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1.  Multiple pathways to the same end: Mechanisms of myonuclear apoptosis in sarcopenia of aging 
TheScientificWorldJournal  2010;10:340-349.
Sarcopenia, the age-related decline in muscle mass and function, represents a significant health issue due to the high prevalence of frailty and disability associated with this condition. Nevertheless, the cellular mechanisms responsible for the loss of muscle mass in old age are still largely unknown. An altered regulation of myocyte apoptosis has recently emerged as a possible contributor to the pathogenesis of sarcopenia. Studies in animal models have shown that the severity of skeletal muscle apoptosis increases over the course of aging and correlates with the degree of muscle mass and strength decline. Several apoptotic pathways are operative in aged muscles, with the mitochondria- and TNF-α-mediated pathways likely being the most relevant to sarcopenia. However, despite the growing number of studies on the subject, a definite mechanistic link between myocyte apoptosis and age-related muscle atrophy has not yet been established. Furthermore, the evidence on the role played by apoptosis in human sarcopenia is still sparse. Clearly, further research is required to better define the involvement of myocyte apoptosis in the pathogenesis of muscle loss at advanced age. This knowledge will likely help in the design of more effective therapeutic strategies to preserve muscle mass into old age, thus fostering independence of the elderly population and reducing the socioeconomic burden associated with sarcopenia.
doi:10.1100/tsw.2010.27
PMCID: PMC4311890  PMID: 20191247
aging; sarcopenia; myonuclear apoptosis; mitochondria; tumor necrosis factor-alpha (TNF-α); caspases; endonuclease G (EndoG); apoptosis inducing factor (AIF)
2.  EFFECTS OF ACE-INHIBITION ON IGF-1 AND IGFBP-3 CONCENTRATIONS IN OLDER ADULTS WITH HIGH CARDIOVASCULAR RISK PROFILE 
Objectives
The present study evaluates the effects of a 6-month treatment with an ACE-inhibitor (ie, fosinopril) on serum concentrations of total IGF-1 and IGF binding protein (IGFBP)-3 in older adults at high risk for cardiovascular disease.
Design
Data are from the Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN) study, a double-blind, crossover, randomized, placebo-controlled trial.
Setting
Participants were recruited from the communities of Winston Salem, NC, and Greensboro, NC.
Participants
Subjects ≥55 years old with high cardiovascular disease risk profile.
Intervention
The intervention consisted of 6-month administration of fosinopril vs. placebo.
Measurements
Serum concentrations of total IGF-1 and IGFBP-3 were measured in 100 participants of the TRAIN study at baseline, 6-month and 12-month follow-up visits. Differences in total IGF-1 and IGFBP-3 concentrations were assessed using two-sided paired t-tests.
Results
The mean age of participants (47% women) was 66.5 (standard deviation 7.2) years. Serum concentrations of total IGF-1 were significantly higher after 6-month treatment with fosinopril compared to placebo (203.73 ng/mL vs 194.24 ng/mL; p=0.02): After ACE-inhibitor intervention, significantly higher serum IGFBP-3 concentrations compared to controls (4308.81 ng/mL vs 4086.93 ng/mL; p=0.03) were also reported.
Conclusions
A six-month treatment with fosinopril increases systemic levels of total IGF-1 and IGFBP-3 in older adults with high cardiovascular risk profile. This may represent a potential biological explanation to the beneficial effects of ACE-inhibition on stroke, ischemic heart disease and insulin resistance.
