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author:("paho, Marco")
1.  Ankle Brachial Index Values, Leg Symptoms, and Functional Performance Among Community‐Dwelling Older Men and Women in the Lifestyle Interventions and Independence for Elders Study 
Background
The prevalence and significance of low normal and abnormal ankle brachial index (ABI) values in a community‐dwelling population of sedentary, older individuals is unknown. We describe the prevalence of categories of definite peripheral artery disease (PAD), borderline ABI, low normal ABI, and no PAD and their association with lower‐extremity functional performance in the LIFE Study population.
Methods and Results
Participants age 70 to 89 in the LIFE Study underwent baseline measurement of the ABI, 400‐m walk, and 4‐m walking velocity. Participants were classified as follows: definite PAD (ABI <0.90), borderline PAD (ABI 0.90 to 0.99), low normal ABI (ABI 1.00 to 1.09), and no PAD (ABI 1.10 to 1.40). Of 1566 participants, 220 (14%) had definite PAD, 250 (16%) had borderline PAD, 509 (33%) had low normal ABI, and 587 (37%) had no PAD. Among those with definite PAD, 65% were asymptomatic. Adjusting for age, sex, race, body mass index, smoking, and comorbidities, lower ABI was associated with longer mean 400‐m walk time: (definite PAD=533 seconds; borderline PAD=514 seconds; low normal ABI=503 seconds; and no PAD=498 seconds [P<0.001]). Among asymptomatic participants with and without PAD, lower ABI values were also associated with longer 400‐m walk time (P<0.001) and slower walking velocity (P=0.042).
Conclusion
Among older community‐dwelling men and women, 14% had PAD and 49% had borderline or low normal ABI values. Lower ABI values were associated with greater functional impairment, suggesting that lower extremity atherosclerosis may be a common preventable cause of functional limitations in older people.
Clinical Trial Registration
URL: http://clinicaltrials.gov/ Unique identifier: NCT01072500.
doi:10.1161/JAHA.113.000257
PMCID: PMC3886743  PMID: 24222666
aging; exercise; peripheral vascular disease
2.  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
3.  Total and Abdominal Adiposity Are Associated With Inflammation in Older Adults Using a Factor Analysis Approach 
Background.
Obesity-related increases in multiple inflammatory markers may contribute to the persistent subclinical inflammation common with advancing age. However, it is unclear if a specific combination of markers reflects the underlying inflammatory state. We used factor analysis to identify inflammatory factor(s) and examine their associations with adiposity in older adults at risk for disability.
Methods.
Adiponectin, CRP, IL-1ra, IL-1sRII, IL-2sRα, IL-6, IL-6sR, IL-8, IL-15, sTNFRI, sTNFRII, and TNF-α were measured in 179 participants from the Lifestyle Interventions and Independence for Elders Pilot (Mean ± SD age 77 ± 4 years, 76% white, 70% women). Body mass index, waist circumference, and total fat mass were assessed by anthropometry and dual-energy x-ray absorptiometry.
Results.
IL-2sRα, sTNFRI, and sTNFRII loaded highest on the first factor (factor 1). CRP, IL-1ra, and IL-6 loaded highest on the second factor (factor 2). Factor 2, but not factor 1, was positively associated with 1-SD increments in waist circumference (β = 0.160 ± 0.057, p = .005), body mass index (β = 0.132 ± 0.053, p = .01), and total fat mass (β = 0.126 ± 0.053, p = .02) after adjusting for age, gender, race/ethnicity, site, smoking, anti-inflammatory medications, comorbidity index, health-related quality of life, and physical function. These associations remained significant after further adjustment for grip strength, but only waist circumference remained associated with inflammation after adjusting for total lean mass. There were no significant interactions between adiposity and muscle mass or strength for either factor.
Conclusions.
Greater total and abdominal adiposity are associated with higher levels of an inflammatory factor related to CRP, IL-1ra, and IL-6 in older adults, which may provide a clinically useful measure of inflammation in this population.
doi:10.1093/gerona/gls077
PMCID: PMC3437966  PMID: 22451470
Aging; Adiposity; Inflammation; Muscle impairment; Factor analysis
4.  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
5.  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
6.  Making preventive medicine more personalized: implications for exercise-related research 
Preventive medicine  2012;55(1):34-36.
