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Water is essential for survival, but one in three individuals worldwide (2.2 billion people) lacks access to safe drinking water. Water intake requirements largely reflect water turnover (WT), the water used by the body each day. We investigated the determinants of human WT in 5604 people from the ages of 8 days to 96 years from 23 countries using isotope-tracking (2H) methods. Age, body size, and composition were significantly associated with WT, as were physical activity, athletic status, pregnancy, socioeconomic status, and environmental characteristics (latitude, altitude, air temperature, and humidity). People who lived in countries with a low human development index (HDI) had higher WT than people in high-HDI countries. On the basis of this extensive dataset, we provide equations to predict human WT in relation to anthropometric, economic, and environmental factors.

In mammals, trait variation is often reported to be greater among males than females. However, to date, mainly only morphological traits have been studied. Energy expenditure represents the metabolic costs of multiple physical, physiological, and behavioral traits. Energy expenditure could exhibit particularly high greater male variation through a cumulative effect if those traits mostly exhibit greater male variation, or a lack of greater male variation if many of them do not. Sex differences in energy expenditure variation have been little explored. We analyzed a large database on energy expenditure in adult humans (1494 males and 3108 females) to investigate whether humans have evolved sex differences in the degree of interindividual variation in energy expenditure. We found that, even when statistically comparing males and females of the same age, height, and body composition, there is much more variation in total, activity, and basal energy expenditure among males. However, with aging, variation in total energy expenditure decreases, and because this happens more rapidly in males, the magnitude of greater male variation, though still large, is attenuated in older age groups. Considerably greater male variation in both total and activity energy expenditure could be explained by greater male variation in levels of daily activity. The considerably greater male variation in basal energy expenditure is remarkable and may be explained, at least in part, by greater male variation in the size of energy-demanding organs. If energy expenditure is a trait that is of indirect interest to females when choosing a sexual partner, this would suggest that energy expenditure is under sexual selection. However, we present a novel energetics model demonstrating that it is also possible that females have been under stabilizing selection pressure for an intermediate basal energy expenditure to maximize energy available for reproduction.

Lower ambient temperature (Ta) requires greater energy expenditure to sustain body temperature. However, effects of Ta on human energetics may be buffered by environmental modification and behavioral compensation. We used the IAEA DLW database for adults in the USA (n = 3213) to determine the effect of Ta (-10 to +30°C) on TEE, basal (BEE) and activity energy expenditure (AEE) and physical activity level (PAL). There were no significant relationships (p > 0.05) between maximum, minimum and average Ta and TEE, BEE, AEE and PAL. After adjustment for fat-free mass, fat mass and age, statistically significant (p

Low total energy expenditure (TEE, MJ/d) has been a hypothesized risk factor for weight gain, but repeatability of TEE, a critical variable in longitudinal studies of energy balance, is understudied. We examine repeated doubly labeled water (DLW) measurements of TEE in 348 adults and 47 children from the IAEA DLW Database (mean ± SD time interval: 1.9 ± 2.9 y) to assess repeatability of TEE, and to examine if TEE adjusted for age, sex, fat-free mass, and fat mass is associated with changes in weight or body composition. Here, we report that repeatability of TEE is high for adults, but not children. Bivariate Bayesian mixed models show no among or within-individual correlation between body composition (fat mass or percentage) and unadjusted TEE in adults. For adults aged 20-60 y (N = 267; time interval: 7.4 ± 12.2 weeks), increases in adjusted TEE are associated with weight gain but not with changes in body composition; results are similar for subjects with intervals >4 weeks (N = 53; 29.1 ± 12.8 weeks). This suggests low TEE is not a risk factor for, and high TEE is not protective against, weight or body fat gain over the time intervals tested.

