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1.  Lower Extremity Muscle Function After Strength or Power Training in Older Adults 
It is unclear whether strength training (ST) or power training (PT) is the more effective intervention at improving muscle strength and power and physical function in older adults. The authors compared the effects of lower extremity PT with those of ST on muscle strength and power in 45 older adults (74.8 ± 5.7 yr) with self-reported difficulty in common daily activities. Participants were randomized to 1 of 3 treatment groups: PT, ST, or wait-list control. PT and ST trained 3 times/wk for 12 wk using knee-extension (KE) and leg-press (LP) machines at ~70% of 1-repetition maximum (1RM). For PT, the concentric phase of the KE and LP was completed “as fast as possible,” whereas for ST the concentric phase was 2–3 s. Both PT and ST paused briefly at the midpoint of the movement and completed the eccentric phase of the movement in 2–3 s. PT and ST groups showed significant improvements in KE and LP 1RM compared with the control group. Maximum KE and LP power increased approximately twofold in PT compared with ST. At 12 wk, compared with control, maximum KE and LP power were significantly increased for the PT group but not for the ST group. In older adults with compromised function, PT leads to similar increases in strength and larger increases in power than ST.
PMCID: PMC4318571  PMID: 19940322
aging; resistance training; disability; physical function
2.  Adipose Tissue Density, a Novel Biomarker Predicting Mortality Risk in Older Adults 
Knowledge of adipose composition in relation to mortality may help delineate inconsistent relationships between obesity and mortality in old age. We evaluated relationships between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density, mortality, biomarkers, and characteristics.
VAT and SAT density were determined from computed tomography scans in persons aged 65 and older, Health ABC (n = 2,735) and AGES-Reykjavik (n = 5,131), and 24 nonhuman primates (NHPs). Associations between adipose density and mortality (4–13 years follow-up) were assessed with Cox proportional hazards models. In NHPs, adipose density was related to serum markers and tissue characteristics.
Higher density adipose tissue was associated with mortality in both studies with adjustment for risk factors including adipose area, total fat, and body mass index. In women, hazard ratio and 95% CI for the densest quintile (Q5) versus least dense (Q1) for VAT density were 1.95 (1.36–2.80; Health ABC) and 1.88 (1.31–2.69; AGES-Reykjavik) and for SAT density, 1.76 (1.35–2.28; Health ABC) and 1.56 (1.15–2.11; AGES-Reykjavik). In men, VAT density was associated with mortality in Health ABC, 1.52 (1.12–2.08), whereas SAT density was associated with mortality in both Health ABC, 1.58 (1.21–2.07), and AGES-Reykjavik, 1.43 (1.07–1.91). Higher density adipose tissue was associated with smaller adipocytes in NHPs. There were no consistent associations with inflammation in any group. Higher density adipose tissue was associated with lower serum leptin in Health ABC and NHPs, lower leptin mRNA expression in NHPs, and higher serum adiponectin in Health ABC and NHPs.
VAT and SAT density provide a unique marker of mortality risk that does not appear to be inflammation related.
PMCID: PMC3859360  PMID: 23707956
Obesity; Aging; Leptin; Adiponectin.
3.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | O’Connor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
PMCID: PMC4140093  PMID: 24929828
4.  Soluble Tumor Necrosis Factor Receptors and Heart Failure Risk in Older Adults: The Health, Aging, and Body Composition Study 
Circulation. Heart failure  2013;7(1):5-11.
Tumor necrosis factor (TNF) levels are associated with risk for heart failure (HF). The soluble TNF type-1 (sTNF-R1) and type-2 (sTNF-R2) receptors are elevated in patients with manifest HF, but whether they are associated with risk for incident HF is unclear.
Methods and Results
Using Cox proportional hazard models, we examined the association between baseline levels of sTNF-R1 and sTNF-R2 with incident HF risk among 1285 participants of the Health, Aging, and Body Composition Study (age 74.0±2.9 years; 51.4% women; 41.1% black). At baseline, median (interquartile range) of TNF, sTNF-R1, and sTNF R2 levels were 3.14 (2.42-4.06) pg/ml, 1.46 (1.25-1.76) ng/ml, and 3.43 (2.95-4.02) ng/ml, respectively. During a median follow-up of 11.4 (6.9, 11.7) years, 233 (18.1%) participants developed HF. In models controlling for other HF risk factors, TNF (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.02-1.61 per log2 increase), and sTNF-R1 (HR, 1.68; 95%CI, 1.15-2.46 per log2 increase), but not sTNF-R2 (HR, 1.15; 95%CI, 0.80-1.63 per log2 increase), were associated with a higher risk for HF. These associations were consistent across whites and blacks (TNF, sTNF-R1, sTNF-R2, interaction P=0.531, 0.091 and 0.795, respectively), and in both genders (TNF, sTNF-R1, sTNF-R2, interaction P=0.491, 0.672 and 0.999, respectively). TNF-R1 was associated with a higher risk for HF with preserved versus reduced ejection fraction (HR, 1.81; 95%CI, 1.03, 3.18; P=0.038 for preserved vs. HR, 0.90; 95%CI, 0.56, 1.44; P=0.667 for reduced ejection fraction, interaction P=0.05).
