Multisystem physiological perspective of human frailty and its modulation by physical activity.

"Frailty" is a term used to refer to a state characterized by enhanced vulnerability to, and impaired recovery from, stressors compared with a nonfrail state, which is increasingly viewed as a loss of resilience. With increasing life expectancy and the associated rise in years spent with physical frailty, there is a need to understand the clinical and physiological features of frailty and the factors driving it. We describe the clinical definitions of age-related frailty and their limitations in allowing us to understand the pathogenesis of this prevalent condition. Given that age-related frailty manifests in the form of functional declines such as poor balance, falls, and immobility, as an alternative we view frailty from a physiological viewpoint and describe what is known of the organ-based components of frailty, including adiposity, the brain, and neuromuscular, skeletal muscle, immune, and cardiovascular systems, as individual systems and as components in multisystem dysregulation. By doing so we aim to highlight current understanding of the physiological phenotype of frailty and reveal key knowledge gaps and potential mechanistic drivers of the trajectory to frailty. We also review the studies in humans that have intervened with exercise to reduce frailty. We conclude that more longitudinal and interventional clinical studies are required in older adults. Such observational studies should interrogate the progression from a nonfrail to a frail state, assessing individual elements of frailty to produce a deep physiological phenotype of the syndrome. The findings will identify mechanistic drivers of frailty and allow targeted interventions to diminish frailty progression.

Does exercise attenuate age- and disease-associated dysfunction in unconventional T cells? Shining a light on overlooked cells in exercise immunology.

Unconventional T Cells (UTCs) are a unique population of immune cells that links innate and adaptive immunity. Following activation, UTCs contribute to a host of immunological activities, rapidly responding to microbial and viral infections and playing key roles in tumor suppression. Aging and chronic disease both have been shown to adversely affect UTC numbers and function, with increased inflammation, change in body composition, and physical inactivity potentially contributing to the decline. One possibility to augment circulating UTCs is through increased physical activity. Acute exercise is a potent stimulus leading to the mobilization of immune cells while the benefits of exercise training may include anti-inflammatory effects, reductions in fat mass, and improved fitness. We provide an overview of age-related changes in UTCs, along with chronic diseases that are associated with altered UTC number and function. We summarize how UTCs respond to acute exercise and exercise training and discuss potential mechanisms that may lead to improved frequency and function.

Factors associated with falls in older women with breast cancer: the use of a brief geriatric screening tool in clinic.

PURPOSE: Unintentional falls and breast cancer are common among older women, but the associations between them are understudied. We aimed to identify factors associated with falls in older women with breast cancer. METHODS: We retrospectively reviewed clinical records of older women with breast cancer at Duke Medical Center who had completed the Senior Adult Oncology Program geriatric assessment. Characteristics were compared between women had had at least one fall in the past year and those who did not. Pearson's Chi-square tests and t tests were used for comparison of groups' characteristics. Logistic regression determined factors associated with falling. RESULTS: We identified 425 women, age 76.2 years (range 65-89 years), at the time of the assessment. 118 (27.8%) women reported a fall in the prior year. Age, race, ethnicity, and time since diagnosis (all p > 0.05) were similar between groups. In univariate analyses, metastatic disease (p = 0.023) and history of endocrine therapy (p = 0.042) were more common among women who fell. Women who fell had lower systolic (p = 0.001), diastolic (p < 0.001) blood pressures, and SpO2 (p = 0.018). Women who had fallen had a higher Charlson Comorbidity Index (CCI: p = 0.033), and were more likely to report using a walking aide (p < 0.001), nutritional issues (p = 0.006), and depression symptoms (p = 0.038). In multivariate analysis, falling was associated with low DBP (OR 0.93; p = 0.0017), low SpO2 (OR 0.79; p = 0.0169), a higher CCI (OR 1.23; p = 0.0076), and depression symptoms (OR 1.61; p = 0.039). CONCLUSIONS: Among older women with breast cancer, depressive symptoms, higher comorbidity level, and vital sign measurements were associated with having fallen.

Natural killer cell mobilization and egress following acute exercise in men with prostate cancer.