Objective
This commentary offers a discussion of the need to consider behavioral interventions such as physical exercise as integral components of personalized medicine.
Methods
We discuss the concept of personalized medicine and review existing evidence of variability in response to exercise training.
Results
We argue that increased understanding is needed regarding sources of variability in exercise responsiveness, and that such understanding should lead to more tailored, often multi-modal interventions.
Conclusion
Studies of personalized medicine to date have primarily investigated heterogeneity in drug responsiveness; we believe it is time to begin considering preventive strategies such as exercise within a broader scope of personalized care.
doi:10.1016/j.ypmed.2012.05.001
PMCID: PMC3612277  PMID: 22588227
Personalized Medicine; Physical Activity; Non-responder; Genomics; Phenomics
7.  Lipid Peroxidation and Depressed Mood in Community-Dwelling Older Men and Women 
PLoS ONE  2013;8(6):e65406.
It has been hypothesized that cellular damage caused by oxidative stress is associated with late-life depression but epidemiological evidence is limited. In the present study we evaluated the association between urinary 8-iso-prostaglandin F2α (8-iso-PGF2α), a biomarker of lipid peroxidation, and depressed mood in a large sample of community-dwelling older adults. Participants were selected from the Health, Aging and Body Composition study, a community-based longitudinal study of older persons (aged 70–79 years). The present analyses was based on a subsample of 1027 men and 948 women free of mobility disability. Urinary concentration of 8-iso-PGF2α was measured by radioimmunoassay methods and adjusted for urinary creatinine. Depressed mood was defined as a score greater than 5 on the 15-item Geriatric Depression Scale and/or use of antidepressant medications. Depressed mood was present in 3.0% of men and 5.5% of women. Depressed men presented higher urinary concentrations of 8-iso-PGF2α than non-depressed men even after adjustment for multiple sociodemographic, lifestyle and health factors (p = 0.03, Cohen’s d = 0.30). This association was not present in women (depressed status-by-sex interaction p = 0.04). Our study showed that oxidative damage may be linked to depression in older men from a large sample of the general population. Further studies are needed to explore whether the modulation of oxidative stress may break down the link between late-life depression and its deleterious health consequences.
doi:10.1371/journal.pone.0065406
PMCID: PMC3679197  PMID: 23776478
8.  Oxidative Damage, Platelet Activation, and Inflammation to Predict Mobility Disability and Mortality in Older Persons: Results From the Health Aging and Body Composition Study 
Background.
Inflammation, oxidative damage, and platelet activation are hypothesized biological mechanisms driving the disablement process. The aim of the present study is to assess whether biomarkers representing these mechanisms predicted major adverse health-related events in older persons.
Methods.
Data are from 2,234 community-dwelling nondisabled older persons enrolled in the Health Aging and Body Composition study. Biomarkers of lipid peroxidation (ie, urinary levels of 8-iso-prostaglandin F2α), platelet activation (ie, urinary levels of 11-dehydro-thromboxane B2), and inflammation (serum concentrations of interleukin-6) were considered as independent variables of interest and tested in Cox proportional hazard models as predictors of (severe) mobility disability and overall mortality.
Results.
The sample’s (women 48.0%, whites 64.3%) mean age was 74.6 (SD 2.9) years. During the follow-up (median 11.4 years), 792 (35.5%), 269 (12.0%), and 942 (42.2%) events of mobility disability, severe mobility disability, and mortality occurred, respectively. Only interleukin-6 showed significant independent associations with the onset of all the study outcomes. Higher levels of urinary 8-iso-prostaglandin F2α and 11-dehydro-thromboxane B2 independently predicted increased risk of death (hazard ratio 1.10, 95% confidence interval 1.03–1.19 and hazard ratio 1.14, 95% confidence interval 1.06–1.23, respectively). No significant interactions of gender, race, cardiovascular disease, diabetes, and antiplatelet drugs were detected on the studied relationships.
Conclusions.