PMCID: PMC4311891  PMID: 20617288
Angiotensin Converting Enzyme inhibitor; Insulin like growth factor 1; Insulin like growth factor binding protein 3; older adults
3.  Mitochondrial dysfunction and sarcopenia of aging: from signaling pathways to clinical trials 
Sarcopenia, the age-related loss of muscle mass and function, imposes a dramatic burden on individuals and society. The development of preventive and therapeutic strategies against sarcopenia is therefore perceived as an urgent need by health professionals and has instigated intensive research on the pathophysiology of this syndrome. The pathogenesis of sarcopenia is multifaceted and encompasses lifestyle habits, systemic factors (e.g., chronic inflammation and hormonal alterations), local environment perturbations (e.g., vascular dysfunction), and intramuscular specific processes. In this scenario, derangements in skeletal myocyte mitochondrial function are recognized as major factors contributing to the age-dependent muscle degeneration. In this review, we summarize prominent findings and controversial issues on the contribution of specific mitochondrial processes – including oxidative stress, quality control mechanisms and apoptotic signaling – on the development of sarcopenia. Extramuscular alterations accompanying the aging process with a potential impact on myocyte mitochondrial function are also discussed. We conclude with presenting methodological and safety considerations for the design of clinical trials targeting mitochondrial dysfunction to treat sarcopenia. Special emphasis is placed on the importance of monitoring the effects of an intervention on muscle mitochondrial function and identifying the optimal target population for the trial.
doi:10.1016/j.biocel.2013.06.024
PMCID: PMC3759621  PMID: 23845738
mitophagy; vascular dysfunction; fusion and fission; apoptosis; biomarkers
4.  Screening, diagnosis and treatment of osteoporosis: a brief review 
Summary
Osteoporosis is a highly prevalent condition characterized by decreases in bone mass and microarchitectural alterations. Bone fractures, especially of the hip and vertebrae, are the most burdensome complications of osteoporosis, being associated with high risk of disability, institutionalization and mortality. The detection of osteoporosis relies on the quantification of bone mineral density via imaging techniques such as dual-energy X-ray absorptiometry. However, therapeutic decision-making should be based on a comprehensive fracture risk assessment, which may be obtained through validated algorithms. Once the decision of treating has been taken, non-pharmacological strategies should be implemented together with the prescription of anti-osteoporotic agents. Numerous drugs are currently available to treat osteoporosis and the choice of a specific compound should be guided by efficacy and safety considerations. The present review provides a concise synopsis of the current evidence in the management of osteoporosis, from screening to drug prescription. Novel anti-osteoporotic agents are also briefly presented.
PMCID: PMC4269144  PMID: 25568654
vitamin D; denosumab; bisphosphonates; teriparatide; strontium ranelate
5.  Late-life enalapril administration induces nitric oxide-dependent and independent metabolic adaptations in the rat skeletal muscle 
Age  2012;35(4):1061-1075.
Recently, we showed that administration of the angiotensin-converting enzyme inhibitor enalapril to aged rats attenuated muscle strength decline and mitigated apoptosis in the gastrocnemius muscle. The aim of the present study was to investigate possible mechanisms underlying the muscle-protective effects of enalapril. We also sought to discern the effects of enalapril mediated by nitric oxide (NO) from those independent of this signaling molecule. Eighty-seven male Fischer 344 × Brown Norway rats were randomly assigned to receive enalapril (n = 23), the NO synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME; n = 22), enalapril + l-NAME (n = 19), or placebo (n = 23) from 24 to 27 months of age. Experiments were performed on the tibialis anterior muscle. Total NOS activity and the expression of neuronal, endothelial, and inducible NOS isoforms (nNOS, eNOS, and iNOS) were determined to investigate the effects of enalapril on NO signaling. Transcript levels of tumor necrosis factor-alpha (TNF-α) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were assessed to explore actions of enalapril on inflammation and mitochondrial biogenesis, respectively. Protein expression of energy-sensing and insulin signaling mediators, including protein kinase B (Akt-1), phosphorylated Akt-1 (pAkt-1), mammalian target of rapamycin (mTOR), AMP-activated protein kinase subunit alpha (AMPKα), phosphorylated AMPKα (pAMPKα), and the glucose transporter GLUT-4, was also determined. Finally, the generation of hydrogen peroxide (H2O2) was quantified in subsarcolemmal (SSM) and intermyofibrillar (IFM) mitochondria. Enalapril increased total NOS activity, which was prevented by l-NAME co-administration. eNOS protein content was enhanced by enalapril, but not by enalapril + l-NAME. Gene expression of iNOS was down-regulated by enalapril either alone or in combination with l-NAME. In contrast, protein levels of nNOS were unaltered by treatments. The mRNA abundance of TNF-α was reduced by enalapril relative to placebo, with no differences among any other group. PCG-1α gene expression was unaffected by enalapril and lowered by enalapril + l-NAME. No differences in protein expression of Akt-1, pAkt-1, AMPKα, pAMPKα, or GLUT-4 were detected among groups. However, mTOR protein levels were increased by enalapril compared with placebo. Finally, all treatment groups displayed reduced SSM, but not IFM H2O2 production relative to placebo. Our data indicate that enalapril induces a number of metabolic adaptations in aged skeletal muscle. These effects result from the concerted modulation of NO and angiotensin II signaling, rather than from a dichotomous action of enalapril on the two pathways. Muscle protection by enalapril administered late in life appears to be primarily mediated by mitigation of oxidative stress and pro-inflammatory signaling.
