Social relevance:
For 30 years, people have been confused about how much plain water to drink. Over 30 years, health professionals have criticized media advice to drink 8 glasses of water per day, citing lack of evidence (Valtin et al, 2002; Yamada et al, 2022). Health authorities have not set drinking water-specific recommendations, assuming 1) that any or all types of drinks hydrate equivalently, i.e. that people do not need to drink plain water to replace lost body water, and 2) the average healthy person can rely on thirst as guide for water intake.
The lack of drinking water-specific recommendations significantly impacts daily lives because it translates into limited or no support for drinking water in public health services, laws, and retail options.
Scientific relevance:
Thirst is considered the primary driver of water intake and main defense against body water deficit in healthy young adults (IOM, 2005). Health authorities set total water intake recommendations for the average healthy man and woman (e.g. 2.5 L/d for men and 2.0 L/d for women in Europe) but, additionally, advise people to use thirst as a guide for water intake, recognizing that individual water requirements vary widely (EFSA, 2010; IOM, 2005).
Although thirst can be satiated by water intake, it can also be ignored per custom (Greenleaf, 1992) or suppressed by an upward-shifted thirst threshold. The thirst threshold, the set-point where osmoreceptor cells shrink and release their neural or hormonal signal, is a function of the solute concentration or osmolality inside and outside the osmoreceptor cells (Nose et al, 1988a,b). Cells with higher intracellular solute content require a higher external osmolality to shrink.
Specific Aims The ultimate goal of this study is to address gaps in the literature about drinking water and check assumptions that limit the development of drinking water-specific recommendations. The study will examine if osmoadaptation to chronic hypertonicity, due to daily intake of hypertonic fluid sources, can explain suppressed thirst in healthy individuals under conditions of daily life. To facilitate causal inference about drinking water effects for long-term health, this study was designed to link experimental data about osmoadaptation at the cellular level with clinical data relevant for conditions of daily life in Salzburg Austria with population-based data about water intake and chronic disease risk in Salzburg Austria.
This study will test effects of drinking enough plain water to dilute urine everyday for 4 weeks (about 500 mL 4 times per day in summer). The study will include healthy, normal weight, young, men and women, who all usually meet European adequate intake recommendations for total water intake (TWI), but usually consume less than 1L/d PWI, and have biomarkers of chronic hypertonic stress (concentrated urine and saliva) for 4 consecutive weeks before starting the randomized study.
4 weeks of 3-day mean total water intake of 35 ml/kg body weight
4 weeks of <1L/d drinking water
4 weeks of <1 hr/d moderate or vigorous physical activity given daily life conditions in Salzburg, Austria
No history of chronic disease
Individuals will be excluded from participation if the gender-specific target numbers have already been reached
Perceived stress score of > 20 at any time during Weeks 1-4
Schedule that does not allow continuous study participation
Intention to spend more than a day outside the Salzburg area during the study period (to reduce exposure to ground water with different background D2O as potential source of error)
Parallel
Drinking water to dilute urine
Other interventionAfter Weeks 1-4 baseline data collection, people randomized in Week 5 will be instructed to increase drinking water to approx. 4 times 500 mL/d in Weeks 6-9 to reach a volume that is enough to dilute urine specific gravity below 1.013 everyday. The PWI exposure is approx. 20 mL/kg PWI for men, 25 mL/kg PWI for women. Addition of PWI to the diet may increase TWI and minimally displace some other beverage intake. Based on Adapt Study data, the hypo-osmotic share of TWI is expected to increase from below 50% to 50% or higher. The intervention dose is also aligned with observational data from the Paracelsus 10000 study in Salzburg, which found that healthy adults who met hydration criteria reported at least 1L/d PWI. The intervention will be communicated to participants in terms of L/d instead of mL/kg, because L/d are easier to translate into portion size and drinking behavior.
