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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

Circulating immune cell numbers and phenotypes are impacted by high-intensity acute bouts of exercise and infection history with the latent herpesviruses cytomegalovirus (CMV). In particular, CMV infection history impairs the exercise-induced mobilization of cytotoxic innate lymphoid cells 1 (ILC1) cells, also known as NK cells, in the blood. However, it remains unknown whether exercise and CMV infection modulate the mobilization of traditionally tissue-resident non-cytotoxic ILCs into the peripheral blood compartment. To address this question, 22 healthy individuals with or without CMV (20–35 years—45% CMVpos) completed 30 min of cycling at 70% VO2 max, and detailed phenotypic analysis of circulating ILCs was performed at rest and immediately post-exercise. We show for the first time that a bout of high-intensity exercise is associated with an influx of ILCs that are traditionally regarded as tissue-resident. In addition, this is the first study to highlight that latent CMV infection blunts the exercise-response of total ILCs and progenitor ILCs (ILCPs). These promising data suggest that acute exercise facilitates the circulation of certain ILC subsets, further advocating for the improvements in health seen with exercise by enhancing cellular mobilization and immunosurveillance, while also highlighting the indirect deleterious effects of CMV infection in healthy adults.

Long-duration spaceflights reportedly induce immune dysregulation, which is considered a risk to astronaut safety and mission success. Recent studies have examined the impact of spaceflight on markers of adaptive and innate immunity, but no study, to date, has comprehensively evaluated humoral immunity and serological markers of B cell function. The aim of this study was to characterize changes in B cell numbers and phenotypes, along with plasma Igs and polyclonal free light chains (FLCs)—near-“real-time” biomarkers of Ig synthesis—in response to an ~6-mo mission to the International Space Station (ISS). Whole-blood samples were collected before flight, during flight (“Early flight,” “Mid-flight,” and “Late flight”), immediately upon return, and during a recovery period (R + 18, R + 30/R + 33, and R + 60/R + 66) from 23 ISS crew members. B Cell counts and phenotypes were measured throughout the duration of the mission, along with total plasma Ig and FLC levels. There was no effect of spaceflight on the number and proportion of the different B cell subsets. There was no difference in kappa FLC between preflight samples and either in-flight or recovery samples ( P > 0.05), and only a marginal reduction was observed in lambda FLC levels upon return to Earth ( P < 0.05). Furthermore, IgG and IgM remained unchanged during and after spaceflight compared with preflight values ( P > 0.05). Of note, plasma IgA concentrations were elevated in-flight compared with baseline and recovery values ( P < 0.05). These results indicate that B cell homeostasis is maintained during long-duration spaceflight, advocating for potential in-flight vaccination as viable countermeasures against viral reactivation during exploration-class missions.

BACKGROUND: Acute hyperglycemia reduces NO bioavailability and causes macro- and microvascular dysfunction. Watermelon juice (WMJ) is a natural source of the amino acid citrulline, which is metabolized to form arginine for the NO cycle and may improve vascular function. OBJECTIVES: We examined the effects of 2 weeks of WMJ compared to a calorie-matched placebo (PLA) to attenuate acute hyperglycemia-induced vascular dysfunction. METHODS: In a randomized, placebo-controlled, double-blind, crossover trial, 6 men and 11 women (aged 21–25; BMI, 23.5 ± 3.2 kg/m(2)) received 2 weeks of daily WMJ (500 mL) or a PLA drink followed by an oral-glucose-tolerance test. Postprandial flow-mediated dilation (FMD) was measured by ultrasound (primary outcome), while postprandial microvascular blood flow (MVBF) and ischemic reperfusion were measured by near-infrared spectroscopy (NIRS) vascular occlusion test (VOT). RESULTS: The postprandial FMD area AUC was higher after WMJ supplementation compared to PLA supplementation (838 ± 459% · 90 min compared with 539 ± 278% · 90 min; P = 0.03). The postprandial MVBF (AUC) was higher (P = 0.01) following WMJ supplementation (51.0 ± 29.1 mL blood · 100 mL tissue(–1) · min(–1) · 90 min) compared to the PLA (36.0 ± 20.5 mL blood · 100 mL tissue(–1) · min(–1) · 90 min; P = 0.01). There was a significant treatment effect (P = 0.048) for WMJ supplementation (71.2 ± 1.5%) to increase baseline tissue oxygen saturation (StO(2)%) when compared to PLA (65.9 ± 1.7%). The ischemic-reperfusion slope was not affected by WMJ treatment (P = 0.83). CONCLUSIONS: Two weeks of daily WMJ supplementation improved FMD and some aspects of microvascular function (NIRS-VOT) during experimentally induced acute hyperglycemia in healthy adults. Preserved postprandial endothelial function and enhanced skeletal muscle StO(2)% are likely partially mediated by increased NO production (via citrulline conversion into arginine) and by the potential antioxidant effect of other bioactive compounds in WMJ.