In older adults, elevated levels of sTNF-R1 are associated with an increased risk for incident HF. However, addition of TNF-R1 to the previously validated Health ABC HF risk model did not demonstrate material improvement in net discrimination or reclassification.
PMCID: PMC3990649  PMID: 24323631
heart failure; tumor necrosis factor; inflammation
5.  Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE Study randomized clinical trial 
JAMA  2014;311(23):2387-2396.
In older adults reduced mobility is common and is an independent risk factor for morbidity, hospitalization, disability, and mortality. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining if physical activity prevents or delays mobility disability.
To test the hypothesis that a long-term structured physical activity program is more effective than a health education program (also referred to as a successful aging program) in reducing the risk of major mobility disability.
Design, Setting, and Participants
The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial that enrolled participants between February 2010 and December 2011, who participated for an average of 2.6 years. Follow-up ended in December 2013. Outcome assessors were blinded to the intervention assignment. Participants were recruited from urban, suburban and rural communities at 8 field centers throughout the US. We randomized a volunteer sample of 1,635 sedentary men and women aged 70–89 years who had physical limitations, defined as a score on the Short Physical Performance Battery of 9 or below, but were able to walk 400 m.
Participants were randomized to a structured moderate intensity physical activity program (n=818) done in a center and at home that included including aerobic, resistance and flexibility training activities or to a health education program (n=817) consisting of workshops on topics relevant to older adults and upper extremity stretching exercises.
Main Outcomes and Measures
The primary outcome was major mobility disability objectively defined by loss of ability to walk 400 m.
Incident major mobility disability occurred in 30.1% (n=246/818) of physical activity and 35.5% (n=290/817) of health education participants (HR=0.82, 95%CI=0.69–0.98, p=0.03). Persistent mobility disability was experienced by 120/818 (14.7%) physical activity and 162/817 (19.8%) health education participants (HR=0.72; 95%CI=0.57–0.91; p=0.006). Serious adverse events were reported by 404/818 (49.4%) of the physical activity and 373/817 (45.7%) of the health education participants (Risk Ratio=1.08; 95%CI=0.98–1.20).
Conclusions and Relevance
A structured moderate intensity physical activity program, compared with a health education program, reduced major mobility disability over 2.6 years among older adults at risk of disability. These findings suggest mobility benefit from such a program in vulnerable older adults.
Registration identifier NCT01072500.
PMCID: PMC4266388  PMID: 24866862
6.  Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins 
Postmus, Iris | Trompet, Stella | Deshmukh, Harshal A. | Barnes, Michael R. | Li, Xiaohui | Warren, Helen R. | Chasman, Daniel I. | Zhou, Kaixin | Arsenault, Benoit J. | Donnelly, Louise A. | Wiggins, Kerri L. | Avery, Christy L. | Griffin, Paula | Feng, QiPing | Taylor, Kent D. | Li, Guo | Evans, Daniel S. | Smith, Albert V. | de Keyser, Catherine E. | Johnson, Andrew D. | de Craen, Anton J. M. | Stott, David J. | Buckley, Brendan M. | Ford, Ian | Westendorp, Rudi G. J. | Eline Slagboom, P. | Sattar, Naveed | Munroe, Patricia B. | Sever, Peter | Poulter, Neil | Stanton, Alice | Shields, Denis C. | O’Brien, Eoin | Shaw-Hawkins, Sue | Ida Chen, Y.-D. | Nickerson, Deborah A. | Smith, Joshua D. | Pierre Dubé, Marie | Matthijs Boekholdt, S. | Kees Hovingh, G. | Kastelein, John J. P. | McKeigue, Paul M. | Betteridge, John | Neil, Andrew | Durrington, Paul N. | Doney, Alex | Carr, Fiona | Morris, Andrew | McCarthy, Mark I. | Groop, Leif | Ahlqvist, Emma | Bis, Joshua C. | Rice, Kenneth | Smith, Nicholas L. | Lumley, Thomas | Whitsel, Eric A. | Stürmer, Til | Boerwinkle, Eric | Ngwa, Julius S. | O’Donnell, Christopher J. | Vasan, Ramachandran S. | Wei, Wei-Qi | Wilke, Russell A. | Liu, Ching-Ti | Sun, Fangui | Guo, Xiuqing | Heckbert, Susan R | Post, Wendy | Sotoodehnia, Nona | Arnold, Alice M. | Stafford, Jeanette M. | Ding, Jingzhong | Herrington, David M. | Kritchevsky, Stephen B. | Eiriksdottir, Gudny | Launer, Leonore J. | Harris, Tamara B. | Chu, Audrey Y. | Giulianini, Franco | MacFadyen, Jean G. | Barratt, Bryan J. | Nyberg, Fredrik | Stricker, Bruno H. | Uitterlinden, André G. | Hofman, Albert | Rivadeneira, Fernando | Emilsson, Valur | Franco, Oscar H. | Ridker, Paul M. | Gudnason, Vilmundur | Liu, Yongmei | Denny, Joshua C. | Ballantyne, Christie M. | Rotter, Jerome I. | Adrienne Cupples, L. | Psaty, Bruce M. | Palmer, Colin N. A. | Tardif, Jean-Claude | Colhoun, Helen M. | Hitman, Graham | Krauss, Ronald M. | Wouter Jukema, J | Caulfield, Mark J.