BackgroundPhysical activity may be a way to increase and maintain fat-free mass (FFM) in later life, similar to the prevention of fractures by increasing peak bone mass.ObjectivesA study is presented of the association between FFM and physical activity in relation to age.MethodsIn a cross-sectional study, FFM was analyzed in relation to physical activity in a large participant group as compiled in the International Atomic Energy Agency Doubly Labeled Water database. The database included 2000 participants, age 3-96 y, with measurements of total energy expenditure (TEE) and resting energy expenditure (REE) to allow calculation of physical activity level (PAL = TEE/REE), and calculation of FFM from isotope dilution.ResultsPAL was a main determinant of body composition at all ages. Models with age, fat mass (FM), and PAL explained 76% and 85% of the variation in FFM in females and males

Understanding the impacts of activity on energy balance is crucial. Increasing levels of activity may bring diminishing returns in energy expenditure because of compensatory responses in non-activity energy expenditures.1-3 This suggestion has profound implications for both the evolution of metabolism and human health. It implies that a long-term increase in activity does not directly translate into an increase in total energy expenditure (TEE) because other components of TEE may decrease in response-energy compensation. We used the largest dataset compiled on adult TEE and basal energy expenditure (BEE) (n = 1,754) of people living normal lives to find that energy compensation by a typical human averages 28% due to reduced BEE; this suggests that only 72% of the extra calories we burn from additional activity translates into extra calories burned that day. Moreover, the degree of energy compensation varied considerably between people of different body compositions. This association between compensation and adiposity could be due to among-individual differences in compensation: people who compensate more may be more likely to accumulate body fat. Alternatively, the process might occur within individuals: as we get fatter, our body might compensate more strongly for the calories burned during activity, making losing fat progressively more difficult. Determining the causality of the relationship between energy compensation and adiposity will be key to improving public health strategies regarding obesity.

Total daily energy expenditure ("total expenditure") reflects daily energy needs and is a critical variable in human health and physiology, but its trajectory over the life course is poorly studied. We analyzed a large, diverse database of total expenditure measured by the doubly labeled water method for males and females aged 8 days to 95 years. Total expenditure increased with fat-free mass in a power-law manner, with four distinct life stages. Fat-free mass-adjusted expenditure accelerates rapidly in neonates to ~50% above adult values at ~1 year; declines slowly to adult levels by ~20 years; remains stable in adulthood (20 to 60 years), even during pregnancy; then declines in older adults. These changes shed light on human development and aging and should help shape nutrition and health strategies across the life span.

The doubly labeled water (DLW) method measures total energy expenditure (TEE) in free-living subjects. Several equations are used to convert isotopic data into TEE. Using the International Atomic Energy Agency (IAEA) DLW database (5,756 measurements of adults and children), we show considerable variability is introduced by different equations. The estimated rCO2 is sensitive to the dilution space ratio (DSR) of the two isotopes. Based on performance in validation studies, we propose a new equation based on a new estimate of the mean DSR. The DSR is lower at low body masses (

Periodic breathing during sleep at high altitude is almost universal among sojourners. Here, in the context of acclimatization and adaptation, we provide a contemporary review on periodic breathing at high altitude, and explore whether this is an adaptive or maladaptive process. The mechanism(s), prevalence and role of periodic breathing in acclimatized lowlanders at high altitude are contrasted with the available data from adapted indigenous populations (e.g. Andean and Tibetan highlanders). It is concluded that (1) periodic breathing persists with acclimatization in lowlanders and the severity is proportional to sleeping altitude; (2) periodic breathing does not seem to coalesce with poor sleep quality such that, with acclimatization, there appears to be a lengthening of cycle length and minimal impact on the average sleeping oxygen saturation; and (3) high altitude adapted highlanders appear to demonstrate a blunting of periodic breathing, compared to lowlanders, comprising a feature that withstands the negative influences of chronic mountain sickness. These observations indicate that periodic breathing persists with high altitude acclimatization with no obvious negative consequences; however, periodic breathing is attenuated with high altitude adaptation and therefore potentially reflects an adaptive trait to this environment. [ABSTRACT FROM AUTHOR]