Neutrophil dysfunction is a common feature of aging, and is associated with the pathogenesis of many age-related diseases, including type 2 diabetes mellitus (T2DM). Although exercise training improves metabolic health, decreases risk of T2DM, and is associated with improving neutrophil functions, involvement in regular physical activity declines with age. The aim of this study was to determine if neutrophil functions could be improved in association with changes in fitness and metabolic parameters in older adults at risk for T2DM using 10-weeks of low volume high-intensity interval exercise training (HIIT). Ten older (71 ± 5 years) sedentary adults with prediabetes (HbA1c: 6.1 ± 0.3%) completed 10 weeks of a supervised HIIT program. Three 30 min sessions/week consisted of ten 60 s intervals of low intensity [50–60% heart rate reserve (HRR)] separated with similar durations of high intensity intervals (80–90% HRR). Before and after training, glucose and insulin sensitivity, neutrophil chemotaxis, bacterial phagocytosis, reactive oxygen species (ROS) production, and mitochondrial functions were assessed. Exercise-mediated changes in cardiorespiratory fitness (VO2peak) and neutrophil functions were compared to six young (23 ± 1 years) healthy adults. Following training, significant reductions in fasting glucose and insulin were accompanied by improved glucose control and insulin sensitivity (all p < 0.05). Before exercise training, VO2peak in the old participants was significantly less than that of the young controls (p < 0.001), but increased by 16 ± 11% following training (p = 0.002) resulting in a 6% improvement of the deficit. Neutrophil chemotaxis, phagocytosis and stimulated ROS production were significantly less than that of the young controls, while basal ROS were higher before training (all p < 0.05). Following training, chemotaxis, phagocytosis and stimulated ROS increased while basal ROS decreased, similar to levels observed in the young controls (all p < 0.05) and reducing the deficit of the young controls between 2 and 154%. In five of the adults with prediabetes, neutrophil mitochondrial functions were significantly poorer than the six young controls before training. Following training, mitochondrial functions improved toward those observed in young controls (all p < 0.05), reducing the deficit of the young controls between 14.3 and 451%. Ten weeks of HIIT in older adults at risk for T2DM reduced disease risk accompanied by improved primary and bioenergetic neutrophil functions. Our results are consistent with a reduced risk of infections mediated by relationships in exercise induced systemic and cellular metabolic features.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT02441205, registered on May 12th, 2015.

Long duration spaceflights are associated with profound dysregulation of the immune system and latent viral reactivations. However, little is known on the impact of long duration spaceflight on innate immunity which raises concerns on crewmembers' ability to fight infections during a mission. The aim of this study was to determine the effects of spaceflight on plasma antimicrobial proteins (AMPs) and how these changes impact latent herpesvirus reactivations. Plasma, saliva and urine samples were obtained from 23 crewmembers before, during and after a 6-month mission on the International Space Station (ISS). Plasma AMP concentrations were determined by ELISA, and saliva Epstein-Barr virus (EBV) and varicella zoster virus (VZV) and urine cytomegalovirus (CMV) DNA levels were quantified by Real-Time PCR. There was a non-significant increase in plasma HNP1-3 and LL-37 during the early and middle stages of the missions, which was significantly associated with changes in viral DNA during and after spaceflight. Plasma HNP1-3 and Lysozyme increased at the late mission stages in astronauts who had exhibited EBV and VZV reactivations during the early flight stages. Following return to Earth and during recovery, HNP1-3 and lysozyme concentrations were associated with EBV and VZV viral DNA levels, reducing the magnitude of viral reactivation. Reductions in plasma LL-37 upon return were associated with greater CMV reactivation. This study shows that biomarkers of innate immunity appeared to be partially restored after 6-months in space and suggests that following adaptation to the space environment, plasma HNP1-3 and lysozyme facilitate the control of EBV and VZV reactivation rate and magnitude in space and upon return on earth. However, the landing-associated decline in plasma LL-37 may enhance the rate of CMV reactivation in astronauts following spaceflight, potentially compromising crewmember health after landing.

