Large Neutral Amino Acids Moderate the Effects of Metabolic Syndrome on Cognitive Performance in Middle-Aged Adults.

Introduction Two large neutral amino acids (LNAA), tryptophan and tyrosine, are precursors to cerebral neurotransmitters and are involved in cognitive function. Higher levels of LNAA in young adults are associated with improved cognition, although these associations appear to reverse over time. Given that exposure to metabolic syndrome (MetS) may induce premature cognitive aging, the current project aims to fill the gap in the literature by examining the effect of LNAA on cognitive performance in midlife adults with metabolic risks. Methods Eighty-eight adults, ages 40-61 years, participated in this cross-sectional study. LNAA metabolites were quantified, MetS components were measured using high-performance liquid chromatography, and MetS components were assessed in the laboratory. Composite verbal memory and executive functioning scores were computed using principal component analysis. We used linear regression models to test the interaction between LNAA and MetS while covarying for sex, age, and education. Results The kynurenine/tryptophan ratio (KTR) moderated the relation between MetS and verbal memory, even after adjusting for relevant covariates. Tyrosine metabolites were not significant moderators of the association between MetS and executive functioning. Conclusion Our findings suggest that the detected weaker memory performance in adults with a high number of MetS components may be related to relative tryptophan depletion and possible decreases in serotonin production. Further investigation is warranted to examine the potential role of LNAA in associations between cognitive performance and metabolic risks over time.

Brain-Periphery Interactions in Huntington's Disease: Mediators and Lifestyle Interventions.

Prominent pathological features of Huntington's disease (HD) are aggregations of mutated Huntingtin protein (mHtt) in the brain and neurodegeneration, which causes characteristic motor (such as chorea and dystonia) and non-motor symptoms. However, the numerous systemic and peripheral deficits in HD have gained increasing attention recently, since those factors likely modulate disease progression, including brain pathology. While whole-body metabolic abnormalities and organ-specific pathologies in HD have been relatively well described, the potential mediators of compromised inter-organ communication in HD have been insufficiently characterized. Therefore, we applied an exploratory literature search to identify such mediators. Unsurprisingly, dysregulation of inflammatory factors, circulating mHtt, and many other messenger molecules (hormones, lipids, RNAs) were found that suggest impaired inter-organ communication, including of the gut-brain and muscle-brain axis. Based on these findings, we aimed to assess the risks and potentials of lifestyle interventions that are thought to improve communication across these axes: dietary strategies and exercise. We conclude that appropriate lifestyle interventions have great potential to reduce symptoms and potentially modify disease progression (possibly via improving inter-organ signaling) in HD. However, impaired systemic metabolism and peripheral symptoms warrant particular care in the design of dietary and exercise programs for people with HD.

Intestinal microbiome in normal ageing, frailty and cognition decline.

PURPOSE OF REVIEW: The intestinal microbiome modulates the risk of several age-related chronic diseases and syndromes, including frailty and neurodegenerative diseases. Herein we provided an update on the influence of gut microbiota on physical and cognitive performance in older age and suggest microbiota-targeted interventions for healthy ageing. RECENT FINDINGS: Low uniqueness index of the gut microbiome and high representation of Bacteroides are independently associated with mortality in older individuals, while the centenarian microbiome is characterized by high abundance of Lactobacilli and Bifidobacteria . Frailty syndrome, sarcopenia and cognitive decline are associated with reduced faecal microbiota biodiversity, reduced abundance of bacteria able to synthetize short-chain fatty acids (SCFA), including Faecalibacterium prausnitzii , and reduced faecal butyrate levels. Dietary intervention, especially involving Mediterranean diet, and exercise training seem to be associated with improved biodiversity of the microbiota, increased capacity of SCFA synthesis and, probably, protection against the onset of frailty and cognitive decline. SUMMARY: The gut microbiota biodiversity and composition may reflect the different ageing trajectory, but further research is needed to understand potential independent and combined effects of environmental and lifestyle factors in older adults, especially from a clinical point of view.

Role of dietary protein and exercise on biomarkers of immune activation in older patients during hospitalization.

The aim of this study was to examine the effect of short-term protein supplementation (aiming to consume 1.2 g protein/kg body weight per day) combined with moderate resistance training on 3 days of the week on tryptophan-kynurenine metabolism in 40 older patients with hip fracture. Secondary outcomes for physical recovery were hand-grip strength and chair-rise score. Older patients with hip fracture exhibited higher degrees of immune activation, detected by increased neopterin and kynurenine to tryptophan levels compared with reference values for healthy elderly with no significant differences between those who received the exercise-protein intervention compared to the control. Increasing dietary protein intake during hospitalization did not alleviate the Th1-type immune response in the elderly patient. On the other hand, muscularity per se may affect immune activation responses following injury, as improvements in maximum hand-grip strength with the intervention were related to decreases in neopterin levels.

