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A venous thromboembolism (VTE) event occurred in a female astronaut during long-duration spaceflight. Multiple factors may have contributed to this risk, including the use of combined (progestin + estrogen) oral contraceptives (cOC). Biochemistry data from 65 astronauts were evaluated for associations with cOC use and with sex. The female astronauts who used cOCs had lower concentrations of serum albumin and higher concentrations of transferrin, a protein involved in the clotting cascade, than the male astronauts and the female astronauts who were not taking cOCs (P < 0.001). The women who used cOCs had higher serum concentrations of the acute phase reactant ceruloplasmin and cortisol during flight (P < 0.001) than the men and the women who were not taking cOCs; they also had higher calculated whole blood viscosity than women not taking cOCs (P < 0.001). Lower circulating concentrations of albumin, higher concentrations of transferrin, and elevated markers of inflammation all could contribute to an increased risk of VTE during spaceflight. These changes, in association with a higher blood viscosity, can directly affect endothelial glycocalyx integrity and hypercoagulability status, both of which contribute to VTE risk in terrestrial populations. NEW & NOTEWORTHY We report here evidence of an association between oral contraceptive use and serum albumin, among other factors, which potentially increase the risk of venous thromboembolism in astronauts. These findings highlight potential risks to astronaut health while providing potential alternative countermeasures for decreasing VTE risk during spaceflight. These findings also highlight an underrecognized potential mechanism for hypoalbuminemia to increase VTE risk in terrestrial populations.

Spaceflight poses a unique set of challenges to humans and the hostile spaceflight environment can induce a wide range of increased health risks, including dermatological issues. The biology driving the frequency of skin issues in astronauts is currently not well understood. To address this issue, we used a systems biology approach utilizing NASA’s Open Science Data Repository (OSDR) on spaceflown murine transcriptomic datasets focused on the skin, biomedical profiles from fifty NASA astronauts, and confirmation via transcriptomic data from JAXA astronauts, the NASA Twins Study, and the first civilian commercial mission, Inspiration4. Key biological changes related to skin health, DNA damage & repair, and mitochondrial dysregulation were determined to be involved with skin health risks during spaceflight. Additionally, a machine learning model was utilized to determine key genes driving spaceflight response in the skin. These results can be used for determining potential countermeasures to mitigate spaceflight damage to the skin.

Spaceflight entails a variety of environmental and psychological stressors that may have long-term physiological and genomic consequences. Metabolomics, an approach that investigates the terminal metabolites of complex physiological alterations, takes into account the dynamic state of the human body and allows the identification and quantification of down-stream metabolic outputs linked to up-stream physiological and genomic regulation by stress. Employing a metabolomics-based approach, this study investigated the longitudinal metabolic perturbations of male (n=40) and female (n=11) astronauts on 4-6-month missions to the International Space Station. Proton nuclear magnetic resonance (1H-NMR) spectroscopy followed by univariate, multivariate and machine learning analyses were used on blood serum to examine sex-specific metabolic changes at various time points throughout the astronauts’ missions, and the metabolic effects of long-duration space travel. Space travel generated sex-specific changes in energy metabolism, bone mineral and muscle regulation, immunity, and macromolecule maintenance and synthesis. Additionally, metabolic signatures suggest differential metabolic responses especially during the recovery period, with females requiring more time to adjust to return to Earth. These findings provide insight into the perturbations in glucose and amino acid metabolism and macromolecule biosynthesis that result from the stressors of long-duration spaceflight. Metabolomic biomarkers may provide a viable approach to predicting and diagnosing health risks associated with prolonged space travel and other physiological challenges on Earth.

International audience; Background Immobilization and related oxidative stress are associated with bone loss. Antioxidants like polyphenols, omega-3 fatty acids, vitamins, and micronutrients may mitigate these negative effects on bone metabolism through scavenging of free radicals. Objectives We hypothesized that antioxidant supplementation during 60 days of 6° head-down tilt bed rest (HDBR) would reduce bone resorption and increase bone formation compared to nonsupplemented controls. Methods This exploratory randomized, controlled, single-blind intervention study conducted in a parallel design included 20 healthy male volunteers (age, 34 ± 8 years; weight, 74 ± 6 kg). The study consisted of a 14-day adaptation phase [baseline data collection (BDC)], followed by 60 days of HDBR and a 14-day recovery period (R). In the antioxidant group, volunteers received an antioxidant cocktail (741 mg/d polyphenols, 2.1 g/d omega-3 fatty acids, 168 mg/d vitamin E, and 80 μg/d selenium) with their daily meals. In the control group, volunteers received no supplement. Based on their body weight, all volunteers received an individually tailored and strictly controlled diet, consistent with DRIs. We analyzed biomarkers of calcium homeostasis, bone formation, and bone resorption during BDC, HDBR, and R, as well as for 30 days after the end of HDBR. Data were analyzed by linear mixed models. Results The antioxidant supplement did not affect serum calcium, parathyroid hormone, urinary C-telopeptide of type I collagen (CTX), urinary N-telopeptide of type I collagen, serum β–C-telopeptide of type I collagen (β-CTX), bone alkaline phosphatase, aminoterminal propeptide of type I collagen, osteocalcin, or urinary calcium excretion. In both groups, typical bed rest–related changes were observed. Conclusions Supplementation of an antioxidant cocktail to a diet matching the DRIs did not affect bone resorption or formation during 60 days of HDBR in healthy young men. This trial was registered at clinicaltrials.gov as NCT03594799.