As the international space community plans for manned missions to Mars, spaceflight-associated immune dysregulation has been identified as a potential risk to the health and safety of the flight crew. There is a need to determine whether salivary antimicrobial proteins, which act as a first line of innate immune defense against multiple pathogens, are altered in response to long-duration (>6 mo) missions. We collected 7 consecutive days of whole and sublingual saliva samples from eight International Space Station (ISS) crewmembers and seven ground-based control subjects at nine mission time points, ~180 and ~60 days before launch (L−180/L−60), on orbit at flight days ~10 and ~90 (FD10/FD90) and ~1 day before return (R−1), and at R+0, R+18, R+33, and R+66 days after returning to Earth. We found that salivary secretory (s)IgA, lysozyme, LL-37, and the cortisol-to-dehydroepiandrosterone ratio were elevated in the ISS crew before (L−180) and during (FD10/FD90) the mission. “Rookie” crewmembers embarking on their first spaceflight mission had lower levels of salivary sIgA but increased levels of α-amylase, lysozyme, and LL-37 during and after the mission compared with the “veteran” crew who had previously flown. Latent herpesvirus reactivation was distinct to the ~6-mo mission crewmembers who performed extravehicular activity (“spacewalks”). Crewmembers who shed at least one latent virus had higher cortisol levels than those who did not shed. We conclude that long-duration spaceflight alters the concentration and/or secretion of several antimicrobial proteins in saliva, some of which are related to crewmember flight experience, biomarkers of stress, and latent viral reactivation. NEW & NOTEWORTHY Spaceflight-associated immune dysregulation may jeopardize future exploration-class missions. Salivary antimicrobial proteins act as a first line of innate immune defense. We report here that several of these proteins are elevated in astronauts during an International Space Station mission, particularly in those embarking on their first space voyage. Astronauts who shed a latent herpesvirus also had higher concentrations of salivary cortisol compared with those who did not shed. Stress-relieving countermeasures are needed to preserve immunity and prevent viral reactivation during prolonged voyages into deep space.

Collegiate athletes are exposed to varying levels of academic and physical stressors, placing them at increased risk for stress-activated latent viral infections. However, the impact of allostatic stress load on the immune response to maximal exercise in athletes remains largely unknown. This study examined the effects of a 7-mo training period and cytomegalovirus (CMV) serostatus on immune cell response to high-intensity swim tests within a group of collegiate swimmers. Samples were collected from 15 National Collegiate Athletic Association Division I swimmers (9 men, 6 women: 19.87 ± 0.64 yr) before and after exhaustive in-pool swims at 2 time points (V1: immediately post-season 1 and V3: beginning of season 2). An additional off-season (V2) time point was collected in a subset of 9 swimmers. Natural killer (NK) cell, B cell, and T cells were quantified by flow cytometry. Linear mixed models were used to determine the effects of exercise, time point, and CMV serostatus (α = 0.05). Resting senescent CD8+ T cells were higher in CMV-seropositive participants at V3 ( P = 0.005). CMV-seronegative participants had a decrease in resting senescent CD8+ T cells from V1 to V3 ( P = 0.021). After acute exercise, CMV-seropositive participants had lower naïve CD8+ T cells ( P < 0.001) and higher senescent CD8+ T cells ( P < 0.001). Increased cumulative stress levels did not appear to affect B-cell and NK-cell compartments. Immune response to exercise was impacted by CMV serostatus and allostatic stress load. Young CMV-seropositive athletes exposed to elevated stressors should be monitored to determine long-term effects of training and academic stressors. NEW & NOTEWORTHY Allostatic stress load is associated with impaired immune response to maximal exercise in cytomegalovirus (CMV)-seropositive subjects but not in CMV-seronegative young healthy adults.

We assessed metabolic flexibility (MF) via a mixed meal in a group of young, healthy participants with a positive family history of maternal type 2 diabetes (T2D) (FH+) and those without a family history of T2D (FH−) under three distinct conditions; baseline (BL; no previous exercise), 1‐h post high intensity interval exercise (1H), and 48‐h post exercise recovery. On separate visits, participants completed a single bout of high intensity interval exercise (HIIE) and repeated the MMTT 1‐h (1H) and 48 h (48H) postexercise. FH+ participants were not able to suppress fat oxidation 1‐h post exercise (1H) as effectively as FH− participants were, however, this response was improved when measured at the 48H visit. Insulin AUC was significantly lowered at both 1H and 48H when compared to the BL visit. Serum NEFA AUC was elevated 1‐h post exercise, when compared to BL, but was significantly reduced at the 48H visit. Young, healthy participants with a maternal history of T2D demonstrate impaired MF (related to the inability to suppress fat oxidation) in response to acute HIIE (1H) that was improved 48H. The overall effect of HIIE showed improved insulin AUC and NEFA AUC up to 48H post that did not differ by FH.