Nature Communications  2014;5:5068.
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.
PMCID: PMC4220464  PMID: 25350695
7.  Frailty and Risk for Heart Failure in Older Adults 
American heart journal  2013;166(5):10.1016/j.ahj.2013.07.032.
To assess the association between frailty and risk for heart failure (HF) in older adults.
Frailty is common in the elderly and is associated with adverse health outcomes. Impact of frailty on HF risk is not known.
We assessed the association between frailty, using the Health ABC Short Physical Performance Battery (HABC battery) and the Gill index, and incident HF in 2825 participants aged 70-79 years.
Mean age of participants was 74±3years; 48% were men and 59% were white. During a median follow up of 11.4 (7.1-11.7) years, 466 participants developed HF. Compared to non-frail participants, moderate (hazard ratio HR 1.36, 95%CI 1.08-1.71) and severe frailty (HR 1.88, 95%CI 1.02-3.47) by Gill index was associated with a higher risk for HF. HABC battery score was linearly associated with HF risk after adjusting for the Health ABC HF Model (HR 1.24, 95%CI 1.13, 1.36 per SD decrease in score), and remained significant when controlled for death as a competing risk (HR 1.30; 95%CI 1.00-1.55). Results were comparable across age, sex, and race, and in sub-groups based on diabetes mellitus or cardiovascular disease at baseline. Addition of HABC battery scores to the Health ABC HF Risk Model improved discrimination (change in C-index, 0.014; 95%CI 0.018-0.010) and appropriately reclassified 13.4% (NRI 0.073, 95%CI 0.021-0.125; P=0.006) of participants (8.3% who developed HF and 5.1% who did not).
Frailty is independently associated with risk of HF in older adults.
PMCID: PMC3844525  PMID: 24176445
Frailty; Heart Failure; Elderly
8.  The association of pericardial fat with calcified coronary plaque 
Obesity (Silver Spring, Md.)  2008;16(8):1914-1919.
Pericardial fat has a higher secretion of inflammatory cytokines than subcutaneous fat. Cytokines released from pericardial fat around coronary arteries may act locally on the adjacent cells.
We examined the relationship between pericardial fat and calcified coronary plaque.
Participants in the community-based Multi-Ethnic Study of Atherosclerosis underwent a computed tomography scan for the assessment of calcified coronary plaque in 2001/02. We measured the volume of pericardial fat using these scans in 159 whites and blacks without symptomatic coronary heart disease from Forsyth County, NC, aged 55–74 years.
Calcified coronary plaque was observed in 91 participants (57%). After adjusting for height, a one standard deviation increment in pericardial fat was associated with an increased odds of calcified coronary plaque (odds ratio (95% confidence interval): 1.92 (1.27, 2.90)). With further adjustment of other cardiovascular factors, pericardial fat was still significantly associated with calcified coronary plaque. This relationship did not differ by gender and ethnicity. On the other hand, body mass index and height-adjusted waist circumference were not associated with calcified coronary plaque.
Pericardial fat is independently associated with calcified coronary plaque.
PMCID: PMC4098129  PMID: 18535554
coronary heart disease; body mass index; waist circumference
9.  Resistance Training and Pioglitazone Lead to Improvements in Muscle Power During Voluntary Weight Loss in Older Adults 
The prevalence of obesity in older adults is increasing but concerns exist about the effect of weight loss on muscle function. Demonstrating that muscle strength and power are not adversely affected during “intentional” weight loss in older adults is important given the wide-ranging negative health effects of excess adiposity.
Participants (N = 88; age = 70.6 ± 3.6 years; body mass index = 32.8 ± 4.5kg/m2) were randomly assigned to one of four intervention groups: pioglitazone or placebo and resistance training (RT) or no RT, while undergoing intentional weight loss via a hypocaloric diet. Outcomes were leg press power and isometric knee extensor strength. Analysis of covariance, controlling for baseline values, compared follow-up means of power and strength according to randomized groups.
