESULTS All four outcomes decreased from the lowest quartile to the highest quartile of skeletal muscle index (SMI), the ratio of total skeletal muscle mass (estimated by bioelectrical impedance) to total body weight. After adjusting for age, ethnicity, sex, and generalized and central obesity, each 10% increase in SMI was associated with 11% relative reduction in HOMA-IR (95% confidence interval, 6-15%) and 12% relative reduction in PDM prevalence (95% CI, 1-21%). In nondiabetics, SMI associations with HOMA-IR and PDM prevalence were stronger. CONCLUSIONS Across the full range, higher muscle mass (relative to body size) is associated with better insulin sensitivity and lower risk of PDM. Further research is needed to examine the effect of appropriate exercise interventions designed to increase muscle mass on incidence of diabetes.

Disability trends among older Americans: National Health and Nutrition Examination Surveys, 1988-1994 and 1999-2004.

OBJECTIVES We investigated trends in disability among older Americans from 1988 through 2004 to test the hypothesis that more recent cohorts show increased burdens of disability. METHODS We used data from 2 National Health and Nutrition Examination Surveys (1988-1994 and 1999-2004) to assess time trends in basic activities of daily living, instrumental activities, mobility, and functional limitations for adults aged 60 years and older. We assessed whether changes could be explained by sociodemographic, body weight, or behavioral factors. RESULTS With the exception of functional limitations, significant increases in each type of disability were seen over time among respondents aged 60 to 69 years, independent of sociodemographic characteristics, health status, relative weight, and health behaviors. Significantly greater increases occurred among non-Whites and persons who were obese or overweight (2 of the fastest-growing subgroups within this population). We detected no significant trends among respondents aged 70 to 79 years; in the oldest group (aged>or=80 years), time trends suggested lower prevalence of functional limitations among more recent cohorts. CONCLUSIONS Our results have significant and sobering implications: older Americans face increased disability, and society faces increased costs to meet the health care needs of these disabled Americans.

Sarcopenia Exacerbates Obesity-Associated Insulin Resistance and Dysglycemia: Findings from the National Health and Nutrition Examination Survey III

Background Sarcopenia often co-exists with obesity, and may have additive effects on insulin resistance. Sarcopenic obese individuals could be at increased risk for type 2 diabetes. We performed a study to determine whether sarcopenia is associated with impairment in insulin sensitivity and glucose homeostasis in obese and non-obese individuals. Methodology We performed a cross-sectional analysis of National Health and Nutrition Examination Survey III data utilizing subjects of 20 years or older, non-pregnant (N = 14,528). Sarcopenia was identified from bioelectrical impedance measurement of muscle mass. Obesity was identified from body mass index. Outcomes were homeostasis model assessment of insulin resistance (HOMA IR), glycosylated hemoglobin level (HbA1C), and prevalence of pre-diabetes (6.0≤ HbA1C<6.5 and not on medication) and type 2 diabetes. Covariates in multiple regression were age, educational level, ethnicity and sex. Principal Findings Sarcopenia was associated with insulin resistance in non-obese (HOMA IR ratio 1.39, 95% confidence interval (CI) 1.26 to 1.52) and obese individuals (HOMA-IR ratio 1.16, 95% CI 1.12 to 1.18). Sarcopenia was associated with dysglycemia in obese individuals (HbA1C ratio 1.021, 95% CI 1.011 to 1.043) but not in non-obese individuals. Associations were stronger in those under 60 years of age. We acknowledge that the cross-sectional study design limits our ability to draw causal inferences. Conclusions Sarcopenia, independent of obesity, is associated with adverse glucose metabolism, and the association is strongest in individuals under 60 years of age, which suggests that low muscle mass may be an early predictor of diabetes susceptibility. Given the increasing prevalence of obesity, further research is urgently needed to develop interventions to prevent sarcopenic obesity and its metabolic consequences.

Hispanic Paradox in Biological Risk Profiles

OBJECTIVES We examined biological risk profiles by race, ethnicity, and nativity to evaluate evidence for a Hispanic paradox in measured health indicators. METHODS We used data on adults aged 40 years and older (n = 4206) from the National Health and Nutrition Examination Surveys (1999-2002) to compare blood pressure, metabolic, and inflammatory risk profiles for Whites, Blacks, US-born and foreign-born Hispanics, and Hispanics of Mexican origin. We controlled for age, gender, and socioeconomic status. RESULTS Hispanics have more risk factors above clinical risk levels than do Whites but fewer than Blacks. Differences between Hispanics and Whites disappeared after we controlled for socioeconomic status, but results differed by nativity. After we controlled for socioeconomic status, the differences between foreign-born Hispanics and Whites were eliminated, but US-born Mexican Americans still had higher biological risk scores than did both Whites and foreign-born Mexican Americans. CONCLUSIONS There is no Hispanic paradox in biological risk profiles. However, our finding that foreign-born Hispanics and Whites had similar biological risk profiles, but US-born Mexican Americans had higher risk, was consistent with hypothesized effects of migrant health selectivity (healthy people in-migrating and unhealthy people out-migrating) as well as some differences in health behaviors between US-born and foreign-born Hispanics.