Purpose: Obesity is an independent risk factor for the development, morbidity, and mortality of breast cancer. Calorie restriction (CR) is the first line therapy for obesity management, with growing evidence and application in the treatment of breast cancer. In non-tumor bearing patients, ~20% of weight loss is attributed to reductions in skeletal muscle mass. However, little is known of how CR in a tumorigenic environment may influence muscle function and content. Methods: Obese C57BL/6J female mice were used to develop an allograft breast cancer model by orthotopically injecting the mammary fat pad with basal-like breast cancer (E0771 cells). Mice were randomized (1:1) by tumor size and body weight to high fat diet (HFD; 60% kcal from fat) or calorie restriction diet (CRD; ~40% restriction of HFD via an incremental reduction in food intake) for 2.5 weeks. Daily food intake, body weight and temperature, as well as twice weekly tumor measurements were obtained during treatment. Organ weights and size were obtained at the time of necropsy. Whole blood was collected for immunophenotyping and assessed via flow cytometry. Mitochondrial function was determined in tumor homogenates and permeabilized gastrocnemius fibers by high resolution respirometry (O2k). Results: CRD reduced body weight (HFD: 27.8±0.8 vs CRD: 22.9±0.5 g, P=0.0003) and tumor growth (HFD: 3.6±0.2 g vs. CRD: 2.7±0.3 g, P=0.03). There was no difference in the proportions of total NK cells, helper and cytotoxic T-cells between HFD and CRD (P>0.05). Respirometry studies of tumor mitochondria revealed diminished complex I uncoupled rate following CRD (HFD: 3.2±0.4 vs. CRD: 1.6±0.3 pmol/sec/mg, P= 0.02). Additionally, skeletal muscle mitochondria of CRD animals contained a defect in complex I oxidation (HFD: 49.2±6.5 vs. CRD: 28.6±4.0 pmol/sec/mg, P=0.03). Furthermore, soleus muscle mass was reduced (HFD: 7.7±0.8 mg vs. CRD: 4.5±1.1 mg, P=0.04). Conclusions: This study demonstrates that CRD induces complex I (CI) defects in tumor and skeletal muscle mitochondria. Suppression of CI was associated with a favorable reduction in tumor growth and unfavorable loss of skeletal muscle mass. Future studies formally evaluating skeletal muscle function and cachexia as well as muscle preserving therapies in combination with CR are warranted. Funding: Research was supported by NIGMS (GM104940 - JPK) and the Pennington Biomedical Research Foundation (LAG) Citation Format: Elizabeth R. Zunica, Christopher L. Axelrod, Gangarao Davuluri, Wagner S. Dantas, Guillaume Spielmann, Eunhan Cho, Brian A. Irving, John P. Kirwan, L. Anne Gilmore. Calorie restriction induces skeletal muscle wasting and a complex I defect while reducing mammary tumor growth in a mouse model of diet induced obesity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4796.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease in which adults have significant joint issues leading to poor health. Poor health is compounded by many factors, including exercise avoidance and increased risk of opportunistic infection. Exercise training can improve the health of patients with RA and potentially improve immune function; however, information on the effects of high-intensity interval training (HIIT) in RA is limited. We sought to determine whether 10 weeks of a walking-based HIIT program would be associated with health improvements as measured by disease activity and aerobic fitness. Further, we assessed whether HIIT was associated with improved immune function, specifically antimicrobial/bacterial functions of neutrophils and monocytes.Methods: Twelve physically inactive adults aged 64 ± 7 years with either seropositive or radiographically proven (bone erosions) RA completed 10 weeks of high-intensity interval walking. Training consisted of 3 × 30-minute sessions/week of ten ≥ 60-second intervals of high intensity (80–90% VO2reserve) separated by similar bouts of lower-intensity intervals (50–60% VO2reserve). Pre- and postintervention assessments included aerobic and physical function; disease activity as measured by Disease Activity score in 28 joints (DAS28), self-perceived health, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR); plasma interleukin (IL)-1β, IL-6, chemokine (C-X-C motif) ligand (CXCL)-8, IL-10, and tumor necrosis factor (TNF)-α concentrations; and neutrophil and monocyte phenotypes and functions.Results: Despite minimal body composition change, cardiorespiratory fitness increased by 9% (change in both relative and absolute aerobic capacity; p p p = 0.001) with significant reductions in ESR and swollen joints as well as improved self-perceived health. Neutrophil migration toward CXCL-8 (p = 0.003), phagocytosis of Escherichia coli (p = 0.03), and ROS production (p +)/CD16+ monocytes was reduced (p = 0.002), with both nonclassical (CD14dim/CD16bright) and intermediate (CD14bright/CD16positive) monocytes being reduced (both p p E. coli increased (p = 0.02). No changes were observed for inflammatory markers IL-1β, IL-6, CXCL-8, IL-10, CRP, or TNF-α.Conclusions: We report for the first time, to our knowledge, that a high-intensity interval walking protocol in older adults with stable RA is associated with reduced disease activity, improved cardiovascular fitness, and improved innate immune functions, indicative of reduced infection risk and inflammatory potential. Importantly, the exercise program was well tolerated by these patients.Trial registration: ClinicalTrials.gov, NCT02528344. Registered on 19 August 2015.