ObjectivesBone loss remains a primary health concern for astronauts, despite in-flight exercise. We examined changes in bone microarchitecture, density and strength before and after long-duration spaceflight in relation to biochemical markers of bone turnover and exercise.MethodsSeventeen astronauts had their distal tibiae and radii imaged before and after space missions to the International Space Station using high-resolution peripheral quantitative CT. We estimated bone strength using finite element analysis and acquired blood and urine biochemical markers of bone turnover before, during and after spaceflight. Pre-flight exercise history and in-flight exercise logs were obtained. Mixed effects models examined changes in bone and biochemical variables and their relationship with mission duration and exercise.ResultsAt the distal tibia, median cumulative losses after spaceflight were −2.9% to −4.3% for bone strength and total volumetric bone mineral density (vBMD) and −0.8% to −2.6% for trabecular vBMD, bone volume fraction, thickness and cortical vBMD. Mission duration (range 3.5–7 months) significantly predicted bone loss and crewmembers with higher concentrations of biomarkers of bone turnover before spaceflight experienced greater losses in tibia bone strength and density. Lower body resistance training volume (repetitions per week) increased 3–6 times in-flight compared with pre-spaceflight. Increases in training volume predicted preservation of tibia bone strength and trabecular vBMD and thickness.ConclusionsFindings highlight the fundamental relationship between mission duration and bone loss. Pre-flight markers of bone turnover and exercise history may identify crewmembers at greatest risk of bone loss due to unloading and may focus preventative measures.

Alpine areas are well known biodiversity hotspots, but their future may be threatened by expanding forest and changing human land use. Here, we reconstructed past vegetation, climate, and livestock over the past ~ 12,000 years from Lake Sulsseewli (European Alps), based on sedimentary ancient DNA, pollen, spores, chironomids, and microcharcoal. We assembled a highly-complete local DNA reference library (PhyloAlps, 3,923 plant species), and used this to obtain an exceptionally rich sedaDNA record of 366 plant taxa. The vegetation mainly responded to temperature during the first half of the Holocene, while human activity drove changes from 6 ka onwards. Land-use shifted from episodic grazing (Neolithic, Bronze Age) to agropastoral intensification (Medieval Age). This prompted a coexistence of species typically found at different elevational belts, thereby increasing plant richness to levels that characterise present-day alpine diversity. Our results indicate that traditional agropastoral activities should be maintained to prevent reforestation and preserve alpine plant biodiversity.

OBJECTIVES: 2020 marks the 20(th) anniversary of a continuous human presence off the planet. Space flight is physically and physiologically challenging, with environmental stressors, a closed food system, and adaptations affecting virtually all body systems. Key objectives for this effort included evaluating the time course of biochemical changes that occur during flight, the effects of exercise countermeasures, and the relationship between dietary intake and physiological outcomes. METHODS: Blood and urine samples were collected before, during, and after flight from 65 astronauts. These were analyzed for a broad-based survey of physiological systems. Detailed diet records were available from 27 astronauts using an iPad App designed for use on ISS. RESULTS: The average intake of fruits and vegetables was lower than recommended (2.6 ± 0.9 servings per day), but intakes correlated with outcomes at landing. Specifically, higher intakes were positively correlated with vitamin C status (R2 = 0.43, P

