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1.  Modifying effect of obesity on the association between sitting time and incident diabetes in post-menopausal women 
Obesity (Silver Spring, Md.)  2013;22(4):1133-1141.
Objective
To evaluate the association between self-reported daily sitting time and the incidence of type II diabetes in a cohort of postmenopausal women.
Design and Methods
Women (N = 88,829) without diagnosed diabetes reported the number of hours spent sitting over a typical day. Incident cases of diabetes were identified annually by self-reported initiation of using oral medications or insulin for diabetes over 14.4 years follow-up.
Results
Each hour of sitting time was positively associated with increased risk of diabetes (Risk ratio (RR): 1.05; 95% confidence interval (CI): 1.02–1.08]. However, sitting time was only positively associated with incident diabetes in obese women. Obese women reporting sitting 8–11 (RR: 1.08; 95% CI 1.0–1.1), 12–15 (OR: 1.13; 95% CI 1.0–1.2), and ≥16 hours (OR: 1.25; 95% CI 1.0–1.5) hours per day had an increased risk of diabetes compared to women sitting ≤ 7 hours per day. These associations were adjusted for demographics, health conditions, behaviors (smoking, diet and alcohol intake) and family history of diabetes. Time performing moderate to vigorous intensity physical activity did not modify these associations.
Conclusion
Time spent sitting was independently associated with increased risk of diabetes diagnosis among obese women— a population already at high risk of the disease.
doi:10.1002/oby.20620
PMCID: PMC3968183  PMID: 24123945
sedentary; glucose control; overweight; glycemia
2.  Obesity and Survival to Age 85 Years without Major Disease or Disability in Older Women 
JAMA internal medicine  2014;174(1):98-106.
Context
The impact of obesity on late-age survival without disease or disability in women is unknown.
Objective
To investigate if higher baseline body mass index and waist circumference affects women’s survival to age 85 years without major chronic disease (coronary disease, stroke, cancer, diabetes, or hip fracture) and mobility disability.
Design, Setting, Participants
Examination of 36,611 women from the Women’s Health Initiative who could have reached age 85 years or older if they survived to the last outcomes evaluation on September 17, 2012. Recruitment was from 40 US Clinical Centers from October 1993–December 1998. Multinomial logistic regression models were used to estimate odds ratios and 95% confidence intervals for the association of baseline body mass index and waist circumference with the outcomes, adjusting for demographic, behavioral, and health characteristics.
Main Outcome Measures
Mutually-exclusive classifications: 1) survived without major chronic disease and without mobility disability (“healthy”); 2) survived with ≥1 major chronic disease at baseline, but without new disease or disability (“prevalent diseased”); 3) survived and developed ≥1 major chronic disease but not disability during study follow-up (“incident diseased”); 4) survived and developed mobility disability with or without disease (“disabled”); and 5) did not survive (“died”).
Results
Mean (SD) baseline age was 72.4 (3.0) years (range: 66–81). The distribution of women classified as healthy, prevalent diseased, incident diseased, disabled, and died was 19%, 15%, 23%, 18%, and 25%, respectively. Compared to normal-weight women, underweight and obese women were more likely to die before age 85 years. Overweight and obese women had higher risks of incident disease and mobility disability. Disability risks were striking. Relative to normal-weight women, adjusted odds ratios (95% confidence intervals) of mobility disability was 1.6 (1.5–1.8) for overweight women and 3.2 (2.9–3.6), 6.6 (5.4–8.1), and 6.7 (4.8–9.2), for class I, II, and III obesity, respectively. Waist circumference >88 centimeters was also associated with higher risk of earlier death, incident disease, and mobility disability.
Conclusions
Overall and abdominal obesity were important and potentially modifiable factors associated with dying or developing mobility disability and major chronic disease before age 85 years in older women.
doi:10.1001/jamainternmed.2013.12051
PMCID: PMC3963496  PMID: 24217806
3.  Effect of Dietary Restriction and Exercise on Lower Extremity Tissue Compartments in Obese, Older Women: A Pilot Study 
Background.
Accumulating evidence suggests that both dietary restriction and exercise (DR + E) should be incorporated in weight loss interventions to treat obese, older adults. However, more information is needed on the effects to lower extremity tissue composition—an important consideration for preserving mobility in older adults.
Methods.
Twenty-seven sedentary women (body mass index: 36.3±5.4kg/m2; age: 63.6±5.6 yrs) were randomly assigned to 6 months of DR + E or a health education control group. Thigh and calf muscle, subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT) size were determined using magnetic resonance imaging. Physical function was measured using a long-distance corridor walk and knee extension strength.
Results.
Compared with control, DR + E significantly reduced body mass (-6.6±3.7kg vs control: -0.05±3.5kg; p < .01). Thigh and calf muscle volumes responded similarly between groups. Within the DR + E group, adipose tissue was reduced more in the thigh than in the calf (p < .04). Knee extension strength was unaltered by DR + E, but a trend toward increased walking speed was observed in the DR + E group (p = .09). Post hoc analyses showed that reductions in SAT and IMAT within the calf, but not the thigh, were associated with faster walking speed achieved with DR + E (SAT: r = -0.62; p = .01; IMAT: r = -0.62; p = .01).