NEW FINDINGS: What is the central question of this study? What are the characteristics of the NK cell response following acute moderate-intensity aerobic exercise in prostate cancer survivors and is there a relationship between stress hormones and NK cell mobilization? What is the main finding and its importance? NK cell numbers and proportions changed similarly between prostate cancer survivors and controls following acute exercise. Consecutive training sessions can likely be used without adverse effects on the immune system during prostate cancer treatment. ABSTRACT: Prostate cancer treatment affects multiple physiological systems, although the immune response during exercise has been minimally investigated. The objective was to characterize the natural killer (NK) cell response following acute exercise in prostate cancer survivors. Prostate cancer survivors on androgen deprivation therapy (ADT) and those without (PCa) along with non-cancer controls (CON) completed a moderate intensity cycling bout. NK cells were phenotyped before and 0, 2 and 24 h after acute exercise using flow cytometry. CD56 total NK cell frequency increased by 6.2% at 0 h (P < 0.001) and decreased by 2.5% at 2 h (P < 0.01) with similar findings in CD56dim cells. NK cell counts also exhibited a biphasic response. Independent of exercise, ADT had intracellular interferon γ (IFNγ) expression that was nearly twofold higher than CON (P < 0.01). PCa perforin expression was reduced by 11.4% (P < 0.05), suggesting these cells may be more prone to degranulation. CD57- NK cells demonstrated increased perforin and IFNγ frequencies after exercise with no change within the CD57+ populations. All NK and leukocyte populations returned to baseline by 24 h. NK cell mobilization and egress with acute exercise appear normal, as cell counts and frequencies in prostate cancer survivors change similarly to CON. However, lower perforin proportions (PCa) and higher IFNγ expression (ADT) may alter NK cytotoxicity and require further investigation. The return of NK cell proportions to resting levels overnight suggests that consecutive training sessions can be used without adverse effects on the immune system during prostate cancer treatment.

Moderate physical activity associated with a higher naïve/memory T-cell ratio in healthy old individuals: potential role of IL15.

INTRODUCTION: ageing is accompanied by impairments in immune responses due to remodelling of the immune system (immunesenescence). Additionally, a decline in habitual physical activity has been reported in older adults. We have recently published that specific features of immunesenescence, such as thymic involution and naïve/memory T-cell ratio, are prevented by maintenance of a high level of physical activity. This study compares immune ageing between sedentary and physically active older adults. METHODS: a cross-sectional study recruited 211 healthy older adults (60-79 years) and assessed their physical activity levels using an actigraph. We compared T- and B-cell immune parameters between relatively sedentary (n = 25) taking 2,000-4,500 steps/day and more physically active older adults (n = 25) taking 10,500-15,000 steps/day. RESULTS: we found a higher frequency of naïve CD4 (P = 0.01) and CD8 (P = 0.02) and a lower frequency of memory CD4 cells (P = 0.01) and CD8 (P = 0.04) T cells in the physically active group compared with the sedentary group. Elevated serum IL7 (P = 0.03) and IL15 (P = 0.003), cytokines that play an essential role in T-cell survival, were seen in the physically active group. Interestingly, a positive association was observed between IL15 levels and peripheral CD4 naïve T-cell frequency (P = 0.023). DISCUSSION: we conclude that a moderate level of physical activity may be required to give a very broad suppression of immune ageing, though 10,500-15,000 steps/day has a beneficial effect on the naïve T-cell pool.

Maximal exercise increases mucosal associated invariant T cell frequency and number in healthy young men.

PURPOSE: Mucosal associated invariant T (MAIT) cells have properties of the innate and acquired immune systems. While the response to vigorous exercise has been established for most leukocytes, MAIT cells have not been investigated. Therefore, the purpose was to determine if MAIT cell lymphocytosis occurs with acute maximal aerobic exercise and if this response is influenced by exercise duration, cardiovascular fitness, or body composition. METHODS: Twenty healthy young males with moderate fitness levels performed an extended graded exercise test until volitional fatigue. Peripheral blood mononuclear cells were isolated from venous blood obtained prior and immediately after exercise and were labeled to identify specific T cell populations using flow cytometry. RESULTS: The percentage of MAIT cells relative to total T cells significantly increased from 3.0 to 3.8% and absolute MAIT cell counts increased by 2.2-fold following maximal exercise. MAIT cell subpopulation proportions were unchanged with exercise. Within cytotoxic T lymphocytes (CTL), MAIT cells consisted of 8% of these cells and this remained constant after exercise. MAIT cell counts and changes with exercise were not affected by body composition, VO2peak, or exercise duration. CONCLUSIONS: Maximal exercise doubled MAIT cell numbers and showed preferential mobilization within total T cells but the response was not influenced by fitness levels, exercise duration, or body composition. These results suggest that acute exercise could be used to offset MAIT cell deficiencies observed with certain pathologies. MAIT cells also make up a substantial proportion of CTLs, which may have implications for cytotoxicity assays using these cells.