Background and Aims In daily clinical practice, individual-level sodium (Na) intake is often estimated by measuring Na excretion in a single 24h urine collection, but long-term Na balance studies indicate that 7 consecutive 24h urine collections are needed. However, this approach is not feasible in clinical settings. In this study, we investigate whether the use of repeated spot urine sampling is an appropriate alternative for repeated 24h urine collections. Method We performed a post-hoc analysis of a metabolic ward study in 8 healthy male adults who consumed a 7-day diet with a fixed amount of Na (200 mmol/d). Urine was collected in four daily intervals: 7-13h, 13-19h, 19-23h and 23-7h. After reaching steady state, we estimated Na intake with 1 and 3 consecutive 24h urine collections and 3-day spot urine sampling, using the Kawasaki formula with measured 24h urine creatinine excretion. Results: On day 5, mean 24h Na excretion matched intake, indicating that steady state was achieved (Fig A). Mean and standard deviation of absolute differences between estimated and measured Na intake (ΔNa) for each method were: 18.8 ±14.6 mmol (3 x spot urine 7-13h), 32.3 ±18.7 mmol (3 x spot urine 13-19h), 74.6 ±30.0 mmol (3 x spot urine 19-23h), 28.2 ±19.8 mmol (3 x spot urine 23-7h), 29.8 ±23.9 mmol (1 x 24h urine) and 22.9 ±11.3 mmol (3 x 24h urine) (Fig B). With the exception of the 19-23h spot urine collection period, the accuracy of 3-day spot urine sampling did not significantly differ from accuracy of 1 and 3 consecutive 24h urine collections. When combining the pre-night and morning spot urine collections (19-7h), the accuracy of the estimation did not improve (ΔNa 28.7 ±19.6 mmol). Conclusion 3-day spot urine sampling did not perform significantly different than 1 and 3 24h urine collections for estimation of individual-level Na intake. Adequately powered studies need to confirm whether repeated spot urine sampling is an accurate and low burden alternative to repeated 24h urine collections.

The increase in plant species richness in the Alps over the last century has been described as a direct response to climate warming. Alpine ecosystems are expected to have an upward displacement of vegetation, resulting in shifts of species ranges, high replacement rates, and species loss. To apply proper management measures, it is necessary to understand how drivers of change affect species and ecosystem tipping points. Palaeoecological studies allow us to understand how species responded to similar situations in the past. However, such studies are often challenged by proxy preservation and taxonomic resolution. Metabarcoding approaches based on sedimentary ancient DNA (sedaDNA) can overcome these caveats. Here we use plant sedaDNA and the new PhyloAlps taxonomic reference database, which covers 4500 plant taxa from the Alps, to explore alpine floral diversity of Sulseewlii, a subalpine lake in the Central Alps (Switzerland). We present a 12,000 year record of vegetational composition and structural changes in a subalpine ecosystem. To disentangle the relationship between climate and vegetation, we used a novel local temperature reconstruction inferred from chironomids of the same lake. We also used coprophilous fungal spores and charcoal, together with pastoral and arable indicators, to infer human pressure. With 377 identified taxa, including 140 at species level, Sulseewlii has yielded the richest dataset of plant sedaDNA to date and emphasizes the Alps as an important biodiversity hotspot in Europe. Out of the identified taxa, 91 are indicators that allowed us to reconstruct the vegetation stages and altitudinal shifts of the main vegetation groups. Total taxonomic richness increases from the onset of the Holocene and has a similar pattern to subalpine-montane DNA taxa, with three marked drops at 8200, 3200, and ~500 cal yr BP. Plant sedaDNA registered a marked transition from alpine to subalpine communities at the onset of the Holocene. The highest proportions of montane taxa occurred during the Holocene climatic optimum (9,000-6,000 cal yr BP). Finally, a shift back to subalpine-montane species with some lowland influence occurs as we approach the present.

International audience; Muscle atrophy is a deleterious consequence of physical inactivity and is associated with increased morbidity and mortality. The aim of this study was to decipher the mechanisms involved in disuse muscle atrophy in eight healthy men using a 21 day bed rest with a cross-over design (control, with resistive vibration exercise (RVE), or RVE combined with whey protein supplementation and an alkaline salt (NEX)). The main physiological findings show a significant reduction in whole-body fat-free mass (CON −4.1%, RVE −4.3%, NEX −2.7%, p < 0.05), maximal oxygen consumption (CON −20.5%, RVE −6.46%, NEX −7.9%, p < 0.05), and maximal voluntary contraction (CON −15%, RVE −12%, and NEX −9.5%, p < 0.05) and a reduction in mitochondrial enzyme activity (CON −30.7%, RVE −31.3%, NEX −17%, p < 0.05). The benefits of nutrition and exercise countermeasure were evident with an increase in leg lean mass (CON −1.7%, RVE +8.9%, NEX +15%, p < 0.05). Changes to the vastus lateralis muscle proteome were characterized using mass spectrometry-based label-free quantitative proteomics, the findings of which suggest alterations to cell metabolism, mitochondrial metabolism, protein synthesis, and degradation pathways during bed rest. The observed changes were partially mitigated during RVE, but there were no significant pathway changes during the NEX trial. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the dataset identifier PXD006882. In conclusion, resistive vibration exercise, when combined with whey/alkalizing salt supplementation, could be an effective strategy to prevent skeletal muscle protein changes, muscle atrophy, and insulin sensitivity during medium duration bed rest.