Immune biomarkers in older adults: Role of physical activity.

Aging is associated with a decline in the normal functioning of the immune system. Several studies described the relationship between immunological alterations, including immunosenescence and inflammation, and aging or age-related outcomes, such as sarcopenia, depression, and neurodegenerative disorders. Physical activity is known to improve muscle function and to exert a number of benefits on older adult health, including reduced risk for heart and metabolic system chronic diseases. However, the positive influence of physical activity on the immune system has not been elucidated. In order to shed light on the role of physical activity in immune responses of older individuals, a number of immunological parameters comprising % lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, and CD16+56+) and serum levels of neopterin and tryptophan metabolism products were evaluated in peripheral blood samples of older adults performing normal (N = 170) or reduced (N = 89) physical activity. In addition, the potential influence of other clinical and epidemiological factors was also considered. Results showed that subjects with reduced physical activity displayed significantly higher levels of CD4+/CD8+ ratio, kynurenine/tryptophan ratio, and serum neopterin, along with lower %CD19+ cells and tryptophan concentrations. Further, some immunological biomarkers were associated with cognitive impairment and functional status. These data contribute to reinforce the postulation that physical activity supports healthy aging, particularly by helping to protect the immunological system from aging-related changes.

Influence of Antioxidants on Leptin Metabolism and its Role in the Pathogenesis of Obesity.

Obesity is associated with low-grade inflammation. Leptin, a hormone made by fat cells regulates appetite and hunger and thus food intake behavior. Interestingly, , food preservatives like sodium sulfite and sodium benzoate and also natural colorant and spice compounds such as curcumin were found to decrease the release of leptin in murine 3T3-L1 adipocytes, after co-incubation with LPS, which was added to mimic the pro-inflammatory status in obesity. Several of these compounds are well known food antioxidants.Whilst reducing oxidation events is beneficial in states of elevated oxidative stress, overexposure to food antioxidant can lead to adverse effects. There are hints from in vivo data, that antioxidant stress in younger age plays a role in the development of adiposity in later life. The insufficient exposure to oxidizing compounds like reactive oxygen species (ROS) cannot only cause an insufficient burning of calories but there is also a link to the regulation of food intake behavior. If the in vitro findings can be extrapolated to the in vivo situation, consumption of antioxidant supplemented food could lead to decreased leptin release and contribute to an obesogenic environment. This aspect sheds some new critical light on the potential role of an antioxidant-enriched nutrition in the obesity epidemic during the past few centuries. Doing sports could represent not only a proper strategy to initiate physiological ROS production and burning of calories, but also may shift the hormone milieu towards a reduction of hunger feelings and thus reduce appetite and food intake.

Mood, food, and cognition: role of tryptophan and serotonin.

PURPOSE OF REVIEW: Food is not only necessary as a metabolic fuel for the body, it becomes more and more evident that there exists an association between food and brain functions like mood and cognition. Tryptophan represents a key element for brain functioning, because of its role as a precursor for production of neurotransmitter serotonin (5-hydroxytryptamine). In clinical conditions, which involve chronic immune system activation or under cytokine therapy, lower tryptophan levels because of high catabolism of tryptophan as indicated by the kynurenine to tryptophan ratio are common and often associate with depressive mood. RECENT FINDINGS: Studies in the in vitro model of mitogen-stimulated peripheral blood mononuclear cells revealed that several phytocompounds, mainly antioxidants like polyphenols and vitamins, can interfere with inflammatory signaling cascades including tryptophan breakdown. If extrapolated to the in vivo situation, such compounds could increase blood and brain tryptophan availability for serotonin production. Although there is some in vivo evidence for the effect of such compounds, outcomes are hardly predictable and most likely depend on the individual's immunological state. SUMMARY: Not only a diet rich in tryptophan but also a diet rich in antioxidants can have a positive impact on mood and cognition. This could be of special relevance for individuals who present with low grade inflammation conditions.

Tryptophan Metabolism in Allergic Disorders.