The inflammatory marker interleukin-6 is confirmed to be a robust predictor for the onset of negative health-related events. Participants with higher urinary levels of 8-iso-prostaglandin F2α and 11-dehydro-thromboxane B2 presented a higher mortality risk.
doi:10.1093/gerona/glr246
PMCID: PMC3348494  PMID: 22389462
Oxidative damage; Platelet activation; Inflammation; Disability; Mortality
9.  Angiotensin-Converting Enzyme Inhibitor Use by Older Adults Is Associated with Greater Functional Responses to Exercise 
OBJECTIVES
To assess the association between angiotensin converting enzyme inhibitors (ACEis) and improvements in the physical function of older adults in response to chronic exercise training.
DESIGN
Secondary analysis of the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) study, a multisite randomized clinical trial to evaluate the effects of chronic exercise on the physical function of older adults at risk for mobility disability.
SETTING
Four academic research centers within the United States.
PARTICIPANTS
Four hundred twenty-four individuals aged 70 to 89 with mild to moderate functional impairments categorized for this analysis as ACEi users, users of other antihypertensive drugs, or antihypertensive nonusers.
INTERVENTION
A 12-month intervention of structured physical activity (PA) or health education promoting successful aging (SA).
MEASUREMENTS
Change in walking speed during a 400-m test and performance on a battery of short-duration mobility tasks (Short Physical Performance Battery (SPPB)).
RESULTS
Physical activity significantly improved the adjusted walking speed of ACEi users (P < .001) but did not of nonusers. PA improved the adjusted SPPB score of ACEi users (P < .001) and of persons who used other antihypertensive drugs (P = .005) but not of antihypertensive nonusers (P = .91). The percentage of ACEi users deriving clinically significant benefit from exercise training for walking speed (30%) and SPPB score (48%) was dramatically higher than for nonusers (14% and 12%, respectively).
CONCLUSION
For older adults at risk for disability, exercise-derived improvements in physical function were greater for ACEi users than users of other antihypertensive drugs and antihypertensive nonusers.
doi:10.1111/j.1532-5415.2012.04045.x
PMCID: PMC3625953  PMID: 22726232
aging; exercise; physical function; LIFE Study; ACE inhibitors
10.  Effects of a 12-Month Physical Activity Intervention on Prevalence of Metabolic Syndrome in Elderly Men and Women 
Background.
There is a lack of information on whether exercise training alone can reduce the prevalence of metabolic syndrome (MetS) in elderly men and women.
Methods.
This study was an ancillary to the Lifestyle Interventions and Independence for Elders Pilot Study, a four-site, single-blind, randomized controlled clinical trial comparing a 12-month physical activity (PA) intervention (N = 180) with a successful aging intervention (N = 181) in elderly (70–89 years) community-dwelling men and women at risk for physical disability. The PA intervention included aerobic, strength, and flexibility exercises, with walking as the primary mode. MetS was defined using the National Cholesterol Education Program criteria.
Results.
There was no significant change in body weight or fat mass after either intervention. The trend of MetS prevalence over the intervention period was similar between PA and successful aging groups (p = .77). Overall, the prevalence of MetS decreased significantly from baseline to 6 months (p = .003) but did not change further from 6- to 12-month visits (p = .11). There were no group differences in any individual MetS components (p > .05 for all group by visit interactions). However, in individuals not using medications at any visit to treat MetS components, those in the PA intervention had lower odds of having MetS than those in the successful aging group during follow-up (odds ratio = 0.28, 95% confidence interval = 0.08–0.96).
Conclusions.
In this sample, a 12-month PA intervention did not reduce the prevalence of MetS more than a successful aging intervention, perhaps due to the large proportion of individuals taking medications for treating MetS components.
doi:10.1093/gerona/glr187
PMCID: PMC3309873  PMID: 22024949
Metabolic syndrome; Elderly; Physical activity
11.  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
12.  Muscle Strength and BMI as Predictors of Major Mobility Disability in the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) 
Background.
Muscle weakness and obesity are two significant threats to mobility facing the increasing number of older adults. To date, there are no studies that have examined the association of strength and body mass index (BMI) on event rates on a widely used performance measure of major mobility disability.