When astronauts enter weightlessness, cephalad fluid shifts increase left ventricular dimensions, whereas central venous pressure is surprisingly reduced. More chronically, counterregulatory adjustments attenuate total blood volume; however, the internal jugular vein remains grossly dilated.1 This finding would raise suspicion for central volume overload in terrestrial medicine. Moreover, a single astronaut retained substantial amounts of sodium in space without body mass gain. It is possible that weightlessness alters osmotically inactive sodium storage, a recently recognized mechanism for human volume regulation.2,3 Prolonged −6° head-down bed rest, which produces cephalad volume shifts similar to those in weightlessness, elicited sustained increases in circulating atrial natriuretic peptide concentrations.4 Conversely, individual astronauts have shown reduced natriuretic peptide signalling in space.5 Cardiac natriuretic peptide deficiency could exacerbate central hypervolemia. We assessed natriuretic peptides in astronauts in the first study comparing lower-sodium and higher-sodium diets in space and on Earth. The SOLO study (Sodium Load in Microgravity) was approved by the Johnson Space Center institutional review board and the European Space Agency medical board. After giving informed consent, we tested 8 male astronauts (50±2.8 years old; weight, 85.61±8.89 kg) on both lower-sodium (2 g/d) and higher-sodium (5.5 g/d) diets for 5 consecutive days in space and 6 to 12 months after landing on Earth. In space, diets were applied in random order no earlier than 4 weeks into the mission. Dietary nutrient and water intakes were kept constant. Blood samples were obtained on day 5 of each intervention and analyzed for sodium, creatinine, midregional proatrial natriuretic peptide (MRproANP), NT-proBNP (N-terminal pro-B-type natriuretic peptide), and aldosterone. On Earth, samples were obtained while subjects were seated in the morning after they had traveled from the hotel to the study center. The same day, urinary sodium, creatinine, and body mass were measured. Body mass on the International Space Station was measured with the National Aeronautics and Space Administration’s Space Linear Acceleration Mass Measurement Device; on Earth, we used a standard scale. To gauge changes in central blood volume, we assessed thoracic bioimpedance in 16 cosmonauts (45.56±5.59 years old; weight, 79.88±6.94 kg) before launch, monthly onboard the International Space Station, and after return to Earth. The study in cosmonauts was approved by the Biomedicine Ethics Committee of the State Research Center of the Russian Federation, the Institute of Biomedical Problems, the Russian Academy of Science, and the subjects gave informed consent. On the lower-sodium diet, astronauts excreted 74.3±7.0 mmol of sodium per day (mean+SEM) in space and 82.6±10.3 mmol/d on Earth (P=0.172). On the higher-sodium diet, astronauts excreted 175±12 mmol/d in space and 196±13 mmol/d on Earth (P=0.249). Glomerular filtration rate was unchanged, whereas fractional sodium excretion increased similarly on the higher-sodium diet (P

Biomarkers of cartilage metabolism are sensitive to changes in the biological and mechanical environment and can indicate early changes in cartilage homeostasis. The purpose of this study was to determine if a daily locomotion replacement program can serve as a countermeasure for changes in cartilage biomarker serum concentration caused by immobilization. Ten healthy male subjects (mean ± 1 standard deviation; age: 29.4 ± 5.9 years; body mass: 77.7 ± 4.1 kg) participated in the crossover 5-day bed rest study with three interventions: control (CON), standing (STA), and locomotion replacement training (LRT). Serum samples were taken before, during, and after bed rest. Biomarker concentrations were measured using commercial enzyme-linked immunosorbent assays. Cartilage oligomeric matrix protein (COMP) levels after 24 hours of bed rest decreased independently of the intervention (-16.8% to -9.8%) and continued to decrease until 72 hours of bed rest (minimum, -23.2% to -20.6%). LRT and STA did not affect COMP during bed rests (P = .056) but there was a strong tendency for a slower decrease with LRT (-9.4%) and STA (-11.7%) compared with CON (-16.8%). MMP-3 levels decreased within the first 24 hours of bed rest (CON: -22.3%; STA: -14.7%; LRT: -17%) without intervention effect. Both COMP and MMP-3 levels recovered to baseline levels during the 6-day recovery period. MMP-1, MMP-9, and TNF-α levels were not affected by immobilization or intervention. COMP and MMP-3 are mechano-sensitive cartilage biomarkers affected by immobilization, and simple interventions such as standing upright or LRT during bed rest cannot prevent these changes. Clinical significance: simple locomotion interventions cannot prevent cartilage biomarker change during bed rest.