Habitual physical activity is associated with the maintenance of neutrophil migratory dynamics in healthy older adults.

BACKGROUND: Dysfunctional neutrophils with advanced age are a hallmark of immunosenescence. Reduced migration and bactericidal activity increase the risk of infection. It remains unclear why neutrophil dysfunction occurs with age. Physical activity and structured exercise have been suggested to improve immune function in the elderly. The aim of this study was to assess a comprehensive range of neutrophil functions and determine their association with habitual physical activity. METHOD: Physical activity levels were determined in 211 elderly (67±5years) individuals by 7-days of accelerometry wear. Twenty of the most physically active men and women were matched for age and gender to twenty of the least physically active individuals. Groups were compared for neutrophil migration, phagocytosis, oxidative burst, cell surface receptor expression, metabolic health parameters and systemic inflammation. Groups were also compared against ten young participants (23±4years). RESULTS: The most active group completed over twice as many steps/day as the least active group (p<0.001), had lower BMI's (p=0.007) and body fat percentages (p=0.029). Neutrophils migrated towards IL-8 better in the most active group compared to the least active (p<0.05) and was comparable to that of the young (p>0.05). These differences remained after adjusting for BMI, body fat and plasma metabolic markers which were different between groups. Correlations revealed that steps/day, higher adiponectin and lower insulin were positively associated with migratory ability (p<0.05). There was no difference in expression of the chemokine receptors CXCR1 or CXCR2 (p>0.05 for both). CD11b was higher in the most active group compared to the least active (p=0.048). No differences between activity groups or young controls were observed for neutrophil phagocytosis or oxidative burst in response to Escherichia coli (p>0.05). The young group had lower concentrations of IL-6, IL-8, MCP-1, CRP, IL-10 and IL-13 (p<0.05 for all) with no differences between the two older groups. CONCLUSION: These data suggest that impaired neutrophil migration, but not bactericidal function, in older adults may be, in part, the result of reduced physical activity. A 2-fold difference in physical activity is associated with better preserved neutrophil migratory dynamics in healthy older people. As a consequence increasing habitual physical activity may be beneficial for neutrophil mediated immunity.

Inflammation, telomere length, and grip strength: a 10-year longitudinal study.

Telomere attrition has been associated with age-related diseases, although causality is unclear and controversial; low-grade systemic inflammation (inflammaging) has also been implicated in age-related pathogenesis. Unpicking the relationship between aging, telomere length (TL), and inflammaging is hence essential to the understanding of aging and management of age-related diseases. This longitudinal study explored whether telomere attrition is a cause or consequence of aging and whether inflammaging explains some of the associations between TL and one marker of aging, grip strength. We studied 253 Hertfordshire Ageing Study participants at baseline and 10-year follow-up (mean age at baseline 67.1 years). Participants completed a health questionnaire and had blood samples collected for immune-endocrine and telomere analysis at both time points. Physical aging was characterized at follow-up using grip strength. Faster telomere attrition was associated with lower grip strength at follow-up (ß = 0.98, p = 0.035). This association was completely attenuated when adjusted for inflammaging burden (p = 0.86) over the same period. Similarly, greater inflammaging burden was associated with lower grip strength at follow-up (e.g., interleukin [IL]-1ß: ß = -2.18, p = 0.001). However, these associations were maintained when adjusted for telomere attrition (IL-1ß, p = 0.006). We present evidence that inflammaging may be driving telomere attrition and in part explains the associations that have previously been reported between TL and grip strength. Thus, biomarkers of physical aging, such as inflammaging, may require greater exploration. Further work is now indicated.

Immunomodulatory Function of Interleukin-15 and Its Role in Exercise, Immunotherapy, and Cancer Outcomes.