We examined the extent to which apnoea‐induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra‐elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end‐apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri‐iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015–0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative–nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S‐nitrosohaemoglobin consumption and plasma S‐nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative–nitrosative stress. Key points: Local sampling of blood across the cerebral circulation in ultra‐elite apnoeists determined the extent to which severe end‐apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical‐mediated nitric oxide bioavailability and global cerebral bioenergetic function.Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative–nitrosative stress.The apnoea‐induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose.Cerebral oxidative–nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea‐induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia.This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production. [ABSTRACT FROM AUTHOR]

Platelets are known primarily for their role in blood clotting; however, it is becoming clear that they play diverse roles beyond that of haemostasis. Exercise has been shown to activate platelets and stimulate neurogenesis, neuroplasticity and improve cognitive function, highlighting a potentially powerful link between platelet function and brain health. Despite this clear link between platelets and the brain, very little is known about the behaviour of platelets through the cerebral circulation in humans. We examined platelet concentration across the brain in exercising humans at sea level (340 m) and high altitude (6–8 days at 3800 m; a stimulus known to modify platelet function). During intense exercise at sea level, platelet concentration increased similarly by 27 ± 17% in the arterial and internal jugular venous circulations (exercise: P < 0.001, interaction: P = 0.262), indicating no uptake or release of platelets into/from the brain. At high altitude, resting platelet concentrations were similar to sea level values in both the arterial and jugular venous circulations (P = 0.590); however, intense exercise at high altitude caused a 31 ± 35% decrease in platelet concentration across the brain (P = 0.016). This divergent response across the brain was not observed in any other haematological or metabolic variables. These data highlight a unique situation where the combination of intense exercise and high altitude hypoxia cause a decrease in platelet concentration across the cerebral circulation. The physiological implications and mechanisms that might influence platelet function across the brain during exercise at high altitude remain to be established. Key points: Platelets are known primarily for their role in blood clotting; however, it is becoming clear that they play diverse roles beyond that of haemostasis.Exercise has been shown to activate platelets, which in turn stimulate neurogenesis, neuroplasticity and improve cognitive function, highlighting a powerful link between platelet function and brain health.At sea level, platelet concentration in blood going into and out of the brain was similar at rest, during maximal exercise and in recovery from exercise.During maximal exercise at high altitude, platelet concentration was 31% lower in the blood exiting the brain; the final destination of these platelets is unknown.The physiological implications and mechanisms that might influence platelet function across the cerebral circulation during exercise at high altitude remain to be established. [ABSTRACT FROM AUTHOR]

The cerebral vasculature manages oxygen delivery by adjusting arterial blood in‐flow in the face of reductions in oxygen availability. Hypoxic cerebral vasodilatation, and the associated hypoxic cerebral blood flow reactivity, involve many vascular, erythrocytic and cerebral tissue mechanisms that mediate elevations in cerebral blood flow via micro‐ and macrovascular dilatation. This contemporary review focuses on in vivo human work – with reference to seminal preclinical work where necessary – on hypoxic cerebrovascular reactivity, particularly where recent advancements have been made. We provide updates with the following information: in humans, hypoxic cerebral vasodilatation is partially mediated via a – likely non‐obligatory – combination of: (1) nitric oxide synthases, (2) deoxygenation‐coupled S‐nitrosothiols, (3) potassium channel‐related vascular smooth muscle hyperpolarization, and (4) prostaglandin mechanisms with some contribution from an interrelationship with reactive oxygen species. And finally, we discuss the fact that, due to the engagement of deoxyhaemoglobin‐related mechanisms, reductions in O2 content via haemoglobin per se seem to account for ∼50% of that seen with hypoxic cerebral vasodilatation during hypoxaemia. We further highlight the issue that methodological impediments challenge the complete elucidation of hypoxic cerebral reactivity mechanisms in vivo in healthy humans. Future research is needed to confirm recent advancements and to reconcile human and animal findings. Further investigations are also required to extend these findings to address questions of sex‐, heredity‐, age‐, and disease‐related differences. The final step is to then ultimately translate understanding of these mechanisms into actionable, targetable pathways for the prevention and treatment of cerebral vascular dysfunction and cerebral hypoxic brain injury. [ABSTRACT FROM AUTHOR]