Conclusions.
DR + E preserved lower extremity muscle size and function and reduced regional lower extremity adipose tissue. Although the magnitude of reduction in adipose tissue was greater in the thigh than the calf region, post hoc analyses demonstrated that reductions in calf SAT and IMAT were associated with positive adaptations in physical function.
doi:10.1093/gerona/gls337
PMCID: PMC4158399  PMID: 23682155
Body composition; Weight loss; Obesity; Aging; Disability.
4.  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.
SUMMARY
Importance
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.
Objective
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.
Interventions
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.
Results
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
ClinicalsTrials.gov identifier NCT01072500.
doi:10.1001/jama.2014.5616
PMCID: PMC4266388  PMID: 24866862
5.  The LIFE Cognition Study: design and baseline characteristics 
Observational studies have shown beneficial relationships between exercise and cognitive function. Some clinical trials have also demonstrated improvements in cognitive function in response to moderate–high intensity aerobic exercise; however, these have been limited by relatively small sample sizes and short durations. The Lifestyle Interventions and Independence for Elders (LIFE) Study is the largest and longest randomized controlled clinical trial of physical activity with cognitive outcomes, in older sedentary adults at increased risk for incident mobility disability. One LIFE Study objective is to evaluate the effects of a structured physical activity program on changes in cognitive function and incident all-cause mild cognitive impairment or dementia. Here, we present the design and baseline cognitive data. At baseline, participants completed the modified Mini Mental Status Examination, Hopkins Verbal Learning Test, Digit Symbol Coding, Modified Rey–Osterrieth Complex Figure, and a computerized battery, selected to be sensitive to changes in speed of processing and executive functioning. During follow up, participants completed the same battery, along with the Category Fluency for Animals, Boston Naming, and Trail Making tests. The description of the mild cognitive impairment/dementia adjudication process is presented here. Participants with worse baseline Short Physical Performance Battery scores (prespecified at ≤7) had significantly lower median cognitive test scores compared with those having scores of 8 or 9 with modified Mini Mental Status Examination score of 91 versus (vs) 93, Hopkins Verbal Learning Test delayed recall score of 7.4 vs 7.9, and Digit Symbol Coding score of 45 vs 48, respectively (all P<0.001). The LIFE Study will contribute important information on the effects of a structured physical activity program on cognitive outcomes in sedentary older adults at particular risk for mobility impairment. In addition to its importance in the area of prevention of cognitive decline, the LIFE Study will also likely serve as a model for exercise and other behavioral intervention trials in older adults.
doi:10.2147/CIA.S65381
PMCID: PMC4154884  PMID: 25210447
exercise; physical activity; older adults; dementia
6.  Functional Language Networks in Sedentary and Physically Active Older Adults 
Functional magnetic resonance imaging (fMRI) studies have identified consistent age-related changes during various cognitive tasks, such that older individuals display more positive and less negative task-related activity than young adults. Recently, evidence shows that chronic physical exercise may alter aging-related changes in brain activity; however, the effect of exercise has not been studied for the neural substrates of language function. Additionally, the potential mechanisms by which aging alters neural recruitment remain understudied. To address these points, the present study enrolled elderly adults who were either sedentary or physically active to characterize the neural correlates of language function during semantic fluency between these groups in comparison to a young adult sample. Participants underwent fMRI during semantic fluency and transcranial magnetic stimulation to collect the ipsilateral silent period, a measure of interhemispheric inhibition. Results indicated that sedentary older adults displayed reductions in negative task-related activity compared to the active old group in areas of the attention network. Longer interhemispheric inhibition was associated with more negative task-related activity in the right and left posterior perisylvian cortex, suggesting that sedentary aging may result in losses in task facilitatory cortical inhibition. However, these losses may be mitigated by regular engagement in physical exercise.
doi:10.1017/S1355617713000246
PMCID: PMC3691286  PMID: 23458438
Cognitive aging; Physical activity; Functional magnetic resonance imaging; Semantic fluency; Attention network; Transcranial magnetic stimulation
7.  Age-related Differences in Lower Extremity Tissue Compartments and Associations with Physical Function in Older Adults 
Experimental gerontology  2011;47(1):38-44.