Increase in thirst rating after overnight food and water restriction
Thirst rating on a visual analog scale ranging from 0 to 100 is expected to be significantly higher in Week 9, by +10 or more (out of 100) units, compared to a baseline rating below 70 (ensured by screening criteria). Participants will be asked to rate their thirst at the same time in the morning, each week, after food and water restriction at the weekly in-person study site visit.
Change in serum, urine, saliva metabolomic profile
Methods will replicate those reported by the Adapt Study (Stookey et al, 2023): First-morning urine, post-water bolus urine, and serum specimen from Weeks 4 and 9 will be sent to the University of California Davis, West Coast Metabolomics Center (WCMC) for untargeted analysis of primary metabolism. MetaboAnalyst 6.0 software will be used to normalize and test for significantly different untargeted metabolomic profiles in Weeks 4 and 9, based on non-overlapping 95% confidence ellipses in Orthogonal Partial Least Square-Discriminant Analysis. The study hypothesizes overlap (no difference) between profiles for the intervention and control groups in Week 4; and No overlap (i.e. significant difference) between intervention and control in Week 9. For each participant, the within-person change in metabolite abundance between Weeks 4 and 9 will also be calculated. Changes in profile by intervention vs control will also be compared.
Change in brain functional MRI (fMRI)
In Weeks 5 and 10, participants will have brain fMRI after overnight food and water restriction and also 30 min after drinking 500 mL water. Brain activation will be compared for loci considered important for the stimulation and/or inhibition of thirst (hypothalamus, medulla oblongata, midbrain, and cerebral cortex, anterior wall of the third ventricle, Brodmann area 32, pregenual anterior cingulate cortex, anterior midcingulate cortex), parahippocampal gyrus, inferior and middle frontal gyri, insula, and cerebellum). Intervention and control groups will be compared with respect to the overnight water restricted result (t=0), the 30-min post-500mL water challenge result (t+30), and the acute change from t=0 to t+30min, expressed as acute percentage change in slope. Week 10 (post-intervention) results will be compared to Week 5 results (baseline).
Change in zinc excretion
In Weeks 2 and 7, the stable (non-radioactive) isotopic tracer zinc-70 will be administered orally during the study center visit. The concentrations of zinc and zinc-70 will be measured in plasma and urine samples by ICP-MS using methods (Hall et al, 2006). Urinary zinc excretion over 2-weeks will be determined from 24-hour urine and first morning urine samples, and the kinetic relationship between plasma zinc exchange with tissues and urinary losses modeled using WinSAAM (University of Pennsylvania, Kennett Square, PA). The analysis will assume 70% absorption of the zinc tracer, given as less than 10 mg, in the overnight fasted state (Tran et al, 2004). Intervention and control group mean change in excretion will be compared.
Change in total body protein breakdown
WBP turnover will be indexed by the end-product method. In weeks 4 and 9, participants will be given a single oral dose of 200mg 13C,15N-glycine, and collect all urine and record dietary intake for 24hrs. Per Hinde et al (2021), total nitrogen enrichment of urinary ammonia and urea will be measured. WBP flux (Q), protein synthesis, protein breakdown, and protein balance will be calculated as: 1. Q(gN·kg-1·d-1) = d/(corrected tr:T)/24×body mass (BM) 2. WBP synthesis (g·kg-1·d-1) = Q(E/24×BM)×6.25 3. WBP breakdown (g·kg-1·d-1) = Q(I/24×BM ×6.25 4. WBP balance (g·kg-1·d-1) = whole body protein synthesis-whole-body protein breakdown WBP: whole-body protein; Q = WBP flux, d = 15N oral dose (g glycine×0.1972), tr:T = ratio of tracer to tracee (corrected for background isotope enrichment), E = 24 h urinary nitrogen excretion, I = 24 h nitrogen intake, BM = body mass, 6.25 = conversion factor for nitrogen to protein.
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Jodi Stookey
Lead sponsor
Water and Hydration Translational Epidemiological Research, LLC
Sponsor institution
Paracelsus Medical University
Collaborator
University of Salzburg
Collaborator
University of California, Davis
Collaborator
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