Suchergebnisse

Purpose. This study describes the prevalence and characteristics of physician health promotion referrals and patient adherence to referrals in a community-based primary care clinic and associated wellness facility. The role of reimbursement for attendance to the wellness facility was specifically examined. Design. Retrospective cohort study. Setting. The Church Health Center of Memphis, Tennessee: a low-income urban clinic and its affiliated wellness center. Subjects. Patients were primarily African-American, lower-income, urban residents of Shelby County, Tennessee. Measures. All study data came from existing medical clinic and wellness facility records of utilization, patient history, and diagnoses. Results. Of 6321 clinic patients, 16.7% (n = 1069) received a provider health promotion referral. Logistic regression analyses identified that physician referral was related to patient factors of access to free wellness-facility membership, employment status, receiving a behavior-related diagnosis, and being African-American and female. Of patients receiving a referral, 17.2% (n = 184) adhered to this advice and visited the wellness facility. New patients were more likely to adhere to a referral than established patients. Conclusion. Demographic, financial, and patient characteristics influenced whether health behavior change referrals were made by primary care physicians in a community clinic. Removing financial barriers did not influence patient adherence, but new patients were more likely to follow the recommendation than those previously seen at the clinic.

Abstract

Background
Observational research has identified several mortality biomarkers; however, their responsiveness to change is unknown. We tested whether the Healthy Aging Index (HAI) and other mortality biomarkers were responsive to intentional weight loss (WL), which is associated with lower mortality risk in recent meta-analyses.


Methods
Older adults (70.3 ± 3.7 years) with obesity were randomized into a 6-month WL (n = 47) or weight stability (WS: ±5% baseline weight; n = 48) program. Baseline and 6-month HAI score (0–10) was calculated from component sum (each 0–2: systolic blood pressure, forced vital capacity [FVC], creatinine, fasting blood glucose [FBG], Montreal Cognitive Assessment), and gait speed, grip strength, Digit Symbol Substitution Test, FEV1, Interleukin-6, C-Reactive Protein, and Cystatin-C were assessed at baseline and 6 months.


Results
Mean baseline HAI was 3.2 ± 1.6. By 6 months, WL participants lost 8.87 (95% CI: −10.40, −7.34) kg, whereas WS participants remained weight stable. WL group reduced HAI score (WL: −0.75 [95% CI: −1.11, −0.39] vs WS: −0.22 [95% CI: −0.60, 0.15]; p = .04), and components changing the most were FBG (WL: −3.89 [95% CI: −7.78, 0.00] mg/dL vs WS: 1.45 [95% CI: −2.61, 5.50] mg/dL; p = .047) and FVC (WL: 0.11 [95% CI: −0.01, 0.23] L vs WS: −0.05 [95% CI: −0.17, 0.08] L; p = .06). Among other biomarkers, only Cystatin-C significantly changed (WL: −2.53 [95% CI: −4.38, −0.68] ng/mL vs WS: 0.07 [95% CI: −1.85, 1.98] ng/mL; p = .04). Combining treatment groups, 1 kg WL was associated with a 0.07 (95% CI: 0.03, 0.12) HAI reduction (p < .01).


Conclusion
Intentional WL via caloric restriction reduced HAI score by 0.53 points, largely attributable to metabolic and pulmonary improvements.