Participants lost an average of 6.6% of initial body mass, and significant declines were observed in fat mass, lean body mass, and appendicular lean body mass. Compared with women not randomized to RT, women randomized to RT had significant improvements in leg press power (p < .001) but not in knee extensor strength (p = 0.12). No significant differences between groups in change in power or strength from baseline were detected in men (both p > .25). A significant pioglitazone-by-RT interaction for leg press power was detected in women (p = .006) but not in men (p = .88).
In older overweight and obese adults, a hypocaloric weight loss intervention led to significant declines in lean body mass and appendicular lean body mass. However, in women assigned to RT, leg power significantly improved following the intervention, and muscle strength or power was not adversely effected in the other groups. Pioglitazone potentiated the effect of RT on muscle power in women but not in men; mechanisms underlying this sex effect remain to be determined.
PMCID: PMC3693600  PMID: 23292287
Obesity; Resistance training; Muscle strength; Muscle power; Voluntary weight loss.
10.  Unhealthy lifestyles do not mediate the relationship between socioeconomic status and incident depressive symptoms; The Health ABC study 
The relationship between low socioeconomic status (SES) and depressive symptoms is well described, also in older persons. Although studies have found associations between low SES and unhealthy lifestyle factors and between unhealthy lifestyle factors and depressive symptoms, not much is known about unhealthy lifestyles as a potential explanation of socioeconomic differences in depressive symptoms in older persons.
To study the independent pathways between SES (education, income, perceived income, and financial assets), lifestyle factors (smoking, alcohol use, body mass index, and physical activity), and incident depressive symptoms (CES-D 10 and reported use of antidepressant medication), we used 9 years of follow-up data (1997–2007) from 2,694 American black and white participants aged 70–79 from the Health, Aging, and Body Composition (Health ABC) study. At baseline, 12.1% of the study population showed prevalent depressive symptoms, use of antidepressant medication, or treatment of depression in the five years prior to baseline. These persons were excluded from the analyses.
Over a period of 9 years time, 860 participants (31.9%) developed depressive symptoms. Adjusted hazard ratios for incident depressive symptoms were higher in participants from lower SES groups compared to the highest SES group. The strongest relationships were found for black men. Although unhealthy lifestyle factors were consistently associated with low SES, they were weakly related to incident depressive symptoms. Lifestyle factors did not significantly reduce hazard ratios for depressive symptoms by SES.
In generally healthy persons aged 70–79 years lifestyle factors do not explain the relationship between SES and depressive symptoms. (250)
PMCID: PMC3402597  PMID: 23567402
Health ABC study; Socioeconomic status; Lifestyle factors; Depressive symptoms; Elderly; United States
11.  Aging-Related Geniohyoid Muscle Atrophy Is Related to Aspiration Status in Healthy Older Adults 
Age-related muscle weakness due to atrophy and fatty infiltration in orofacial muscles may be related to swallowing deficits in older adults. An important component of safe swallowing is the geniohyoid (GH) muscle, which helps elevate and stabilize the hyoid bone, thus protecting the airway. This study aimed to explore whether aging and aspiration in older adults were related to GH muscle atrophy and fatty infiltration.
Eighty computed tomography scans of the head and neck from 40 healthy older (average age 78 years) and 40 younger adults (average age 32 years) were analyzed. Twenty aspirators and 20 nonaspirators from the 40 older adults had been identified previously. Two-dimensional views in the sagittal and coronal planes were used to measure the GH cross-sectional area and fatty infiltration.
GH cross-sectional area was larger in men than in women (p < .05). Decreased cross-sectional area was associated with aging (p < .05), and cross-sectional area was significantly smaller in aspirators compared with nonaspirators, but only among the older men (p < .01). Increasing fatty infiltration was associated with aging in the middle (p < .05) and posterior (p < .01) portions of the GH muscle. There was no significant difference in fatty infiltration of the GH muscle among aspirators and nonaspirators.
GH muscle atrophy was associated with aging and aspiration. Fatty infiltration in the GH muscle was increased with aging but not related to aspiration status. These findings suggest that GH muscle atrophy may be a component of decreased swallowing safety and aspiration in older adults and warrants further investigation.
PMCID: PMC3732109  PMID: 23112114
Atrophy; Geniohyoid muscle; Older adults; Fatty infiltration; Aspiration; Swallow; CT scans.