doi:10.1007/s11357-012-9428-4
PMCID: PMC3705103  PMID: 22639176
Aging; Nitric oxide synthase (NOS) isoforms; Mitochondria; mTOR; Glucose tolerance; l-NAME; Inflammation; ACE inhibitors
6.  Correlation between compliance and brace treatment in juvenile and adolescent idiopathic scoliosis: SOSORT 2014 award winner 
Scoliosis  2014;9:6.
Background
Over the last years, evidence has accumulated in support of bracing as an effective treatment option in patients with idiopathic scoliosis. Yet, little information is available on the impact of compliance on the outcome of conservative treatment in scoliotic subjects. The aim of the present study was to prospectively evaluate the association between compliance to brace treatment and the progression of scoliotic curve in patients with idiopathic adolescent (AIS) or juvenile scoliosis (JIS).
Methods
Among 1.424 patients treated for idiopathic scoliosis, 645 were eligible for inclusion criteria. Three outcomes were distinguished in agreement with the SRS criteria: curve correction, curve stabilization and curve progression. Brace wearing was assessed by one orthopaedic surgeon (LA) and scored on a standardized form. Compliance to treatment was categorized as complete (brace worn as prescribed), incomplete A (brace removed for 1 month), incomplete B (brace removed for 2 months), incomplete C (brace removed during school hours), and incomplete D (brace worn overnight only). Chi square test, T test or ANOVA and ANOVA for repeated measures tests were used as statistical tests.
Results
The results from our study showed that at follow-up the compliance was: Complete 61.1%; Incomplete A 5.2%; Incomplete B 10.7%; Incomplete C 14.2%; Incomplete D 8.8%. Curve correction was accomplished in 301/319 of Complete, 19/27 Incomplete A, 25/56 Incomplete B, 52/74 Incomplete C, 27/46 Incomplete D. Cobb mean value was 29.8 ± 7.5 SD at beginning and 17.1 ± 10.9 SD at follow-up. Both Cobb and Perdriolle degree amelioration was significantly higher in patients with complete compliance over all other groups, both in juvenile, both in adolescent scoliosis. In the intention-to-treat analysis, the rate of surgical treatment was 2.1% among patients with definite outcome and 12.1% among those with drop-out. Treatment compliance showed significant interactions with time.
Conclusion
Curve progression and referral to surgery are lower in patients with high brace compliance. Bracing discontinuation up to 1 month does not impact on the treatment outcome. Conversely, wearing the brace only overnight is associated with a high rate of curve progression.
doi:10.1186/1748-7161-9-6
PMCID: PMC4080685  PMID: 24995038
Compliance; Juvenile idiopathic scoliosis; Adolescent idiopathic scoliosis; PASB brace; Conservative treatment
7.  Brace treatment in juvenile idiopathic scoliosis: a prospective study in accordance with the SRS criteria for bracing studies - SOSORT award 2013 winner 
Scoliosis  2014;9:3.
Background
The Juvenile idiopathic scoliosis by age of onset, severity and evolutivity is source of great doubts concerning the purpose and use of conservative treatment. The different clinical experiences leave unsolved the question that arises in applying a conservative treatment when the patients are effectively forward a long growing period, in scoliosis characterized by inevitable evolutivity. The purpose of the present prospective study was to determine the effectiveness of conservative treatment in Juvenile idiopathic scoliosis.