International audience; The intention to send a crewed mission to Mars involves a huge amount of planning to ensure a safe and successful mission. Providing adequate amounts of food for the crew is a major task, but 20 years of feeding astronauts on the International Space Station (ISS) have resulted in a good knowledge base. A crucial observation from the ISS is that astronauts typically consume only 80% of their daily calorie requirements when in space. This is despite daily exercise regimes that keep energy usage at very similar levels to those found on Earth. This calorie deficit seems to have little effect on astronauts who spend up to 12 months on the ISS, but given that a mission to Mars would take 30 to 36 months to complete, there is concern that a calorie deficit over this period may lead to adverse effects in crew members. The key question is why astronauts undereat when they have a supply of food designed to fully deliver their nutritional needs. This review focuses on evidence from astronauts that foods taste different in space, compared to on Earth. The underlying hypothesis is that conditions in space may change the perceived flavor of the food, and this flavor change may, in turn, lead to underconsumption by astronauts. The key areas investigated in this review for their potential impact on food intake are the effects of food shelf life, physiological changes, noise, air and water quality on the perception of food flavor, as well as the link between food flavor and food intake.

Optimal function of the immune system is impaired in the presence of malnutrition. This led to the concept of immunonutrition which describes diets that are specifically designed to enhance immune functions and, without adequate nutrition, the immune system is clearly deprived of the components needed to generate an effective immune response (Beisel 1992; Mizock 2010). Nutrients act as antioxidants and as cofactors at the level of cytokine regulation (Cunningham-Rundles et al. 2005). Crews during spaceflight generally have lower dietary intake compared with normal conditions on ground (Lane et al. 1998). It is well known from ground research that a lack of macronutrients or selected micronutrients, like zinc, selenium, and the antioxidant vitamins can have profound effects on immune function (Chandra 1992; Chandra and Kumari 1994; Keith and Jeejeebhoy 1997). Micronutrient deficiency suppresses immune functions by affecting the innate T-cell-mediated immune response and adaptive antibody response. It leads also to a dysregulation of the balanced host response (Wintergerst et al. 2007). Disruption of nutritional balance and dietary intake of astronauts and cosmonauts during spaceflight, which is often accompanied by a stress response, might influence their immune response as the nutrition status can influence host immune responses and resistance to infection (Sonnenfeld 2002; Sonnenfeld and Shearer 2002). Some of the immune function alterations documented in astronauts (see Chaps. 9–12) have been reported also in states of nutrient deficiencies, and could potentially be counteracted by improving their nutrition. Detailed information on the absorption and metabolism of many micronutrients during spaceflight are mandatory before specific nutritional recommendations can be made, especially with regard to their relationship with the immune system function.

Previous chapters have provided some insight into the regulation of immune responses under spaceflight conditions which correspond to a unique combination of psychosocial and physical stressors. This multitude of factors affect almost all components of the immune system, potentially leading to compromised host defense against infections, and could consequently have an immediate impact on mission performance. This chapter introduces some strategies that are potentially helpful to mitigate the risk of immune dysfunction under conditions of long-duration spaceflight. Indeed, in a foreseeable time frame, man may voyage and explore the surfaces of solid bodies whose surface conditions are not too hostile for humans such as those of the Moon, Mars, phobos, and deimos (the two satellites of Mars).

Background Bed rest studies document that a lower dietary acid load is associated with lower bone resorption. Objective We tested the effect of dietary acid load on bone metabolism during spaceflight. Design Controlled 4-d diets with a high or low animal protein–to-potassium (APro:K) ratio (High and Low diets, respectively) were given to 17 astronauts before and during spaceflight. Each astronaut had 1 High and 1 Low diet session before flight and 2 High and 2 Low sessions during flight, in addition to a 4-d session around flight day 30 (FD30), when crew members were to consume their typical in-flight intake. At the end of each session, blood and urine samples were collected. Calcium, total protein, energy, and sodium were maintained in each crew member's preflight and in-flight controlled diets. Results Relative to preflight values, N-telopeptide (NTX) and urinary calcium were higher during flight, and bone-specific alkaline phosphatase (BSAP) was higher toward the end of flight. The High and Low diets did not affect NTX, BSAP, or urinary calcium. Dietary sulfur and age were significantly associated with changes in NTX. Dietary sodium and flight day were significantly associated with urinary calcium during flight. The net endogenous acid production (NEAP) estimated from the typical dietary intake at FD30 was associated with loss of bone mineral content in the lumbar spine after the mission. The results were compared with data from a 70-d bed rest study, in which control (but not exercising) subjects’ APro:K was associated with higher NTX during bed rest. Conclusions Long-term lowering of NEAP by increasing vegetable and fruit intake may protect against changes in loss of bone mineral content during spaceflight when adequate calcium is consumed, particularly if resistive exercise is not being performed. This trial was registered at clinicaltrials.gov as NCT01713634.