AbstractBackgroundDepressive symptoms and hearing loss (HL) are independently associated with increased risk of incident disability; whether the increased risk is additive is unclear.MethodsCox Proportional Hazards models were used to assess joint associations of HL (normal, mild, moderate/severe) and late-life depressive symptoms (defined by a score of ≥8 on the 10-item Center for Epidemiologic Studies-Depression scale) with onset of mobility disability (a lot of difficulty or inability to walk ¼ mile and/or climb 10 steps) and any disability in activities of daily living (ADL), among 2,196 participants of the Health, Aging and Body Composition Study, a cohort of well-functioning older adults aged 70–79 years. Models were adjusted for age, race, sex, education, diabetes, hypertension, and body mass index.ResultsRelative to participants with normal hearing and without depressive symptoms, participants without depressive symptoms who had mild or moderate/severe HL had increased risk of incident mobility and ADL disability (hazard ratio [HR] for mobility disability, mild HL:1.34, 95% confidence interval [CI]: 1.09, 1.64 and HR for mobility disability, moderate/severe HL: 1.37, 95% CI: 1.08, 1.75 and HR for ADL disability, mild HL: 1.32, 95% CI: 1.08, 1.63, and HR for ADL disability, moderate/severe HL: 1.42, 95% CI: 1.11, 1.82). Among participants with depressive symptoms, mild HL (HR: 1.71, 95% CI: 1.09, 2.70) was associated with increased risk of incident mobility disability.ConclusionsIndependent of depressive symptoms, risk of incident disability was greater in older adults with HL, regardless of severity. Further research into HL interventions may delay disability onset.

Abstract
Racial disparities in adverse health outcomes with aging have been well described. Yet, much of the research focuses on racial comparisons, with relatively less attention to the identification of underlying mechanisms. To address these gaps, the Research Centers Collaborative Network held a workshop on aging, race, and health disparities to identify research priorities and inform the investigation, implementation, and dissemination of strategies to mitigate disparities in healthy aging. This article provides a summary of the key recommendations and highlights the need for research that builds a strong evidence base with both clinical and policy implications. Successful execution of these recommendations will require a concerted effort to increase participation of underrepresented groups in research through community engagement and partnerships. In addition, resources to support and promote the training and development of health disparities researchers will be critical in making health equity a shared responsibility for all major stakeholders.

Abstract

Background
Fatigability in community-dwelling older adults is highly prevalent and disabling, but lacks a treatment. Greater nigrostriatal dopaminergic signaling can ameliorate performance fatigability in healthy young adults, but its role in community-dwelling older adults is not known. We hypothesized that higher nigrostriatal dopaminergic integrity would be associated with lower performance fatigability, independent of cardiopulmonary and musculoskeletal energetics and other health conditions.


Methods
In 125 older adults participating in the Study of Muscle, Mobility and Aging, performance fatigability was measured as performance deterioration during a fast 400 m walk (% slowing down from the 2nd to the 9th lap). Nigrostriatal DA integrity was measured using (+)-[11C] dihydrotetrabenazine (DTBZ) PET imaging. The binding signal was obtained separately for the subregions regulating sensorimotor (posterior putamen), reward (ventral striatum), and executive control processes (dorsal striatum). Multivariable linear regression models of performance fatigability (dependent variable) estimated the coefficients of dopamine integrity in striatal subregions, adjusted for demographics, comorbidities, and cognition. Models were further adjusted for skeletal muscle energetics (via biopsy) and cardiopulmonary fitness (via cardiopulmonary exercise testing).


Results
Higher [11C]-DTBZ binding in the posterior putamen was significantly associated with lower performance fatigability (demographic-adjusted standardized β = −1.08, 95% CI: −1.96, −0.20); results remained independent of adjustment for other covariates, including cardiopulmonary and musculoskeletal energetics. Associations with other striatal subregions were not significant.


Discussion
Dopaminergic integrity in the sensorimotor striatum may influence performance fatigability in older adults without clinically overt diseases, independent of other aging systems.