12.  Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function 
Tang, Wenbo | Kowgier, Matthew | Loth, Daan W. | Soler Artigas, María | Joubert, Bonnie R. | Hodge, Emily | Gharib, Sina A. | Smith, Albert V. | Ruczinski, Ingo | Gudnason, Vilmundur | Mathias, Rasika A. | Harris, Tamara B. | Hansel, Nadia N. | Launer, Lenore J. | Barnes, Kathleen C. | Hansen, Joyanna G. | Albrecht, Eva | Aldrich, Melinda C. | Allerhand, Michael | Barr, R. Graham | Brusselle, Guy G. | Couper, David J. | Curjuric, Ivan | Davies, Gail | Deary, Ian J. | Dupuis, Josée | Fall, Tove | Foy, Millennia | Franceschini, Nora | Gao, Wei | Gläser, Sven | Gu, Xiangjun | Hancock, Dana B. | Heinrich, Joachim | Hofman, Albert | Imboden, Medea | Ingelsson, Erik | James, Alan | Karrasch, Stefan | Koch, Beate | Kritchevsky, Stephen B. | Kumar, Ashish | Lahousse, Lies | Li, Guo | Lind, Lars | Lindgren, Cecilia | Liu, Yongmei | Lohman, Kurt | Lumley, Thomas | McArdle, Wendy L. | Meibohm, Bernd | Morris, Andrew P. | Morrison, Alanna C. | Musk, Bill | North, Kari E. | Palmer, Lyle J. | Probst-Hensch, Nicole M. | Psaty, Bruce M. | Rivadeneira, Fernando | Rotter, Jerome I. | Schulz, Holger | Smith, Lewis J. | Sood, Akshay | Starr, John M. | Strachan, David P. | Teumer, Alexander | Uitterlinden, André G. | Völzke, Henry | Voorman, Arend | Wain, Louise V. | Wells, Martin T. | Wilk, Jemma B. | Williams, O. Dale | Heckbert, Susan R. | Stricker, Bruno H. | London, Stephanie J. | Fornage, Myriam | Tobin, Martin D. | O′Connor, George T. | Hall, Ian P. | Cassano, Patricia A.
PLoS ONE  2014;9(7):e100776.
Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
PMCID: PMC4077649  PMID: 24983941
14.  Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake1234 
Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.
Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.
Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10−6 were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.
Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10−8) and lower fat (β ± SE: −0.21 ± 0.04%; P = 1.57 × 10−9) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)–increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10−10), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10−7).
Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
PMCID: PMC3652928  PMID: 23636237
15.  Candidate Gene Association Study of BMI-Related Loci, Weight, and Adiposity in Old Age 
Most genome-wide association studies are confined to middle-aged populations. It is unclear whether associations between single nucleotide polymorphisms (SNPs) and obesity persist in old age. We aimed to relate 10 body mass index (BMI)–associated SNPs to weight, BMI, % fat, visceral and subcutaneous adipose tissue in Health ABC and AGES-Reykjavik comprising 4,846 individuals of European Ancestry, and 1,139 African Americans over age 65. SNPs were scaled using effect estimates from candidate SNPs. In Health ABC, a SNP near GNPDA2 was modestly associated with weight and SAT area (p = .008, p = .001). Risk score (sum of scaled SNPs) was associated with weight, BMI, and SAT area (p < .0001 for all), but neither GNPDA2 nor risk score was associated with weight, BMI, visceral adippose tissue, subcutaneous adipose tissue, or % fat in AGES-Reykjavik. In African Americans, a SNP near SEC16B was weakly associated with weight (p = .04). In this sample of older adults, no BMI-associated SNPs were associated with weight or adiposity.
PMCID: PMC3660116  PMID: 23160366
Obesity; Aging; Genetics; SNPs.
16.  The Role of Metabolic Syndrome, Adiposity, and Inflammation in Physical Performance in the Health ABC Study 
Metabolic syndrome (MetS) and functional limitation have been linked, but whether and how specific components of MetS and associated factors, such as inflammation, drive this relationship is unknown.
Data are from 2,822 men and women, aged 70–79 years, participating in the Health, Aging, and Body Composition (Health ABC) study and followed for 5 years. Presence of MetS at baseline was defined according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Interleukin-6, C-reactive protein, and body fat mass were measured at baseline. Measures of physical performance, including 400-m walk time, 20-m walking speed, and the Health ABC physical performance battery (PPB) were obtained at baseline and examination years 2, 4, and 6.
A total of 1,036 (37%) individuals met criteria for MetS. MetS was associated with poorer physical performance at baseline. Effect estimates between MetS and gait speed, and components of the Health ABC PPB (standing balance and repeated sit-to-stand performance) were modestly attenuated after adjustment for inflammation. All associations were attenuated to nonsignificance after adding total body fat mass to the model. Longitudinal analyses yielded similar results. Individual MetS component analysis revealed that abdominal obesity explained the largest fraction of the variation in physical performance.
Although inflammatory biomarkers partially accounted for the relationship between MetS and aspects of physical performance, overall findings implicate adiposity as the primary factor explaining poorer physical performance in older adults with MetS.
PMCID: PMC3623483  PMID: 23109678
Metabolic syndrome; Physical function; Inflammation; Obesity.