The objective of the study was to test the hypothesis that serum levels of cartilage oligomeric matrix protein (COMP) would decrease and serum levels of tumor-necrosis factor alpha (TNF-α) and selected matrix metalloproteinases (MMPs) would increase in response to bed rest (BR) and that these changes are unaffected by the intake of potassium bicarbonate or whey protein. Seven and nine healthy male subjects participated in two 21-day 6° head down tilt crossover BR-studies with nutrition interventions. Serum samples were taken before, during, and after BR and biomarker concentrations were measured using commercial enzyme-linked immunosorbent assays. MMP-3 during BR was significantly lower than at baseline (reduction greater 20%; p

BACKGROUND & AIMS: Physical inactivity is associated with lean body mass wasting, oxidative stress and pro-inflammatory changes of cell membrane lipids. Alkalinization may potentially counteract these alterations. We evaluated the effects of potassium bicarbonate supplementation on protein kinetics, glutathione status and pro- and anti-inflammatory polyunsaturated fatty acids (PUFA) in erythrocyte membranes in humans, during experimental bed rest. METHODS: Healthy, young, male volunteers were investigated at the end of two 21-day bed rest periods, one with, and the other without, daily potassium bicarbonate supplementation (90 mmol × d-1), according to a cross-over design. Oxidative stress in erythrocytes was evaluated by determining the ratio between reduced (GSH) and oxidized glutathione (GSSG). Glutathione turnover and phenylalanine kinetics, a marker of whole body protein metabolism, were determined by stable isotope infusions. Erythrocyte membranes PUFA composition was analyzed by gas-chromatography. RESULTS: At the end of the two study periods, urinary pH was 10 ± 3% greater in subjects receiving potassium bicarbonate supplementation (7.23 ± 0.15 vs. 6.68 ± 0.11, p < 0.001). Alkalinization increased total glutathione concentrations by 5 ± 2% (p < 0.05) and decreased its rate of clearance by 38 ± 13% (p < 0.05), without significantly changing GSH-to-GSSG ratio. After alkalinization, net protein balance in the postabsorptive state improved significantly by 17 ± 5% (p < 0.05) as well as the sum of n-3 PUFA and the n-3-to-n-6 PUFA ratio in erythrocyte membranes (p < 0.05). CONCLUSIONS: Alkalinization during long-term inactivity is associated with improved glutathione status, anti-inflammatory lipid pattern in cell membranes and reduction in protein catabolism at whole body level. This study suggests that, in clinical conditions characterized by inactivity, oxidative stress and inflammation, alkalinization could be a useful adjuvant therapeutic strategy.

Physical inactivity and sedentary behaviors are independent risk factors for numerous diseases. We examined the ability of a nutrient cocktail composed of polyphenols, omega-3 fatty acids, vitamin E, and selenium to prevent the expected metabolic alterations induced by physical inactivity and sedentary behaviors. Healthy trained men ( n = 20) (averaging ∼14,000 steps/day and engaged in sports) were randomly divided into a control group (no supplementation) and a cocktail group for a 20-day free-living intervention during which they stopped exercise and decreased their daily steps (averaging ∼3,000 steps/day). During the last 10 days, metabolic changes were further triggered by fructose overfeeding. On days 0, 10, and 20, body composition (dual energy X-ray), blood chemistry, glucose tolerance [oral glucose tolerance test (OGTT)], and substrate oxidation (indirect calorimetry) were measured. OGTT included 1% fructose labeled with (U-13C) fructose to assess liver de novo lipogenesis. Histological changes and related cellular markers were assessed from muscle biopsies collected on days 0 and 20. While the cocktail did not prevent the decrease in insulin sensitivity and its muscular correlates induced by the intervention, it fully prevented the hypertriglyceridemia, the drop in fasting HDL and total fat oxidation, and the increase in de novo lipogenesis. The cocktail further prevented the decrease in the type-IIa muscle fiber cross-sectional area and was associated with lower protein ubiquitination content. The circulating antioxidant capacity was improved by the cocktail following the OGTT. In conclusion, a cocktail of nutrient compounds from dietary origin protects against the alterations in lipid metabolism induced by physical inactivity and fructose overfeeding. NEW & NOTEWORTHY This is the first study to test the efficacy of a novel dietary nutrient cocktail on the metabolic and physiological changes occurring during 20 days of physical inactivity along with fructose overfeeding. The main findings of this study are that 1) reduction in daily steps leads to decreased insulin sensitivity and total fat oxidation, resulting in hyperlipemia and increased de novo lipogenesis and 2) a cocktail supplement prevents the alterations on lipid metabolism.