Publisher's version (útgefin grein) ; Importance: Dual decline in both memory and gait speed may characterize a group of older individuals at high risk for future dementia. Objective: To assess the risk of dementia in older persons who experience parallel declines in memory and gait speed compared with those who experience no decline or decline in either memory or gait speed only. Design, Setting, and Participants: A multicohort meta-analysis was performed of 6 prospective cohort studies conducted between 1997 and 2018 in the United States and Europe. Participants were 60 years or older, had an initial gait speed of more than 0.6 m/s (ie, free of overt dismobility), with repeated measures of memory and gait speed before dementia diagnosis during a mean follow-up of 6.6 to 14.5 years. Within each study, participants were divided into 4 groups: memory decline only, gait speed decline only, dual decline, or no decline (hereafter referred to as usual agers). Gait decline was defined as a loss of 0.05 m/s or more per year; memory decline was defined as being in the cohort-specific lowest tertile of annualized change. Main Outcomes and Measures: Risk of incident dementia according to group membership was examined by Cox proportional hazards regression with usual agers as the reference, adjusted for baseline age, sex, race/ethnicity, educational level, study site, and baseline gait speed and memory. Results: Across the 6 studies of 8699 participants, mean age ranged between 70 and 74 years and mean gait speed ranged between 1.05 and 1.26 m/s. Incident dementia ranged from 5 to 21 per 1000 person-years. Compared with usual agers, participants with only memory decline had 2.2 to 4.6 times higher risk for developing dementia (pooled hazard ratio, 3.45 [95% CI, 2.45-4.86]). Those with only gait decline had 2.1 to 3.6 times higher risk (pooled hazard ratio, 2.24 [95% CI, 1.62-3.09]). Those with dual decline had 5.2 to 11.7 times the risk (pooled hazard ratio, 6.28 [95% CI, 4.56-8.64]). Conclusions and Relevance: In this study, dual decline of memory and gait speed was associated with increased risk of developing dementia among older individuals, which might be a potentially valuable group for preventive or therapeutic interventions. Why dual decline is associated with an elevated risk of dementia and whether these individuals progress to dementia through specific mechanisms should be investigated by future studies. ; This research work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (Drs Tian, Resnick, Launer, Simonsick, Studenski, and Ferrucci). The BLSA was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The AGES-Reykjavik Study was funded by contract N01-AG-12100 from the National Institutes of Health; by the Intramural Research Program of the National Institute on Aging; and by the Icelandic Heart Association and the Icelandic Parliament. The Health ABC study was supported by National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; National Institute on Aging grant R01-AG028050; and National Institute of Nursing Research grant R01-NR012459, and was funded in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The MCSA was supported by funding from the National Institutes of Health, National Institute on Aging (U01 AG006786), the Gerald and Henrietta Rauenhorst Foundation, and the Mayo Foundation for Medical Education and Research; and was made possible by the Rochester Epidemiology Project (R01 AG034676). The SNAC-K was supported by the funders of the Swedish National Study on Aging and Care; the Ministry of Health and Social Affairs, Sweden; the participating County Councils and Municipalities; and the Swedish Research Council. The InCHIANTI study was supported by National Institute on Aging contracts 263MD9164 (Dr Ferrucci) and 263 MD 821336, N01-AG-1-1, N01-AG-10211, and N01-AG-5-0002 (Dr Bandinelli), and partially supported by grant n PE 2011 02350413 of the Italian Ministry of Health (Dr Cherubini). ; Peer Reviewed

Abstract

Background
The geroscience hypothesis posits that aging biological processes contribute to many age-related deficits, including the accumulation of multiple chronic diseases. Though only one facet of mitochondrial function, declines in muscle mitochondrial bioenergetic capacities may contribute to this increased susceptibility to multimorbidity.


Methods
The Study of Muscle, Mobility and Aging (SOMMA) assessed ex vivo muscle mitochondrial energetics in 764 older adults (mean age = 76.4, 56.5% women, and 85.9% non-Hispanic White) by high-resolution respirometry of permeabilized muscle fibers. We estimated the proportional odds ratio (POR [95% CI]) for the likelihood of greater multimorbidity (4 levels: 0 conditions, N = 332; 1 condition, N = 299; 2 conditions, N = 98; or 3+ conditions, N = 35) from an index of 11 conditions, per SD decrement in muscle mitochondrial energetic parameters. Distribution of conditions allowed for testing the associations of maximal muscle energetics with some individual conditions.


