Development of Pharmacotherapies for the Treatment of Sarcopenia.

Sarcopenia, the associated loss of skeletal muscle mass and strength and impaired physical function seen with aging, is a growing, global public health challenge in need of accepted, proven treatments that address the needs of a broad range of older adults. While exercise, primarily resistance training, and increased dietary protein have been shown to delay and even reverse losses in muscle mass, strength and physical function seen with aging, proven treatments that are accessible globally, cost effective and sustainable by patients are needed. While no drug has yet demonstrated the substantial safety and clinical value needed to be the first pharmacological therapy registered for muscle wasting or sarcopenia, the field is active. Several approaches to treating the muscle loss and subsequent functional decline are being studied in a variety of patient populations across every continent. We provide a review of the leading programs and approaches and available findings from recent studies. In addition, we briefly discuss several related issues needed to facilitate the development of a safe and efficacious pharmacotherapeutic that could be used as part of a treatment plan for older men and women with sarcopenia.

Implications of ICD-10 for Sarcopenia Clinical Practice and Clinical Trials: Report by the International Conference on Frailty and Sarcopenia Research Task Force.

Establishment of an ICD-10-CM code for sarcopenia in 2016 was an important step towards reaching international consensus on the need for a nosological framework of age-related skeletal muscle decline. The International Conference on Frailty and Sarcopenia Research Task Force met in April 2017 to discuss the meaning, significance, and barriers to the implementation of the new code as well as strategies to accelerate development of new therapies. Analyses by the Sarcopenia Definitions and Outcomes Consortium are underway to develop quantitative definitions of sarcopenia. A consensus conference is planned to evaluate this analysis. The Task Force also discussed lessons learned from sarcopenia trials that could be applied to future trials, as well as lessons from the osteoporosis field, a clinical condition with many constructs similar to sarcopenia and for which ad hoc treatments have been developed and approved by regulatory agencies.

Sarcopenia Trials in Specific Diseases: Report by the International Conference on Frailty and Sarcopenia Research Task Force.

Muscle atrophy occurs as a consequence of a number of conditions, including cancer, chronic obstructive pulmonary disease (COPD), diabetes mellitus, heart failure, and other chronic diseases, where it is generally a predictor of poor survival. It also occurs as a consequence of disuse and an age-related loss of muscle mass and strength (sarcopenia). The aims of the 2016, International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force were to examine how these specific chronic conditions have been employed in treatment trials thus far and how future trials using these patient groups might be designed for efficient identification of effective sarcopenia interventions. Functional limitations assessed as gait speed, distance walked over a set time period, or other attributes of physical performance have been suggested as outcome measures in sarcopenia trials. Indeed, such measures have already been used successfully in a number of trials aimed at preventing disability in older adults.

PHARMACOLOGICAL INTERVENTIONS IN FRAILTY AND SARCOPENIA: REPORT BY THE INTERNATIONAL CONFERENCE ON FRAILTY AND SARCOPENIA RESEARCH TASK FORCE.

Sarcopenia and frailty often co-exist and both have physical function impairment as a core component. Yet despite the urgency of the problem, the development of pharmaceutical therapies for sarcopenia and frailty has lagged, in part because of the lack of consensus definitions for the two conditions. A task force of clinical and basic researchers, leaders from the pharmaceutical and nutritional industries, and representatives from non-profit organizations was established in 2012 with the aim of addressing specific issues affecting research and clinical activities on frailty and sarcopenia. The task force came together on April 22, 2015 in Boston, Massachusetts, prior to the International Conference on Frailty and Sarcopenia Research (ICFSR). The theme of this meeting was to discuss challenges related to drugs designed to target the biology of frailty and sarcopenia as well as more general questions about designing efficient drug trials for these conditions. The present article reports the results of the task force's deliberations based on available evidence and preliminary results of ongoing activities. Overall, the lack of a consensus definition for sarcopenia and frailty was felt as still present and severely limiting advancements in the field. However, agreement appears to be emerging that low mass alone provides insufficient clinical relevance if not combined with muscle weakness and/or functional impairment. In the next future, it will be important to build consensus on clinically meaningful functional outcomes and test/validate them in long-term observational studies.