Salivary antimicrobial proteins (sAMPs) protect the upper respiratory tract (URTI) from invading microorganisms and have been linked with URTI infection risk in athletes. While high training volume is associated with increased URTI risk, it is not known if fitness affects the sAMP response to acute exercise. This study compared the sAMP responses to various exercising workloads of highly fit experienced cyclists with those who were less fit. Seventeen experienced cyclists (nine highly fit; eight less fit) completed three 30-min exercise trials at workloads corresponding to −5, +5 and +15 % of the individual blood lactate threshold. Saliva samples were collected pre- and post-exercise to determine the concentration and secretion of α-amylase, human neutrophil proteins 1–3 (HNP1–3) lactoferrin, LL-37, lysozyme, and salivary SIgA. The concentration and/or secretion of all sAMPs increased post-exercise, but only α-amylase was sensitive to exercise workload. Highly fit cyclists had lower baseline concentrations of α-amylase, HNP1–3, and lactoferrin, although secretion rates did not differ between the groups. Highly fit cyclists did, however, exhibit greater post-exercise increases in the concentration and/or secretion of a majority of measured sAMPs (percentage difference between highly fit and less fit in parentheses), including α-amylase concentration (+107 %) and secretion (+148 %), HNP1–3 concentration (+97 %) and secretion (+158 %), salivary SIgA concentration (+181 %), lactoferrin secretion (+209 %) and LL-37 secretion (+138 %). We show for the first time that fitness level is a major determinant of exercise-induced changes in sAMPs. This might be due to training-induced alterations in parasympathetic and sympathetic nervous system activation.

The redeployment of NK-cells in response to an acute bout of exercise is thought to be an integral component of the “fight-or-flight” response, preparing the body for potential injury or infection. We showed previously that CMV seropositivity impairs the redeployment of NK-cells with exercise in the young. In the current study, we examined the effect of aging on the redeployment of NK-cells with exercise in the context of CMV. We show here that CMV blunts the exercise-induced redeployment of NK-cells in both younger (23–39 yrs) and older (50–64 yrs) subjects with olderCMVnegsubjects showing the largest postexercise mobilization and 1 h postexercise egress of NK-cells. The blunted exercise response inCMVposindividuals was associated with a decreased relative redeployment of the CD158a+ and CD57+ NK-cell subsets in younger and older individuals. In addition, we show that aging is associated with a CMV-independent increase in the proportion of NK-cells expressing the terminal differentiation marker CD57, while CMV is associated with an age-dependent decrease in the proportion of NK-cells expressing the inhibitory receptors KLRG1 (in the younger group) and CD158a (in the older group). Collectively, these data suggest that CMV may decrease NK-cell mediated immunosurveillance after exercise in both younger and older individuals.

Latent cytomegalovirus (CMV) infection has been shown to alter the lymphocyte response to acute aerobic exercise, likely due to the corresponding increase in exercise-responsive memory CD8(+) T cells. It is unknown if latent infection with another herpesvirus, herpes simplex virus 1 (HSV-1), also plays a role in shaping the lymphocyte response to exercise.Thirty-two men (ages 39.3 ± 14.7 yr) counterbalanced by CMV and HSV-1 serostatus (positive/negative) cycled for 30 min at ∼80% peak power. Blood sampled before, immediately after, and 1 h after exercise was analyzed by flow cytometry for T-cell subset enumeration.In resting blood, HSV-1(+) had fewer lymphocytes, CD4(+) T cells, KLRG1(-) CD28(+) CD4(+) T cells, and CD45RA(-)CCR7(+)CD4(+) T cells than HSV-1(-), whereas CMV(+) had increased numbers of lymphocytes, CD8(+) T cells, KLRG1(+)CD28(-)CD4(+) and CD8(+) T cells, and CD45RA(+)CCR7(-)CD8(+) T cells and a lower CD4:CD8 T-cell ratio than CMV(-). After exercise, CMV(+) had a greater mobilization of CD8(+) T cells, KLRG1+CD28(-)CD4+ and CD8(+) T cells, and CD45RA+CCR7(-)CD8+ T cells independently of HSV-1 serostatus, as well as a greater egress of these subsets 1 h after exercise. HSV serostatus did not influence total CD8(+) T-cell response to exercise.The impact of latent CMV infection on the redeployment of T-cell subsets with exercise is independent of HSV-1 infection. This is most likely due to the unique ability of CMV to alter the composition of the memory T-cell pool in favor of exercise-responsive T-cell subsets.

