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1.  Objective measurements of daily physical activity patterns and sedentary behaviour in older adults: Age, Gene/Environment Susceptibility-Reykjavik Study 
Age and Ageing  2012;42(2):222-229.
Background: objectively measured population physical activity (PA) data from older persons is lacking. The aim of this study was to describe free-living PA patterns and sedentary behaviours in Icelandic older men and women using accelerometer.
Methods: from April 2009 to June 2010, 579 AGESII-study participants aged 73–98 years wore an accelerometer (Actigraph GT3X) at the right hip for one complete week in the free-living settings.
Results: in all subjects, sedentary time was the largest component of the total wear time, 75%, followed by low-light PA, 21%. Moderate-vigorous PA (MVPA) was <1%. Men had slightly higher average total PA (counts × day−1) than women. The women spent more time in low-light PA but less time in sedentary PA and MVPA compared with men (P < 0.001). In persons <75 years of age, 60% of men and 34% of women had at least one bout ≥10 min of MVPA, which decreased with age, with only 25% of men and 9% of women 85 years and older reaching this.
Conclusion: sedentary time is high in this Icelandic cohort, which has high life-expectancy and is living north of 60° northern latitude.
PMCID: PMC3575120  PMID: 23117467
physical activity; accelerometry; sedentary behaviour; older adults; BMI; AGES-Reykjavik; older people
2.  Educational Attainment and Late Life Telomere Length in the Health, Aging and Body Composition Study 
Brain, behavior, and immunity  2012;27(1):15-21.
Morbidity and mortality are greater among socially disadvantaged racial/ethnic groups and those of lower socioeconomic status (SES). Greater chronic stress exposure in disadvantaged groups may contribute to this by accelerating cellular aging, indexed by shorter age-adjusted telomere length. While studies consistently relate shorter leukocyte telomere length (LTL) to stress, the few studies, mostly from the UK, examining associations of LTL with SES have been mixed. The current study examined associations between educational attainment and LTL among 2,599 high-functioning black and white adults age 70-79 from the Health, Aging and Body Composition Study. Multiple regression analyses tested associations of race/ethnicity, educational attainment and income with LTL, adjusting for potential confounders. Those with only a high school education had significantly shorter mean LTL (4806 basepairs) than those with post-high school education (4926 basepairs; B=125, SE= 47.6, p = .009). A significant interaction of race and education (B = 207.8, SE = 98.7, p = .035) revealed more beneficial effects of post-high school education for blacks than for whites. Smokers had shorter LTL than non-smokers, but the association of education and LTL remained significant when smoking was covaried (B = 119.7, SE = 47.6, p = .012). While higher income was associated with longer LTL, the effect was not significant (p > .10). This study provides the first demonstration of an association between educational attainment and LTL in a US population where higher education appears to have a protective effect against telomere shortening, particularly in blacks.
PMCID: PMC3543785  PMID: 22981835
Socioeconomic status; education; telomere length; race; health disparities
3.  Development of a questionnaire to assess sedentary time in older persons – a comparative study using accelerometry 
BMC Geriatrics  2013;13:80.
There is currently no validated questionnaire available to assess total sedentary time in older adults. Most studies only used TV viewing time as an indicator of sedentary time. The first aim of our study was to investigate the self-reported time spent by older persons on a set of sedentary activities, and to compare this with objective sedentary time measured by accelerometry. The second aim was to determine what set of self-reported sedentary activities should be used to validly rank people’s total sedentary time. Finally we tested the reliability of our newly developed questionnaire using the best performing set of sedentary activities.
The study sample included 83 men and women aged 65–92 y, a random sample of Longitudinal Aging Study Amsterdam participants, who completed a questionnaire including ten sedentary activities and wore an Actigraph GT3X accelerometer for 8 days. Spearman correlation coefficients were calculated to examine the association between self-reported time and objective sedentary time. The test-retest reliability was calculated using the intraclass correlation coefficient (ICC).
Mean total self-reported sedentary time was 10.4 (SD 3.5) h/d and was not significantly different from mean total objective sedentary time (10.2 (1.2) h/d, p = 0.63). Total self-reported sedentary time on an average day (sum of ten activities) correlated moderately (Spearman’s r = 0.35, p < 0.01) with total objective sedentary time. The correlation improved when using the sum of six activities (r = 0.46, p < 0.01), and was much higher than when using TV watching only (r = 0.22, p = 0.05). The test-retest reliability of the sum of six sedentary activities was 0.71 (95% CI 0.57-0.81).
A questionnaire including six sedentary activities was moderately associated with accelerometry-derived sedentary time and can be used to reliably rank sedentary time in older persons.
PMCID: PMC3733654  PMID: 23899190
Sedentary behavior; Accelerometry; Physical activity; Aging
4.  Socioeconomic factors from midlife predict mobility limitation and depressed mood three decades later; Findings from the AGES-Reykjavik Study 
BMC Public Health  2013;13:101.
Taking into account our rapidly ageing population, older people are of particular interest in studying health inequalities. Most studies of older persons only include measures of current socioeconomic status (SES) and do not take into account data from earlier stages of life. In addition, only classic SES measures are used, while alternative measures, such as car ownership and house ownership, might equally well predict health. The present study aims to examine the effect of midlife socioeconomic factors on mobility limitation and depressed mood three decades later.
Data were from 4,809 men and women aged 33–65 years who participated in the Reykjavik Study (1967–1992) and who were re-examined in old age in the Age, Gene/Environment Susceptibility (AGES) -Reykjavik Study (2002–2006).