Exercise has been shown to improve physical and psychosocial outcomes for people across the cancer care continuum. A proposed mechanism underpinning the relationship between exercise and cancer outcomes is exercise-induced immunomodulation via secretion of anti-inflammatory myokines from skeletal muscle tissue. Myokines have the potential to impair cancer growth through modulation of natural killer (NK) cells and CD8+ T cells while improving the effectiveness of cancer therapies. Interleukin-15 (IL-15), one of the most abundant myokines found in skeletal muscle, has a key immunoregulatory role in supporting the proliferation and maturation of T cells and NK cells, which have a key role in the host's immune response to cancer. Furthermore, IL-15 is being explored clinically as an immunotherapy agent with doses similar to the IL-15 concentrations released by skeletal muscle during exercise. Here we review the role of IL-15 within the immune system, examine how IL-15 is produced as a myokine during exercise, and how it may improve outcomes for people with cancer, specifically as an adjuvant or neoadjuvant to immunotherapy. We summarize the available evidence showing changes in IL-15 in response to both acute exercise and training, and the results are inconsistent; higher quality research is needed to advance the understanding of how exercise-mediated increases in IL-15 potentially benefit those who are being treated for, or who have had, cancer.

Effects of high-intensity interval training on health-related quality of life in chronic lymphocytic leukemia: A pilot study.

INTRODUCTION: Chronic lymphocytic leukemia (CLL) is the most common incurable leukemia/lymphoma in the United States. Individuals with CLL are at risk for disability, frailty, and cancer-specific complications that negatively affect health-related quality of life (HRQOL). High-intensity interval training (HIIT) and resistance training (RT) are safe and feasible for individuals with chronic diseases and when combined, they may be beneficial for reducing cancer-related fatigue, symptom burden, and global quality of life. However, no studies have examined the impact of HIIT or RT on HRQOL in CLL. The purpose of this study was to investigate the effects of a 12-week HIIT and RT (HIIT+RT) intervention on HRQOL in adults with treatment naïve CLL. MATERIALS AND METHODS: Changes in HRQOL was a secondary outcome in this pilot study. Individuals with CLL (63.9 ± 8.5 yrs) were non-randomly assigned to 12 weeks of HIIT+RT or a control group. The HIIT+RT protocol consisted of three 30-min sessions/week of HIIT and two sessions/week of RT. The control group maintained usual daily activities. We assessed pre and post HRQOL using the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) questionnaire with domains of physical (PWB), social (SWB), emotional (EWB), functional (FWB), and general (FACT-G) well-being as well as a lymphoma-specific subscale (LymS). We used a two-way mixed analysis of variance to assess changes in HRQOL. We calculated effect size (ES) using Cohen's d. RESULTS: Fifteen participants (HIIT+RT: n = 9; Control: n = 6) completed the study and questionnaire. Scores for FWB improved following HIIT+RT (21.7 ± 3.4 to 23.9 ± 3.2; ES = 1.38) compared to controls (25.7 ± 2.2 to 25.7 ± 2.3). The HIIT+RT group experienced clinically meaningful improvements in total FACT-Lym, FWB, FACT-G, and LymS. The control group had clinically meaningful changes only in LymS. DISCUSSION: The large effect sizes and clinically meaningful improvements associated with 12 weeks of HIIT+RT support the potential benefits of this type of exercise program for FWB, lymphoma-specific symptoms, and general well-being in CLL. A future randomized trial with an adequately powered sample size is needed to evaluate these findings. TRIAL REGISTRATION: NCT04950452.

Acute exercise induces distinct quantitative and phenotypical T cell profiles in men with prostate cancer.

Background: Reduced testosterone levels can influence immune system function, particularly T cells. Exercise during cancer reduces treatment-related side effects and provide a stimulus to mobilize and redistribute immune cells. However, it is unclear how conventional and unconventional T cells (UTC) respond to acute exercise in prostate cancer survivors compared to healthy controls. Methods: Age-matched prostate cancer survivors on androgen deprivation therapy (ADT) and those without ADT (PCa) along with non-cancer controls (CON) completed ∼45 min of intermittent cycling with 3 min at 60% of peak power interspersed by 1.5 min of rest. Fresh, unstimulated immune cell populations and intracellular perforin were assessed before (baseline), immediately following (0 h), 2 h, and 24 h post-exercise. Results: At 0 h, conventional T cell counts increased by 45%-64% with no differences between groups. T cell frequency decreased by -3.5% for CD3+ and -4.5% for CD4+ cells relative to base at 0 h with CD8+ cells experiencing a delayed decrease of -4.5% at 2 h with no group differences. Compared to CON, the frequency of CD8+CD57+ cells was -18.1% lower in ADT. Despite a potential decrease in maturity, ADT increased CD8+perforin+ GMFI. CD3+Vα7.2+CD161+ counts, but not frequencies, increased by 69% post-exercise while CD3+CD56+ cell counts increased by 127% and were preferentially mobilized (+1.7%) immediately following the acute cycling bout. There were no UTC group differences. Cell counts and frequencies returned to baseline by 24 h. Conclusion: Following acute exercise, prostate cancer survivors demonstrate normal T cell and UTC responses that were comparable to CON. Independent of exercise, ADT is associated with lower CD8+ cell maturity (CD57) and perforin frequency that suggests a less mature phenotype. However, higher perforin GMFI may attenuate these changes, with the functional implications of this yet to be determined.