Methods
From 1238 patients treated for idiopathic scoliosis between 1995 and 2012 fulfill the inclusion criteria 163 patients treated with PASB, Lyon brace and Milwaukee. Of these, 113 patients had a definite outcome, 27 have abandoned treatment e 23 are still in treatment. The minimum follow-up was 24 months. Radiographs were used to estimate the curve magnitude (CM) and the torsion of the apical vertebra (TA) at 5 time points: beginning (t1), 6 months after the beginning (t2), intermediate time between t1 and t4 (t3), end of weaning (t4), 2-years minimum follow-up (t5). Three outcomes were distinguished in agreement with SRS criteria: correction, stabilization and progression.
Results
The results from our study showed that of the 113 patients with a definite outcome CM mean value was 29.6 ± 7.5 SD at t1 and 16.9 ± 11.1 SD at t5. TA was 13.5 ± 5.4 SD at t1 and 8.5 ± 5.6 at t5. The variations between CM t5-t1 and TA t5-t1 were statistically significantly different. Curve correction was accomplished in 88 patients (77.8%), stabilization was obtained in 18 patients (15.9%). 7 patients (6.19%) have a progression and 4 of these were recommended for surgery. Of 26 patients who abandoned the treatment, at the time of abandonment (12.5 age) have achieved curve correction in 19 cases (70.0%), stabilization in 5 cases (19%) and progression in 3 cases (11%). Of these patients, reviewed at the end of growing, four have been operated on.
Conclusions
Our study confirmed that conservative treatment with brace is highly effective in treating juvenile idiopathic scoliosis, in particular most patients reaching a complete curve correction and only 4.9% of patients need surgery.
doi:10.1186/1748-7161-9-3
PMCID: PMC4016774  PMID: 24817906
Juvenile idiopathic scoliosis; Scoliosis research society criteria (SRS); PASB brace; Lyon brace; SOSORT guidelines; Conservative treatment
8.  Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy 
Biological chemistry  2013;394(3):393-414.
Muscle loss during aging and disuse is a highly prevalent and disabling condition, but knowledge about cellular pathways mediating muscle atrophy is still limited. Given the postmitotic nature of skeletal myocytes, the maintenance of cellular homeostasis relies on the efficiency of cellular quality control mechanisms. In this scenario, alterations in mitochondrial function are considered a major factor underlying sarcopenia and muscle atrophy. Damaged mitochondria are not only less bioenergetically efficient, but also generate increased amounts of reactive oxygen species, interfere with cellular quality control mechanisms, and display a greater propensity to trigger apoptosis. Thus, mitochondria stand at the crossroad of signaling pathways that regulate skeletal myocyte function and viability. Studies on these pathways have sometimes provided unexpected and counterintuitive results, which suggests that they are organized into a complex, heterarchical network that is currently insufficiently understood. Untangling the complexity of such a network will likely provide clinicians with novel and highly effective therapeutics to counter the muscle loss associated with aging and disuse. In this review, we summarize the current knowledge on the mechanisms whereby mitochondrial dysfunction intervenes in the pathogenesis of sarcopenia and disuse atrophy, and highlight the prospect of targeting specific processes to treat these conditions.
doi:10.1515/hsz-2012-0247
PMCID: PMC3976204  PMID: 23154422
apoptosis; autophagy; fission; fusion; mitophagy; oxidative stress
9.  Sarcopenia and Physical Frailty: Two Sides of the Same Coin 
doi:10.3389/fnagi.2014.00192
PMCID: PMC4112807  PMID: 25120482
elderly; aging; disability; preventive medicine; physical performance; geriatric assessment; skeletal muscle; definition and concepts
10.  Shorter Telomeres in Peripheral Blood Mononuclear Cells from Older Persons with Sarcopenia: Results from an Exploratory Study 
Background: Telomere shortening in peripheral blood mononuclear cells (PBMCs) has been associated with biological age and several chronic degenerative diseases. However, the relationship between telomere length and sarcopenia, a hallmark of the aging process, is unknown. The aim of the present study was therefore to determine whether PBMC telomeres obtained from sarcopenic older persons were shorter relative to non-sarcopenic peers. We further explored if PBMC telomere length was associated with frailty, a major clinical correlate of sarcopenia.