Education and occupation predicted mobility limitation and depressed mood. Independently, home and car ownership and the availability of housing features predicted mobility limitation. Shortages of food in childhood and lack of a car in midlife predicted depressed mood.
Socioeconomic factors from midlife and from childhood affect mobility limitation and depressed mood in old age. Prevention of health problems in old age should begin as early as midlife.
PMCID: PMC3599346  PMID: 23379351
Socioeconomic status; Mobility limitation; Depressed mood; Midlife; Old age
5.  Racial Differences in Mortality in Older Adults: Factors Beyond Socioeconomic Status 
Little is known about the simultaneous effect of socioeconomic status (SES), psychosocial, and health-related factors on race differences in mortality in older adults.
This study examined the association between race and mortality and the role of SES, health insurance, psychosocial factors, behavioral factors, and health-related factors in explaining these differences.
Data consisted of 2,938 adults participating in the Health, Aging and Body Composition study. Mortality was assessed over 8 years.
SES differences accounted for 60% of the racial differences in all-cause mortality; behavioral factors and self-rated health further reduced the disparity. The racial differences in coronary heart disease mortality were completely explained by SES. Health insurance and behavioral factors accounted for some, but not all, of the race differences in cancer mortality.
Race-related risk factors for mortality may differ by the underlying cause of mortality.
PMCID: PMC3520064  PMID: 22180315
Race; SES; Behavior; Psychosocial; Mortality; Older adults; Aging
6.  Validation of an Armband to Measure Daily Energy Expenditure in Older Adults 
Objective methods to measure daily energy expenditure in studies of aging are needed. We sought to determine the accuracy of total energy expenditure (TEE) and activity energy expenditure (AEE) estimates from the SenseWear Pro armband (SWA) using software versions 6.1 (SWA 6.1) and 5.1 (SWA 5.1) relative to criterion methods in free-living older adults.
Participants (n = 19, mean age 82.0 years) wore a SWA for a mean ± SD 12.5 ± 1.1 days, including while sleeping. During this same period, criterion values for TEE were assessed with doubly labeled water and for resting metabolic rate (RMR) with indirect calorimetry. AEE was calculated as 0.9 TEE – RMR.
For TEE, there was no difference in mean ± SD values from doubly labeled water (2,040 ± 472 kcal/day) versus SWA 6.1 (2,012 ± 497 kcal/day, p = .593) or SWA 5.1 (2,066 ± 474 kcal/day, p = .606); individual values were highly correlated between methods (SWA 6.1 r = .893, p < .001; SWA 5.1 r = .901, p < .001) and demonstrated strong agreement (SWA 6.1 intraclass correlation coefficient = .896; SWA 5.1 intraclass correlation coefficient = .904). For AEE, mean values from SWA 6.1 (427 ± 304 kcal/day) were lower by 26.8% than criterion values (583 ± 242 kcal/day, p = .003), and mean values from SWA 5.1 (475 ± 299 kcal/day) were lower by 18.5% than criterion values (p = .021); however, individual values were highly correlated between methods (SWA 6.1 r = .760, p < .001; SWA 5.1 r = .786, p < .001) and demonstrated moderate agreement (SWA 6.1 intraclass correlation coefficient = .645; SWA 5.1 intraclass correlation coefficient = .720). Bland–Altman plots identified no systematic bias for TEE or AEE.
Acceptable levels of agreement were observed between SWA and criterion measurements of TEE and AEE in older adults.
PMCID: PMC3172563  PMID: 21734231
Accelerometer; Activity monitor; Physical activity; Aged; DLW
7.  Race, Socioeconomic Resources, and Late-Life Mobility and Decline: Findings From the Health, Aging, and Body Composition Study 
This study examines the relationship between race and mobility over 5 years in initially well-functioning older adults and evaluates how a broad set of socioeconomic status indicators affect this relationship.
Data were from 2,969 black and white participants aged 70–79 from the Health, Aging, and Body Composition study. Mobility parameters included self-reported capacity to walk a quarter mile and climb 10 steps and usual gait speed. Incident mobility limitation was defined as reported difficulty walking a quarter mile or climbing 10 steps at two consecutive semiannual assessments. Gait speed decline was defined as a 4% reduction in speed per year.
At baseline, even though all participants were free of mobility limitation, blacks had slower walking speed than their white counterparts, which was not explained by poverty, education, reading level, or income adequacy. After 5 years, accounting for age, site, and baseline mobility, blacks were more likely to develop mobility limitation than whites. Adjusting for prevalent conditions at baseline eliminated this difference in women; controlling for education eliminated this difference in men. No differences in gait speed decline were identified.
Higher rates of mobility loss observed in older blacks relative to older whites appear to be a function of both poorer initial mobility status and existing health conditions particularly for women. Education may also play a role especially for men.
PMCID: PMC3172564  PMID: 21743093
Race disparities—Functional limitations—SES—Disability
8.  Correlates of insulin resistance in older individuals with and without kidney disease 
Nephrology Dialysis Transplantation  2011;26(9):2814-2819.
Background. Chronic kidney disease (CKD) is associated with insulin resistance (IR). Prior studies have found that in individuals with CKD, leptin is associated with fat mass but resistin is not and the associations with adiponectin are conflicting. This suggests that the mechanism and factors associated with IR in CKD may differ.