Cardiometabolic risks during anabolic hormone supplementation in older men.

OBJECTIVE: To determine the cardiometabolic risks of testosterone and growth hormone (GH) replacement therapy to youthful levels during aging. DESIGN AND METHODS: A double-masked, partially placebo controlled study in 112 men 65-90 years-old was conducted. Transdermal testosterone (5 g vs. 10 g/day) using a Leydig Cell Clamp and subcutaneous recombinant GH (rhGH) (0 vs. 3 vs. 5 µg/kg/day) were administered for 16-weeks. Measurements included testosterone and IGF-1 levels, body composition by DEXA, and cardiometabolic risk factors (upper body fat, blood pressure, insulin sensitivity, fasting triglycerides, HDL-cholesterol, and serum adiponectin) at baseline and after 16 weeks of treatment. RESULTS: Some cardiometabolic factors improved (total and trunk fat, triglycerides, HDL-cholesterol) and others worsened (systolic blood pressure, insulin sensitivity index [QUICKI], adiponectin). Cardiometabolic risk composite scores (CRCSs) improved (-0.69 ± 1.55, P < 0.001). In multivariate analyses, QUICKI, triglycerides, and HDL-cholesterol contributed 33%, 16%, and 14% of the variance in CRCS, respectively. Pathway analyses indicated that changes in fat and lean mass were related to individual cardiometabolic variables and CRCS in a complex manner. Changes in BMI, reflecting composite effects of changes in fat and lean mass, were more robustly associated with cardiometabolic risks than changes in fat mass or LBM individually. CONCLUSIONS: Testosterone and rhGH administration was associated with diverse changes in individual cardiometabolic risk factors, but in aggregate appeared not to worsen cardiometabolic risk in healthy older men after 4-months. The long-term effects of these and similar anabolic therapies on cardiovascular events should be investigated in populations with greater functional limitations along with important health disabilities including upper body obesity and other cardiometabolic risks.

Associations between human leukocyte antigen, PTPN22, CTLA4 genotypes and rheumatoid arthritis phenotypes of autoantibody status, age at diagnosis and erosions in a large cohort study.

BACKGROUND: HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA). OBJECTIVE: We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine associations with radiographic erosions and age of diagnosis. METHODS: A total of 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4 (rs3087243). Association between genotypes and CCP, rheumatoid factor (RF) erosive phenotypes and age at diagnosis were assessed with multivariable models adjusting for age, sex and disease duration. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions. RESULTS: In multivariable analysis, presence of any HLA-SE was strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI 2.18-4.25), and RF+ (OR 2.53, 95% CI 1.83-3.5) phenotypes; presence of any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI 1.24-2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27-2.66). CTLA4 was not associated with CCP or RF phenotypes. While HLA-SE was associated with erosive RA phenotype (OR 1.52, 95% CI 1.01-2.17), this was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. Presence of any HLA-SE was associated with an average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6 years, p = 0.002). CTLA4 genotypes were not associated with age at diagnosis of RA. CONCLUSIONS: In this large clinical cohort, we replicated the association between HLA-SE and PTPN22, but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is not significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.

Inflammatory markers and the risk of Alzheimer disease: the Framingham Study.