Methods: Analyses were conducted in 142 persons aged ≥65 years referred to a geriatric outpatient clinic (University Hospital). The presence of sarcopenia was established according to the European Working Group on Sarcopenia in Older People criteria, with bioelectrical impedance analysis used for muscle mass estimation. The frailty status was determined by both the Fried’s criteria (physical frailty, PF) and a modified Rockwood’s frailty index (FI). Telomere length was measured in PBMCs by quantitative real-time polymerase chain reaction according to the telomere/single-copy gene ratio (T/S) method.
Results: Among 142 outpatients (mean age 75.0 ± 6.5 years, 59.2% women), sarcopenia was diagnosed in 23 individuals (19.3%). The PF phenotype was detected in 74 participants (52.1%). The average FI score was 0.46 ± 0.17. PBMC telomeres were shorter in sarcopenic subjects (T/S = 0.21; 95% CI: 0.18–0.24) relative to non-sarcopenic individuals (T/S = 0.26; 95% CI: 0.24–0.28; p = 0.01), independent of age, gender, smoking habit, or comorbidity. No significant associations were determined between telomere length and either PF or the FI.
Conclusion: PBMC telomere length, expressed as T/S values, is shorter in older outpatients with sarcopenia. The cross-sectional assessment of PBMC telomere length is not sufficient at capturing the complex, multidimensional syndrome of frailty.
doi:10.3389/fnagi.2014.00233
PMCID: PMC4147848  PMID: 25221511
frailty; biological age; muscle aging; oxidative stress; inflammation; bioelectrical impedance analysis
11.  Pre-Hospital Dietary Intake Correlates with Muscle Mass at the Time of Fracture in Older Hip-Fractured Patients 
Background: Failure to meet an adequate dietary intake is involved in the pathogenesis of sarcopenia and osteoporosis, which in turn increase the risk for falls and fractures, respectively. Older people with hip fracture are often protein-malnourished at hospitalization. Whether low protein-energy intake is associated with muscle atrophy in hip-fractured patients is presently unknown. This information is necessary for the development of novel strategies to manage this especially vulnerable patient population. The aim of this study was, therefore, to explore the relationship between dietary intake and muscle mass in older hip-fractured patients.
Methods: Analyses were conducted in hip-fractured elderly admitted to an orthopedic and trauma surgery ward (University Hospital). Muscle mass was estimated by bioelectrical impedance analysis within 24 h from admission. Dietary information was collected via 24-h dietary recall and nutrient intake calculated by a nutrition software.
Results: Among 62 hip-fractured patients (mean age 84.6 ± 7.6 years, 84% women), the average energy intake was 929.2 ± 170.3 Kcal day−1, with higher values reported by men (1.046.8 ± 231.4 Kcal day−1) relative to women (906.5 ± 148.3 Kcal day−1; p = 0.01). Absolute and normalized protein intake was 50.0 ± 13.5 g day−1 and 0.88 ± 0.27 g kg (body weight)–1 day–1, respectively, with no gender differences. A positive correlation was determined between total energy intake and muscle mass (r = 0.384; p = 0.003). Similarly, protein and leucine consumption was positively correlated with muscle mass (r = 0.367 and 0.311, respectively; p = 0.005 for both).
Conclusion: A low intake of calories, protein, and leucine is associated with reduced muscle mass in hip-fractured elderly. Given the relevance of sarcopenia as a risk factor for adverse outcomes in this patient population, our findings highlight the importance of a comprehensive dietary assessment for the detection of nutritional deficits predisposing to or aggravating muscle atrophy.
doi:10.3389/fnagi.2014.00269
PMCID: PMC4236534  PMID: 25477815
sarcopenia; diet; recommended dietary allowance; leucine; disability; malnutrition; bioelectrical impedance analysis; muscle atrophy
12.  Mitochondrial iron accumulation with age and functional consequences 
Aging cell  2008;7(5):706-716.