Cancer incidence increases with advancing age. Over 60% of new cancers and 70% of cancer deaths occur in individuals aged 65 years or older. One factor that may contribute to this is immunosenescence - a canopy term that is used to describe age-related declines in the normal functioning of the immune system. There are multiple age-related deficits in both the innate and adaptive systems that may play a role in the increased incidence of cancer. These include decreased NK-cell function, impaired antigen uptake and presentation by monocytes and dendritic cells, an increase in 'inflammaging', a decline in the number of naïve T-cells able to respond to evolving tumor cells, and an increase in functionally exhausted senescent cells. There is consensus that habitual physical exercise can offer protection against certain types of cancer; however the evidence linking immunological mechanisms, exercise, and reduced cancer risk remain tentative. Multiple studies published over the last two decades suggest that exercise can mitigate the deleterious effects of age on immune function, thus increasing anti-cancer immunity. The potential ameliorative effect of exercise on these mechanisms include evidence that physical activity is able to stimulate greater NK-cell activity, enhance antigen-presentation, reduce inflammation, and prevent senescent cell accumulation in the elderly. Here we discuss the role played by the immune system in preventing and controlling cancer and how aging may retard these anti-cancer mechanisms. We also propose a pathway by which exercise-induced alterations in immunosenescence may decrease the incidence of cancer and help improve prognosis in cancer patients.

For more than two decades, physicians have prescribed metformin as the frontline pharmacological therapy to treat type 2 diabetes (T2D) despite knowing little about its underlying mechanisms of action (1). Metformin reduces hepatic glucose production (1) and has pleotropic effects on multiple tissues, including liver (1), muscle (2), and adipose (3) tissue, as well as on immune cells (4). Clinically, metformin also reduces the risk for cardiovascular diseases, cancers, and other diseases (5,6). Pharmacometabolomics provides an opportunity to measure changes in absolute and/or relative concentrations of hundreds to thousands of small molecules in biofluids and tissue extracts to determine the response and variations in response to therapy (7). Pharmacometabolomics could facilitate identification of metabolic pathways and mechanisms of action that contribute to metformin’s widespread salutatory effects (7). In this issue of Diabetes , Adam et al. (8) utilize this approach to “uncover” metformin’s effect on citrulline metabolism in individuals with and without T2D participating in the KORA (Cooperative Health Research in the Region of Augsburg) study. Adam et al. should be commended on conducting a thorough investigation of metformin’s impact on serum metabolites in individuals with T2D using nontargeted, semiquantitative liquid chromatography–tandem mass spectrometry coupled with rigorous statistical and bioinformatic analyses. The cross-sectional “human discovery” study revealed that out of a total of 353 identified serum metabolites, the concentrations of citrulline were significantly lower and X-21365 significantly higher in metformin-treated participants with T2D compared with nontreated participants. The longitudinal “human validation” study further demonstrated that the initiation of metformin treatment during the 7-year follow-up significantly reduced citrulline and increased X-21365 serum concentrations. Subsequently, the “translational” study showed that daily treatment with metformin in db/db diabetic mice decreased plasma, skeletal muscle, and epididymal …

Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The adoptive transfer of donor-derived viral-specific cytotoxic T-cells (VSTs) is an effective treatment for controlling CMV and EBV infections after HSCT; however, new practical methods are required to augment the ex vivo manufacture of multi-VSTs from healthy donors. This study investigated the effects of a single exercise bout on the ex vivo manufacture of multi-VSTs. PBMCs isolated from healthy CMV/EBV seropositive participants before (PRE) and immediately after (POST) 30-minutes of cycling exercise were stimulated with CMV (pp65 and IE1) and EBV (LMP2A and BMLF1) peptides and expanded over 8 days. The number (fold difference from PRE) of T-cells specific for CMV pp65 (2.6), EBV LMP2A (2.5) and EBV BMLF1 (4.4) was greater among the VSTs expanded POST. VSTs expanded PRE and POST had similar phenotype characteristics and were equally capable of MHC-restricted killing of autologous target cells. We conclude that a single exercise bout enhances the manufacture of multi-VSTs from healthy donors without altering their phenotype or function and may serve as a simple and economical adjuvant to boost the production of multi-VSTs for allogeneic adoptive transfer immunotherapy.