OBJECTIVE: To examine whether serum cytokines and spontaneous production of peripheral blood mononuclear cell (PBMC) cytokines are associated with the risk of incident Alzheimer disease (AD). METHODS: We followed 691 cognitively intact community-dwelling participants (mean age 79 years, 62% women) and related PBMC cytokine production (tertiles of spontaneous production of interleukin 1 [IL-1], IL-1 receptor antagonist, and tumor necrosis factor alpha [TNF-alpha]) and serum C-reactive protein and interleukin 6 (IL-6) to the risk of incident AD. RESULTS: Adjusting for clinical covariates, individuals in the top two tertiles (T2 and T3) of PBMC production of IL-1 or the top tertile (T3) of PBMC production of TNF-alpha were at increased risk of developing AD (multivariable-adjusted hazard ratio [HR] for IL-1 T2 = 2.84, 95% CI 1.09 to 7.43; p = 0.03 and T3 = 2.61, 95% CI 0.96 to 7.07; p = 0.06; for TNF-alpha, adjusted HR for T2 = 1.30, 95% CI 0.53 to 3.17; p = 0.57 and T3 = 2.59, 95% CI 1.09 to 6.12; p = 0.031]) compared with those in the lowest tertile (T1). INTERPRETATION: Higher spontaneous production of interleukin 1 or tumor necrosis factor alpha by peripheral blood mononuclear cells may be a marker of future risk of Alzheimer disease (AD) in older individuals. These data strengthen the evidence for a pathophysiologic role of inflammation in the development of clinical AD.

Opposing effects of the D70 mutation and the shared epitope in HLA-DR4 on disease activity and certain disease phenotypes in rheumatoid arthritis.

BACKGROUND: Certain sequences present in the hypervariable region of human leucocyte antigen (HLA)-DRB1 known as the shared epitope (SE) are hypothesised to increase the risk of rheumatoid arthritis (RA), whereas alleles encoding aspartic acid at position 70 (D70 alleles) may have a protective effect. METHODS: Patient HLA-DRB1 serotypes were assessed and the genotypes encoding the SE motif or the putatively protective D70 motif identified in a large RA cohort. Logistic regression was used to analyse associations of genotype with presence of disease, comorbidities and disease severity, and association between genotype and change in disease activity over time. RESULTS: The 689 patients enrolled had a mean (SD) age of 57.9 (13.7) years and mean (SD) disease duration of 15.3 (12.7) years. In a comparison with 482 ethnicity matched population-based controls, the D70 sequence exerted a strong protective effect (OR = 0.52, p<0.001) that remained significant when the SE at the same locus was accounted for (OR = 0.72, 95% CI 0.60 to 0.86, p<0.001). The SE assessed on all HLA-DRB1 serotypic backgrounds except DR1 was associated with RA susceptibility (additive OR = 2.43, p<0.001). Associations were found between SE and serum levels of rheumatoid factor (p<0.001, with correlation of 0.18) and anti-cyclic citrullinated peptide antibodies (p<0.001, with correlation of 0.25) but not with serum C-reactive protein. CONCLUSION: The D70 allele has a significant protective effect that is mitigated but still significant when the risk effect of the SE at the same locus is taken into account. The presence of the SE on DR4 is associated with greater RA susceptibility and certain disease-activity measures.

Resistance training alters cytokine gene expression in skeletal muscle of adults with type 2 diabetes.

Resistance training results in muscle hypertrophy and improves glycemic control in patients with type 2 diabetes. Whether resistance training modulates inflammation in muscles of diabetic patients remains unknown. We examined the expression of genes encoding the cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and transforming growth factor-beta1 (TGF-beta1) as well as the pan-leukocyte marker CD18. Thirty men and women (67+/-7 years) were randomized to either 16 weeks of resistance training and usual diabetes care (EX) or to usual diabetes care only (CON). Muscle biopsies were obtained from the vastus lateralis muscle prior to the 16-week intervention, and 72 h following the maximal strength test post-intervention. Fiber cross-sectional area (CSA) was determined following ATPase staining. Cytokine and CD18 transcript levels were assessed by real-time PCR. Resistance training increased CSA of type I and II fibers (both P <0.05) and IL-1beta transcript levels (P = 0.05). TNF-alpha (P<0.05) and TGF-beta1 transcripts (P<0.05) increased over time in the EX group, but these increases did not differ from those in the CON group. In both groups, the increase in CD18 transcripts remained minimal. The two groups differ by the relationship between changes in CD18 and changes in cytokine transcripts, suggesting that resistance training affects the source of cytokines in muscle. Our studies establish that resistance training in older adults with type 2 diabetes results in muscle fiber hypertrophy, despite a greater accumulation of inflammatory cytokine transcripts in muscle.