Allergic diseases such as asthma and rhinitis, as well the early phase of atopic dermatitis, are characterized by a Th2-skewed immune environment. Th2-type cytokines are upregulated in allergic inflammation, whereas there is downregulation of the Th1-type immune response and related cytokines, such as interferon-x03B3; (IFN-x03B3;). The latter is a strong inducer of indoleamine 2,3-dioxygenase-1 (IDO-1), which degrades the essential amino acid tryptophan, as part of an antiproliferative strategy of immunocompetent cells to halt the growth of infected and malignant cells, and also of T cells - an immunoregulatory intervention to avoid overactivation of the immune system. Raised serum tryptophan concentrations have been reported in patients with pollen allergy compared to healthy blood donors. Moreover, higher baseline tryptophan concentrations have been associated with a poor response to specific immunotherapy. It has been shown that the increase in tryptophan concentrations in patients with pollen allergy only exists outside the pollen season, and not during the season. Interestingly, there is only a minor alteration of the kynurenine to tryptophan ratio (Kyn/Trp, an index of tryptophan breakdown). The reason for the higher tryptophan concentrations in patients with pollen allergy outside the season remains a matter of discussion. To this regard, the specific interaction of nitric oxide (NO∙) with the tryptophan-degrading enzyme IDO-1 could be important, because an enhanced formation of NO∙ has been reported in patients with asthma and allergic rhinitis. Importantly, NO∙ suppresses the activity of the heme enzyme IDO-1, which could explain the higher tryptophan levels. Thus, inhibitors of inducible NO∙ synthase should be reconsidered as candidates for antiallergic therapy out of season that may abrogate the arrest of IDO-1 by decreasing the production of NO∙. Considering its association with the pathophysiology of atopic disease, tryptophan metabolism may play a relevant role in the pathophysiology of allergic disorders.

Gender differences in the association between grip strength and mortality in older adults: results from the KORA-age study.

BACKGROUND: Reduced muscular strength in the old age is strongly related to activity impairment and mortality. However, studies evaluating the gender-specific association between muscularity and mortality among older adults are lacking. Thus, the objective of the present study was to examine gender differences in the association between muscular strength and mortality in a prospective population-based cohort study. METHODS: Data used in this study derived from the Cooperative Health Research in the Region of Augsburg (KORA)-Age Study. The present analysis includes 1,066 individuals (mean age 76 ± 11 SD years) followed up over 3 years. Handgrip strength was measured using the Jamar Dynamometer. A Cox proportional hazard model was used to determine adjusted hazard ratios of mortality with 95% confidence intervals (95% CI) for handgrip strength. Potential confounders (i.e. age, nutritional status, number of prescribed drugs, diseases and level of physical activity) were pre-selected according to evidence-based information. RESULTS: During the follow-up period, 56 men (11%) and 39 women (7%) died. Age-adjusted mortality rates per 1,000 person years (95% CI) were 77 (59-106), 24 (13-41) and 14 (7-30) for men and 57 (39-81), 14 (7-27) and 1 (0-19) for women for the first, second and third sex-specific tertile of muscular strength, respectively. Low handgrip strength was significantly associated with all-cause mortality among older men and women from the general population after controlling for significant confounders. Hazard ratios (95% CI) comparing the first and second tertile to the third tertle were 3.33 (1.53-7.22) and 1.42 (0.61-3.28), respectively. Respective hazard ratios (95% CI) for mortality were higher in women than in men ((5.23 (0.67-40.91) and 2.17 (0.27-17.68) versus 2.36 (0.97-5.75) and 0.97 (0.36-2.57)). CONCLUSIONS: Grip strength is inversely associated with mortality risk in older adults, and this association is independent of age, nutritional status, number of prescribed drugs, number of chronic diseases and level of physical activity. The association between muscular strength and all-cause mortality tended to be stronger in women. It seems to be particularly important for the weakest to enhance their levels of muscular strength in order to reduce the risk of dying early.

Central Adiposity and Cortical Thickness in Midlife.

OBJECTIVES: Excessive visceral fat is associated with greater metabolic fluctuation and increased risk for dementia in older adults. The aim of the current study is to directly determine the impact of central adiposity on brain structure at midlife by examining the thickness of the cerebral cortex. METHODS: High-resolution magnetization-prepared rapid acquisition gradient-echo images were obtained from 103 participants aged 40 to 60 years (mean [standard deviation] = 49.63 [6.47] years) on a 3-T Siemens Skyra scanner. Visceral fat was measured using dual-energy x-ray absorptiometry. RESULTS: Individuals with higher visceral fat mass and volume had significantly thicker cortex in the right posterior cingulate gyrus (ß = 0.29 [p = .019] and ß = 0.31 [p = .011], respectively), controlling for age, systolic blood pressure, total cholesterol level, and blood glucose level. CONCLUSIONS: Visceral fat was significantly associated with thicker cortex in the posterior cingulate gyrus. Although future studies are necessary, these results indicate that central adiposity is associated with significant metabolic changes that impinge upon the central nervous system in middle age.