Longitudinal Patterns and Predictors of Alcohol Consumption in the United States

OBJECTIVES We examined demographic predictors of longitudinal patterns in alcohol consumption. METHODS We used mixed-effects models to describe individual alcohol consumption and change in consumption with age, as well as the associations between consumption and birth year, national alcohol consumption, and demographic factors, among 14 105 adults from the National Health and Nutrition Examination Survey I Epidemiologic Follow-Up Study. RESULTS Alcohol consumption declined with increasing age, and individual consumption mirrored national consumption. Higher consumption was associated with male gender, being White, being married, having a higher educational level, having a higher income, being employed, and being a smoker. Faster age-related decline in consumption was associated with earlier cohorts, being male, being married, having a lower educational level, and being a smoker. CONCLUSIONS Compared with alcohol consumption among earlier cohorts, that among recent cohorts declined more slowly with increasing age, suggesting that negative health effects of alcohol could increase in the future.

Reduction in allostatic load in older adults is associated with lower all-cause mortality risk: MacArthur studies of successful aging.

Objectives: To study the association between change in allostatic load (a risk score constructed from multiple biological markers) over a 2.5-year period and mortality in the following 4.5 years in older adults. Methods: We measured 10 physiologic parameters at baseline (1988) in a cohort of 171 high-functioning, community-dwelling, 70- to 79-year-old adults. These measurements were repeated 2.5 years later, in 1991. Summary allostatic load scores for 1988 and 1991 were created as the weighted sum of the 10 biological markers and their second-order terms. Mortality status (alive or dead) for participants was determined 4.5 years later, in 1995. The association between change in allostatic load score (1988–1991) and subsequent mortality (1991–1995) was studied using logistic regression. Results: Compared with participants whose allostatic load score decreased between 1988 and 1991, individuals whose allostatic load score increased had higher risk of all-cause mortality between 1991 and 1995 (15% versus 5%, p = .047). Adjusted for age and baseline allostatic load, each unit increment in the allostatic load change score was associated with mortality odds ratio of 3.3 (95% confidence interval, 1.1–9.8). Conclusion: Our results suggest that even in older ages, change in risk scores can be followed to improve assessment of mortality risk. DHEA-S = dehydroepiandosterone sulfate; HDL = high-density lipoprotein; CVD = cardiovascular disease; ROC = receiver operating curve.

Combinations of biomarkers predictive of later life mortality

A wide range of biomarkers, reflecting activity in a number of biological systems (e.g., neuroendocrine, immune, cardiovascular, and metabolic), have been found to prospectively predict disability, morbidity, and mortality outcomes in older adult populations. Levels of these biomarkers, singly or in combination, may serve as an early warning system of risk for future adverse health outcomes. In the current investigation, 13 biomarkers were examined as predictors of mortality occurrence over a 12-year period in a sample of men and women (n = 1,189) 70–79 years of age at enrollment into the study. Biomarkers examined in analyses included markers of neuroendocrine functioning (epinephrine, norepinephrine, cortisol, and dehydroepiandrosterone), immune activity (C-reactive protein, fibrinogen, IL-6, and albumin), cardiovascular functioning (systolic and diastolic blood pressure), and metabolic activity [high-density lipoprotein (HDL) cholesterol, total to HDL cholesterol ratio, and glycosylated hemoglobin]. Recursive partitioning techniques were used to identify a set of pathways, composed of combinations of different biomarkers, that were associated with a high-risk of mortality over the 12-year period. Of the 13 biomarkers examined, almost all entered into one or more high-risk pathways although combinations of neuroendocrine and immune markers appeared frequently in high-risk male pathways, and systolic blood pressure was present in combination with other biomarkers in all high-risk female pathways. These findings illustrate the utility of recursive partitioning techniques in identifying biomarker combinations predictive of mortal outcomes in older adults, as well as the multiplicity of biological pathways to mortality in elderly populations.

History of socioeconomic disadvantage and allostatic load in later life.

There is a growing interest in understanding how the experience of socioeconomic status (SES) adversity across the life course may accumulate to negatively affect the functioning of biological regulatory systems important to functioning and health in later adulthood. The goal of the present analyses was to examine whether greater life course SES adversity experience would be associated with higher scores on a multi-system allostatic load (AL) index of physiological function in adulthood. Data for these analyses are from 1008 participants (92.2% White) from the Biomarker Substudy of the Study of Midlife in the US (MIDUS). Multiple indicators of SES adversity in childhood (parent educational attainment, welfare status, financial situation) and two points in adulthood (educational attainment, household income, difficulty paying bills, availability of money to meet basic needs, current financial situation) were used to construct SES adversity measures for each life course phase. An AL score was constructed using information on 24 biomarkers from 7 different physiological systems (sympathetic and parasympathetic nervous systems, hypothalamic-pituitary-adrenal axis, cardiovascular, lipid metabolism, glucose metabolism, inflammatory immune activity). Analyses indicate higher AL as a function of greater SES adversity at each phase of, and cumulatively across, the life course. Associations were only moderately attenuated when accounting for a wide array of health status, behavioral and psychosocial factors. Findings suggest that SES adversity experience may cumulate across the life course to have a negative impact on multiple biological systems in adulthood. An important aim of future research is the replication of current findings in this predominantly White sample in more ethnically diverse populations.