The impact of physiological stressors on cerebral sympathetic nervous activity (SNA) remains controversial. We hypothesized that cerebral noradrenaline (NA) spillover, an index of cerebral SNA, would not change during both submaximal isometric handgrip (HG) exercise followed by a post-exercise circulatory occlusion (PECO), and supine dynamic cycling exercise. Twelve healthy participants (5 females) underwent simultaneous blood sampling from the right radial artery and right internal jugular vein. Right internal jugular vein blood flow was measured using Duplex ultrasound, and tritiated NA was infused through the participants' right superficial forearm vein. Heart rate was recorded via electrocardiogram and blood pressure was monitored using the right radial artery. Total NA spillover increased during HG (P = 0.049), PECO (P = 0.006), and moderate cycling exercise (P = 0.03) compared to rest. Cerebral NA spillover remained unchanged during isometric HG exercise (P = 0.36), PECO after the isometric HG exercise (P = 0.45), and during moderate cycling exercise (P = 0.94) compared to rest. These results indicate that transient increases in blood pressure during acute exercise involving both small and large muscle mass do not engage cerebral SNA in healthy humans. Our findings suggest that cerebral SNA may be non-obligatory for exercise-related cerebrovascular adjustments. [ABSTRACT FROM AUTHOR]

The mammalian dive reflex, characterized by bradycardia and peripheral vasoconstriction, occurs in all mammals, including humans, in response to apnea. However, the dive reflex to a single, maximal, dry, dynamic apnea (DYN) and how it compares to a time-matched exercise control trial (EX) or dry static apnea (SA) has not been studied. We examined the hypotheses that, compared with EX and SA, the magnitude of the 1) cardiovascular response and 2) hematological response to DYN would be greater. Cardiovascular parameters [heart rate (HR), systolic (SBP), diastolic (DBP), and mean arterial (MAP) blood pressure] were continuously collected in 23 (F = 6 females) moderate and elite freedivers, first during a maximal DYN, then during a time-matched SA and EX on a swimming ergometer in randomized order. Venous blood draws were made before and following each trial. The change in calculated oxygen saturation (DYN: −17 ± 13%, EX: −2 ± 1%, ΔSA: −2 ± 1%; P < 0.05, all comparisons) was greater during DYN compared with EX and SA. During DYN, ΔSBP (DYN: 104 ± 31 mmHg; EX: 38 ± 23 mmHg; and SA: 20 ± 11 mmHg), ΔDBP (DYN: 45 ± 12 mmHg; EX: 14 ± 10 mmHg; and SA: 15 ± 8 mmHg), and ΔMAP (DYN: 65 ± 17 mmHg; EX: 22 ± 13 mmHg; and SA: 16 ± 9 mmHg) were increased compared with EX and SA, while ΔHR was greater during EX (DYN: −24 ± 23 beats/min; EX: 33 ± 13 beats/min; and SA: −1 ± 10 beats/min) than either DYN or SA (P < 0.0001, all comparisons). Females had a greater pressor response to EX (ΔSBP: 59 ± 30 mmHg; ΔDBP: 24 ± 14 mmHg; and ΔMAP: 35 ± 8 mmHg) than males (ΔSBP: 31 ± 15 mmHg; ΔDBP: 11 ± 6 mmHg; and ΔMAP: 18 ± 8 mmHg; P < 0.01, all comparisons). Together, these data indicate that DYN elicits a distinct, exaggerated cardiovascular response compared with EX or SA alone. NEW & NOTEWORTHY: This study performed a dry dynamic apnea with sport-specific equipment to closely mimic the physiological demands of competition diving. We found the cardiovascular and hematological responses to dynamic apnea were more robust compared with time-matched exercise and dry static apnea control trials. [ABSTRACT FROM AUTHOR]