Methods. Of the 2418 individuals without reported diabetes at baseline, participating in the Health, Aging and Body Composition study, a study in older individuals aged 70–79 years, 15.6% had CKD defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 based on cystatin C. IR was defined as the upper quartile of the homeostasis model assessment. The association of visceral and subcutaneous abdominal fat, percent body fat, muscle fat, lipids, inflammatory markers and adiponectin were tested with logistic regression. Interactions were checked to assess whether the factors associated with IR were different in those with and without CKD.
Results. Individuals with IR had a lower eGFR (80.7 ± 20.9 versus 75.6 ± 19.6, P < 0.001). After multivariable adjustment, eGFR (odds ratio per 10 mL/min/1.73m2 0.92, 95% confidence interval 0.87–0.98) and CKD (1.41, 1.04–1.92) remained independently associated with IR. In individuals with and without CKD, the significant predictors of IR were male sex, black race, higher visceral fat, abdominal subcutaneous fat and triglycerides. In individuals without CKD, IR was associated with lower high-density lipoprotein and current nonsmoking status in multivariate analysis. In contrast, among individuals with CKD, interleukin-6 (IL-6) was independently associated with IR. There was a significant interaction of eGFR with race and IL-6 with a trend for adionectin but no significant interactions with CKD (P > 0.1). In the fully adjusted model, there was a trend for an interaction with adiponectin for eGFR (P = 0.08) and significant for CKD (P = 0.04 ), where adiponectin was associated with IR in those without CKD but not in those with CKD.
Conclusions. In mainly Stage 3 CKD, kidney function is associated with IR; except for adiponectin, the correlates of IR are similar in those with and without CKD.
PMCID: PMC3203409  PMID: 21248294
chronic kidney disease; cystatin C; insulin resistance; subcutaneous fat
9.  Does the Amount of Fat Mass Predict Age-Related Loss of Lean Mass, Muscle Strength, and Muscle Quality in Older Adults? 
An excessive amount of adipose tissue may contribute to sarcopenia and may be one mechanism underlying accelerated loss of muscle mass and strength with aging. We therefore examined the association of baseline total body fat with changes in leg lean mass, muscle strength, and muscle quality over 7 years of follow-up and whether this link was explained by adipocytokines and insulin resistance.
Data were from 2,307 men and women, aged 70–79 years, participating in the Health, Aging, and Body Composition study. Total fat mass was acquired from dual energy X-ray absorptiometry. Leg lean mass was assessed by dual energy X-ray absorptiometry in Years 1, 2, 3, 4, 5, 6, and 8. Knee extension strength was measured by isokinetic dynamometer in Years 1, 2, 4, 6, and 8. Muscle quality was calculated as muscle strength divided by leg lean mass.
Every SD greater fat mass was related to 1.3 kg more leg lean mass at baseline in men and 1.5 kg in women (p < .01). Greater fat mass was also associated with a greater decline in leg lean mass in both men and women (0.02 kg/year, p < .01), which was not explained by higher levels of adipocytokines and insulin resistance. Larger fat mass was related to significantly greater muscle strength but significantly lower muscle quality at baseline (p < .01). No significant differences in decline of muscle strength and quality were found.
High fatness was associated with lower muscle quality, and it predicts accelerated loss of lean mass. Prevention of greater fatness in old age may decrease the loss of lean mass and maintain muscle quality and thereby reducing disability and mobility impairments.
PMCID: PMC3184893  PMID: 21572082
Adipose tissue; Muscle mass; Muscle strength; Obesity; Aging
10.  A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation 
Coviello, Andrea D. | Haring, Robin | Wellons, Melissa | Vaidya, Dhananjay | Lehtimäki, Terho | Keildson, Sarah | Lunetta, Kathryn L. | He, Chunyan | Fornage, Myriam | Lagou, Vasiliki | Mangino, Massimo | Onland-Moret, N. Charlotte | Chen, Brian | Eriksson, Joel | Garcia, Melissa | Liu, Yong Mei | Koster, Annemarie | Lohman, Kurt | Lyytikäinen, Leo-Pekka | Petersen, Ann-Kristin | Prescott, Jennifer | Stolk, Lisette | Vandenput, Liesbeth | Wood, Andrew R. | Zhuang, Wei Vivian | Ruokonen, Aimo | Hartikainen, Anna-Liisa | Pouta, Anneli | Bandinelli, Stefania | Biffar, Reiner | Brabant, Georg | Cox, David G. | Chen, Yuhui | Cummings, Steven | Ferrucci, Luigi | Gunter, Marc J. | Hankinson, Susan E. | Martikainen, Hannu | Hofman, Albert | Homuth, Georg | Illig, Thomas | Jansson, John-Olov | Johnson, Andrew D. | Karasik, David | Karlsson, Magnus | Kettunen, Johannes | Kiel, Douglas P. | Kraft, Peter | Liu, Jingmin | Ljunggren, Östen | Lorentzon, Mattias | Maggio, Marcello | Markus, Marcello R. P. | Mellström, Dan | Miljkovic, Iva | Mirel, Daniel | Nelson, Sarah | Morin Papunen, Laure | Peeters, Petra H. M. | Prokopenko, Inga | Raffel, Leslie | Reincke, Martin | Reiner, Alex P. | Rexrode, Kathryn | Rivadeneira, Fernando | Schwartz, Stephen M. | Siscovick, David | Soranzo, Nicole | Stöckl, Doris | Tworoger, Shelley | Uitterlinden, André G. | van Gils, Carla H. | Vasan, Ramachandran S. | Wichmann, H.-Erich | Zhai, Guangju | Bhasin, Shalender | Bidlingmaier, Martin | Chanock, Stephen J. | De Vivo, Immaculata | Harris, Tamara B. | Hunter, David J. | Kähönen, Mika | Liu, Simin | Ouyang, Pamela | Spector, Tim D. | van der Schouw, Yvonne T. | Viikari, Jorma | Wallaschofski, Henri | McCarthy, Mark I. | Frayling, Timothy M. | Murray, Anna | Franks, Steve | Järvelin, Marjo-Riitta | de Jong, Frank H. | Raitakari, Olli | Teumer, Alexander | Ohlsson, Claes | Murabito, Joanne M. | Perry, John R. B. | Gibson, Greg
PLoS Genetics  2012;8(7):e1002805.
Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10−106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10−11), GCKR (rs780093, 2p23.3, p = 2.2×10−16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10−09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10−35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10−08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10−12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10−14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10−14), LHCGR (rs10454142, 2p16.3, p = 1.3×10−07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10−08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10−06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10−08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
Author Summary
Sex hormone-binding globulin (SHBG) is the key protein responsible for binding and transporting the sex steroid hormones, testosterone and estradiol, in the circulatory system. SHBG regulates their bioavailability and therefore their effects in the body. SHBG has been linked to chronic diseases including type 2 diabetes and to hormone-sensitive cancers such as breast and prostate cancer. SHBG concentrations are approximately 50% heritable in family studies, suggesting SHBG concentrations are under significant genetic control; yet, little is known about the specific genes that influence SHBG. We conducted a large study of the association of SHBG concentrations with markers in the human genome in ∼22,000 white men and women to determine which loci influence SHBG concentrations. Genes near the identified genomic markers in addition to the SHBG protein coding gene included PRMT6, GCKR, ZBTB10, JMJD1C, SLCO1B1, NR2F2, ZNF652, TDGF3, LHCGR, BAIAP2L1, and UGT2B15. These genes represent a wide range of biologic pathways that may relate to SHBG function and sex steroid hormone biology, including liver function, lipid metabolism, carbohydrate metabolism and type 2 diabetes, and the development and progression of sex steroid hormone-responsive cancers.
PMCID: PMC3400553  PMID: 22829776
11.  Association of Sedentary Time with Mortality Independent of Moderate to Vigorous Physical Activity 
PLoS ONE  2012;7(6):e37696.
Sedentary behavior has emerged as a novel health risk factor independent of moderate to vigorous physical activity (MVPA). Previous studies have shown self-reported sedentary time to be associated with mortality; however, no studies have investigated the effect of objectively measured sedentary time on mortality independent of MVPA. The objective our study was to examine the association between objectively measured sedentary time and all-cause mortality.
7-day accelerometry data of 1906 participants aged 50 and over from the U.S. nationally representative National Health and Nutrition Examination Survey (NHANES) 2003–2004 were analyzed. All-cause mortality was assessed from the date of examination through December 31, 2006.
Over an average follow-up of 2.8 years, there were 145 deaths reported. In a model adjusted for sociodemographic factors, lifestyle factors, multiple morbidities, mobility limitation, and MVPA, participants in third quartile (hazard ratio (HR):4.05; 95%CI:1.55–10.60) and fourth quartile (HR:5.94; 95%CI: 2.49–14.15) of having higher percent sedentary time had a significantly increased risk of death compared to those in the lowest quartile.
Our study suggests that sedentary behavior is a risk factor for mortality independent of MVPA. Further investigation, including studies with longer follow-up, is needed to address the health consequences of sedentary behavior.
PMCID: PMC3374810  PMID: 22719846
12.  Lung Function and Risk for Heart Failure Among Older Adults 
The American journal of medicine  2011;124(4):334-341.
The impact of abnormal spirometric findings on risk for incident heart failure among older adults without clinically apparent lung disease is not well elucidated.
We evaluated the association of baseline lung function with incident heart failure, defined as first hospitalization for heart failure, in 2125 participants of the community-based Health, Aging, and Body Composition Study (age, 73.6±2.9 years; 50.5% men; 62.3% white; 37.7% black) without prevalent lung disease or heart failure. Abnormal lung function was defined either as forced vital capacity (FVC) or forced expiratory volume in 1st second (FEV1) to FVC ratio below lower limit of normal. Percent predicted FVC and FEV1 were also assessed as continuous variables.
During follow-up (median, 9.4years), heart failure developed in 68 of 350 (19.4%) participants with abnormal baseline lung function, as compared to 172 of 1775 (9.7%) participants with normal lung function (hazard ratio [HR], 2.31; 95% confidence interval [CI], 1.74-3.07; P<.001). This increased risk persisted after adjusting for previously identified heart failure risk factors in the Health ABC Study, body mass index, incident coronary heart disease, and inflammatory markers (HR, 1.83; 95% CI, 1.33-2.50; P<.001). Percent predicted (%) FVC and FEV1 had a linear association with heart failure risk (HR, 1.21; 95%CI, 1.11-1.32 and 1.18; 95%CI, 1.10-1.26, per 10% lower %FVC and %FEV1, respectively; both P<.001 in fully adjusted models). Findings were consistent in sex and race subgroups, and for heart failure with preserved or reduced ejection fraction.
Abnormal spirometric findings in older adults without clinical lung disease are associated with increased heart failure risk.