Acute exercise alters the surface expression of toll-like receptors (TLRs) and HLA.DR on blood monocytes, which could transiently compromise immunity. As serum factors might be responsible, we examined the effects of autologous post-exercise serum exposure on TLR2, TLR4 and HLA.DR expression on resting blood monocytes and their subtypes. Eight trained cyclists completed an ergometer 60 km time trial. PBMCs and serum were obtained before, immediately after and 1 h after exercise. TLR2, TLR4 or HLA.DR expression (gMFI) was determined on blood monocyte subtypes expressing combinations of CD14 and CD16 by flow cytometry, and on resting monocytes exposed to 50% autologous serum (pre, immediately after or 1 h after exercise) for 18 h in culture. Immediately after exercise, total monocyte expression of TLR2 and TLR4 increased by 41 and 27%, respectively, while HLA.DR expression was 39% lower than baseline. TLR2 and TLR4 was 53 and 84% greater 1 h after exercise, respectively, while HLA.DR was 48% lower. Changes in TLR2 and TLR4 expression occurred on the CD14(++bright)/CD16(+dim) monocyte subtype only, while HLA.DR expression changed on the CD14(+dim)/CD16(++bright) subtype. Serum did not affect monocyte TLR2 or TLR4 expression but 1 h post serum increased expression of HLA.DR on total monocytes and the CD14(+dim)/CD16(++bright) subtype, which was in contrast to the change observed at this time after exercise. We conclude that a bout of strenuous aerobic exercise alters the surface expression of TLR2, TLR4 and HLA.DR on blood monocytes and some of their subtypes, but these changes appear to be unrelated to blood serum factors.

Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development and progression of multiple age- and lifestyle-related diseases. While l-arginine is the precursor for the synthesis of NO by endothelial-nitric oxide synthase (eNOS), oral l-arginine supplementation is largely ineffective at increasing NO synthesis and/or bioavailability for a variety of reasons. l-citrulline, found in high concentrations in watermelon, is a neutral alpha-amino acid formed by enzymes in the mitochondria that also serves as a substrate for recycling l-arginine. Unlike l-arginine, l-citrulline is not quantitatively extracted from the gastrointestinal tract (i.e., enterocytes) or liver and its supplementation is therefore more effective at increasing l-arginine levels and NO synthesis. Supplementation with l-citrulline has shown promise as a blood pressure lowering intervention (both resting and stress-induced) in adults with pre-/hypertension, with pre-clinical (animal) evidence for atherogenic-endothelial protection. Preliminary evidence is also available for l-citrulline-induced benefits to muscle and metabolic health (via vascular and non-vascular pathways) in susceptible/older populations. In this review, we examine the impact of supplementing this important urea cycle intermediate on cardiovascular and metabolic health outcomes and identify future directions for investigating its therapeutic impact on cardiometabolic health.

Regular physical exercise is associated with increased longevity and a lower risk of developing several age-associated diseases. In addition, regular exercise has been purported as a simple lifestyle intervention to counteract the deleterious effects of age-associated changes in immunity known as immunosenescence. Etiology of immunosenescence is multifaceted and can impact on both arms of the immune system. Since 1990, several longitudinal ageing studies using aerobic- and/or resistance-based exercise provided growing information on the benefits of exercise in both innate immunity and adaptive immunity. Regular exercise can improve responses to vaccines, NK-cell function, neutrophil phagocytic activity, and T-cell proliferation. It also reduces circulatory inflammatory mediators and inflammatory response to bacterial challenge. These findings provide a strong indication that habitual exercise has immune regulatory properties and may help delay the onset of immunosenescence.