Methods.
This study was a secondary analysis of a randomized controlled trial in which sedentary functionally limited participants (70–89 years, Short Physical Performance Battery ≤ 9) who were able to complete a 400-m walk test at baseline were randomized to a physical activity or health education intervention and reassessed for major mobility disability every 6 months for up to 18 months. We evaluated whether baseline grip strength and BMI predicted failure to complete the 400-m walk test in 15 minutes or less (major mobility disability).
Results.
Among N = 406 participants with baseline measures, lower grip strength was associated with an increased risk for developing major mobility disability, with and without covariate adjustment (p < .01): The hazard ratio (95% confidence interval) for the lowest versus high sex-specific quartile of grip strength was 6.11 (2.24–16.66). We observed a U-shaped relationship between baseline BMI and the risk of developing major mobility disability, such that the risk for participants with a BMI of 25–29 kg/m2 was approximately half that of participants with BMI less than 25 or 30 kg/m2 or more (p = .04 in fully adjusted analyses).
Conclusions.
Our data highlight the importance of muscle weakness, low BMI, and obesity as risk factors for major mobility disability in older adults. Being overweight may be protective for major mobility disability.
doi:10.1093/gerona/glr158
PMCID: PMC3210962  PMID: 21975090
Physical disability; Physical activity; Older adults
13.  Biomarkers of sarcopenia in clinical trials—recommendations from the International Working Group on Sarcopenia 
Sarcopenia, the age-related skeletal muscle decline, is associated with relevant clinical and socioeconomic negative outcomes in older persons. The study of this phenomenon and the development of preventive/therapeutic strategies represent public health priorities. The present document reports the results of a recent meeting of the International Working Group on Sarcopenia (a task force consisting of geriatricians and scientists from academia and industry) held on June 7–8, 2011 in Toulouse (France). The meeting was specifically focused at gaining knowledge on the currently available biomarkers (functional, biological, or imaging-related) that could be utilized in clinical trials of sarcopenia and considered the most reliable and promising to evaluate age-related modifications of skeletal muscle. Specific recommendations about the assessment of aging skeletal muscle in older people and the optimal methodological design of studies on sarcopenia were also discussed and finalized. Although the study of skeletal muscle decline is still in a very preliminary phase, the potential great benefits derived from a better understanding and treatment of this condition should encourage research on sarcopenia. However, the reasonable uncertainties (derived from exploring a novel field and the exponential acceleration of scientific progress) require the adoption of a cautious and comprehensive approach to the subject.
doi:10.1007/s13539-012-0078-2
PMCID: PMC3424187  PMID: 22865205
14.  An Exploratory Analysis of the Effects of a Weight Loss Plus Exercise Program on Cellular Quality Control Mechanisms in Older Overweight Women 
Rejuvenation Research  2011;14(3):315-324.
Abstract
Obese older adults are particularly susceptible to sarcopenia and have a higher prevalence of disability than their peers of normal weight. Interventions to improve body composition in late life are crucial to maintaining independence. The main mechanisms underlying sarcopenia have not been determined conclusively, but chronic inflammation, apoptosis, and impaired mitochondrial function are believed to play important roles. It has yet to be determined whether impaired cellular quality control mechanisms contribute to this process. The objective of this study was to assess the effects of a 6-month weight loss program combined with moderate-intensity exercise on the cellular quality control mechanisms autophagy and ubiquitin-proteasome, as well as on inflammation, apoptosis, and mitochondrial function, in the skeletal muscle of older obese women. The intervention resulted in significant weight loss (8.0 ± 3.9 % vs. 0.4 ± 3.1% of baseline weight, p = 0.002) and improvements in walking speed (reduced time to walk 400 meters, − 20.4 ± 16% vs. − 2.5 ± 12%, p = 0.03). In the intervention group, we observed a three-fold increase in messenger RNA (mRNA) levels of the autophagy regulators LC3B, Atg7, and lysosome-associated membrane protein-2 (LAMP-2) compared to controls. Changes in mRNA levels of FoxO3A and its targets MuRF1, MAFBx, and BNIP3 were on average seven-fold higher in the intervention group compared to controls, but these differences were not statistically significant. Tumor necrosis factor-α (TNF-α) mRNA levels were elevated after the intervention, but we did not detect significant changes in the downstream apoptosis markers caspase 8 and 3. Mitochondrial biogenesis markers (PGC1α and TFAm) were increased by the intervention, but this was not accompanied by significant changes in mitochondrial complex content and activity. In conclusion, although exploratory in nature, this study is among the first to report the stimulation of cellular quality control mechanisms elicited by a weight loss and exercise program in older obese women.