PMCID: PMC3073738  PMID: 21435424
Elderly; Epidemiology; Heart Failure; Pulmonary Function Test
13.  Association between Obesity History and Hand Grip Strength in Older Adults—Exploring the Roles of Inflammation and Insulin Resistance as Mediating Factors 
To examine the association between obesity history and hand grip strength, and whether the association is partly explained by subclinical inflammation and insulin resistance.
Data are from 2,021 men and women aged 55 years and older participating in the representative population-based Health 2000 Survey in Finland. Body mass and body height, maximal hand grip strength, C-reactive protein, and insulin resistance based on homeostasis model assessment (HOMA-IR) were measured in a health examination. Recalled weight at 20, 30, 40, and 50 years of age were recorded to obtain a hierarchical classification of obesity history. Obesity was defined as body mass index ≥ 30 kg/m2.
Earlier onset of obesity was associated with lower hand grip strength (p < .001) after controlling for age, sex, education, smoking, alcohol use, physical activity, several chronic diseases, and current body weight. Based on adjusted logistic regression models, the odds (95% confidence interval) for very low relative hand grip strength were 2.76 (1.78–4.28) for currently obese, 5.57 (3.02–10.28) for obese since age of 50 years, 6.53 (2.98–14.30) for obese since age of 40 years, and 10.36 (3.55–30.24) for obese since age of 30 years compared with never obese participants. The associations remained highly significant even after adjusting for current C-reactive protein and HOMA-IR, but these variables had only minor role in explaining the association between obesity history and hand grip strength.
Long-term exposure to obesity is associated with poor hand grip strength later in life. Maintaining healthy body weight throughout the life span may help to maintain adequate muscle strength in old age. Prospective studies with information on prior muscle strength are needed to examine in detail the causal association between obesity history and muscle strength.
PMCID: PMC3041473  PMID: 21310808
Muscle strength; Obesity; Inflammation; Insulin resistance; Aging
14.  Association of BMD and FRAX Score with Risk of Fracture in Older Adults with Type 2 Diabetes 
Jama  2011;305(21):2184-2192.
Type 2 diabetes is associated with higher bone density (BMD) and, paradoxically, with increased fracture risk. It is not known if low BMD, central to fracture prediction in older adults, identifies fracture risk in diabetic patients.
Determine if femoral neck (FN) BMD T-score and FRAX score are associated with fracture in older diabetic adults.
Three observational studies: Study of Osteoporotic Fractures, Osteoporotic Fractures in Men, and Health, Aging and Body Composition study.
Older community-dwelling adults in U.S.
9,449 women; 7,436 men.
Main outcome measure(s)
Self-reported incident fractures, verified by radiology reports.
Of 770 diabetic women, 84 experienced a hip and 262 a non-spine fracture during mean (SD) follow-up of 12.6 (5.3) years. Of 1,199 diabetic men, 32 experienced a hip and 133 a non-spine fracture during mean follow-up of 7.9 (2.5) years. Age-adjusted hazard ratios (HR) for one unit decrease in FN BMD T-score in diabetic women were 1.88 (95% confidence interval [CI], 1.43–2.48) for hip and 1.52 (95% CI, 1.31–1.75) for non-spine fracture. HRs in diabetic men were 5.71 (95% CI, 3.42–9.53) for hip and 2.17 (95% CI, 1.75–2.69) for non-spine fracture. FRAX score was also associated with fracture risk in diabetic participants. However, for a given T-score and age or FRAX score, diabetic participants had a higher fracture risk than those without diabetes. For a similar hip fracture risk, diabetic participants had a higher T-score than non-diabetic participants. The difference in T-score was 0.59 (95% CI, 0.31–0.87) for women and 0.38 (95% CI, 0.09–0.66) for men.
Among older adults with type 2 diabetes, FN BMD T-score and FRAX score were associated with hip and non-spine fracture risk. However, in these patients, compared with participants without diabetes, fracture risk was higher for a given T-score and age or a given FRAX score.
PMCID: PMC3287389  PMID: 21632482
15.  Is age-related decline in lean mass and physical function accelerated by Obstructive Lung Disease or smoking? 
Thorax  2011;66(11):961-969.
Background and aims
Cross-sectional studies suggest that Obstructive Lung Disease (OLD) and smoking affect lean mass and mobility. We aimed to investigate whether OLD and smoking accelerate aging-related decline in lean mass and physical functioning.
260 persons with OLD (FEV1 63±18 %predicted), 157 smoking controls (FEV1 95±16 %predicted), 866 formerly smoking controls (FEV1 100±16 %predicted) and 891 never-smoking controls (FEV1 104±17 %predicted) participating in the Health, Aging and Body Composition (ABC) Study were studied. At baseline, the mean age was 74±3 y and participants reported no functional limitations. Baseline and seven-year longitudinal data were investigated of body composition (by Dual-energy X-ray absorptiometry), muscle strength (by hand and leg dynamometry) and Short Physical Performance Battery (SPPB).
Compared to never-smoking controls, OLD persons and smoking controls had a significantly lower weight, fat mass, lean mass and bone mineral content (BMC) at baseline (p<0.05). While the loss of weight, fat mass, lean mass and strength was comparable between OLD persons and never-smoking controls, the SPPB declined 0.12 points/yr faster in OLD men (p=0.01) and BMC 4 g/yr faster in OLD women (p=0.02). In smoking controls, only lean mass declined 0.1 kg/yr faster in women (p=0.03) and BMC 8 g/yr faster in men (p=0.02) compared to never-smoking controls.