The lower extremities are important to performing physical activities of daily life. This study investigated lower extremity tissue composition, i.e. muscle and fat volumes, in young and older adults and the relative importance of individual tissue compartments to the physical function of older adults. A total of 43 older (age 78.3 ± 5.6 yr) and 20 younger (age 23.8 ± 3.9 yr) healthy men and women participated in the study. Older participants were further classified as either high- (HF) or low-functioning (LF) according to the Short Physical Performance Battery (SPPB). Magnetic resonance images were used to determine the volumes of skeletal muscle, subcutaneous fat (SAT), and intermuscular fat (IMAT) in the thigh (femoral) and calf (tibiofibular) regions. After adjusting for the sex of participants, younger participants had more femoral muscle mass than older adults (p < 0.001 for between group differences) as well as less femoral IMAT (p = 0.008) and tibiofibular IMAT (p < 0.001). Femoral muscle was the only tissue compartment demonstrating a significant difference between the two older groups, with HF participants having 31% more femoral muscle mass than LF participants (mean difference = 103.0 ± 34.0 cm3; p = 0.011). In subsequent multiple regression models including tissue compartments and demographic confounders, femoral muscle was the primary compartment associated with both SPPB score (r2 = 0.264, p= 0.001) and 4-meter gait speed (r2 = 0.187, p= 0.007). These data suggest that aging affects all lower extremity compartments, but femoral muscle mass is the major compartment associated with physical function in older adults.
doi:10.1016/j.exger.2011.10.001
PMCID: PMC3245356  PMID: 22015325
Aging; Sarcopenia; Older Adults; Disability; SPPB; IMAT
8.  Dynapenia and Aging: An Update 
In 2008, we published an article arguing that the age-related loss of muscle strength is only partially explained by the reduction in muscle mass and that other physiologic factors explain muscle weakness in older adults (Clark BC, Manini TM. Sarcopenia =/= dynapenia. J Gerontol A Biol Sci Med Sci. 2008;63:829–834). Accordingly, we proposed that these events (strength and mass loss) be defined independently, leaving the term “sarcopenia” to be used in its original context to describe the age-related loss of muscle mass. We subsequently coined the term “dynapenia” to describe the age-related loss of muscle strength and power. This article will give an update on both the biological and clinical literature on dynapenia—serving to best synthesize this translational topic. Additionally, we propose a working decision algorithm for defining dynapenia. This algorithm is specific to screening for and defining dynapenia using age, presence or absence of risk factors, a grip strength screening, and if warranted a test for knee extension strength. A definition for a single risk factor such as dynapenia will provide information in building a risk profile for the complex etiology of physical disability. As such, this approach mimics the development of risk profiles for cardiovascular disease that include such factors as hypercholesterolemia, hypertension, hyperglycemia, etc. Because of a lack of data, the working decision algorithm remains to be fully developed and evaluated. However, these efforts are expected to provide a specific understanding of the role that dynapenia plays in the loss of physical function and increased risk for disability among older adults.
doi:10.1093/gerona/glr010
PMCID: PMC3260480  PMID: 21444359
Strength; Weakness; Atrophy; Function; Disability
9.  Mitochondrial DNA sequence associations with dementia and amyloid-β in elderly African Americans 
Neurobiology of aging  2013;35(2):442.e1-442.e8.
Mitochondrial dysfunction occurs early in the course of several neurodegenerative diseases, and is potentially related to increased oxidative damage and amyloid-β (Aβ) formation in Alzheimer’s disease. The goals of this study were to assess mtDNA sequence associations with dementia risk, 10-year cognitive change, and markers of oxidative stress and Aβ among 1089 African-Americans in the population-based Health, Aging, and Body Composition Study. Participants were free of dementia at baseline, and incidence was determined in 187 (18%) cases over 10 to 12 follow-up years. Haplogroup L1 participants were at increased risk for developing dementia (odds ratio = 1.88, 95% confidence interval = 1.23–2.88, p = 0.004), lower plasma Aβ42 levels (p = 0.03), and greater 10-year decline on the Digit Symbol Substitution Test (p = 0.04) when compared with common haplogroup L3. The p.V193I, ND2 substitution was associated with significantly higher Aβ42 levels (p = 0.0012), and this association was present in haplogroup L3 (p = 0.018) but not L1 (p = 0.90) participants. All associations were independent of potential confounders, including APOEε4 status and nuclear genetic ancestry. Identification of mtDNA sequence variation associated with dementia risk and cognitive decline may contribute to the development of new treatment targets and diagnostic tests that identify responders to interventions targeting mitochondria.
doi:10.1016/j.neurobiolaging.2013.05.023
PMCID: PMC4019378  PMID: 24140124
Dementia; Mitochondria; mtDNA; Amyloid-β; Oxidative stress
10.  Mitochondrial DNA variation in human metabolic rate and energy expenditure 
Mitochondrion  2011;11(6):855-861.
The role of climate in driving selection of mtDNA as Homo sapiens migrated out of Africa into Eurasia remains controversial. We evaluated the role of mtDNA variation in resting metabolic rate (RMR) and total energy expenditure (TEE) among 294 older, community-dwelling African and European American adults from the Health, Aging and Body Composition Study. Common African haplogroups L0, L2 and L3 had significantly lower RMRs than European haplogroups H, JT and UK with haplogroup L1 RMR being intermediate to these groups. This study links mitochondrial haplogroups with ancestry-associated differences in metabolic rate and energy expenditure.
doi:10.1016/j.mito.2011.04.005
PMCID: PMC3998521  PMID: 21586348
Metabolic rate; Energetics; Mitochondria; Mitochondrial haplogroups; mtDNA; Oxidative phosphorylation
11.  Skeletal Muscle Mitochondrial Energetics Are Associated With Maximal Aerobic Capacity and Walking Speed in Older Adults 
Background.