doi:10.1089/rej.2010.1132
PMCID: PMC3136739  PMID: 21631380
15.  Skeletal Muscle Apoptotic Signaling Predicts Thigh Muscle Volume and Gait Speed in Community-Dwelling Older Persons: An Exploratory Study 
PLoS ONE  2012;7(2):e32829.
Background
Preclinical studies strongly suggest that accelerated apoptosis in skeletal myocytes may be involved in the pathogenesis of sarcopenia. However, evidence in humans is sparse. In the present study, we investigated whether apoptotic signaling in the skeletal muscle was associated with indices of muscle mass and function in older persons.
Methodology/Principal Findings
Community-dwelling older adults were categorized into high-functioning (HF) or low-functioning (LF) groups according to their short physical performance battery (SPPB) summary score. Participants underwent an isokinetic knee extensor strength test and 3-dimensional magnetic resonance imaging of the thigh. Vastus lateralis muscle samples were obtained by percutaneous needle biopsy and assayed for the expression of a set of apoptotic signaling proteins. Age, sex, number of comorbid conditions and medications as well as knee extensor strength were not different between groups. HF participants displayed greater thigh muscle volume compared with LF persons. Multivariate partial least squares (PLS) regressions showed significant correlations between caspase-dependent apoptotic signaling proteins and the muscular percentage of thigh volume (R2 = 0.78; Q2 = 0.61) as well as gait speed (R2 = 0.81; Q2 = 0.56). Significant variables in the PLS model of percent muscle volume were active caspase-8, cleaved caspase-3, cytosolic cytochrome c and mitochondrial Bak. The regression model of gait speed was mainly described by cleaved caspase-3 and mitochondrial Bax and Bak. PLS predictive apoptotic variables did not differ between functional groups. No correlation was determined between apoptotic signaling proteins and muscle strength or quality (strength per unit volume).
Conclusions/Significance
Data from this exploratory study show for the first time that apoptotic signaling is correlated with indices of muscle mass and function in a cohort of community-dwelling older persons. Future larger-scale studies are needed to corroborate these preliminary findings and determine if down-regulation of apoptotic signaling in skeletal myocytes will provide improvements in the muscle mass and functional status of older persons.
doi:10.1371/journal.pone.0032829
PMCID: PMC3289676  PMID: 22389725
16.  Body Composition Measures from CT and Inflammation 
Obesity (Silver Spring, Md.)  2009;17(5):1062-1069.
Background
A growing body of evidence has consistently shown a correlation between obesity and chronic sub-clinical inflammation. Several studies have suggested that measures of body fat distribution, rather than overall adiposity, may be more closely associated with inflammation level.
Objective
To investigate the relationship between levels of inflammatory markers and specific measures of abdominal visceral and subcutaneous fat and thigh intermuscular and subcutaneous fat of older white and black adults.
Design
Data of 2,651 black and white men and women aged 70-79 participating in the Health, Aging and Body Composition (Health ABC) study were used. Levels of the inflammatory markers, IL-6, CRP, and TNF-α were obtained from blood samples. The areas of abdominal visceral and subcutaneous fat and thigh intermuscular and subcutaneous fat were quantified on CT images. Linear regression analysis was used to evaluate the cross-sectional relationship between each body composition measure and serum levels of inflammatory markers in the four race/gender groups.
Results
Abdominal visceral adiposity was most consistently associated with significantly higher IL-6 and CRP levels in all race/gender groups (p<0.05). Thigh intermuscular fat had an inconsistent but significant association with inflammation, and there was a trend toward lower inflammation level with increasing thigh subcutaneous fat in white and black women.