Rheumatoid cachexia: metabolic abnormalities, mechanisms and interventions.

We have previously identified the phrase 'rheumatoid cachexia' to describe the loss of body cell mass (BCM) that may occur among patients with rheumatoid arthritis (RA). Specifically, rheumatoid cachexia is characterized by altered energy and protein metabolism (reduced total energy expenditure, increased resting energy expenditure and increased whole-body protein catabolism) and increased inflammatory cytokine production (interleukin-1beta and tumour necrosis factor-alpha). Patients with rheumatoid cachexia consistently have a diet that appears adequate in protein and calories (based on US Dietary Reference Intakes), but with reduced physical activity. These phenomena are similar to some of the metabolic abnormalities that occur with normal ageing, but the aetiology appears to be different in RA. This review will focus on describing the metabolic abnormalities observed in rheumatoid cachexia, identifying potential mechanisms for loss of BCM and discussing strategies for intervention.

Effects of aging and cytokine blockade on inflammatory cachexia.

OBJECTIVE: To evaluate the role of aging and specific cytokine blockade in the etiology of cachexia caused by adjuvant arthritis (AA), a model of cytokine-associated cachexia. METHODS: AA was induced in Lewis rats using CFA. In Experiment 1, severity of AA and inflammatory cachexia was assessed in young (Y, age 2-6 months, n = 132) and old rats (O, age 18-22 months, n = 40). In Experiment 2, young rats were divided into 5 different intervention groups: Saline-injected (n = 66); CFA-injected (n = 78); CFA-injected and treated with IL-1 receptor antagonist (IL-1Ra, n = 18); CFA-injected and treated with soluble TNF receptor type I (sTNFrI, n = 27); and CFA-injected and treated with both IL-1Ra and sTNFrI (both treatments, n = 8). RESULTS: In Experiment 1, young Lewis rats developed more severe arthritis (mean joint score on day 21 = 5.1 +/- 0.3) compared to the old group (0.6 +/- 0.6, p < 0.0001). The young group with AA lost 2.1% of baseline total body weight loss compared to 13.8% total body weight gain in controls (p < 0.0001). In contrast, old rats injected with CFA lost as much weight (-11%) as age-matched saline injected controls (-13%, p > 0.05, n = 18, age 18-22 months). In Experiment 2, mean joint scores in rats treated with IL-1Ra, sTNFrI or both were higher then untreated rats injected with CFA (p < 0.0001). Despite this, rats given both IL-1Ra and sTNFrI lost less weight on day 16 (p < 0.01) and 21 (p < 0.002) than untreated rats or those rats treated with either IL-1Ra or sTNFrI. CONCLUSION: Lewis rats aged 2-6 months are more susceptible to developing AA than older rats (age range 18-22 months). Inhibition of both IL-1 and TNF is needed to mitigate AA-associated weight loss, and this effect is dissociated from the effect of such inhibition on joint inflammation.

Changes in lean body mass and total body weight are weakly associated with physical functioning in patients with HIV infection.