Life expectancy in the developed world has increased exponentially over the last century, predisposing the elderly population to an unprecedented risk of infectious disease and malignancy. This apparent increase in disease susceptibility appears to be due to inexorable declines in the normal functioning of the immune system, with this age-related effect commonly being referred to as immunosenescence. The decline in functioning of the immune system is thought to be multifactorial (see Chaps. 1 and 2) and in part reflects a manifestation of repeated exposures to external pathogens and persistent viral infections throughout the lifespan, although certain lifestyle factors (i.e. smoking, inactivity, socio-economic status ) have also been linked with impaired immunity and biomarkers of ageing. Immunosenescence describes a progressive deterioration of systemic immunity, however, ageing is associated with a more pronounced functional decline in adaptive (i.e. T- and B-lymphocytes and their products) compared to innate immunity. Many of these age-related changes within the T-cell compartment (i.e. inverted CD4/CD8 T-cell ratio, low mitogen-induced T-cell proliferation, memory cell inflation, low IL-2 synthesis) have been clustered together over the years to form an “immune risk profile” (IRP) that has proven to be a useful set of biomarkers to predict morbidity and mortality in the elderly (Pawelec et al., J Comp Pathol 142(Suppl 1):S39–44, 2010). However, circulating levels of inflammatory mediators such as IL-6, IL-1ra and C-reactive protein have also been found to be useful prognostic markers in very old people (Jylha et al., J Gerontol A Biol Sci Med Sci 62(9):1016–1021, 2007).

Viral infections are a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The adoptive transfer of multi-virus specific cytotoxic T-cell lines (CTLs) expanded from a suitably matched donor can reproducibly control infections after HSCT. However, the failure to generate sufficient numbers of virus-specific CTLs ex vivo can often result in inadequate restoration of antiviral immunity and poor prognosis. Because exercise mobilizes large numbers of viral specific T-cells into the bloodstream, we hypothesized that a single bout of exercise would increase the expansion of multi-viral-specific CTLs in would be HSCT donors. Healthy CMV and EBV seropositive subjects performed 30-min of cycling exercise at +15% of the individual blood lactate threshold. A fixed number of PBMCs isolated before and immediately after exercise were pulsed with overlapping peptides spanning all target viral antigens and expanded with IL-4, IL-7 and IL-15 over 9-days. Exercise remarkably increased the expansion of cytomegalovirus (CMV) pp65 (∼3.8-fold), CMV IE-1 (∼4.7-fold) and Epstein-Barr virus (EBV) BMLF-1 (∼2.8-fold) specific CTLs over 9-days, although did not reliably increase the expansion of EBV LMP-2 specific CTLs. All virus-reacting cells were of a CD62L- memory phenotype and remained elevated after exercise even when adjusted for input T-cell numbers. We conclude that exercise may serve as a simple strategy to reliably augment the ex vivo expansion of viral-specific CTLs for adoptive transfer immunotherapy after HSCT.

Human space exploration provides great technological, medical and academic advances to humanity, but also poses many threats to the health of the crew. Astronauts are subjected to a myriad of both physical and psychological stressors that may negatively affect the immune system and increase the risk of an adverse health event in flight. In this ongoing study, we compared immune cell phenotypes and NK-cell activity (NKCA) between astronauts and controls 5-months before a 6-month mission to the International Space Station (ISS). Blood samples were taken from 6 astronauts and 6 non-astronaut controls and assayed for immune cell phenotypes and NKCA by flow cytometry. Astronauts had lower proportions and numbers of naive KLRG1−/CD28+ (p 0.05). We conclude that astronauts display only small baseline differences in T-cell phenotype and NKCA compared to controls when assessed 5-months prior to launch. This study will continue to monitor immune function changes in these astronauts and ground-based controls during and after a 6-month mission to the ISS.

Salivary antimicrobial proteins (sAMPs) protect the upper respiratory tract from invading microorganisms. Maintaining mucosal immune integrity is important for elite-level endurance athletes as high levels of training are associated with increased risks of upper respiratory tract infection (URTI). This study examined the effects of exercising workload and training status on the sAMP response to acute exercise. Seventeen trained cyclists completed three 30-min exercise trials at −5%, +5% and +15% of the individual blood lactate threshold (BLT). Saliva samples were collected pre and post-exercise to determine the concentration and secretion of α-amylase, HNP1–3, lactoferrin, LL-37, lysozyme, and sIgA. The concentration and/or secretion of all sAMPs increased post-exercise, but only α-amylase was sensitive to exercise workload. Highly trained cyclists (BLT power output/kg body mass > 2.8 w) had lower baseline concentrations of α-amylase, HNP1–3, and lactoferrin, although no group differences were found for baseline sAMP secretion rates. Highly trained cyclists did, however, exhibit greater post-exercise increases in the concentration and/or secretion of all measured sAMPs. This study shows that acute dynamic exercise increases sAMP concentration and secretion, and that α-amylase is sensitive marker of the sympathetic response that is associated with different exercising workloads. We also show for the first time that training status is a major determinant of both resting and exercise-induced changes in sAMPs, indicating a potential adaptive response to acute exercise in highly trained athletes.