Bone loss and renal stone risk are longstanding concerns for astronauts. Bone resorption brought on by spaceflight elevates urinary calcium and the risk of renal stone formation. Loss of bone calcium leads to concerns about fracture risk and increased long-term risk of osteoporosis. Bone metabolism involves many factors and is interconnected with muscle metabolism and diet. We report here bone biochemistry and renal stone risk data from astronauts on 4- to 6-month International Space Station missions. All had access to a type of resistive exercise countermeasure hardware, either the Advanced Resistance Exercise Device (ARED) or the Interim Resistance Exercise Device (iRED). A subset of the ARED group also tested the bisphosphonate alendronate as a potential anti-resorptive countermeasure (Bis+ARED). While some of the basic bone marker data have been published, we provide here a more comprehensive evaluation of bone biochemistry with a larger group of astronauts. Regardless of exercise, the risk of renal stone formation increased during spaceflight. A key factor in this increase was urine volume, which was lower during flight in all groups at all time points. Thus, the easiest way to mitigate renal stone risk is to increase fluid consumption. ARED use increased bone formation without changing bone resorption, and mitigated a drop in parathyroid hormone in iRED astronauts. Sclerostin, an osteocyte-derived negative regulator of bone formation, increased 10-15% in both groups of astronauts who used the ARED (p

Human studies in space provide unique and often unexpected findings regarding the role of terrestrial gravity for human cardiovascular and renal regulation. While vascular volume is shifted towards the head, which would be expected to increase natriuretic peptide (NP) release, preliminary observations suggested the opposite. Therefore, we assessed natriuretic peptide regulation on different controlled sodium diets in space and on Earth. Eight male astronauts (50±2.8 yrs.) ingested higher (5.5 g/day) and low sodium (2g/day) diets for five days each on Earth and on the International Space Station (ISS) in alternating order. Dietary nutrient intake was individually tailored and kept constant. At day five of each intervention, midregional-pro atrial NP (MRproANP), N-terminal pro B-type NP (NTproBNP), and aldosterone in blood, urinary sodium excretion, and body mass were measured. On Earth, MRproANP was 71.86±4.39 pmol/L on moderately high and 65.13±6.71 pmol/L on low sodium intake. In space, MRproANP was 44.61±4.26 pmol/L on high and 31.37±4.02 pmol/L on low sodium intake (p

INTRODUCTION To date, 559 humans have been flown into space, but long-duration (>300 days) missions are rare (n = 8 total). Long-duration missions that will take humans to Mars and beyond are planned by public and private entities for the 2020s and 2030s; therefore, comprehensive studies are needed now to assess the impact of long-duration spaceflight on the human body, brain, and overall physiology. The space environment is made harsh and challenging by multiple factors, including confinement, isolation, and exposure to environmental stressors such as microgravity, radiation, and noise. The selection of one of a pair of monozygotic (identical) twin astronauts for NASA’s first 1-year mission enabled us to compare the impact of the spaceflight environment on one twin to the simultaneous impact of the Earth environment on a genetically matched subject. RATIONALE The known impacts of the spaceflight environment on human health and performance, physiology, and cellular and molecular processes are numerous and include bone density loss, effects on cognitive performance, microbial shifts, and alterations in gene regulation. However, previous studies collected very limited data, did not integrate simultaneous effects on multiple systems and data types in the same subject, or were restricted to 6-month missions. Measurement of the same variables in an astronaut on a year-long mission and in his Earth-bound twin indicated the biological measures that might be used to determine the effects of spaceflight. Presented here is an integrated longitudinal, multidimensional description of the effects of a 340-day mission onboard the International Space Station. RESULTS Physiological, telomeric, transcriptomic, epigenetic, proteomic, metabolomic, immune, microbiomic, cardiovascular, vision-related, and cognitive data were collected over 25 months. Some biological functions were not significantly affected by spaceflight, including the immune response (T cell receptor repertoire) to the first test of a vaccination in flight. However, significant changes in multiple data types were observed in association with the spaceflight period; the majority of these eventually returned to a preflight state within the time period of the study. These included changes in telomere length, gene regulation measured in both epigenetic and transcriptional data, gut microbiome composition, body weight, carotid artery dimensions, subfoveal choroidal thickness and peripapillary total retinal thickness, and serum metabolites. In addition, some factors were significantly affected by the stress of returning to Earth, including inflammation cytokines and immune response gene networks, as well as cognitive performance. For a few measures, persistent changes were observed even after 6 months on Earth, including some genes’ expression levels, increased DNA damage from chromosomal inversions, increased numbers of short telomeres, and attenuated cognitive function. CONCLUSION Given that the majority of the biological and human health variables remained stable, or returned to baseline, after a 340-day space mission, these data suggest that human health can be mostly sustained over this duration of spaceflight. The persistence of the molecular changes (e.g., gene expression) and the extrapolation of the identified risk factors for longer missions (>1 year) remain estimates and should be demonstrated with these measures in future astronauts. Finally, changes described in this study highlight pathways and mechanisms that may be vulnerable to spaceflight and may require safeguards for longer space missions; thus, they serve as a guide for targeted countermeasures or monitoring during future missions.