Feasibility of home-based exercise training in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Home-based training increases accessibility to exercise and mitigates the side effects of hormone therapy for prostate cancer (PC). However, it is unknown if men with more advanced disease are willing to partake in such interventions. PURPOSE: To determine the feasibility of a home-based exercise intervention in men with metastatic castration-resistant prostate cancer (mCRPC). METHODS: mCRPC patients on androgen receptor signaling inhibitors (ARSI) were prescribed a 12-week, home-based exercise intervention using resistance bands and walking. Feasibility was assessed using recruitment, retention, adherence, and outcome capture. Physiological changes and patient reported outcomes were assessed before and after the intervention. RESULTS: Of the 62 referrals, 47 were eligible with 22 men performing baseline testing (47% recruitment rate) and 16 completing the intervention (73% retention). Task completion was >86% for all physiological tests. Walking adherence was 80% and resistance training was 63%, the latter falling short of the study target (75%). Training increased thigh muscle cross-sectional area by 22%, time to exhaustion by 19% (both p < 0.05) and peak oxygen uptake by 6% (p = 0.057). Improvements in short physical performance battery scores and 400 m walk demonstrated moderate effect sizes that did not reach significance. CONCLUSIONS: Home-based exercise is feasible during ARSI treatment for mCRPC. Greater endurance capacity and localized hypertrophy appear as the primary improvements following training. These preliminary findings suggest home-based training may increase exercise accessibility, with important lessons that will inform subsequent trials investigating the efficacy of home-based exercise interventions during mCRPC.

A pilot study to assess the feasibility of a remotely monitored high-intensity interval training program prior to allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Although allogeneic hematopoietic stem cell transplantation (HCT) can be a curative therapy for hematologic disorders, it is associated with treatment-related complications and losses in cardiorespiratory fitness and physical function. High-intensity interval training (HIIT) may be a practical way to rapidly improve cardiorespiratory fitness and physical function in the weeks prior to HCT. The primary aim of this study was to assess the feasibility of implementing a pre-HCT home-based HIIT intervention. The secondary aim was to evaluate pre to post changes in cardiorespiratory fitness and physical function following the intervention. METHODS: This was a single-arm pilot study with patients who were scheduled to undergo allogeneic HCT within six months. Patients were instructed to complete three 30-minute home-based HIIT sessions/week between the time of study enrollment and sign-off for HCT. Sessions consisted of a 5-minute warm-up, 10 high and low intervals performed for one minute each, and a 5-minute cool-down. Prescribed target heart rates (HR) for the high- and low-intensity intervals were 80-90% and 50-60% of HR reserve, respectively. Heart rates during HIIT were captured via an Apple Watch and were remotely monitored. Feasibility was assessed via retention, session adherence, and adherence to prescribed interval number and intensities. Paired t-tests were used to compare changes in fitness (VO2peak) and physical function [Short Physical Performance Battery (SPPB), 30-second sit to stand, and six-minute walk test (6MWT)] between baseline and sign-off. Pearson correlations were used to determine the relationship between intervention length and changes in cardiorespiratory fitness or functional measures. RESULTS: Thirteen patients (58.8±11.6 years) participated in the study, and nine (69.2%) recorded their training sessions throughout the study. Median session adherence for those nine participants was 100% (IQR: 87-107). Adherence to intervals was 92% and participants met or exceeded prescribed high-intensity HR on 68.8±34.8% of intervals. VO2peak improved from baseline to sign-off (14.6±3.1 mL/kg/min to 17.9±3.3 mL/kg/min; p<0.001). 30-second sit to stand and SPPB chair stand scores significantly improved in adherent participants. Improvements in 30-second sit to stand (13.8±1.5 to 18.3±3.3 seconds) and 6MWT (514.4±43.2 to 564.6±19.3) exceeded minimal clinically important improvements established in other chronic disease populations, representing the minimum improvement considered meaningful to patients. CONCLUSIONS: Findings demonstrate that implementing a pre-HCT home-based remotely monitored HIIT program is feasible and may provide benefits to cardiorespiratory fitness and physical function.