17.  Criteria for Clinically Relevant Weakness and Low Lean Mass and Their Longitudinal Association With Incident Mobility Impairment and Mortality: The Foundation for the National Institutes of Health (FNIH) Sarcopenia Project 
This analysis sought to determine the associations of the Foundation for the National Institutes of Health Sarcopenia Project criteria for weakness and low lean mass with likelihood for mobility impairment (gait speed ≤ 0.8 m/s) and mortality. Providing validity for these criteria is essential for research and clinical evaluation.
Among 4,411 men and 1,869 women pooled from 6 cohort studies, 3-year likelihood for incident mobility impairment and mortality over 10 years were determined for individuals with weakness, low lean mass, and for those having both. Weakness was defined as low grip strength (<26kg men and <16kg women) and low grip strength-to-body mass index (BMI; kg/m2) ratio (<1.00 men and <0.56 women). Low lean mass (dual-energy x-ray absorptiometry) was categorized as low appendicular lean mass (ALM; <19.75kg men and <15.02kg women) and low ALM-to-BMI ratio (<0.789 men and <0.512 women).
Low grip strength (men: odds ratio [OR] = 2.31, 95% confidence interval [CI] = 1.34–3.99; women: OR = 1.99, 95% CI 1.23–3.21), low grip strength-to-BMI ratio (men: OR = 3.28, 95% CI 1.92–5.59; women: OR = 2.54, 95% CI 1.10–5.83) and low ALM-to-BMI ratio (men: OR = 1.58, 95% CI 1.12–2.25; women: OR = 1.81, 95% CI 1.14–2.87), but not low ALM, were associated with increased likelihood for incident mobility impairment. Weakness increased likelihood of mobility impairment regardless of low lean mass. Mortality risk patterns were inconsistent.
These findings support our cut-points for low grip strength and low ALM-to-BMI ratio as candidate criteria for clinically relevant weakness and low lean mass. Further validation in other populations and for alternate relevant outcomes is needed.
PMCID: PMC3991140  PMID: 24737560
Muscle; Sarcopenia; Mobility; Impairment.
18.  Cutpoints for Low Appendicular Lean Mass That Identify Older Adults With Clinically Significant Weakness 
Low lean mass is potentially clinically important in older persons, but criteria have not been empirically validated. As part of the FNIH (Foundation for the National Institutes of Health) Sarcopenia Project, this analysis sought to identify cutpoints in lean mass by dual-energy x-ray absorptiometry that discriminate the presence or absence of weakness (defined in a previous report in the series as grip strength <26kg in men and <16kg in women).
In pooled cross-sectional data stratified by sex (7,582 men and 3,688 women), classification and regression tree (CART) analysis was used to derive cutpoints for appendicular lean body mass (ALM) that best discriminated the presence or absence of weakness. Mixed-effects logistic regression was used to quantify the strength of the association between lean mass category and weakness.
In primary analyses, CART models identified cutpoints for low lean mass (ALM <19.75kg in men and <15.02kg in women). Sensitivity analyses using ALM divided by body mass index (BMI: ALMBMI) identified a secondary definition (ALMBMI <0.789 in men and ALMBMI <0.512 in women). As expected, after accounting for study and age, low lean mass (compared with higher lean mass) was associated with weakness by both the primary (men, odds ratio [OR]: 6.9 [95% CI: 5.4, 8.9]; women, OR: 3.6 [95% CI: 2.9, 4.3]) and secondary definitions (men, OR: 4.3 [95% CI: 3.4, 5.5]; women, OR: 2.2 [95% CI: 1.8, 2.8]).
ALM cutpoints derived from a large, diverse sample of older adults identified lean mass thresholds below which older adults had a higher likelihood of weakness.
PMCID: PMC3991141  PMID: 24737559
Muscle; Sarcopenia; Cutpoints.
19.  The FNIH Sarcopenia Project: Rationale, Study Description, Conference Recommendations, and Final Estimates 
Low muscle mass and weakness are common and potentially disabling in older adults, but in order to become recognized as a clinical condition, criteria for diagnosis should be based on clinically relevant thresholds and independently validated. The Foundation for the National Institutes of Health Biomarkers Consortium Sarcopenia Project used an evidence-based approach to develop these criteria. Initial findings were presented at a conference in May 2012, which generated recommendations that guided additional analyses to determine final recommended criteria. Details of the Project and its findings are presented in four accompanying manuscripts.
The Foundation for the National Institutes of Health Sarcopenia Project used data from nine sources of community-dwelling older persons: Age, Gene/Environment Susceptibility-Reykjavik Study, Boston Puerto Rican Health Study, a series of six clinical trials, Framingham Heart Study, Health, Aging, and Body Composition, Invecchiare in Chianti, Osteoporotic Fractures in Men Study, Rancho Bernardo Study, and Study of Osteoporotic Fractures. Feedback from conference attendees was obtained via surveys and breakout groups.