Potassium bicarbonate was administrated to an already alkaline diet in seven male subjects during a 21-day bed rest study and was able to decrease bed rest induced increased calcium excretion but failed to prevent bed rest-induced bone resorption. Supplementation with alkali salts appears to positively influence calcium and bone metabolism and, thus, could be a countermeasure for population groups with an increased risk for bone loss. However, the extent to which alkalization counteracts acid-induced bone resorption or whether it merely has a calcium and bone maintenance effect is still not completely understood. In the present study, we hypothesized that additional alkalization to an already alkaline diet can further counteract bed rest-induced bone loss. Seven healthy male subjects completed two parts of a crossover designed 21-day bed rest study: bed rest only (control) and bed rest supplemented with 90 mmol potassium bicarbonate (KHCO3) daily. KHCO3supplementation during bed rest resulted in a more alkaline status compared to the control intervention, demonstrated by the increase in pH and buffer capacity level (pH p = 0.023, HCO3p = 0.02, ABE p = 0.03). Urinary calcium excretion was decreased during KHCO3 supplementation (control 6.05 ± 2.74 mmol/24 h; KHCO3 4.87 ± 2.21 mmol/24 h, p = 0.03); whereas, bone formation was not affected by additional alkalization (bAP p = 0.58; PINP p = 0.60). Bone resorption marker UCTX tended to be lower during alkaline supplementation (UCTX p = 0.16). The more alkaline acid-base status, achieved by KHCO3 supplementation, reduced renal calcium excretion during bed rest, but was not able to prevent immobilization-induced bone resorption. However, advantages of alkaline salts on bone metabolism may occur under acidic metabolic conditions or with respect to the positive effect of reduced calcium excretion within a longer time frame. Trial number: NCT01509456

Low-grade metabolic acidosis (LGMA), as induced by high dietary acid load or sodium chloride (NaCl) intake, has been shown to increase bone and protein catabolism. Underlying mechanisms are not fully understood, but from clinical metabolic acidosis interactions of acid-base balance with glucocorticoid (GC) metabolism are known. We aimed to investigate GC activity/metabolism under alkaline supplementation and NaCl-induced LGMA. Eight young, healthy, normal-weight men participated in two crossover designed interventional studies. In Study A, two 10-day high NaCl diet (32 g/d) periods were conducted, one supplemented with 90 mmol KHCO3/day. In Study B, participants received a high and a low NaCl diet (31 vs. 3 g/day), each for 14 days. During low NaCl, the diet was moderately acidified by replacement of a bicarbonate-rich mineral water (consumed during high NaCl) with a non-alkalizing drinking water. In repeatedly collected 24-h urine samples, potentially bioactive-free GCs (urinary-free cortisol + free cortisone) were analyzed, as well as tetrahydrocortisol (THF), 5α-THF, and tetrahydrocortisone (THE). With supplementation of 90 mmol KHCO3, the marker of total adrenal GC secretion (THF + 5α-THF + THE) dropped (p = 0.047) and potentially bioactive-free GCs were reduced (p = 0.003). In Study B, however, GC secretion and potentially bioactive-free GCs did not exhibit the expected fall with NaCl-reduction as net acid excretion was raised by 30 mEq/d. Diet-induced acidification/alkalization affects GC activity and metabolism, which in case of long-term ingestion of habitually acidifying western diets may constitute an independent risk factor for bone degradation and cardiometabolic diseases.

Ophthalmic changes have occurred in a subset of astronauts on International Space Station missions. Visual deterioration is considered the greatest human health risk of spaceflight. Affected astronauts exhibit higher concentrations of 1-carbon metabolites (e.g., homocysteine) before flight. We hypothesized that genetic variations in 1-carbon metabolism genes contribute to susceptibility to ophthalmic changes in astronauts. We investigated 5 polymorphisms in the methionine synthase reductase (MTRR), methylenetetrahydrofolate reductase (MTHFR), serine hydroxymethyltransferase (SHMT), and cystathionine β-synthase (CBS) genes and their association with ophthalmic changes after flight in 49 astronauts. The number of G alleles of MTRR 66 and C alleles of SHMT1 1420 both contributed to the odds of visual disturbances. Preflight dehydroepiandrosterone was positively associated with cotton wool spots, and serum testosterone response during flight was associated with refractive change. Block regression showed that B-vitamin status and genetics were significant predictors of many of the ophthalmic outcomes that we observed. In one example, genetics trended toward improving (P = 0.10) and B-vitamin status significantly improved (P < 0.001) the predictive model for refractive change after flight. We document an association between MTRR 66 and SHMT1 1420 polymorphisms and spaceflight-induced vision changes. This line of research could lead to therapeutic options for both space travelers and terrestrial patients.—Zwart, S. R., Gregory, J. F., Zeisel, S. H., Gibson, C. R., Mader, T. H., Kinchen, J. M., Ueland, P. M., Ploutz-Snyder, R., Heer, M. A., Smith, S. M. Genotype, B-vitamin status, and androgens affect spaceflight-induced ophthalmic changes.