Associations of clinical and circulating metabolic biomarkers with low physical fitness and function in adults with chronic lymphocytic leukemia.

Many patients with chronic lymphocytic leukemia (CLL) experience physical dysfunction and low overall fitness. It remains unknown what factors drive CLL physical dysfunction. We assessed physical function and metabolic lipoprotein panels in 106 patients with CLL. In univariate analyses of clinical factors, a longer time since diagnosis was associated with a higher likelihood of dysfunctional aerobic fitness (OR = 3.56, 95% CI: 1.37-9.22; p = 0.002) and physical performance (SPPB: OR = 2.03, 95% CI: 1.20-3.44; p = 0.004). Having received treatment was associated with a higher likelihood of dysfunctional aerobic fitness (OR = 1.57, 95% CI: 1.02-2.40; p = 0.036), SPPB (OR = 1.85, 95% CI: 1.13-3.03; p = 0.011) and grip strength (OR = 1.67, 95% CI: 1.10-2.55; p = 0.015). We found that several small HDL particle parameters, higher levels of citrate (OR = 2.01, 95% CI: 1.22-3.31; p = 0.030), and lower levels of hemoglobin (OR = 0.50, 95% CI: 0.31-0.82; p = 0.030) were associated with a higher likelihood of dysfunctional aerobic fitness. Multivariable least absolute shrinkage and selection operator (LASSO)-penalized regression analyses using variable importance measures (VIM) showed that 7.8-nm HDL particles (VIM = 1.000) and total HDL particle levels (VIM = 1.000) were more informative than clinical measures for the odds of dysfunctional aerobic fitness and 6-min walk functional fitness, respectively, while 10.3-nm HDL particles (VIM = 0.383) were more informative for grip strength. Time since diagnosis (VIM = 0.680) and having received treatment (VIM = 0.490) were more informative than lipoprotein measures for the odds of having dysfunctional SPPB. Taken together, we establish significant relationships between clinical and metabolic factors and physical characteristics that might prompt early use of ancillary support services.

Rheumatoid arthritis T cell and muscle oxidative metabolism associate with exercise-induced changes in cardiorespiratory fitness.

Rheumatoid arthritis (RA) T cells drive autoimmune features via metabolic reprogramming that reduces oxidative metabolism. Exercise training improves cardiorespiratory fitness (i.e., systemic oxidative metabolism) and thus may impact RA T cell oxidative metabolic function. In this pilot study of RA participants, we took advantage of heterogeneous responses to a high-intensity interval training (HIIT) exercise program to identify relationships between improvements in cardiorespiratory fitness with changes in peripheral T cell and skeletal muscle oxidative metabolism. In 12 previously sedentary persons with seropositive RA, maximal cardiopulmonary exercise tests, fasting blood, and vastus lateralis biopsies were obtained before and after 10 weeks of HIIT. Following HIIT, improvements in RA cardiorespiratory fitness were associated with changes in RA CD4 + T cell basal and maximal respiration and skeletal muscle carnitine acetyltransferase (CrAT) enzyme activity. Further, changes in CD4 + T cell respiration were associated with changes in naïve CD4 + CCR7 + CD45RA + T cells, muscle CrAT, and muscle medium-chain acylcarnitines and fat oxidation gene expression profiles. In summary, modulation of cardiorespiratory fitness and molecular markers of skeletal muscle oxidative metabolism during exercise training paralleled changes in T cell metabolism. Exercise training that improves RA cardiorespiratory fitness may therefore be valuable in managing pathologically related immune and muscle dysfunction.Trial registration: ClinicalTrials.gov, NCT02528344. Registered on 19 August 2015.

A randomized controlled trial comparing changes in fitness with or without supervised exercise in patients initiated on enzalutamide and androgen deprivation therapy for non-metastatic castration-sensitive prostate cancer (EXTEND).