Lower ambulatory performance with aging may be related to a reduced oxidative capacity within skeletal muscle. This study examined the associations between skeletal muscle mitochondrial capacity and efficiency with walking performance in a group of older adults.
Methods.
Thirty-seven older adults (mean age 78 years; 21 men and 16 women) completed an aerobic capacity (VO2 peak) test and measurement of preferred walking speed over 400 m. Maximal coupled (State 3; St3) mitochondrial respiration was determined by high-resolution respirometry in saponin-permeabilized myofibers obtained from percutanous biopsies of vastus lateralis (n = 22). Maximal phosphorylation capacity (ATPmax) of vastus lateralis was determined in vivo by 31P magnetic resonance spectroscopy (n = 30). Quadriceps contractile volume was determined by magnetic resonance imaging. Mitochondrial efficiency (max ATP production/max O2 consumption) was characterized using ATPmax per St3 respiration (ATPmax/St3).
Results.
In vitro St3 respiration was significantly correlated with in vivo ATPmax (r 2 = .47, p = .004). Total oxidative capacity of the quadriceps (St3*quadriceps contractile volume) was a determinant of VO2 peak (r 2 = .33, p = .006). ATPmax (r 2 = .158, p = .03) and VO2 peak (r 2 = .475, p < .0001) were correlated with preferred walking speed. Inclusion of both ATPmax/St3 and VO2 peak in a multiple linear regression model improved the prediction of preferred walking speed (r 2 = .647, p < .0001), suggesting that mitochondrial efficiency is an important determinant for preferred walking speed.
Conclusions.
Lower mitochondrial capacity and efficiency were both associated with slower walking speed within a group of older participants with a wide range of function. In addition to aerobic capacity, lower mitochondrial capacity and efficiency likely play roles in slowing gait speed with age.
doi:10.1093/gerona/gls196
PMCID: PMC3593613  PMID: 23051977
Muscle; Mitochondria; Aging; Walking speed.
12.  Neuromuscular determinants of maximum walking speed in well-functioning older adults 
Experimental gerontology  2013;48(3):358-363.
Maximum walking speed may offer an advantage over usual walking speed for clinical assessment of age-related declines in mobility function that are due to neuromuscular impairment. The objective of this study was to determine the extent to which maximum walking speed is affected by neuromuscular function of the lower extremities in older adults. We recruited two groups of healthy, well functioning older adults who differed primarily on maximum walking speed. We hypothesized that individuals with slower maximum walking speed would exhibit reduced lower extremity muscle size and impaired plantarflexion force production and neuromuscular activation during a rapid contraction of the triceps surae muscle group (soleus (SO) and gastrocnemius (MG)).
All participants were required to have usual 10-meter walking speed >1.0 m/s. If the difference between usual and maximum 10m walking speed was < 0.6 m/s, the individual was assigned to the “Slower” group (n=8). If the difference between usual and maximum 10-meter walking speed was > 0.6 m/s, the individual was assigned to the “Faster” group (n=12). Peak rate of force development (RFD) and rate of neuromuscular activation (rate of EMG rise) of the triceps surae muscle group were assessed during a rapid plantarflexion movement. Muscle cross sectional area of the right triceps surae, quadriceps and hamstrings muscle groups was determined by magnetic resonance imaging.
Across participants, the difference between usual and maximal walking speed was predominantly dictated by maximum walking speed (r=.85). We therefore report maximum walking speed (1.76 and 2.17 m/s in Slower and Faster, p<.001) rather than the difference between usual and maximal. Plantarflexion RFD was 38% lower (p=.002) in Slower compared to Faster. MG rate of EMG rise was 34% lower (p=.01) in Slower than Faster, but SO rate of EMG rise did not differ between groups (p=.73). Contrary to our hypothesis, muscle CSA was not lower in Slower than Faster for the muscle groups tested, which included triceps surae (p=.44), quadriceps (p=.76) and hamstrings (p=.98). MG rate of EMG rise was positively associated with RFD and maximum 10m walking speed, but not usual 10m walking speed.
These findings support the conclusion that maximum walking speed is limited by impaired neuromuscular force and activation of the triceps surae muscle group. Future research should further evaluate the utility of maximum walking speed for use in clinical assessment to detect and monitor age-related functional decline.
doi:10.1016/j.exger.2013.01.010
PMCID: PMC3594593  PMID: 23376102
aging; walking; mobility; muscle; electromyography
13.  ACTIVITY ENERGY EXPENDITURE AND INCIDENT COGNITIVE IMPAIRMENT IN OLDER ADULTS 
Archives of internal medicine  2011;171(14):1251-1257.
Introduction
Studies suggest that physically active people have reduced risk of incident cognitive impairment in late life. However, these studies are limited by reliance on subjective self-reports of physical activity, which only moderately correlate to objective measures and often exclude activity not readily quantifiable by frequency and duration. The objective of this study was to investigate the relationship between activity energy expenditure (AEE), an objective measure of total activity, and incidence of cognitive impairment.