Conclusions
Despite the previously established differences in abdominal fat distribution across gender and race, visceral fat remained a significant predictor of inflammatory marker level across all four subgroups examined.
doi:10.1038/oby.2008.627
PMCID: PMC3268118  PMID: 19165157
17.  Long-Term Physical Activity and Inflammatory Biomarkers in Older Adults 
Purpose
To determine the effects of a 12-month physical activity intervention on inflammatory biomarkers in elderly men and women.
Methods
424 elderly (aged 70–89 years), nondisabled, community-dwelling men and women at risk for physical disability were enrolled in a multicenter, single-blind, randomized controlled-trial. Participants were randomized to participate in either a 12-month moderate-intensity physical activity (PA) intervention or a successful aging (SA) health education intervention. Biomarkers of inflammation (IL-6sR, IL-1sRII, sTNFRI, sTNFRII, IL-8, IL-15, adiponectin, IL-1ra, IL-2sRα, and TNF-α) were measured at baseline, 6 and 12 months.
Results
A baseline blood sample was successfully collected from 368 participants. After adjustment for gender, clinic site, diabetes status, and baseline outcome measure, IL-8 was the only inflammatory biomarker affected by the PA intervention (p=0.03). The adjusted mean IL-8 at month 12 was 9.9% (0.87 pg/mL) lower in the PA compared to the SA group. Secondary interaction analyses between baseline biomarker status and treatment showed one significant interaction (p=0.02) such that the PA intervention reduced IL-15 concentrations in participants with a baseline IL-15 above the median value of 1.67 pg/mL. However, these associations were no longer significant after consideration for multiple comparisons.
Conclusions
Overall, this study does not provide definitive evidence for an effect of regular exercise for altering systemic concentrations of the measured inflammatory biomarkers in older adults.
doi:10.1249/MSS.0b013e3181e3ac80
PMCID: PMC2964389  PMID: 20421832
exercise; aging; inflammation; cytokines; soluble receptors
18.  The Impact of Behavioral Intervention on Obesity Mediated Declines in Mobility Function: Implications for Longevity 
Journal of Aging Research  2011;2011:392510.
A primary focus of longevity research is to identify prognostic risk factors that can be mediated by early treatment efforts. To date, much of this work has focused on understanding the biological processes that may contribute to aging process and age-related disease conditions. Although such processes are undoubtedly important, no current biological intervention aimed at increasing health and lifespan exists. Interestingly, a close relationship between mobility performance and the aging process has been documented in older adults. For example, recent studies have identified functional status, as assessed by walking speed, as a strong predictor of major health outcomes, including mortality, in older adults. This paper aims to describe the relationship between the comorbidities related to decreased health and lifespan and mobility function in obese, older adults. Concurrently, lifestyle interventions, including diet and exercise, are described as a means to improve mobility function and thereby limit the functional limitations associated with increased mortality.
doi:10.4061/2011/392510
PMCID: PMC3195552  PMID: 22013527
19.  PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1): A KEY FACTOR LINKING FIBRINOLYSIS AND AGE-RELATED SUBCLINICAL AND CLINICAL CONDITIONS 
Cardiovascular therapeutics  2010;28(5):e72-e91.
The close relationship existing between aging and thrombosis has growingly been studied in this last decade. The age-related development of a pro-thrombotic imbalance in the fibrinolysis homeostasis has been hypothesized at the basis of this increased cardiovascular and cerebrovascular risk. Fibrinolysis is the resulting of the interactions among multiple plasminogen activators and inhibitors constituing the enzymatic cascade, and ultimately leading to the degradation of fibrin. The plasminogen activator system plays a key role in a wide range of physiological and pathological processes. Plasminogen activator inhibitor-1 (PAI-1) is a member of the superfamily of serine-protease inhibitors (or serpins), and the principal inhibitor of both the tissue-type and the urinary-type plasminogen activator, the two plasminogen activators able to activate plasminogen. In this review, current evidence describing the central role played by PAI-1 in a number of age-related subclinical (i.e., inflammation, atherosclerosis, insulin resistance) and clinical (i.e., obesity, comorbidities, Werner syndrome) conditions is presented. Despite some controversial and unclear issues, PAI-1 represents an extremely promising marker which may become a biological parameter to be growingly considered in the prognostic evaluation, in the disease monitoring, and as treatment target of age-related conditions in the next future.
doi:10.1111/j.1755-5922.2010.00171.x
PMCID: PMC2958211  PMID: 20626406
20.  The Lifestyle Interventions and Independence for Elders Study: Design and Methods 
Background.