BACKGROUND: Androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSI) are associated with deleterious physical effects, which exercise may mitigate; however, exercise has never been studied in patients initiating treatment with ADT and an ARSI. Our objective was to determine whether supervised exercise prior to and during initial therapy could mitigate adverse effects of ADT plus enzalutamide. METHODS: We conducted a single center trial in patients with recurrent prostate cancer treated with ADT and enzalutamide. We randomized 26 patients to 16 weeks of supervised exercise (aerobic and resistance), starting 4 weeks before initiation of ADT and enzalutamide, or usual care. The primary endpoint was change in peak oxygen uptake (VO2peak) as a measure of cardiorespiratory fitness (CRF). Secondary endpoints were functional capacity, maximal strength, body composition, patient-reported outcomes, safety, and feasibility. Analysis of covariance was used to compare outcomes for groups at Week 17 adjusted for baseline values. RESULTS: The usual care group (N = 13) showed declines from baseline to week 17 in both absolute CRF (-0.31 L/min, -10.9%; p < 0.01) and relative CRF (-3.2 mL/kg/min, -8.9%; p = 0.04); worse fatigue (p = 0.01); and worse quality of life (p = 0.01). At week 17, the exercise group (N = 13) demonstrated improved absolute CRF (between-group change +0.20 L/min, p = 0.05), leg strength (+48.6 kg, p < 0.01) and functional capacity (+21.0 m, p = 0.01) at week 17. CONCLUSIONS: This is the first randomized controlled trial demonstrating a clinically significant decline in CRF in patients initiating ADT and enzalutamide. We show the effectiveness of short-term supervised exercise to mitigate declines in absolute CRF, and improve maximal leg strength and functional capacity. GOV IDENTIFIER: NCT02256111.

Geriatric Assessment Reveals Actionable Impairments in Hematopoietic Stem Cell Transplantation Candidates Age 18 to 80 Years.

Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative treatment for both malignant and nonmalignant hematologic diseases; however, reported rates of treatment-related mortality approach 30%. Outcomes are worse in patients who begin HCT with functional impairments. To detect such impairments, a geriatric assessment (GA) is recommended in adults age ≥65 years. Younger HCT candidates also may be impaired because of chemotherapy regimens pre-HCT. Therefore, we hypothesized that GA can be beneficial for adult patients of all ages and subsequently created a clinical pretransplantation optimization program to assess all HCT candidates using a modified GA. One-hundred fifty-seven patients were evaluated in 4 functional domains- physical, cognitive, nutritional, and psychological-at 2 time points prior to HCT-new patient evaluation (NPE) and sign-off (SO)-between October 2017 and January 2020. At NPE, 80.9% of the patients had at least 1 domain with a functional impairment, and physical (P = .006), cognitive (P = .04), and psychological (P = .04) impairments were associated with an increased likelihood of not proceeding to HCT. In addition, patients age 18 to 39 years were more likely than older patients to have a physical function impairment (P = .001). Between NPE and SO, 51.9% of the patients had resolution of 1 or more impairments, and nutritional impairment at SO was predictive of worse overall survival (P = .01). Our study shows that GA can identify functional impairments in patients of all ages. Early identification of impairments could facilitate referrals to supportive care and resolution of impairments prior to HCT, suggesting that GA could be recommended for HCT candidates of all ages.

Mucosal-Associated Invariant T Cell Response to Acute Exercise and Exercise Training in Older Obese Women.

(1) Background: Obesity is a major global public health concern as it is associated with many of the leading causes of preventable deaths. Exercise reduces obesity-induced inflammation; however, it is unknown how exercise training may impact mucosal associated invariant T (MAIT) cells in overweight/obese (OW) post-menopausal women. Therefore, the purpose of this study was to investigate (i) circulating MAIT-cells at rest in OW vs. Lean women, (ii) the response of MAIT-cells to a single bout of combined aerobic and resistance exercise, and (iii) the effects of 12 weeks of exercise training (EX) or educational program (ED) on the MAIT-cell response in OW. (2) Methods: OW completed an acute exercise session or sitting control, underwent 12 weeks of exercise training or received educational materials, and then repeated the exercise session/sitting control. Lean post-menopausal women provided a baseline comparison. (3) Results: OW had lower circulating MAIT-cells at rest than Lean prior to exercise training; however, after training EX displayed improved MAIT-cell frequency. Additionally, prior to training EX did not exhibit MAIT-cell mobilization/egress, however, both improved after training. (4) Conclusions: Reduced MAIT-cell frequency and ability to mobilize/egress were potentially partially rescued in EX after 12 weeks of exercise training; however, further research is needed to elucidate age or obesity-induced attenuations in MAIT-cells.