Effects of a caloric restriction weight loss diet on tryptophan metabolism and inflammatory biomarkers in overweight adults.

PURPOSE: Recent data suggest that chronic low-grade inflammation, a characteristic of obesity, is associated with altered tryptophan (Trp) and tyrosine (Tyr) metabolism and plays a role in neuropsychiatric symptoms. The present study assessed the effect of an extreme short-term diet on Trp breakdown and inflammatory biomarkers in overweight adults. METHODS: Thirty-eight overweight participants (16 women, 22 men; average body mass index: 29 kg/m², mean age 52.8 years) were randomized into two diet groups: a very low kcal diet group (VLCD; Ø 600 kcal/day, n = 21) and a low kcal diet group (LCD; Ø 1,200 kcal/day, n = 17). Assays included the measurement of Trp, kynurenine (Kyn), and their ratio, neopterin, phenylalanine (Phe), Tyr, as biologic markers; leptin, plasma insulin, glucose, and homeostatic model assessment-insulin resistance; and interleukin 6, tumor necrosis factor alpha, and C-reactive protein, as biochemical and inflammatory markers at baseline and after 2 weeks of treatment. RESULTS: Weight loss diet lowered leptin levels in both groups by 46%, although not reaching significance. Trp and Kyn decreased significantly by 21 and 16% for VLCD and by 15 and 17% for the LCD group, respectively. A significant reduction in Phe was only seen after VLCD. Inflammatory biomarkers, neopterin, and Tyr were not significantly altered during the study period. Leptin was significantly correlated with Trp breakdown before and after the intervention (P < 0.02). CONCLUSIONS: Since disturbed metabolism of Trp affects biosynthesis of serotonin and might be associated with increased susceptibility for mood disturbances and carbohydrate craving, strategies to supplement Trp while dieting could be highly useful in treating uncontrolled weight gain or in preventing neuropsychiatric symptoms.

Does climate therapy at moderate altitudes improve pulmonary function in asthma patients? A systematic review.

PURPOSE: Allergic bronchial asthma is one of the most common chronic diseases worldwide. For many years, the climate at moderate altitude has been used as an alternative therapy for patients suffering from bronchial asthma. The aim of such therapy is to reduce the medication dose and to improve the quality of life for each patient. The aim of our current work was to assess published data evaluating the effects of climate therapy at moderate altitude on the health status of patients with bronchial asthma. The health status is represented through surrogate parameters for the pulmonary function (forced expiratory volume in one second (FEV1)), bronchial hyperresponsiveness (PC20), and inflammation (total number of eosinophils, eosinophilic cationic protein, and exhaled nitric oxide). METHODS: Our systematic review included randomized controlled trials (RCTs) and single-armed studies with adults and children participating. Included in our review were climate therapies occurring at moderate altitudes between 1,500 and 2,500 m and evaluation of patient FEV1 or PC20 values. RESULTS: A literature research in MEDLINE and EMBASE identified three RCTs, two clinically controlled trials, and 15 single-armed studies. Analysis revealed a lack of evidence regarding the moderate altitude therapy arising from small sample sizes, deficits in documentation, and heterogeneous results. Most of the studies, however, showed a tendency for improvement of the analyzed parameters. CONCLUSIONS: The currently available data do not allow for valid and generalizable recommendations with respect to moderate altitude therapy for patients with allergic bronchial asthma. There is a need for additional, qualitatively strong research including larger sample sizes and randomized, controlled trial design.

Association between Large Neutral Amino Acids and Brain Integrity in Middle-Aged Adults at Metabolic Risk.