Initially well-functioning older adults with mild-to-moderate OLD and smokers without OLD have a comparable compromised baseline profile of body composition and physical functioning, while seven-year longitudinal trajectories are to a large extent comparable to those observed in never-smokers without OLD. This suggests a common insult earlier in life related to smoking. 3
PMCID: PMC3285455  PMID: 21724748
Obstructive Lung Disease; Body Composition; Aging
16.  Association of fitness with changes in body composition and muscle strength 
This study examined the association of physical fitness, as assessed by ability and time to complete a 400-meter walk, on changes in body composition and muscle strength over a subsequent 7-year period.
Prospective observational cohort study
Memphis, Tennessee and Pittsburgh, Pennsylvania
2,949 black and white men and women aged 70-79 participating in the Health, Aging and Body Composition (Health ABC) study.
Body composition (fat and bone-free lean mass) was assessed by dual-energy x-ray absorptiometry in years 1-6, and 8. Knee extension strength was measured with isokinetic dynamometry and grip strength with isometric dynamometry in years 1,2,4,6, and 8.
Compared to very fit men and women at baseline, less fit people had a higher weight, higher total percent fat, and lower total percent lean mass (p<0.01). Additionally, the least fit lost significantly more weight, fat mass, and lean mass over time compared to the very fit (p<0.01). Very fit people had the highest grip strength and knee extensor strength at baseline and follow-up; the decline in muscle strength was similar in every fitness group.
Low fitness in old age was associated with greater weight loss and loss of lean mass relative to having high fitness. Despite having lower muscle strength, the rate of decline in the least fit persons was similar to the most fit. In clinical practice, a long distance walk test as a measure of fitness might be useful to identify people at risk for these adverse health outcomes.
PMCID: PMC3272580  PMID: 20370856
body composition; aging; fitness; muscle strength; muscle mass
17.  Sedentary Activity Associated With Metabolic Syndrome Independent of Physical Activity 
Diabetes Care  2011;34(2):497-503.
This study examined the association between objectively measured sedentary activity and metabolic syndrome among older adults.
Data were from 1,367 men and women, aged ≥60 years who participated in the 2003–2006 National Health and Nutrition Examination Survey (NHANES). Sedentary time during waking hours was measured by an accelerometer (<100 counts per minute). A sedentary bout was defined as a period of time >5 min. A sedentary break was defined as an interruption in sedentary time (≥100 counts per minute). Metabolic syndrome was defined according to the Adult Treatment Panel (ATP) III criteria.
On average, people spent 9.5 h (65% of wear time) as sedentary. Compared with people without metabolic syndrome, people with metabolic syndrome spent a greater percentage of time as sedentary (67.3 vs. 62.2%), had longer average sedentary bouts (17.7 vs. 16.7 min), had lower intensity during sedentary time (14.8 vs. 15.8 average counts per minute), and had fewer sedentary breaks (82.3 vs. 86.7), adjusted for age and sex (all P < 0.01). A higher percentage of time sedentary and fewer sedentary breaks were associated with a significantly greater likelihood of metabolic syndrome after adjustment for age, sex, ethnicity, education, alcohol consumption, smoking, BMI, diabetes, heart disease, and physical activity. The association between intensity during sedentary time and metabolic syndrome was borderline significant.
The proportion of sedentary time was strongly related to metabolic risk, independent of physical activity. Current results suggest older people may benefit from reducing total sedentary time and avoiding prolonged periods of sedentary time by increasing the number of breaks during sedentary time.
PMCID: PMC3024375  PMID: 21270206
18.  Body Composition Measures from CT and Inflammation 
Obesity (Silver Spring, Md.)  2009;17(5):1062-1069.
A growing body of evidence has consistently shown a correlation between obesity and chronic sub-clinical inflammation. Several studies have suggested that measures of body fat distribution, rather than overall adiposity, may be more closely associated with inflammation level.
To investigate the relationship between levels of inflammatory markers and specific measures of abdominal visceral and subcutaneous fat and thigh intermuscular and subcutaneous fat of older white and black adults.
Data of 2,651 black and white men and women aged 70-79 participating in the Health, Aging and Body Composition (Health ABC) study were used. Levels of the inflammatory markers, IL-6, CRP, and TNF-α were obtained from blood samples. The areas of abdominal visceral and subcutaneous fat and thigh intermuscular and subcutaneous fat were quantified on CT images. Linear regression analysis was used to evaluate the cross-sectional relationship between each body composition measure and serum levels of inflammatory markers in the four race/gender groups.
Abdominal visceral adiposity was most consistently associated with significantly higher IL-6 and CRP levels in all race/gender groups (p<0.05). Thigh intermuscular fat had an inconsistent but significant association with inflammation, and there was a trend toward lower inflammation level with increasing thigh subcutaneous fat in white and black women.
Despite the previously established differences in abdominal fat distribution across gender and race, visceral fat remained a significant predictor of inflammatory marker level across all four subgroups examined.
PMCID: PMC3268118  PMID: 19165157
19.  Body fat distribution and inflammation among obese older adults with and without metabolic syndrome 
Obesity (Silver Spring, Md.)  2010;18(12):2354-2361.