Methods
We calculated AEE as 90% of total energy expenditure (assessed over two weeks using doubly-labeled water) minus resting metabolic rate (measured using indirect calorimetry) in 197 men and women (mean 74.8 years) who were free of mobility and cognitive impairments at study baseline (1998–2000). Cognitive function was assessed at baseline and 2 or 5 years later using the Modified Mini-Mental State Examination (3MS). Cognitive impairment was defined as a decline of >1.0 SD (9 points) between baseline and follow-up.
Results
After adjustment for baseline 3MS, demographics, fat free mass, sleep duration, self-reported health, and diabetes, older adults in the highest sex-specific tertile of AEE had lower odds of incident cognitive impairment than those in the lowest tertile (OR, 95% CI 0.09, 0.01–0.79). There was also a significant dose response between AEE and incidence of cognitive impairment (p-for-trend over tertiles=0.05).
Conclusions
These findings indicate that greater activity energy expenditure may be protective against cognitive impairment in a dose-response manner. The significance of overall activity in contrast to vigorous or light activity should be determined.
doi:10.1001/archinternmed.2011.277
PMCID: PMC3923462  PMID: 21771893
14.  European ancestry and resting metabolic rate in older African Americans 
Background/Objectives
Resting metabolic rate (RMR) contributes 60–80% of total energy expenditure and is consistently lower in populations of African descent compared with populations of European populations. Determination of European ancestry (EA) through SNP analysis would provide an initial step for identifying genetic associations that contribute to low RMR. We sought to evaluate the association between RMR and EA in African Americans.
Subjects/Methods
RMR was measured by indirect calorimetry in 141 African American men and women (aged 74.7 ± 3.0 years) enrolled in a substudy of the Health, Aging and Body Composition Study. Ancestry informative markers were used to estimate individual percent EA. Multivariate regression was used to assess the association between RMR and EA after adjustments for soft tissue fat-free mass (STFFM), fat mass, age, study site, physical activity level and sex.
Results
Mean EA was 23.8 ± 16% (range: 0.1% to 70.7%) and there were no differences by sex. Following adjustments, each percent EA was associated with a 1.6 kcal/day (95% Confidence interval: 0.42, 2.7 kcal/day) higher RMR (p = 0.008). This equates to a 160 kcal/day lower RMR in a population of completely African ancestry with one of completely European ancestry. Additional adjustment for trunk STFFM that partially accounts for high-metabolic rate organs did not affect this association.
Conclusions
European ancestry in African Americans is strongly associated with higher RMR. The data suggest that population differences in RMR may be due to genetic variants.
doi:10.1038/ejcn.2011.22
PMCID: PMC3915864  PMID: 21468093
Admixture; energy metabolism; body composition; genetic mapping
15.  Growth hormone responses to acute resistance exercise with vascular restriction in young and old men 
Objective
Resistance exercise (RE) stimulates growth hormone (GH) secretion in a load-dependent manner, with heavier loads producing larger GH responses. However, new research demonstrates that low-load RE performed with blood flow restriction (BFR) produces potent GH responses that are similar to or exceed those produced following high-load RE. We hypothesized that low-load RE with vascular restriction would attenuate the known age-related reduction in GH response to RE.
Design
In a randomized crossover design, ten young (28±7.8 years) and ten older (67.4±4.6 years) men performed bilateral knee extension RE with low-load [20% of one-repetition maximum (1RM)] with BFR and high-load (80% 1RM) without BFR. GH and lactate were measured every 10 minutes throughout a 150-minute testing session (30 minutes prior to and 120 minutes following completion of the exercise); IGF-I was measured at baseline and 60 minutes post-exercise.
Results
Area under the GH curve indicated that both age groups responded similarly to each exercise condition. However, young men had a significantly greater maximal GH response to low-load RE with BFR than the high-load condition without BFR. Additionally, younger men had greater maximal GH concentrations to low-load RE with BFR than older men (p=0.02). The GH responses were marginally correlated to lactate concentration (r=0.13, p=0.002) and IGF-I levels were unchanged with RE.
Conclusions
GH responses to low-load RE with vascular restriction are slightly higher than high-load RE without vascular restriction in young men. However, low-load RE with vascular restriction did not attenuate the known age-related reduction in GH response with exercise. These data suggest that while low-load RE with vascular restriction is as effective for inducing a GH response than traditionally-based high-load RE, there is a more potent response in young men.
doi:10.1016/j.ghir.2012.05.002
PMCID: PMC3915940  PMID: 22727808
KAATSU; Blood flow restriction; muscle; growth hormone; vascular; hypoxia; ischemia; endocrine
16.  Mobility decline in old age: A time to intervene 
doi:10.1097/JES.0b013e318279fdc5
PMCID: PMC3530168  PMID: 23262463
17.  Metabolic Cost of Daily Activities and Effect of Mobility Impairment in Older Adults 
Journal of the American Geriatrics Society  2011;59(11):10.1111/j.1532-5415.2011.03655.x.