Summary
During the aging process, an accumulation of non-heme iron disrupts cellular homeostasis and contributes to the mitochondrial dysfunction typical of various neuromuscular degenerative diseases. Few studies have investigated the effects of iron accumulation on mitochondrial integrity and function in skeletal muscle and liver tissue. Thus, we isolated liver mitochondria (LM), as well as quadriceps-derived subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM), from male Fischer 344× Brown Norway rats at 8, 18, 29 and 37 months of age. Non-heme iron content in SSM, IFM and LM was significantly higher with age, reaching a maximum at 37 months of age. The mitochondrial permeability transition pore (mPTP) was more susceptible to the opening in aged mitochondria containing high levels of iron (i.e. SSM and LM) compared to IFM. Furthermore, mitochondrial RNA oxidation increased significantly with age in SSM and LM, but not in IFM. Levels of mitochondrial RNA oxidation in SSM and LM correlated positively with levels of mitochondrial iron, whereas a significant negative correlation was observed between the maximum Ca2+ amounts needed to induce mPTP opening and iron contents in SSM, IFM and LM. Overall, our data suggest that age-dependent accumulation of mitochondrial iron may increase mitochondrial dysfunction and oxidative damage, thereby enhancing the susceptibility to apoptosis.
PMCID: PMC3849824  PMID: 18843794
mitochondrial aging; mitochondrial iron homeostasis; mitochondrial permeability transition pore; mitochondrial RNA; oxidative stress; skeletal muscle subsarcolemmal and interfibrillar mitochondria
13.  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
14.  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
15.  Anorexia of Aging: A Modifiable Risk Factor for Frailty 
Nutrients  2013;5(10):4126-4133.
Anorexia of aging, defined as a loss of appetite and/or reduced food intake, affects a significant number of elderly people and is far more prevalent among frail individuals. Anorexia recognizes a multifactorial origin characterized by various combinations of medical, environmental and social factors. Given the interconnection between weight loss, sarcopenia and frailty, anorexia is a powerful, independent predictor of poor quality of life, morbidity and mortality in older persons. One of the most important goals in the management of older, frail people is to optimize their nutritional status. To achieve this objective it is important to identify subjects at risk of anorexia and to provide multi-stimulus interventions that ensure an adequate amount of food to limit and/or reverse weight loss and functional decline. Here, we provide a brief overview on the relevance of anorexia in the context of sarcopenia and frailty. Major pathways supposedly involved in the pathogenesis of anorexia are also illustrated. Finally, the importance of treating anorexia to achieve health benefits in frail elders is highlighted.
doi:10.3390/nu5104126
PMCID: PMC3820063  PMID: 24128975
elderly; sarcopenia; ghrelin; malnutrition; weight loss; disability; energy metabolism
16.  Molecular Inflammation: Underpinnings of Aging and Age-related Diseases 
Ageing research reviews  2008;8(1):18-30.
Recent scientific studies have advanced the notion of chronic inflammation as a major risk factor underlying aging and age-related diseases. In this review, low-grade, unresolved, molecular inflammation is described as an underlying mechanism of aging and age-related diseases, which may serve as a bridge between normal aging and age-related pathological processes. Accumulated data strongly suggest that continuous (chronic) up-regulation of pro-inflammatory mediators (e.g., TNF-α, IL-1β, 6, COX-2, iNOS) are induced during the aging process due to an age-related redox imbalance that activates many pro-inflammatory signaling pathways, including the NF-κB signaling pathway. These pro-inflammatory molecular events are discussed in relation to their role as basic mechanisms underlying aging and age-related diseases. Further, the anti-inflammatory actions of aging-retarding caloric restriction and exercise are reviewed. Thus, the purpose of this review is to describe the molecular roles of age-related physiological functional declines and the accompanying chronic diseases associated with aging. This new view on the role of molecular inflammation as a mechanism of aging and age-related pathogenesis can provide insights into potential interventions that may affect the aging process and reduce age-related diseases, thereby promoting healthy longevity.
doi:10.1016/j.arr.2008.07.002
PMCID: PMC3782993  PMID: 18692159
molecular inflammation; aging; calorie restriction; exercise; cytokines; oxidative stress; inflammatory diseases; age-related diseases; obesity; sarcopenia; dementia; atherosclerosis; cancer; osteoporosis
18.  Clinical management and surgical treatment of distal fibular tumours: a case series and review of the literature 
International Orthopaedics  2012;36(9):1907-1913.