The protective mechanisms by which some obese individuals escape the detrimental metabolic consequences of obesity are not understood. This study examined differences in body fat distribution and adipocytokines in obese older persons with and without metabolic syndrome. Additionally, we examined whether adipocytokines mediate the association between body fat distribution and metabolic syndrome. Data were from 729 obese men and women (BMI≥30kg/m2), aged 70-79 participating in the Health, Aging and Body Composition (Health ABC) study. Thirty-one percent of these obese men and women did not have metabolic syndrome. Obese persons with metabolic syndrome had significantly more abdominal visceral fat (men:p=0.04; women:p<0.01) and less thigh subcutaneous fat (men:p=0.09; women:p<0.01) than those without metabolic syndrome. Additionally, those with metabolic syndrome had significantly higher levels of IL-6, TNF-α and PAI-1 than individuals without metabolic syndrome. Per standard deviation (SD) higher in visceral fat, the likelihood of metabolic syndrome significantly increased in women (odds ratio (OR):2.16, 95% confidence interval (CI):1.59-2.94). In contrast, the likelihood of metabolic syndrome decreased in both men (OR:0.56, 95%CI:0.39-0.80) and women (OR:0.49, 95%CI:0.34-0.69) with each SD higher in thigh subcutaneous fat. These associations were partly mediated by adipocytokines; the association between thigh subcutaneous fat and metabolic syndrome was no longer significant in men. In summary, metabolically healthy obese older persons had a more favorable fat distribution, characterized by lower visceral fat and greater thigh subcutaneous fat and a more favorable inflammatory profile compared to their metabolically unhealthy obese counterparts.
PMCID: PMC3095947  PMID: 20395951
20.  Hospitalization and Change in Body Composition and Strength in a Population-Based Cohort of Older Persons 
To examine the association of hospitalization with annual changes in body composition and strength in older adults.
Design, Setting, & Participants
Participants in the Health, Aging and Body Composition study, a cohort study of well-functioning adults aged 70–79.
Hospitalizations were reported at annual clinic visits and semi-annual phone interviews. In the event of death or reported hospitalization, hospitalizations were adjudicated by medical record review. Dual x-ray absorptiometry (DXA) assessments of total, lean, and fat mass were conducted in six annual exams, and measures of knee extensor strength were conducted in two annual exams.
A total of 2309 hospitalizations were followed by DXA assessments. In men and women respectively, hospitalization in the previous year was associated with additional declines in total mass (−0.76 kg, −0.81 kg), fat mass (−0.41 kg, −0.54 kg) and lean mass (−0.33 kg, −0.25 kg) (p<.001 for all) relative to non-hospitalized participants, after adjustment for demographics and baseline values. Hospitalization was associated with strength declines in men (−4.02 Nm, p<0.05), but not in women. Relationships were similar adjusting for health behaviors and chronic conditions, although the association between hospitalization and strength was attenuated. Associations increased with number of days hospitalized; hospitalizations totaling ≥8 days in the previous year were associated with significantly greater loss of total, lean, and fat mass and loss of strength in both genders relative to non-hospitalized participants.
Hospitalization is associated with significant changes in body composition and strength in older persons. These effects appear particularly important among persons hospitalized for 8 or more days per year.
PMCID: PMC3059115  PMID: 21054288
lean mass; weight loss; function; hospitalization; strength
21.  Genetic Determinants of Serum Testosterone Concentrations in Men 
PLoS Genetics  2011;7(10):e1002313.
Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10−41 and rs6258, p = 2.3×10−22). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10−16). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.
Author Summary
Testosterone is the most important testicular androgen in men. Low serum testosterone concentrations are associated with cardiovascular morbidity, metabolic syndrome, type 2 diabetes mellitus, atherosclerosis, osteoporosis, sarcopenia, and increased mortality risk. Thus, there is growing evidence that serum testosterone is a valuable biomarker of men's overall health status. Studies in male twins indicate that there is a strong heritability of serum testosterone. Here we perform a large-scale genome-wide association study to examine the effects of common genetic variants on serum testosterone concentrations. By examining 14,429 men, we show that genetic variants in the sex hormone-binding globulin (SHBG) locus and on the X chromosome are associated with a substantial variation in serum testosterone concentrations and increased risk of low testosterone. The reported associations may now be used in order to better understand the functional background of recently identified disease associations related to low testosterone. Importantly, we identified the first known genetic variant, which affects SHBG's affinity for binding testosterone and the free testosterone fraction and could therefore influence the calculation of free testosterone. This finding suggests that individual-based SHBG-testosterone affinity constants are required depending on the genotype of this single-nucleotide polymorphism.
PMCID: PMC3188559  PMID: 21998597
22.  Adipocytokines and the metabolic syndrome among older persons with and without obesity - the InCHIANTI Study 
Clinical endocrinology  2010;73(1):55-65.
Adipose tissue-derived inflammation may contribute to metabolic alterations and eventually to the metabolic syndrome (MetS). The purpose of this study was to: 1) examine the role of adipocytokines in the association between obesity and the MetS; and 2) to determine whether the association is different in obese and non-obese persons.
Cross-sectional population-based InCHIANTI study.
944 community-dwelling adults aged 65 years and older living in Tuscany, Italy.
Obesity was defined as body mass index ≥ 30 kg/m2 and MetS as ≥ 3 of the ATP-III criteria. Circulating levels of CRP, IL-6, IL-1ra, IL-18, TNF-α R1, adiponectin, resistin, and leptin were measured. Additionally, insulin resistance was determined using the homeostasis model assessment (HOMA-IR).
The prevalence of the MetS was 32%. Both overall and abdominal obesity were significantly associated with the MetS after adjusting for inflammatory cytokines, adipokines and lifestyle factors. After adjusting for multiple confounders and HOMA-IR, IL-1ra, TNF-α R1 and adiponectin (p < 0.05) remained significantly associated with the MetS. Having multiple cytokines in the highest tertile increased the likelihood of having the MetS in both obese (p for trend 0.002) and non-obese persons (p for trend 0.001) independent of insulin resistance.