CONTEXT: For clinicians managing weight loss in patients with HIV, it would be useful to understand how changes in lean body mass (LBM) effect physical functioning, and whether LBM is more strongly related to physical functioning than total body weight (TBW). OBJECTIVE: To determine the relationship of changes in LBM and changes in total body weight (TBW) to changes in self-reported physical functioning in men and women with HIV infection. METHODS: Study design was longitudinal analysis of 1474 patient-intervals (each interval was approximately 6 months long) in 486 persons. Patients were participants in Nutrition for Healthy Living, a cohort study of HIV positive persons in Massachusetts and Rhode Island. The main outcome measure was change in self-reported physical functioning. RESULTS: Of the 1,474 intervals, 1,165 were contributed by men and 309 by women. The mean CD4 count for the 1,474 intervals was 383 cells/ micro L. In men, 5 kg changes in LBM and TBW were associated with 2.2 (95% confidence interval, 0.9, 3.4, P= 0.001) and 2.6 (95% confidence interval, 1.3, 3.9, P= 0.0002) point changes in physical functioning (on a 100-point scale), respectively, after adjusting for covariates. The relationships of changes in LBM and TBW to changes in physical functioning were linear. In women, there were no significant relationships between changes in LBM or TBW to changes in physical functioning. CONCLUSIONS: In this longitudinal analysis of relatively healthy persons with HIV infection, changes in LBM and TBW were significantly related to changes in physical functioning in men, but the magnitude of the relationship was small. In women, changes in LBM and TBW were not related to changes in physical functioning. Our data suggest that it is not necessary to measure body composition (lean and fat compartments) to understand the impact of changes in weight on physical functioning - it is sufficient to follow total body weight.

Resistance training to counteract the catabolism of a low-protein diet in patients with chronic renal insufficiency. A randomized, controlled trial.

BACKGROUND: Chronic renal insufficiency leads to muscle wasting, which may be exacerbated by low-protein diets prescribed to delay disease progression. Resistance training increases protein utilization and muscle mass. OBJECTIVE: To determine the efficacy of resistance training in improving protein utilization and muscle mass in patients with chronic renal insufficiency treated with a low-protein diet. DESIGN: Randomized, controlled trial. SETTING: Tufts University, Boston, Massachusetts. PATIENTS: 26 older patients with moderate renal insufficiency (17 men, 9 women) who had achieved stabilization on a low-protein diet. INTERVENTION: During a run-in period of 2 to 8 weeks, patients were instructed and their adherence to the low-protein diet (0.6 g/kg of body weight per day) was evaluated. They were randomly assigned to a low-protein diet plus resistance training (n = 14) or a low-protein diet alone (n = 12) for 12 weeks. MEASUREMENTS: Total body potassium, mid-thigh muscle area, type I and II muscle-fiber cross-sectional area, and protein turnover. RESULTS: Mean protein intake was 0.64 +/- 0.07 g/kg per day after stabilization. Total body potassium and type I and II muscle-fiber cross-sectional areas increased in patients who performed resistance training by a mean (+/-SD) of 4% +/- 8%, 24% +/- 31%, and 22% +/- 29%, respectively, compared with those who did not. Leucine oxidation and serum prealbumin levels also improved significantly. Patients assigned to resistance training maintained body weight compared with those who were not. Improvement in muscle strength was significantly greater with resistance training (32% +/- 14%) than without (-13% +/- 20%) (P < 0.001). CONCLUSION: By improving muscle mass, nutritional status, and function, resistance training seems to be effective against the catabolism of a low-protein diet and uremia in patients with renal failure.

Effect of resistance training on self-reported physical functioning in HIV infection.

PURPOSE: To assess whether progressive resistance training (PRT) improves functional status, measured using a validated Physical Function Scale, in both wasted and nonwasted patients with HIV infection, and to compare the relative contributions of increased lean body mass (LBM) and increased strength with the change in physical function. METHODS: Six patients with AIDS wasting and 19 patients with HIV but without wasting trained three times per week for 8 wk, followed by 8 wk of usual activity. Physical function, strength, and LBM were measured at 0, 8, and 16 wk. Self-reported physical functioning was measured using the physical functioning subscale of the Medical Outcomes Study (MOS) Short Form-36 (SF-36) questionnaire. RESULTS: Significant improvements occurred in strength (1-RM averaged for four machines increased 44% in the nonwasted and 60% in the wasted patients, each P < 0.0001) and LBM (2.3% increase in the nonwasted and 5.3% in the wasted patients, each P < 0.05) with resistance training. Physical function increased significantly in the wasted subjects (6 points, P < 0.02) but not in the nonwasted subjects, so that at 16 wk the wasted subjects functioned at a higher level than the nonwasted patients (P < 0.05). Both increase in LBM (P < 0.001) and increase in strength (P < 0.001) were significantly and independently associated with increase in physical function. CONCLUSION: PRT increases functional status in patients with HIV wasting, both by increasing strength and by increasing LBM.