As the number of older adults in the United States rises, maintaining functional independence among older Americans has emerged as a major clinical and public health priority. Older people who lose mobility are less likely to remain in the community; demonstrate higher rates of morbidity, mortality, and hospitalizations; and experience a poorer quality of life. Several studies have shown that regular physical activity improves functional limitations and intermediate functional outcomes, but definitive evidence showing that major mobility disability can be prevented is lacking. A Phase 3 randomized controlled trial is needed to fill this evidence gap.
Methods.
The Lifestyle Interventions and Independence for Elders (LIFE) Study is a Phase 3 multicenter randomized controlled trial designed to compare a supervised moderate-intensity physical activity program with a successful aging health education program in 1,600 sedentary older persons followed for an average of 2.7 years.
Results.
LIFE's primary outcome is major mobility disability, defined as the inability to walk 400 m. Secondary outcomes include cognitive function, serious fall injuries, persistent mobility disability, the combined outcome of major mobility disability or death, disability in activities of daily living, and cost-effectiveness.
Conclusions.
Results of this study are expected to have important public health implications for the large and growing population of older sedentary men and women.
doi:10.1093/gerona/glr123
PMCID: PMC3193523  PMID: 21825283
Disability; Physical activity; Exercise; Geriatrics; Physical function
21.  Effects of a weight loss plus exercise program on physical function in overweight, older women: a randomized controlled trial 
Background:
Obesity and a sedentary lifestyle are associated with physical impairments and biologic changes in older adults. Weight loss combined with exercise may reduce inflammation and improve physical functioning in overweight, sedentary, older adults. This study tested whether a weight loss program combined with moderate exercise could improve physical function in obese, older adult women.
Methods:
Participants (N = 34) were generally healthy, obese, older adult women (age range 55–79 years) with mild to moderate physical impairments (ie, functional limitations). Participants were randomly assigned to one of two groups for 24 weeks: (i) weight loss plus exercise (WL+E; n = 17; mean age = 63.7 years [4.5]) or (ii) educational control (n = 17; mean age = 63.7 [6.7]). In the WL+E group, participants attended a group-based weight management session plus three supervised exercise sessions within their community each week. During exercise sessions, participants engaged in brisk walking and lower-body resistance training of moderate intensity. Participants in the educational control group attended monthly health education lectures on topics relevant to older adults. Outcomes were: (i) body weight, (ii) walking speed (assessed by 400-meter walk test), (iii) the Short Physical Performance Battery (SPPB), and (iv) knee extension isokinetic strength.
Results:
Participants randomized to the WL+E group lost significantly more weight than participants in the educational control group (5.95 [0.992] vs 0.23 [0.99] kg; P < 0.01). Additionally, the walking speed of participants in the WL+E group significantly increased compared with that of the control group (reduction in time on the 400-meter walk test = 44 seconds; P < 0.05). Scores on the SPPB improved in both the intervention and educational control groups from pre- to post-test (P < 0.05), with significant differences between groups (P = 0.02). Knee extension strength was maintained in both groups.
Conclusion:
Our findings suggest that a lifestyle-based weight loss program consisting of moderate caloric restriction plus moderate exercise can produce significant weight loss and improve physical function while maintaining muscle strength in obese, older adult women with mild to moderate physical impairments.
doi:10.2147/CIA.S17001
PMCID: PMC3131984  PMID: 21753869
obesity; weight loss; physical function; oxidative stress; inflammation; walking speed
22.  Psychomotor Speed and Functional Brain MRI 2 Years After Completing a Physical Activity Treatment 
Background.