Results
Lower oxidative phosphorylation supported by fatty acids and/or complex I- and II-linked carbohydrates (eg, Max OXPHOSCI+CII) was associated with a greater multimorbidity index score (POR = 1.32 [1.13, 1.54]) and separately with diabetes mellitus (OR = 1.62 [1.26, 2.09]), depressive symptoms (OR = 1.45 [1.04, 2.00]) and possibly chronic kidney disease (OR = 1.57 [0.98, 2.52]) but not significantly with other conditions (eg, cardiac arrhythmia, chronic obstructive pulmonary disease).


Conclusions
Lower muscle mitochondrial bioenergetic capacities were associated with a worse composite multimorbidity index score. Our results suggest that decrements in muscle mitochondrial energetics may contribute to a greater global burden of disease and are more strongly related to some conditions than others.

CONTEXT: Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry. OBJECTIVE: The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries. DESIGN: Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL). PATIENTS OR OTHER PARTICIPANTS: In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study. MAIN OUTCOME MEASURES: Blood concentrations of 25(OH)D were measured for all participants. RESULTS: Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively. CONCLUSIONS: Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass. ; NIH [N01 AG 12100, U01 HL72515, U01 GM074518, R01 HL088119, R01 AR046838, U01 HL084756, N01-AG-12100, U24AG051129]; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Mid-Atlantic Nutrition and Obesity Research Center of Maryland [P30 DK072488]; NIH/NIAMS [F32AR059469]; American Heart Association [10SDG2690004]; NHLBI [N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239, HL080295, HL087652, HL105756, HL103612, HL120393, HL130114]; NINDS; NIA [AG-023629, AG-15928, AG-20098, AG-027058, 1R01AG032098-01A1]; National Center for Research Resources [UL1RR033176]; CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease grant [DK063491]; Southern California Diabetes Endocrinology Research Center; GlaxoSmithKline; Faculty of Biology and Medicine of Lausanne; Swiss National Science Foundation [33CSCO-122661, 33CS30-139468, 33CS30-148401]; deCODE Genetics, ehf; Cancer Research United Kingdom; Medical Research Council; EU [LSHM-CT-2003-503041]; Wellcome Trust [WT098051, WT089062, WT098017]; Netherlands Organisation for Scientific Research (NWO); Erasmus MC; Centre for Medical Systems Biology (CMSB); European Community's Seventh Framework Programme (FP7), ENGAGE Consortium [HEALTH-F4-2007-201413]; Wellcome Trust; Support for Science Funding programme; CamStrad; Danish Council for Independent Research [DFF-1333-00124, DFF-1331-00730B]; US National Institute for Arthritis, Musculoskeletal and Skin Diseases; National Institute on Aging [U24AG051129, R01 AR 41398, R01AR057118]; FP7-PEOPLE-Marie Curie Career Integration Grants (CIG); National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc. [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; Genome Quebec; Genome Canada; Canadian Institutes of Health Research (CIHR); Swedish Research Council; Swedish Foundation for Strategic Research; ALF/LUA research grant in Gothenburg; Lundberg Foundation; Emil and Vera Cornell Foundation; Torsten and Ragnar Soderberg's Foundation; Petrus and Augusta Hedlunds Foundation; Vastra Gotaland Foundation; Goteborg Medical Society; German Bundesministerium fuer Forschung und Technology [01 AK 803 A-H, 01 IG 07015G]; National Institutes of Aging; National Institutes of Health [HHSN268200782096C, R01 AG 041517, M01 RR-00750]; Intramural Research Program of the NIH, National Library of Medicine. Kora; Helmholtz Center Munich, German Research Center for Environmental Health; German Federal Ministry of Education and Research (BMBF); State of Bavaria; German National Genome Research Network [NGFN-2, NGFNPlus: 01GS0823]; Munich Center of Health Sciences (MC Health) as part of LMUinnovativ; British Heart Foundation; Kidney Research UK; National Institute for Health Research (NIHR) programme grant; Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; National Institute on Aging grants [R01AG17917, R01AG15819, R01AG24480]; Illinois Department of Public Health; Rush Clinical Translational Science Consortium; Arthritis Research UK; Chronic Disease Research Foundation; National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award; Israel Science Foundation [994/10]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); German Federal Ministry of Education and Research (BMBF) [16SV5536K, 16SV5537, 16SV5538, 16SV5837, 01UW0808]; Max Planck Institute for Human Development (MPIB); Max Planck Institute for Molecular Genetics (MPIMG); Charite