Exercise treatment for HIV-associated metabolic and anthropomorphic complications.

Infection with the human immunodeficiency virus (HIV) has been associated with several alterations in body composition and metabolism. We propose that resistance and aerobic exercise training programs are effective nonpharmacologic treatments for managing these HIV-related complications and for improving quality of life.

Effect of highly active antiretroviral therapy on fat, lean, and bone mass in HIV-seropositive men and women.

BACKGROUND: Alterations in body composition have been reported in HIV-positive adults receiving highly active antiretroviral therapy (HAART), but the magnitude and potential determinants of these changes are unclear. OBJECTIVE: We compared total and regional body composition, as measured by dual-energy X-ray absorptiometry, in 203 HIV-positive men and 62 HIV-positive women according to HAART. DESIGN: This was a cross-sectional analysis of a cohort study of nutrition and HIV infection. RESULTS: After adjustment for age, weight, race, and exercise habits, total weight and fat mass did not differ significantly in men or women by HAART. Trunk fat was greater in men (1.0 kg; P < 0.001) and women (1.4 kg; P = 0.005) and leg fat was lower in men (-1.0 kg; P < 0.001) and women (-1.5 kg, P = 0.005) receiving HAART than in those not. This corresponded to a greater percentage of total fat mass located in the trunk (men: 7.5%, P < 0.001; women: 5.1%, P = 0.02). Lean mass was also greater with longer duration of HAART in men (P < 0.002). In men receiving HAART, total and regional bone mineral content were less than in the men not receiving HAART (P < 0.001). These effects increased with longer duration of HAART. Protease inhibitors were associated with the largest differences in regional fat. CONCLUSIONS: HAART is associated with redistribution of fat mass from the legs to the trunk, despite no significant differences in total fat mass or weight. In men, HAART is also associated with a reduction in bone mineral content, suggesting that HAART increases the risk of central obesity and osteoporosis.

Do patients with nonmetastatic non-small cell lung cancer demonstrate altered resting energy expenditure?

BACKGROUND: The cancer cachexia syndrome occurs in patients with non-small cell lung cancer (NSCLC) and includes elevated resting energy expenditure (REE). This increase in REE leads to weight loss, which in turn confers a poor prognosis. This study was undertaken to determine whether the cancer cachexia syndrome occurs in patients with nonmetastatic NSCLC. METHODS: In this case-control study, 18 patients with nonmetastatic NSCLC (stages IA to IIIB) were matched to healthy controls on age (+/- 5 years), gender, and body mass index (+/- 3 kg/m2). Only 4 cancer patients had experienced > 5% weight loss. Cancer patients and controls were compared on the basis of: (1) unadjusted REE, as measured by indirect calorimetry; (2) REE adjusted for lean body mass, as measured by dual x-ray absorptiometry; (3) REE adjusted for body cell mass, as measured by potassium-40 measurement; and (4) REE adjusted for total body water, as measured by tritiated water dilution. RESULTS: We observed no significant difference in unadjusted REE or in REE adjusted for total body water. However, with separate adjustments for lean body mass and body cell mass, cancer patients manifested an increase in REE: mean difference +/- standard error of the mean: 140+/-35 kcal/day (p = 0.001) and 173+/-65 kcal/day (p = 0.032), respectively. Further adjustment for weight loss yielded similarly significant results. CONCLUSIONS: These results suggest that the cancer cachexia syndrome occurs in patients with nonmetastatic NSCLC and raise the question of whether clinical trials that target cancer cachexia should be initiated before weight loss.