Non-obese and obese individuals who develop an intense pro-inflammatory state may be more prone to develop the MetS than those with lower levels of inflammation.
PMCID: PMC2888845  PMID: 19878507
adipocytokines; adiponectin; cytokines; inflammation; metabolic syndrome; obesity
23.  Associations of Visceral and Liver Fat with the Metabolic Syndrome across the Spectrum of Obesity: The AGES–Reykjavik Study 
Obesity (Silver Spring, Md.)  2010;19(6):1265-1271.
Visceral adipose tissue (VAT) is a key pathogenic fat depot in the metabolic syndrome (MetS), but liver fat (LF) may also play an important role. We evaluated associations of VAT and LF with MetS in normal weight, overweight, and obese men and women (BMI <25, 25-29.9, and ≥30 kg/m2, respectively). This analysis included 2495 participants from the AGES-Reykjavik Study with computed tomography measurements for VAT and LF. MetS was defined by ≥3 of the following: larger abdominal circumference, hypertension, elevated TG, low HDL, impaired fasting glucose, and microalbuminuria. We estimated the odds of MetS per 1-SD increase in VAT and LF, adjusting for key covariates. VAT was associated with an increased odds of MetS in normal weight, overweight, and obese women (OR=2.78, 1.63, and 1.43, respectively; all P<0.01) that diminished in magnitude with increasing BMI (VAT*BMI class interaction P<0.001). In men, VAT was related to MetS only among the overweight (OR=1.69, P<0.01). LF was associated with MetS in the overweight and obese groups in women (OR=1.38 and 1.45; both P<0.001) and in men (OR=1.38, P=0.01; and OR=1.27, P=0.10), but not in the normal weight groups. These BMI-specific relationships persisted when both fat depots were included in the model. VAT and LF were associated with MetS independently of each other, and these relationships were modified by BMI class such that, VAT was the more important depot at lower levels of obesity and LF at higher levels. Importantly, fatty liver may be a novel metabolic risk factor in overweight and obese individuals.
PMCID: PMC3081537  PMID: 21183935
24.  Waist Circumference as Compared with Body-Mass Index in Predicting Mortality from Specific Causes 
PLoS ONE  2011;6(4):e18582.
Whether waist circumference provides clinically meaningful information not delivered by body-mass index regarding prediction of cause-specific death is uncertain.
We prospectively examined waist circumference (WC) and body-mass index (BMI) in relation to cause-specific death in 225,712 U.S. women and men. Cox regression was used to estimate relative risks and 95% confidence intervals (CI). Statistical analyses were conducted using SAS version 9.1.
During follow-up from 1996 through 2005, we documented 20,977 deaths. Increased WC consistently predicted risk of death due to any cause as well as major causes of death, including deaths from cancer, cardiovascular disease, and non-cancer/non-cardiovascular diseases, independent of BMI, age, sex, race/ethnicity, smoking status, and alcohol intake. When WC and BMI were mutually adjusted in a model, WC was related to 1.37 fold increased risk of death from any cancer and 1.82 fold increase risk of death from cardiovascular disease, comparing the highest versus lowest WC categories. Importantly, WC, but not BMI showed statistically significant positive associations with deaths from lung cancer and chronic respiratory disease. Participants in the highest versus lowest WC category had a relative risk of death from lung cancer of 1.77 (95% CI, 1.41 to 2.23) and of death from chronic respiratory disease of 2.77 (95% CI, 1.95 to 3.95). In contrast, subjects in the highest versus lowest BMI category had a relative risk of death from lung cancer of 0.94 (95% CI, 0.75 to 1.17) and of death from chronic respiratory disease of 1.18 (95% CI, 0.89 to 1.56).
Increased abdominal fat measured by WC was related to a higher risk of deaths from major specific causes, including deaths from lung cancer and chronic respiratory disease, independent of BMI.
PMCID: PMC3082527  PMID: 21541313
25.  Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms 
PLoS Genetics  2011;7(4):e1002025.
Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands—yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10−36), SULT2A1 (rs2637125; p = 2.61×10−19), ARPC1A (rs740160; p = 1.56×10−16), TRIM4 (rs17277546; p = 4.50×10−11), BMF (rs7181230; p = 5.44×10−11), HHEX (rs2497306; p = 4.64×10−9), BCL2L11 (rs6738028; p = 1.72×10−8), and CYP2C9 (rs2185570; p = 2.29×10−8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
Author Summary
Dehydroepiandrosterone sulphate (DHEAS), mainly secreted by the adrenal gland, is the most abundant circulating steroid in humans. It shows a significant physiological decline after the age of 25 and diminishes about 95% by the age of 85 years, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. Twin- and family-based studies have shown that there is a substantial genetic effect with heritability estimate of 60%, but no specific genes regulating serum DHEAS concentration have been identified to date. Here we take advantage of recent technical and methodological advances to examine the effects of common genetic variants on serum DHEAS concentrations. By examining 14,846 Caucasian individuals, we show that eight common genetic variants are associated with serum DHEAS concentrations. Genes at or near these genetic variants include BCL2L11, ARPC1A, ZKSCAN5, TRIM4, HHEX, CYP2C9, BMF, and SULT2A1. These genes have various associations with steroid hormone metabolism—co-morbidities of ageing including type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins—suggesting a wider functional role for DHEAS than previously thought.
PMCID: PMC3077384  PMID: 21533175

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