OBJECTIVES
There is a shortage of information on metabolic costs of daily physical activities in older adults and the effect of having mobility impairments. The primary purpose of this study was to evaluate metabolic equivalent (MET) values on common daily tasks in men and women aged > 70 years compared to normative criteria. A secondary purpose was to determine the effect of having mobility impairments.
DESIGN
Cross-sectional observational study.
SETTING
University based research clinic
PARTICIPANTS
Forty-five participants aged 70 to 90 years of age (mean: 76.3 ± 5.1) volunteered to complete 17 daily activities, each lasting 10 minutes.
MEASUREMENTS
Oxygen consumption (VO2 = ml•kg−1•min−1) was measured through a mask by a portable gas analyzer and MET values were calculated as measured VO2/3.5 ml•kg−1•min−1. Values were compared to both normative values and between participants with and without mobility impairments.
RESULTS
Compared to the established normative criteria, measured METs were different in 14 of 17 tasks performed. Compared to measured METs, normative values underestimated walking leisurely (0.87 ± 0.12 METs) walking briskly (0.87 ± 0.12 METs ), and bed making (1.07 ± 0.10 METs ), but overestimated gardening (1.46 ± 0.12 METs) and climbing stairs (0.73 ± 0.18). Participants with impairments had significantly lower METs while gardening, vacuuming/sweeping, stair climbing, and walking briskly. However, when METs were adjusted for performance speed the metabolic costs were 16–27% higher for those with mobility impairments.
CONCLUSION
Compared to normative values, metabolic costs of daily activities are substantially different in older adults and having mobility impairments increases this metabolic cost. These results may have implications for practitioners to appropriately prescribe daily physical activities for healthy and mobility impaired older adults.
doi:10.1111/j.1532-5415.2011.03655.x
PMCID: PMC3874461  PMID: 22091979
Energy expenditure; Aging; Disability; Metabolic Efficiency
18.  Activity Energy Expenditure and Mobility Limitation in Older Adults: Differential Associations by Sex 
American Journal of Epidemiology  2009;169(12):1507-1516.
In this study, the authors aimed to determine whether higher activity energy expenditure, assessed by using doubly labeled water, was associated with a reduced decline in mobility limitation among 248 older community-dwelling US adults aged 70–82 years enrolled in 1998–1999. Activity energy expenditure was calculated as total energy expenditure (assessed over 2 weeks by using doubly labeled water) minus resting metabolic rate (measured with indirect calorimetry), with adjustment for the thermic effect of food. Across sex-specific tertiles of activity energy expenditure, men in the lowest activity group experienced twice the rate of mobility limitation as men in the highest activity group (41% (n = 18) vs. 18% (n = 8)). Conversely, women in the lowest and highest activity groups exhibited similarly high rates of mobility limitation (40% (n = 16) vs. 38% (n = 15)). After adjustment for potential confounders, men with higher activity energy expenditure levels continued to show reduced risk of mobility limitation (per standard deviation (284 kcal/day): hazard ratio = 0.61, 95% confidence interval: 0.41, 0.92). Women showed no association (per standard deviation (226 kcal/day): hazard ratio = 1.34, 95% confidence interval: 0.98, 1.85). Greater energy expenditure from any and all physical activity was significantly associated with reduced risk of developing mobility limitation among men, but not among women.
doi:10.1093/aje/kwp069
PMCID: PMC2733767  PMID: 19383938
aging; disability evaluation; energy metabolism; exercise; mobility limitation; motor activity; sex
19.  Role of self-efficacy and anxiety among pre-clinically disabled older adults when using compensatory strategies to complete daily tasks 
Classic developmental theory suggests that aging is associated with using compensatory strategies to prolong independence. While compensatory strategies are typically considered positive adaptations, they also signify an early phase in the disablement process — commonly known as pre-clinical disability. To build a better understanding of psychological constructs related to these early signs of disability, we examined the contribution of self-efficacy and state anxiety on using compensatory strategies among pre-clinically disabled older adults. Compensatory strategies were observed during performance of daily activities in 257 pre-clinically disabled older adults (67.6 ± 7.04), and self-efficacy and state anxiety were evaluated prior to performing each task. In univariate models, lower self-efficacy and higher anxiety were associated with more compensation (Spearman correlations: 0.15-0.48, p < 0.05). Multivariate logistic regression indicated that low self-efficacy [Odds Ratio (OR): 1.70; 95% Confidence Interval (CI): 1.40-2.08) and high anxiety (OR: 1.34; 95% CI: 1.10-1.63) were positively associated with using ≥ 6 compensatory strategies – a level signifying substantial compensation. When considered jointly with self-efficacy, the association with anxiety was reversed— higher anxiety demonstrated a lower likelihood of using compensation (OR: 0.70-0.73; 95% CI: 0.50-0.99). The addition of self-efficacy might remove the self-defeating cognitions characterizing anxiety allowing the remaining arousal component to appear beneficial. In conclusion, lower self-efficacy and higher anxiety are associated with using compensation to complete daily tasks among pre-clinically disabled older adults. Such psychological constructs may contribute to the use of compensatory strategies and represent future intervention targets to help reduce early signs of disability.
doi:10.1016/j.archger.2012.06.007
PMCID: PMC3433642  PMID: 22770713
disablement; confidence; state anxiety; functional task modification
20.  Models of Accelerated Sarcopenia: Critical Pieces for Solving the Puzzle of Age-Related Muscle Atrophy 
Ageing research reviews  2010;9(4):369-383.