This investigation delves into the interplay between large neutral amino acids (LNAA) and metabolic syndrome (MetS) in midlife adults, examining their collective influence on brain structure and cognitive function. While LNAA, such as tryptophan and phenylalanine, are known to bolster cognition in youth, our study hypothesizes a reversal of these benefits in older adults with MetS, potentially signaling premature cognitive aging. Eighty participants between 40-61 years underwent MetS component quantification, LNAA measurement via high-performance liquid chromatography, and brain imaging to evaluate white matter hyperintensity (WMH) volume and medial temporal lobe (MTL) cortical thickness. Our linear regression analysis, adjusting for sex, age, and education, revealed that phenylalanine levels moderated the relationship between MetS and WMH volume (F(6, 69) = 3.134, p < 0.05, R2 = 0.214), suggesting that MetS's cognitive impact may be partly due to phenylalanine catabolism byproducts. However, LNAA metabolites did not significantly modulate the MetS-MTL cortical thickness relationship. The findings suggest that LNAA metabolic dysregulation, marked by elevated levels in the presence of MetS, could correlate with brain structural compromises, particularly in the form of MTL cortical thinning and increased WMH load, detectable in midlife. This nuanced understanding of LNAA's role in cognitive health amid cardiovascular risk factors is pivotal, proposing a potential biomarker for early intervention. Further research is crucial to elucidate the longitudinal influence of LNAA and MetS on brain health, thereby informing strategies to mitigate cognitive decline.

PFT1, the MED25 subunit of the plant Mediator complex, promotes flowering through CONSTANS dependent and independent mechanisms in Arabidopsis.

Two aspects of light are very important for plant development: the length of the light phase or photoperiod and the quality of incoming light. Photoperiod detection allows plants to anticipate the arrival of the next season, whereas light quality, mainly the red to far-red ratio (R:FR), is an early signal of competition by neighbouring plants. phyB represses flowering by antagonising CO at the transcriptional and post-translational levels. A low R:FR decreases active phyB and consequently increases active CO, which in turn activates the expression of FT, the plant florigen. Other phytochromes like phyD and phyE seem to have redundant roles with phyB. PFT1, the MED25 subunit of the plant Mediator complex, has been proposed to act in the light-quality pathway that regulates flowering time downstream of phyB. However, whether PFT1 signals through CO and its specific mechanism are unclear. Here we show that CO-dependent and -independent mechanisms operate downstream of phyB, phyD and phyE to promote flowering, and that PFT1 is equally able to promote flowering by modulating both CO-dependent and -independent pathways. Our data are consistent with the role of PFT1 as an activator of CO transcription, and also of FT transcription, in a CO-independent manner. Our transcriptome analysis is also consistent with CO and FT genes being the most important flowering targets of PFT1. Furthermore, comparison of the pft1 transcriptome with transcriptomes after fungal and herbivore attack strongly suggests that PFT1 acts as a hub, integrating a variety of interdependent environmental stimuli, including light quality and jasmonic acid-dependent defences.

Effects of resistance training on respiratory function in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

PURPOSE: Over the last decade, the potential use of resistance training (RT) for patients with chronic obstructive pulmonary disease (COPD) has gained increasing attention. Many COPD patients experience muscle dysfunction and reduced muscle mass, primarily as a result of chronic immobilization. These symptoms have been associated with reduced exercise tolerance and complaints of fatigue and dyspnea (even after minimal exertion). This paper presents findings from a systematic review that sought to: (1) present a meta-analysis of randomized controlled trials (RCT) investigating the effects of RT on respiratory function measures in patients with COPD and (2) investigate the existence of a dose-response relationship between intensity, duration and frequency of RT and assessed outcomes. METHODS: A systematic literature search of MEDLINE electronic database (January 1980 to December 2009) produced a body of research on the effects of RT with a control group in patients with COPD. Data analysis involved a random effects meta-analysis, in order to determine weighted mean differences with 95 confidence intervals (95% CI) for each endpoint. All data were analyzed with the software package Review Manager V 4.2.10 (of the Cochrane Collaboration); 14 RCTs were included in the meta-analysis. RESULTS: Findings demonstrated that RT did not substantially increase forced expiratory volume in 1 s. In addition, the weighted mean difference was 2.71% of predicted (95% CI, -1.86 to 7.27; p = 0.25) or by absolute 0.08 L (95% CI, -0.03 to 0.19; p = 0.14). It appeared that maximum minute ventilation increased by 3.77 L/min (95% CI, -0.51 to 8.04; p = 0.08). CONCLUSIONS: Based on findings from the meta-analysis, RT produces a clinically and statistically significant effect on respiratory function (such as forced vital capacity) and is therefore recommended in the management of COPD.

Arabidopsis thaliana life without phytochromes.