The pooled sample included 26,625 participants (57% women, mean age in men 75.2 [±6.1 SD] and in women 78.6 [±5.9] years). Conference attendees emphasized the importance of evaluating the influence of body mass on cutpoints. Based on the analyses presented in this series, the final recommended cutpoints for weakness are grip strength <26kg for men and <16kg for women, and for low lean mass, appendicular lean mass adjusted for body mass index <0.789 for men and <0.512 for women.
These evidence-based cutpoints, based on a large and diverse population, may help identify participants for clinical trials and should be evaluated among populations with high rates of functional limitations.
PMCID: PMC3991146  PMID: 24737557
Aging; Sarcopenia; Muscle; Outcomes; Weakness.
20.  Grip Strength Cutpoints for the Identification of Clinically Relevant Weakness 
Weakness is common and contributes to disability, but no consensus exists regarding a strength cutpoint to identify persons at high risk. This analysis, conducted as part of the Foundation for the National Institutes of Health Sarcopenia Project, sought to identify cutpoints that distinguish weakness associated with mobility impairment, defined as gait speed less than 0.8 m/s.
In pooled cross-sectional data (9,897 men and 10,950 women), Classification and Regression Tree analysis was used to derive cutpoints for grip strength associated with mobility impairment.
In men, a grip strength of 26–32 kg was classified as “intermediate” and less than 26 kg as “weak”; 11% of men were intermediate and 5% were weak. Compared with men with normal strength, odds ratios for mobility impairment were 3.63 (95% CI: 3.01–4.38) and 7.62 (95% CI 6.13–9.49), respectively. In women, a grip strength of 16–20 kg was classified as “intermediate” and less than 16 kg as “weak”; 25% of women were intermediate and 18% were weak. Compared with women with normal strength, odds ratios for mobility impairment were 2.44 (95% CI 2.20–2.71) and 4.42 (95% CI 3.94–4.97), respectively. Weakness based on these cutpoints was associated with mobility impairment across subgroups based on age, body mass index, height, and disease status. Notably, in women, grip strength divided by body mass index provided better fit relative to grip strength alone, but fit was not sufficiently improved to merit different measures by gender and use of a more complex measure.
Cutpoints for weakness derived from this large, diverse sample of older adults may be useful to identify populations who may benefit from interventions to improve muscle strength and function.
PMCID: PMC3991145  PMID: 24737558
Muscle; Sarcopenia; Grip strength; Physical function; Gait speed.
21.  Force-Generation Capacity of Single Vastus Lateralis Muscle Fibers and Physical Function Decline With Age in African Green Vervet Monkeys 
Previous studies on the contractile properties of human myofibrils reported increase, decrease, or no change with aging, perhaps due to the differences in physical activity, diet, and other factors. This study examined physical performance and contractile characteristics of myofibrils of vastus lateralis (VL) muscle in young adult and old African green vervet monkeys. Animals were offered the same diet and lived in the same enclosures during development, so we were able to examine skeletal muscle function in vivo and in vitro with fewer potential confounding factors than are typical in human research studies. Fiber atrophy alone did not account for the age-related differences in specific force and maximal power output. Regression modeling used to identify factors contributing to lower fiber force revealed that age is the strongest predictor. Our results support a detrimental effect of aging on the intrinsic force and power generation of myofilament lattice and physical performance in vervet monkeys.
PMCID: PMC3566711  PMID: 22923428
Skeletal muscle; Physical function; Monkey; Aging
22.  Low 25-Hydroxyvitamin D Predicts the Onset of Mobility Limitation and Disability in Community-Dwelling Older Adults: The Health ABC Study 
Although low 25-hydroxyvitamin D (25(OH)D) is prevalent among older adults and is associated with poor physical function, longitudinal studies examining vitamin D status and physical function are lacking. We examined the association between 25(OH)D, parathyroid hormone (PTH), and the onset of mobility limitation and disability over 6 years of follow-up in community-dwelling, initially well-functioning older adults participating in the Health, Aging and Body Composition study (n = 2,099).
Serum 25(OH)D and PTH were measured at the 12-month follow-up visit (1998–1999). Mobility limitation and disability (any/severe difficulty walking 1/4 mile or climbing 10 steps) was assessed semiannually over 6 years of follow-up. The association between 25(OH)D, PTH, and mobility limitation and disability was examined using Cox proportional hazard regression models adjusted for demographics, season, behavioral characteristics, and chronic conditions.
At baseline, 28.9% of the participants had 25(OH)D <50 nmol/L and 36.1% had 25(OH)D of 50 to <75 nmol/L. Participants with 25(OH)D <50 and 50 to <75 nmol/L were at greater risk of developing mobility limitation (HR (95% CI): 1.29 (1.04–1.61) and 1.27 (1.05–1.53), respectively) and mobility disability (HR (95% CI): 1.93 (1.32–2.81) and 1.30 (0.92–1.83), respectively) over 6 years of follow-up compared with participants with 25(OH)D ≥75 nmol/L. Elevated PTH, however, was not significantly associated with developing mobility limitation or disability.