Sarcopenia, the age-related loss of skeletal muscle mass, is a significant public health concern that continues to grow in relevance as the population ages. Certain conditions have the strong potential to coincide with sarcopenia to accelerate the progression of muscle atrophy in older adults. Among these conditions are co-morbid diseases common to older individuals such as cancer, kidney disease, diabetes, and peripheral artery disease. Furthermore, behaviors such as poor nutrition and physical inactivity are well-known to contribute to sarcopenia development. However, we argue that these behaviors are not inherent to the development of sarcopenia but rather accelerate its progression. In the present review, we discuss how these factors affect systemic and cellular mechanisms that contribute to skeletal muscle atrophy. In addition, we describe gaps in the literature concerning the role of these factors in accelerating sarcopenia progression. Elucidating biochemical pathways related to accelerated muscle atrophy may allow for improved discovery of therapeutic treatments related to sarcopenia.
doi:10.1016/j.arr.2010.04.004
PMCID: PMC3788572  PMID: 20438881
Aging; Proteolysis; Satellite Cells; HIV; COPD; Disability
21.  The Impact of Aging on Mitochondrial Function and Biogenesis Pathways in Skeletal Muscle of Sedentary High- and Low-Functioning Elderly Individuals 
Aging cell  2012;11(5):801-809.
Summary
Age-related loss of muscle mass and strength (sarcopenia) leads to a decline in physical function and frailty in the elderly. Among the many proposed underlying causes of sarcopenia, mitochondrial dysfunction is inherent in a variety of aged tissues. The intent of this study was to examine the effect of aging on key groups of regulatory proteins involved in mitochondrial biogenesis and how this relates to physical performance in two groups of sedentary elderly participants, classified as high- and low-functioning based on the Short Physical Performance Battery test. Muscle mass was decreased by 38% and 30% in low-functioning elderly (LFE) participants when compared to young and high-functioning elderly (HFE) participants, respectively, and positively correlated to physical performance. Mitochondrial respiration in permeabilized muscle fibers was reduced (41%) in the LFE group when compared to the young, and this was associated with a 30% decline in COX activity. Levels of key metabolic regulators, SIRT3 and PGC-1α were significantly reduced (50%) in both groups of elderly participants when compared to young. Similarly, the fusion protein OPA1 was lower in muscle from elderly subjects, however no changes were detected in Mfn2, Drp1 or Fis1 among the groups. In contrast, protein import machinery (PIM) components Tom22 and cHsp70 were increased in the LFE group when compared to the young. This study suggests that aging in skeletal muscle is associated with impaired mitochondrial function and altered biogenesis pathways, and that this may contribute to muscle atrophy and the decline in muscle performance observed in the elderly population.
doi:10.1111/j.1474-9726.2012.00844.x
PMCID: PMC3444680  PMID: 22681576
aging; sarcopenia; mitochondria; skeletal muscle; PGC-1α
22.  Promoting physical activity for elders with compromised function: the lifestyle Interventions and Independence for elders (LIFE) study physical activity intervention 
The Lifestyle Interventions and Independence for Elders (LIFE) Study is a Phase III randomized controlled clinical trial (Clinicaltrials.gov identifier: NCT01072500) that will provide definitive evidence regarding the effect of physical activity (PA) on major mobility disability in older adults (70–89 years old) who have compromised physical function. This paper describes the methods employed in the delivery of the LIFE Study PA intervention, providing insight into how we promoted adherence and monitored the fidelity of treatment. Data are presented on participants’ motives and self-perceptions at the onset of the trial along with accelerometry data on patterns of PA during exercise training. Prior to the onset of training, 31.4% of participants noted slight conflict with being able to meet the demands of the program and 6.4% indicated that the degree of conflict would be moderate. Accelerometry data collected during PA training revealed that the average intensity – 1,555 counts/minute for men and 1,237 counts/minute for women – was well below the cutoff point used to classify exercise as being of moderate intensity or higher for adults. Also, a sizable subgroup required one or more rest stops. These data illustrate that it is not feasible to have a single exercise prescription for older adults with compromised function. Moreover, the concept of what constitutes “moderate” exercise or an appropriate volume of work is dictated by the physical capacities of each individual and the level of comfort/stability in actually executing a specific prescription.
doi:10.2147/CIA.S49737
PMCID: PMC3775623  PMID: 24049442
aging; accelerometry; physical disability; compromised physical function; older adults
23.  Mitochondrial DNA sequence variation is associated with free-living activity energy expenditure in the elderly 
Biochimica et Biophysica Acta  2012;1817(9):1691-1700.