Plants use light as a source of energy for photosynthesis and as a source of environmental information perceived by photoreceptors. Testing whether plants can complete their cycle if light provides energy but no information about the environment requires a plant devoid of phytochromes because all photosynthetically active wavelengths activate phytochromes. Producing such a quintuple mutant of Arabidopsis thaliana has been challenging, but we were able to obtain it in the flowering locus T (ft) mutant background. The quintuple phytochrome mutant does not germinate in the FT background, but it germinates to some extent in the ft background. If germination problems are bypassed by the addition of gibberellins, the seedlings of the quintuple phytochrome mutant exposed to red light produce chlorophyll, indicating that phytochromes are not the sole red-light photoreceptors, but they become developmentally arrested shortly after the cotyledon stage. Blue light bypasses this blockage, rejecting the long-standing idea that the blue-light receptors cryptochromes cannot operate without phytochromes. After growth under white light, returning the quintuple phytochrome mutant to red light resulted in rapid senescence of already expanded leaves and severely impaired expansion of new leaves. We conclude that Arabidopsis development is stalled at several points in the presence of light suitable for photosynthesis but providing no photomorphogenic signal.

Short-Term Effects of Dietary Protein Supplementation on Physical Recovery in Older Patients at Risk of Malnutrition during Inpatient Rehabilitation: A Pilot, Randomized, Controlled Trial.

It is estimated that about 50% of geriatric rehabilitation patients suffer from sarcopenia. Thereby, malnutrition is frequently associated with sarcopenia, and dietary intake is the main modifiable risk factor. During hospitalization, older adults are recommended to consume more dietary protein than the current recommended dietary allowance of 0.8 g/kg body weight per day to optimize the recovery of muscular strength and physical function. This prospective pilot study examined the feasibility and preliminary efficacy of short-term protein supplementation with protein-enriched foods and drinks on the hand-grip strength, nutritional status, and physical function of older patients at risk of malnutrition during a three-week inpatient orthopedic rehabilitation stay. The Mini Nutritional Assessment (MNA) tool was used to assess malnutrition. Patients with an MNA score ≤ 23.5 points were randomly assigned to an intervention group (goal: to consume 1.2-1.5 g protein/kg body weight per day) or a control group (standard care). Both groups carried out the same rehabilitation program. Physical recovery parameters were determined at admission and discharge. A trend was recognized for participants in the intervention group to consume more protein than the control group (p = 0.058): 95.3 (SD 13.2) g/day as compared to 77.2 (SD 24.2) g/day, which corresponds to a mean protein intake of 1.6 (SD 0.3) g/kg/day vs. 1.3 (SD 0.5) g/kg/day. Dietary protein supplementation increased body weight by an average of 0.9 (SD 1.1) kg and fat mass by an average of 0.9 (SD 1.2) kg as compared to the baseline (p = 0.039 and p = 0.050, respectively). No significant change in hand-grip strength, body composition, or physical function was observed. In conclusion, short-term intervention with protein-enriched foods and drinks enabled older patients at risk of malnutrition to increase their protein intake to levels that are higher than their required intake. In these older individuals with appropriate protein intake, dietary protein supplementation did not result in a greater improvement in physical recovery outcomes during short-term inpatient rehabilitation. The intervention improved dietary protein intake, but further research (e.g., a full-scale, randomized, controlled trial with sufficient power) is required to determine the effects on physical function outcomes.

Immune consequences of exercise in hypoxia: A narrative review.

Immune outcomes are key mediators of many health benefits of exercise and are determined by exercise type, dose (frequency/duration, intensity), and individual characteristics. Similarly, reduced availability of ambient oxygen (hypoxia) modulates immune functions depending on the hypoxic dose and the individual capacity to respond to hypoxia. How combined exercise and hypoxia (e.g., high-altitude training) sculpts immune responses is not well understood, although such combinations are becoming increasingly popular. Therefore, in this paper, we summarize the impact on immune responses of exercise and of hypoxia, both independently and together, with a focus on specialized cells in the innate and adaptive immune system. We review the regulation of the immune system by tissue oxygen levels and the overlapping and distinct immune responses related to exercise and hypoxia, then we discuss how they may be modulated by nutritional strategies. Mitochondrial, antioxidant, and anti-inflammatory mechanisms underlie many of the adaptations that can lead to improved cellular metabolism, resilience, and overall immune functions by regulating the survival, differentiation, activation, and migration of immune cells. This review shows that exercise and hypoxia can impair or complement/synergize with each other while regulating immune system functions. Appropriate acclimatization, training, and nutritional strategies can be used to avoid risks and tap into the synergistic potentials of the poorly studied immune consequences of exercising in a hypoxic state.