Low 25(OH)D was associated with an increased risk of mobility limitation and disability in community-dwelling, initially well-functioning black and white older adults. Prevention or treatment of low 25(OH)D may provide a pathway for reducing the burden of mobility disability in older adults.
PMCID: PMC3598356  PMID: 22573914
25-hydroxyvitamin D; Mobility limitation; Vitamin D; Parathyroid hormone
23.  Meta-Analysis Investigating Associations Between Healthy Diet and Fasting Glucose and Insulin Levels and Modification by Loci Associated With Glucose Homeostasis in Data From 15 Cohorts 
American Journal of Epidemiology  2012;177(2):103-115.
Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 US and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG (β = −0.004 mmol/L, 95% confidence interval: −0.005, −0.003) and FI (β = −0.008 ln-pmol/L, 95% confidence interval: −0.009, −0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.
PMCID: PMC3707424  PMID: 23255780
diabetes; dietary pattern; gene-environment interaction; glucose; insulin
24.  The Effect of Pioglitazone and Resistance Training on Body Composition in Older Men and Women Undergoing Hypocaloric Weight Loss 
Obesity (Silver Spring, Md.)  2011;19(8):1636-1646.
Age-related increases in ectopic fat accumulation are associated with greater risk for metabolic and cardiovascular diseases, and physical disability. Reducing skeletal muscle fat and preserving lean tissue are associated with improved physical function in older adults. PPARγ-agonist treatment decreases abdominal visceral adipose tissue (VAT) and resistance training preserves lean tissue, but their effect on ectopic fat depots in nondiabetic overweight adults is unclear. We examined the influence of pioglitazone and resistance training on body composition in older (65–79 years) nondiabetic overweight/obese men (n = 48, BMI = 32.3 ± 3.8 kg/m2) and women (n = 40, BMI = 33.3 ± 4.9 kg/m2) during weight loss. All participants underwent a 16-week hypocaloric weight-loss program and were randomized to receive pioglitazone (30 mg/day) or no pioglitazone with or without resistance training, following a 2 × 2 factorial design. Regional body composition was measured at baseline and follow-up using computed tomography (CT). Lean mass was measured using dual X-ray absorptiometry. Men lost 6.6% and women lost 6.5% of initial body mass. The percent of fat loss varied across individual compartments. Men who were given pioglitazone lost more visceral abdominal fat than men who were not given pioglitazone (−1,160 vs. −647 cm3, P = 0.007). Women who were given pioglitazone lost less thigh subcutaneous fat (−104 vs. −298 cm3, P = 0.002). Pioglitazone did not affect any other outcomes. Resistance training diminished thigh muscle loss in men and women (resistance training vs. no resistance training men: −43 vs. −88 cm3, P = 0.005; women: −34 vs. −59 cm3, P = 0.04). In overweight/obese older men undergoing weight loss, pioglitazone increased visceral fat loss and resistance training reduced skeletal muscle loss. Additional studies are needed to clarify the observed gender differences and evaluate how these changes in body composition influence functional status.
PMCID: PMC3091968  PMID: 21233810
25.  Association of a Modified Physiologic Index With Mortality and Incident Disability: The Health, Aging, and Body Composition Study 
Indexes constructed from components may identify individuals who age well across systems. We studied the associations of a Modified Physiologic Index (systolic blood pressure, forced vital capacity, Digit Symbol Substitution Test score, serum cystatin-C, serum fasting glucose) with mortality and incident disability.
Data are from the Health, Aging, and Body Composition study on 2,737 persons (51.2% women, 40.3% black) aged 70–79 years at baseline and followed on average 9.3 (2.9) years. Components were graded 0 (healthiest), 1 (middle), or 2 (unhealthiest) by tertile or clinical cutpoints and summed to calculate a continuous index score (range 0–10). We used multivariate Cox proportional hazards regression to calculate risk of death or disability and determined accuracy predicting death using the area under the curve.
Mortality was 19% greater per index unit (p < .05). Those with highest index scores (scores 7–10) had 3.53-fold greater mortality than those with lowest scores (scores 0–2). The unadjusted index (c-statistic = 0.656, 95% CI 0.636–0.677, p < .0001) predicted death better than age (c-statistic = 0.591, 95% CI 0.568–0.613, p < .0001; for comparison, p < .0001). The index attenuated the age association with mortality by 33%. A model including age and the index did not predict death better than the index alone (c-statistic = 0.671). Prediction was improved with the addition of other markers of health (c-statistic = 0.710, 95% CI 0.689–0.730). The index was associated with incident disability (adjusted hazard ratio per index unit = 1.04, 95% CI 1.01–1.07).
A simple index of available physiologic measurements was associated with mortality and incident disability and may prove useful for identifying persons who age well across systems.
PMCID: PMC3636673  PMID: 22546961
Aging; Index; Mortality; Disability; Longevity

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