University Medicine; German Institute for Economic Research (DIW); University of Lubeck in Lubeck, Germany; Netherlands Organization for Health Research and Development (ZonMw) the Hague [6130.0031]; NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation, the Hague [KB-15-004-003]; Wageningen University, Wageningen; VU University Medical Center, Amsterdam; Erasmus Medical Center, Rotterdam; Healthway Health Promotion Foundation of Western Australia; Australasian Menopause Society; Australian National Health and Medical Research Council [254627, 303169, 572604]; National Health and Medical Research Council of Australia Career Development Fellowship; Karen Elise Jensen foundation; NIH from NHLBI [R01-HL-117078, R01-HL-087700, R01-HL-088215]; NIH from NIDDK [R01-DK-089256, R01-DK-075681]; Academy of Finland Center of Excellence in Complex Disease Genetics [213506, 129680]; Academy of Finland [251217, 136895, 141005, 139635, 129494, 269517]; Finnish foundation for Cardiovascular Research; Sigrid Juselius Foundation; Yrjo Jahnsson Foundation; Finnish Diabetes Research Society; Samfundet Folkhalsann; Novo Nordisk Foundation; Liv och Halsa; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; European Science Foundation (EUROSTRESS); Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Juho Vainio Foundation; Centers for Disease Control and Prevention/Association of Schools of Public Health [S043, S1734, S3486]; NIAMS Multipurpose Arthritis and Musculoskeletal Disease Center grant [5-P60-AR30701]; NIAMS Multidisciplinary Clinical Research Center grant [5 P60 AR49465-03]; Research Program - Korea Centers for Disease Control and Prevention [2001-347-6111-221, 2002-347-6111-221, 2009-E71007-00, 2010-E71004-00]; Helmholtz Center Munich; German Research Center for Environmental Health; British Heart Foundation Grant [SP/04/002]; Academy of Finland; Finnish Diabetes Research Foundation; Finnish Cardiovascular Research Foundation; Strategic Research Funding from the University of Eastern Finland, Kuopio; EVO grant from the Kuopio University Hospital [5263]; Swedish Research Council [2006-3832, K2009-53X-14691-07-3, K2010-77PK-21362-01-2, 2008-2202, 2005-8214]; Greta and Johan Kock Foundation; A. Pahlsson Foundation; A. Osterlund Foundation; Malmo University Hospital Research Foundation; Research and Development Council of Region Skane, Sweden; Swedish Medical Society; National Institutes of Health; National Institute on Aging (NIA); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Center for Advancing Translational Sciences (NCATS); NIH Roadmap for Medical Research [U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, UL1 TR000128]; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [RC2ARO58973]; FAS [2007-2125]; Chief Scientist Office of the Scottish Government [CZB/4/276, CZB/4/710]; Royal Society; MRC Human Genetics Unit; Arthritis Research UK [17539]; European Union framework program 6 EUROSPAN project [LSHG-CT-2006-018947]; ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden; European Union Grant [QLG1-CT-2001-01252]; AstraZeneca; SHIP, part of the Community Medicine Research Network of the University of Greifswald, Germany; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; network "Greifswald Approach to Individualized Medicine (GANI_MED)" - Federal Ministry of Education and Research [03IS2061A]; Siemens Healthcare, Erlangen, Germany; National Institute on Aging (NIA) [R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576]; Wallenberg foundation; Medical Research Council (UK); Republic of Croatia Ministry of Science, Education and Sports [108-1080315-0302]; National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; US National Institutes of Health grants [1-ZIA-HG000024, U01DK062370, R00DK099240]; American Diabetes Association Pathway to Stop Diabetes Grant [1-14-INI-07]; Academy of Finland Grants [271961, 272741, 258753]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, USA; National Heart Lung and Blood Institute of the National Institutes of Health [HL57453]; [HHSN268201200036C] ; This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10−8) or suggestively genome wide (p < 2.3 × 10−6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass. ; We acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in development and support of this manuscript. CHARGE members include the Netherland's Rotterdam Study (RS), Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), the NHLBI's Atherosclerosis Risk in Communities (ARIC) Study, and Iceland's Age, Gene/Environment Susceptibility (AGES) Reykjavik Study. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik): has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Old Order Amish (OOA): this work was supported by NIH research grants U01 HL72515, U01 GM074518, R01 HL088119, R01 AR046838, and U01 HL084756. Partial funding was also provided by the Mid-Atlantic Nutrition and Obesity Research Center of Maryland (P30 DK072488).). L.M.Y.-A. was supported by F32AR059469 from NIH/NIAMS. M.F. was supported by American Heart Association grant 10SDG2690004. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts N01-HC- 85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239, and by HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756, HL103612, HL120393, and HL130114 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources, grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124; in addition to the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. CoLaus: The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468, and 33CS30-148401). We thank Vincent Mooser and Gérard Waeber, Co-PIs of the CoLaus study. Special thanks to Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey, and Sylvie Mermoud for data collection. Data analysis was supervised by Sven Bergmann and Jacques S. Beckmann. The computations for this paper were performed in part at the Vital-IT Center for high-performance computing of the Swiss Institute of Bioinformatics. deCODE Study: The study was funded by deCODE Genetics, ehf. We thank all the participants of this study, the staff of deCODE Genetics core facilities and recruitment center and the densitometry clinic at the University Hospital for their important contributions to this work. The EPIC Study: The EPIC Obesity study is funded by Cancer Research United Kingdom and the Medical Research Council. I.B. acknowledges support from EU FP6 funding (contract no. LSHM-CT-2003-503041) and by the Wellcome Trust (WT098051). Erasmus Rucphen Family (ERF) Study: The study was supported by grants from The Netherlands Organisation for Scientific Research (NWO), Erasmus MC, the Centre for Medical Systems Biology (CMSB), and the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. We are grateful to all general practitioners for their contributions, to Petra Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and Peter Snijders for his help in data collection. Fenland: The Fenland Study is funded by the Wellcome Trust and the Medical Research Council, as well as by the Support for Science Funding programme and CamStrad. We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for help with recruitment. We thank the Fenland Study co-ordination team and the Field Epidemiology team of the MRC Epidemiology Unit for recruitment and clinical testing. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF—1333-00124 and Sapere Aude program grant DFF—1331-00730B). Framingham Osteoporosis Study (FOS)/Framingham Heart Study (FHS): The study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and U24AG051129; D.P.K. and R01AR057118; D.K. D.K. was also supported by FP7-PEOPLE-2012-Marie Curie Career Integration Grants (CIG)). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. eQTL HOb Study: The study was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR). Gothenburg Osteoporosis and Obesity Determinants Study (GOOD): The study was funded by the Swedish Research Council, the Swedish Foundation for Strategic Research, The ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Emil and Vera Cornell Foundation, the Torsten and Ragnar Söderberg's Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, and the Göteborg Medical Society. We would like to thank Dr Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015G for access to their grid resources. We also thank Karol Estrada, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands for advice regarding the grid resources. Health Aging and Body Composition Study (Health ABC): This study was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Indiana: We thank the individuals who participated in this study, as well as the study coordinators, without whom this work would not have been possible. This work was supported by National Institutes of Health grants R01 AG 041517 and M01 RR-00750. Genotyping services were provided by CIDR. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Kora (KORA F3 and KORA F4): The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The London Life Sciences Population (LOLIPOP): The study was funded by the British Heart Foundation, Wellcome Trust, the Medical Research Council, and Kidney Research UK. The study also receives support from a National Institute for Health Research (NIHR) programme grant. Rotterdam Study (RSI, RSII & RSIII): The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project no. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Karol Estrada, PhD, Yurii Aulchenko, PhD, and Carolina Medina-Gomez, PhD, for the creation and analysis of imputed data. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We thank Dr Karol Estrada, Dr Fernando Rivadeneira, Dr Tobias A. Knoch, Anis Abuseiris, and Rob de Graaf (Erasmus MC Rotterdam, The Netherlands) for their help in creating GRIMP, and we thank BigGRID, MediGRID, and Services@MediGRID/D-Grid (funded by the German Bundesministerium fuer Forschung und Technology; grants 01 AK 803 A-H, 01 IG 07015G) for access to their grid computing resources. Rush Memory and Aging Project (MAP): The Memory and Aging Project was supported by National Institute on Aging grants R01AG17917, R01AG15819, and R01AG24480, the Illinois Department of Public Health, the Rush Clinical Translational Science Consortium, and a gift from Ms Marsha Dowd. TwinsUK (TUK): The study was funded by the Wellcome Trust, Arthritis Research UK, and the Chronic Disease Research Foundation. The study also received support from a National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London. We thank the staff and volunteers of the TwinsUK study. The study was also supported by Israel Science Foundation, grant number 994/10. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik) has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Berlin Aging Study II (BASE-II) was supported by the German Federal Ministry of Education and Research (BMBF (grants #16SV5536K, #16SV5537, #16SV5538, and #16SV5837; previously #01UW0808)). Additional contributions (e.g., financial, equipment, logistics, personnel) are made from each of the other participating sites, i.e., the Max Planck Institute for Human Development (MPIB), Max Planck Institute for Molecular Genetics (MPIMG), Charite University Medicine, German Institute for Economic Research (DIW), all located in Berlin, Germany, and University of Lübeck in Lübeck, Germany. B-vitamins in the prevention of osteoporotic fractures (B-PROOF): B-PROOF is supported and funded by The Netherlands Organization for Health Research and Development (ZonMw, grant 6130.0031), the Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project KB-15-004-003), the Hague; Wageningen University, Wageningen; VU University Medical Center, Amsterdam; Erasmus Medical Center, Rotterdam. All organizations are based in the Netherlands. We thank Dr Tobias A. Knoch, Anis Abuseiris, Karol Estrada, and Rob de Graaf as well as their institutions the Erasmus Grid Office, Erasmus MC Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology (grants #01 AK 803 A-H and #01 IG 07015G) for access to their gird resources. Further, we gratefully thank all participants. Calcium Intake Fracture Outcome Study (CAIFOS): This study was funded by Healthway Health Promotion Foundation of Western Australia, Australasian Menopause Society and the Australian National Health and Medical Research Council Project Grants (254627, 303169, and 572604). We are grateful to the participants of the CAIFOS Study. The salary of Dr Lewis is supported by a National Health and Medical Research Council of Australia Career Development Fellowship. Danish Osteoporosis Study (DOPS): The study was supported by Karen Elise Jensen foundation. Family Heart Study (FamHS): The study was supported by NIH grants R01-HL-117078, R01-HL-087700, and R01-HL-088215 from NHLBI; and R01-DK-089256 and R01-DK-075681 from NIDDK. GenMets (Health 2000): S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (213506 and 129680), Academy of Finland (251217), the Finnish foundation for Cardiovascular Research and the Sigrid Juselius Foundation. S.M. was supported by grants #136895 and #141005, V.S. by grants #139635 and 129494, and M.P. by grant #269517 from the Academy of Finland and a grant from the Finnish Foundation for Cardiovascular Research. M.P. was supported by the Yrjö Jahnsson Foundation. Helsinki Birth Cohort Study (HBCS): We thank all study participants as well as everybody involved in the HBCS. HBCS has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Samfundet Folkhälsann, Novo Nordisk Foundation, Liv och Hälsa, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). Johnston County Study: The Johnston County Osteoarthritis Project is supported in part by cooperative agreements S043, S1734, and S3486 from the Centers for Disease Control and Prevention/Association of Schools of Public Health; the NIAMS Multipurpose Arthritis and Musculoskeletal Disease Center grant 5-P60-AR30701; and the NIAMS Multidisciplinary Clinical Research Center grant 5 P60 AR49465-03. Genotyping services were provided by Algynomics company. Korean Genome Epidemiology