Short-term adherence to physical activity (PA) in older adults improves psychomotor processing abilities and is associated with greater brain activation. It is not known whether these associations are also significant for longer-term adherence to moderate-intensity activities.
Methods.
We measured the cross-sectional association of regular walking with brain activation while performing the digit symbol substitution test (DSST). Participants of the lifestyle interventions and independence for elders—pilot study were examined 2 years after completing a 1-year treatment, consisting of either PA or education in successful aging (SA). Data were obtained from 20 PA participants who reported having remained active for 2 years after the end of the treatment and from 10 SA participants who reported having remained sedentary during the same period (mean age: 81.5 and 80.8 years). Complete brain activation and behavioral data were available for 17 PA and 10 SA participants.
Results.
Two years after the formal intervention had ended, the PA group engaged in more minutes of moderate activity and had significantly greater DSST score and higher brain activation within regions important for processing speed (left dorsolateral prefrontal, posterior parietal, and anterior cingulate cortices). Associations were independent of self-reported health, blood pressure, cognition, medication records, gray matter atrophy, and white matter hyperintensities.
Conclusions.
Persistent engagement in PA may have beneficial effects on psychomotor processing speed and brain activation, even for moderate levels and even when started late in life. Future studies are warranted to assess whether these beneficial effects are explained by delayed neuronal degeneration and/or new neurogenesis.
doi:10.1093/gerona/glq038
PMCID: PMC2869531  PMID: 20348185
Physical activity; Sedentary; fMRI; Executive control function; Older adults
23.  Physical activity and maintaining physical function in older adults 
doi:10.1136/bjsm.2008.053736
PMCID: PMC3104323  PMID: 18927164
24.  A Cost Analysis of a Physical Activity Intervention for Older Adults 
We examined the costs of a physical activity (PA) and an educational comparison intervention. 424 older adults at risk for mobility disability were randomly assigned to either condition. The PA program consisted of center-based exercise sessions 3× weekly for 8 weeks, 2× weekly for weeks 9 to 24 and weekly behavioral counseling for 10 weeks. Optional sessions were offered during maintenance weeks (25–52). The comparison intervention consisted of weekly education meetings for 24 weeks, and then monthly for 6 months. Cost analyses were conducted from the “payer’s” perspective, with a 1-year time horizon. Intervention costs were estimated by tracking personnel activities and materials used for each intervention and multiplying by national unit cost averages. The average cost/participant was $1134 and $175 for the PA and the comparison interventions, respectively. A preliminary cost/effectiveness analysis gauged the cost/disability avoided to be $28,206. Costs for this PA program for older adults are comparable to those of other PA interventions. The results are preliminary and a longer study is required to fully assess the costs and health benefits of these interventions.
PMCID: PMC3091594  PMID: 20101920
aging; health behavior; physical activity; interventions
25.  Maximal Fitness Testing in Sedentary Elderly at Substantial Risk of Disability: LIFE-P Study Experience 
Background
The authors sought to evaluate the acceptability and feasibility of maximal fitness testing in sedentary older individuals at risk for mobility disability.
Methods
Maximal cycle-ergometer testing was performed at baseline and 6 and 12 months later in a subset of LIFE-P study participants at the Cooper Institute site. The mean age of the 20 participants (80% female) tested was 74.7 ± 3.4 years. The following criteria were used to determine whether participants achieved maximal effort: respiratory-exchange ratio (RER) ≥1.1, heart rate within 10 beats/min of the maximal level predicted by age, and rating of perceived exertion (RPE) >17.
Results
Participants’ mean peak VO2 was 12.1 (3.7) mL · kg–1 · min–1. At baseline testing, only 20% of participants attained an RER ≥1.10, only 35% achieved a peak heart rate within 10 beats of their age-predicted maximum, and 18% had an RPE of >17. Subsequent testing at 6 and 12 months produced similar results.
Conclusions
In this pilot study of sedentary older persons at risk for mobility disability, very few participants were able to achieve maximal effort during graded cycle-ergometer testing.
PMCID: PMC3056455  PMID: 19033602

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