Aim: How the cerebral metabolic rates of oxygen and glucose utilization (CMRO2 and CMRGlc, respectively) are affected by alterations in arterial PCO2 (PaCO2) is equivocal and therefore was the primary question of this study. Methods: This retrospective analysis involved pooled data from four separate studies, involving 41 healthy adults (35 males/6 females). Participants completed stepwise steady‐state alterations in PaCO2 ranging between 30 and 60 mmHg. The CMRO2 and CMRGlc were assessed via the Fick approach (CBF × arterial‐internal jugular venous difference of oxygen or glucose content, respectively) utilizing duplex ultrasound of the internal carotid artery and vertebral artery to calculate cerebral blood flow (CBF). Results: The CMRO2 was altered by 0.5 mL × min−1 (95% CI: −0.6 to −0.3) per mmHg change in PaCO2 (p < 0.001) which corresponded to a 9.8% (95% CI: −13.2 to −6.5) change in CMRO2 with a 9 mmHg change in PaCO2 (inclusive of hypo‐ and hypercapnia). The CMRGlc was reduced by 7.7% (95% CI: −15.4 to −0.08, p = 0.045; i.e., reduction in net glucose uptake) and the oxidative glucose index (ratio of oxygen to glucose uptake) was reduced by 5.6% (95% CI: −11.2 to 0.06, p = 0.049) with a + 9 mmHg increase in PaCO2. Conclusion: Collectively, the CMRO2 is altered by approximately 1% per mmHg change in PaCO2. Further, glucose is incompletely oxidized during hypercapnia, indicating reductions in CMRO2 are either met by compensatory increases in nonoxidative glucose metabolism or explained by a reduction in total energy production. [ABSTRACT FROM AUTHOR]

Despite elite human free divers achieving incredible feats in competitive free diving, there has yet to be a study that compares consummate divers, (i.e. northern elephant seals) to highly conditioned free divers (i.e., elite competitive free-diving humans). Herein, we compare these two diving models and suggest that hematological traits detected in seals reflect species-specific specializations, while hematological traits shared between the two species are fundamental mammalian characteristics. Arterial blood samples were analyzed in elite human free divers (n = 14) during a single, maximal volitional apnea and in juvenile northern elephant seals (n = 3) during rest-associated apnea. Humans and elephant seals had comparable apnea durations (∼6.5 min) and end-apneic arterial P o 2 [humans: 40.4 ± 3.0 mmHg (means ± SE); seals: 27.1 ± 5.9 mmHg; P = 0.2]. Despite similar increases in arterial P co 2 (humans: 33 ± 5%; seals: 16.3 ± 5%; P = 0.2), only humans experienced reductions in pH from baseline (humans: 7.45 ± 0.01; seals: 7.39 ± 0.02) to end apnea (humans: 7.37 ± 0.01; seals: 7.38 ± 0.02; P < 0.0001). Hemoglobin P50 was greater in humans compared to elephant seals (29.9 ± 1.5 and 28.7 ± 0.6 mmHg, respectively; P = 0.046). Elephant seals overall had higher carboxyhemoglobin (COHb) levels (5.9 ± 2.6%) compared to humans (0.8 ± 1.2%; P < 0.0001); however, following apnea, COHb was reduced in seals (baseline: 6.1 ± 0.3%; end apnea: 5.6 ± 0.3%) and was slightly elevated in humans (baseline: 0.7 ± 0.1%; end apnea: 0.9 ± 0.1%; P < 0.0002, both comparisons). Our data indicate that during static apnea, seals have reduced hemoglobin P50, greater pH buffering, and increased COHb levels. The differences in hemoglobin P50 are likely due to the differences in the physiological environment between the two species during apnea, whereas enhanced pH buffering and higher COHb may represent traits selected for in elephant seals. NEW & NOTEWORTHY: This study uses similar methods and protocols in elite human free divers and northern elephant seals. Using highly conditioned divers (elite free-diving humans) and highly adapted divers (northern elephant seals), we explored which hematological traits are fundamentally mammalian and which may have been selected for. We found differences in P50, which may be due to different physiological environments between species, while elevated pH buffering and carbon monoxide levels might have been selected for in seals. [ABSTRACT FROM AUTHOR]