Study (KoGES): Korean Genome Epidemiology Study (KoGES): This work was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (found 2001-347-6111-221, 2002-347-6111-221, 2009-E71007-00, 2010-E71004-00). Kora F3 and Kora F4: The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. LOLIP-REP-IA610: The study was supported by the Wellcome Trust. We thank the participants and research teams involved in LOLIPOP. LOLIP-REP-IA_I: The study was supported by the British Heart Foundation Grant SP/04/002. LOLIP-REP-IA_P: The study was supported by the British Heart Foundation Grant SP/04/002. METSIM: The study was supported by the Academy of Finland, the Finnish Diabetes Research Foundation, the Finnish Cardiovascular Research Foundation, the Strategic Research Funding from the University of Eastern Finland, Kuopio, and the EVO grant 5263 from the Kuopio University Hospital. MrOS Sweden: Financial support was received from the Swedish Research Council (2006-3832), the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar Söderberg's Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, the Göteborg Medical Society, and the Novo Nordisk foundation. Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. MrOS US: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the MrOS ancillary study "GWAS in MrOS and SOF" under the grant number RC2ARO58973. Osteoporosis Prospective Risk Assessment study (OPRA): This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Orkney Complex Disease Study (ORCADES): ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK (17539) and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. PEAK 25: This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS): The study was supported by grants from the Swedish research council (projects 2008-2202 and 2005-8214) and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC): The RISC study is supported by European Union Grant QLG1-CT-2001-01252 and AstraZeneca. We thank Merck Research Labs for conducting DNA genotyping on RISC samples.Rotterdam III: Rotterdam Study (RS): See discovery. SHIP and SHIP TREND: This work was supported by SHIP, which is part of the Community Medicine Research Network of the University of Greifswald, Germany, by the Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania and the network "Greifswald Approach to Individualized Medicine (GANI_MED)" funded by the Federal Ministry of Education and Research (03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the "Center of Knowledge Interchange" program of the Siemens. A.G. and the Cache´ Campus program of the InterSystems GmbH. The SHIP authors are grateful to the contribution of Florian Ernst, Anja Wiechert, and Astrid Petersmann in generating the SNP data and to Mario Stanke for the opportunity to use his Server Cluster for SNP Imputation. Data analyses were further supported by the German Research Foundation (DFG Vo 955/10-1) and the Federal Ministry of Nutrition, Agriculture and Consumer's Safety. SOF: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the SOF ancillary study "GWAS in MrOS and SOF" under the grant number RC2ARO58973. Uppsala Longitudinal Study of Adult Men (ULSAM): The study was funded by grants from the Swedish research council (projects 2008-2202 and 2005-8214), the Wallenberg foundation, and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Andrew P. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science, grant number WT098017. CROATIA-VIS (VIS): The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). We acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. Women's Health Initiative (WHI): The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221. We thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A listing of WHI investigators can be found at https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf. FUSION: This research was supported in part by US National Institutes of Health grants 1-ZIA-HG000024 (to F.S.C.), U01DK062370 (to M.B.), R00DK099240 (to S.C.J.P.), the American Diabetes Association Pathway to Stop Diabetes Grant 1-14-INI-07 (to S.C.J.P.), and Academy of Finland Grants 271961 and 272741 (to M.L.) and 258753 (to H.A.K.). We thank all the subjects for participation and the study personnel for excellent technical assistance. The Pima Indian Study: This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, USA. Studies of a Targeted Risk Reduction Intervention with Defined Exercise (STRRIDE): This study was supported by the National Heart Lung and Blood Institute of the National Institutes of Health, HL57453 (WEK). Gene expression in old and young muscle biopsies: S.M. and T.G. were supported in part by NIH U24AG051129. ; Peer Reviewed