The decline in activity energy expenditure underlies a range of age-associated pathological conditions, neuromuscular and neurological impairments, disability, and mortality. The majority (90%) of the energy needs of the human body are met by mitochondrial oxidative phosphorylation (OXPHOS). OXPHOS is dependent on the coordinated expression and interaction of genes encoded in the nuclear and mitochondrial genomes. We examined the role of mitochondrial genomic variation in free-living activity energy expenditure (AEE) and physical activity levels (PAL) by sequencing the entire (~16.5 kilobases) mtDNA from 138 Health, Aging, and Body Composition Study participants. Among the common mtDNA variants, the hypervariable region 2 m.185G>A variant was significantly associated with AEE (p=0.001) and PAL (p=0.0005) after adjustment for multiple comparisons. Several unique nonsynonymous variants were identified in the extremes of AEE with some occurring at highly conserved sites predicted to affect protein structure and function. Of interest is the p.T194M, CytB substitution in the lower extreme of AEE occurring at a residue in the Qi site of complex III. Among participants with low activity levels, the burden of singleton variants was 30% higher across the entire mtDNA and OXPHOS complex I when compared to those having moderate to high activity levels. A significant pooled variant association across the hypervariable 2 region was observed for AEE and PAL. These results suggest that mtDNA variation is associated with free-living AEE in older persons and may generate new hypotheses by which specific mtDNA complexes, genes, and variants may contribute to the maintenance of activity levels in late life.
doi:10.1016/j.bbabio.2012.05.012
PMCID: PMC3389152  PMID: 22659402
metabolic rate; energy expenditure; mitochondria; mtDNA; oxidative phosphorylation; DNA sequencing
24.  Physical activity and neural correlates of aging: A combined TMS/fMRI study 
Behavioural brain research  2011;222(1):158-168.
Aerobic exercise has been suggested to ameliorate aging-related decline in humans. Recently, evidence has indicated chronological aging is associated with decreases in measures of interhemispheric inhibition during unimanual movements, but that such decreases may be mitigated by long-term physical fitness. The present study investigated measures of ipsilateral (right) primary motor cortex activity during right-hand movements using functional magnetic resonance imaging and transcranial magnetic stimulation (TMS). Healthy, right-handed participant groups were comprised of 12 sedentary older adults, 12 physically active older adults, and 12 young adults. Active older adults and younger adults evidenced longer ipsilateral silent periods (iSP) and less positive BOLD of ipsilateral motor cortex (iM1) as compared to sedentary older adults. Across groups, duration of iSP from TMS was inversely correlated with BOLD activity in iM1 during unimanual movement. These findings suggest that increased physical activity may have a role in decreasing aging-related losses of interhemispheric inhibition.
doi:10.1016/j.bbr.2011.03.042
PMCID: PMC3713467  PMID: 21440574
Aging; Physical activity; fMRI; TMS; Interhemispheric communication
25.  Longitudinal change in energy expenditure and effects on energy requirements of the elderly 
Nutrition Journal  2013;12:73.
Background
Very little is known about the longitudinal changes in energy requirements in late life. The purposes of this study were to: (1) determine the energy requirements in late life and how they changed during a 7 year time-span, (2) determine whether changes in fat free mass (FFM) were related to changes in resting metabolic rate (RMR), and (3) determine the accuracy of predicted total energy expenditure (TEE) to measured TEE.
Methods
TEE was assessed via doubly labeled water (DLW) technique in older adults in both 1999 (n = 302; age: 74 ± 2.9 yrs) and again in 2006 (n = 87 age: 82 ± 3.1 yrs). RMR was measured with indirect calorimetry, and body composition was assessed with dual-energy x-ray absorptiometry.
Results
The energy requirements in the 9th decade of life were 2208 ± 376 kcal/d for men and 1814 ± 337 kcal/d for women. This was a significant decrease from the energy requirements in the 8th decade of life in men (2482 ± 476 kcal/d vs. 2208 ± 376 kcal/d) but not in women (1892 ± 271 kcal/d vs. 1814 ± 337 kcal/d). In addition to TEE, RMR, and activity EE (AEE) also decreased in men, but not women, while FFM decreased in both men and women. The changes in FFM were correlated with changes in RMR for men (r = 0.49, p < 0.05) but not for women (r = −0.08, ns). Measured TEE was similar to Dietary Reference Intake (DRI) predicted TEE for men (2208 ± 56 vs. 2305 ± 35 kcal/d) and women (1814 ± 42 vs. 1781 ± 20 kcal/d). However, measured TEE was different than the World Health Organization (WHO) predicted TEE in men (2208 ± 56 vs. 2915 ± 31 kcal/d (p < 0.05)) and women (1814 ± 42 vs. 2315 ± 21 kcal/d (p < 0.05)).
Conclusions
TEE, RMR and AEE decreased in men, but not women, from the 8th to 9th decade of life. The DRI equation to predict TEE was comparable to measured TEE, while the WHO equation over-predicted TEE in our elderly population.
doi:10.1186/1475-2891-12-73
PMCID: PMC3679966  PMID: 23742706
Doubly labeled water; Energy expenditure; Elderly; Energy requirements

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