Purpose
Study reports clinical and functional outcomes of surgical treatment in a case series of nine patients with distal fibular tumours.
Methods
Nine patients with distal fibular tumours were observed between 2005 and 2010. A PubMed search was performed using the terms “fibula”, “lower limb tumour [cancer]”, “sarcoma”, “Ewing”, “peroneal”, “fibular metastasis”, and “limb-salvage surgery”.
Results
In all our patients, lesions were unilateral. All patients complained of pain; limping was present in 5 of 9 tumours. Patients were managed surgically, except one who underwent local radiotherapy. In six patients, a benign or tumor-like lesion was detected. Malignancies consisted of metastatic lung adenocarcinoma (two cases) or multifocal mesenchymal cancer (one case). Non-malignant lesions were treated by curettage and filling, followed by internal fixation when needed. In malignant or locally aggressive lesions, metadiaphyseal fibular resection was performed. The literature search retrieved either case reports or small case series, reflecting the rarity of distal fibular tumours. Surgical treatment was successful in all patients with benign lesions, whereas the rate of success was 40–100 % in case of malignancies.
Conclusions
Given the low incidence of distal fibular tumours, controversies exist about the optimal surgical management. Clinical observation and imaging should be reserved to asymptomatic benign lesions. In non-malignant tumours causing pain, limping, and pathological fractures; in malignancies, surgery is recommended. Finally, in patients with asymptomatic lesions of uncertain nature, biopsy and histological examination should be performed to plan appropriate management.
doi:10.1007/s00264-012-1536-3
PMCID: PMC3427430  PMID: 22527336
19.  Contribution of impaired mitochondrial autophagy to cardiac aging: mechanisms and therapeutic opportunities 
Circulation Research  2012;110(8):1125-1138.
The prevalence of cardiovascular disease (CVD) increases with advancing age. While the long-term exposure to cardiovascular risk factors plays a major role in the etiopathogenesis of CVD, intrinsic cardiac aging enhances the susceptibility to developing heart pathologies in late life. The progressive decline of cardiomyocyte mitochondrial function is considered to be a major mechanism underlying heart senescence. Damaged mitochondria not only produce less ATP, but also generate increased amounts of reactive oxygen species (ROS) and display a greater propensity to trigger apoptosis. Given the post-mitotic nature of cardiomyocytes, the efficient removal of dysfunctional mitochondria is critical for the maintenance of cell homeostasis, as damaged organelles cannot be diluted by cell proliferation. The only known mechanism whereby mitochondria are turned over is through macroautophagy (MA). The efficiency of this process declines with advancing age which may play a critical role in heart senescence as well as in age-related CVD. This review illustrates the putative mechanisms whereby alterations in the autophagic removal of damaged mitochondria intervene in the process of cardiac aging as well as in the pathogenesis of specific heart diseases especially prevalent in late life (e.g., left ventricular hypertrophy, ischemic heart disease, heart failure, and diabetic cardiomyopathy). Interventions proposed to counter cardiac aging through improvements in MA (e.g., calorie restriction and calorie restriction mimetics) are also presented.
doi:10.1161/CIRCRESAHA.111.246108
PMCID: PMC3353545  PMID: 22499902
heart senescence; mitophagy; oxidative stress; resveratrol; calorie restriction
20.  Misdiagnosis of soft tissue sarcomas of the lower limb associated with deep venous thrombosis: report of two cases and review of the literature 
Background
Deep venous thrombosis (DVT) or pulmonary embolism (PE) is a rare, but not exceptional presentation of soft tissue sarcomas (STSs). Due to the remarkable difference in the incidence between DVT or PE and STSs, this type of STS presentation is usually associated with a considerable delay in tumor diagnosis and treatment.