Altered skeletal muscle metabolic pathways, age, systemic inflammation, and low cardiorespiratory fitness associate with improvements in disease activity following high-intensity interval training in persons with rheumatoid arthritis.

BACKGROUND: Exercise training, including high-intensity interval training (HIIT), improves rheumatoid arthritis (RA) inflammatory disease activity via unclear mechanisms. Because exercise requires skeletal muscle, skeletal muscle molecular pathways may contribute. The purpose of this study was to identify connections between skeletal muscle molecular pathways, RA disease activity, and RA disease activity improvements following HIIT. METHODS: RA disease activity assessments and vastus lateralis skeletal muscle biopsies were performed in two separate cohorts of persons with established, seropositive, and/or erosive RA. Body composition and objective physical activity assessments were also performed in both the cross-sectional cohort and the longitudinal group before and after 10 weeks of HIIT. Baseline clinical assessments and muscle RNA gene expression were correlated with RA disease activity score in 28 joints (DAS-28) and DAS-28 improvements following HIIT. Skeletal muscle gene expression changes with HIIT were evaluated using analysis of covariance and biological pathway analysis. RESULTS: RA inflammatory disease activity was associated with greater amounts of intramuscular adiposity and less vigorous aerobic exercise (both p < 0.05). HIIT-induced disease activity improvements were greatest in those with an older age, elevated erythrocyte sedimentation rate, low cardiorespiratory fitness, and a skeletal muscle molecular profile indicative of altered metabolic pathways (p < 0.05 for all). Specifically, disease activity improvements were linked to baseline expression of RA skeletal muscle genes with cellular functions to (1) increase amino acid catabolism and interconversion (GLDC, BCKDHB, AASS, PYCR, RPL15), (2) increase glycolytic lactate production (AGL, PDK2, LDHB, HIF1A), and (3) reduce oxidative metabolism via altered beta-oxidation (PXMP2, ACSS2), TCA cycle flux (OGDH, SUCLA2, MDH1B), and electron transport chain complex I function (NDUFV3). The muscle mitochondrial glycine cleavage system (GCS) was identified as critically involved in RA disease activity improvements given upregulation of multiple GCS genes at baseline, while GLDC was significantly downregulated following HIIT. CONCLUSION: In the absence of physical activity, RA inflammatory disease activity is associated with transcriptional remodeling of skeletal muscle metabolism. Following exercise training, the greatest improvements in disease activity occur in older, more inflamed, and less fit persons with RA. These exercise training-induced immunomodulatory changes may occur via reprogramming muscle bioenergetic and amino acid/protein homeostatic pathways. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02528344 . Registered on 19 August 2015.

A Pilot Study of Home-Based Exercise and Personalized Nutrition Counseling Intervention in Endometrial Cancer Survivors.

INTRODUCTION: To assess the feasibility of a home-based aerobic exercise and nutrition counseling intervention and effect on cardiorespiratory fitness, cardiovascular disease risk profile, and immune response in obese endometrial cancer survivors. METHODS: A longitudinal pilot study assessed a 12-week home-based aerobic exercise and nutrition counseling intervention in obese endometrial cancer survivors. The primary outcome was feasibility defined as 80% adherence to weekly walking sessions calculated among individuals that completed the intervention. Secondary outcomes comprised pre- and post-intervention differences in cardiorespiratory fitness, cardiovascular risk factors, and T-cell function. Descriptive statistics summarized data. Wilcoxon sign tests identified differences between and pre and post-intervention variables. RESULTS: Nineteen women with stage 1 endometrial cancer consented; 9 withdrew and one was a screen failure. Median adherence to weekly walking sessions was 83.3%. Body composition was significantly altered with a reduction in median fat mass from 52.5 kg to 46.9 kg (p=0.04), and BMI from 37.5 kg/m2 to 36.2 kg/m2 (p = 0.004). There was no significant difference in cardiorespiratory fitness or cardiovascular parameters. The percentage of CD4+ and CD8+ T-cells producing IFNγ towards MAGE-A4 significantly increased from and 5.9% to 7.2% (p=0.043) and 13.9% to 14.8% (p=0.046), respectively. There were 3 related adverse events: hip pain, back sprain, and abdominal pain. DISCUSSION: Our home-based exercise and nutrition counseling program was feasible based on 80% adherence to walking sessions and favored altered body composition. However, the discontinuation rate was high and further research is needed to overcome barriers to implementation. Improvement in cardiovascular parameters will most likely require longer and more intensive programs.