Case Presentation
We describe two cases of STS who presented with DVT and PE. Physical and radiographic examination only showed the presence of DVT. Both patients were treated for DVT or PE for several months. Due to the persistence of symptoms and the inefficacy of anticoagulant therapy, magnetic resonance imaging (MRI) was performed, which revealed the presence of a lower limb mass in both cases. The definite diagnosis was reached via excisional biopsy and histological examination.
In one case, MRI showed a large tumor in the anterior muscle compartment of the right thigh, with thrombosis of the right common femoral vein and involvement of the ipsilateral common iliac vein and inferior vena cava until the confluence of the renal veins. In the other case, MRI showed a large tumor in the middle third of the right thigh. The lesion was in close proximity to the superficial femoral vein that appeared compressed and showed signs of thrombosis. In both cases, histological examination revealed a high-grade leiomyosarcoma.
Conclusion
STSs of the lower extremities can rarely present with DVT or PE. This possibility should be considered in the differential diagnosis of painful leg swelling, especially in patients with recurrent or refractory venous thrombosis. When a STS is suspected, MRI should be obtained followed by excisional biopsy of the eventual mass. A delay in diagnosis and treatment of STSs often results in very poor prognosis.
Level of evidence. IV
doi:10.1186/1471-2474-14-64
PMCID: PMC3599198  PMID: 23421389
Leiomyosarcoma; Venous thromboembolism; Lower extremity sarcoma; Pulmonary embolism
21.  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
22.  Usefulness of Preclinical Models for Assessing the Efficacy of Late-Life Interventions for Sarcopenia 
Caloric restriction and physical exercise have proven beneficial against age-associated changes in body composition and declining physical performance; however, little is known regarding what benefit these interventions might have when initiated late in life. The study of mimetics of diet and exercise and the combination thereof may provide additional treatments for a vulnerable elderly population; however, how and when to initiate such interventions requires consideration in developing the most safe and efficacious treatment strategies. In this review, we focus on preclinical late-life intervention studies, which assess the relationship between physical function, sarcopenia, and body composition. We provide a conceptual framework for the ever-changing definition of sarcopenia and a rationale for the use of an appropriate rodent model of this condition. We finish by providing our perspective regarding the implications of this body of work and future areas of research that may also contribute to the ultimate goal of extending healthspan.
doi:10.1093/gerona/glr042
PMCID: PMC3260483  PMID: 21636833
Renin angiotensin system; Enalapril repamycin; Physical function; Body composition
24.  Differential effects of enalapril and losartan on body composition and indices of muscle quality in aged male Fischer 344 × Brown Norway rats 
Age  2010;33(2):167-183.
The primary purpose of the present set of studies was to provide a direct comparison of the effects of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin receptor blocker losartan on body composition, physical performance, and muscle quality when administered late in life to aged rats. Overall, enalapril treatment consistently attenuated age-related increases in adiposity relative to both placebo and losartan. The maximal effect was achieved after 3 months of treatment (between 24 and 27 months of age), at a dose of 40 mg/kg and was observed in the absence of any changes in physical activity, body temperature, or food intake. In addition, the reduction in fat mass was not due to changes in pathology given that enalapril attenuated age-related increases in tumor development relative to placebo- and losartan-treated animals. Both enalapril and losartan attenuated age-related decreases in grip strength, suggesting that changes in body composition appear dissociated from improvements in physical function and may reflect a differential impact of enalapril and losartan on muscle quality. To link changes in adiposity to improvements in skeletal muscle quality, we performed gene array analyses to generate hypotheses regarding cell signaling pathways altered with enalapril treatment. Based on these results, our primary follow-up pathway was mitochondria-mediated apoptosis of myocytes. Relative to losartan- and placebo-treated rats, only enalapril decreased DNA fragmentation and caspase-dependent apoptotic signaling. These data suggest that attenuation of the severity of skeletal muscle apoptosis promoted by enalapril may represent a distinct mechanism through which this compound improves muscle strength/quality.
doi:10.1007/s11357-010-9196-y
PMCID: PMC3127467  PMID: 21153712
Age-related adiposity; Body composition; Sarcopenia; Renin–angiotensin system; Physical function; Muscle quality
25.  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

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