Osmoreceptor cells in the brain and periphery, which are collectively responsible for perceived thirst, accumulate intracellular solute (Bourque, 2008), such as amino acids, to adapt to chronic hypertonic stress. Increased protein breakdown is a well-established strategy for coping with chronic hypertonic stress, observed across species with drought/aestivation (Yancey et al, 1982). Evidence of increased protein breakdown is observed in patients with excess body water loss due to skin or renal damage (Kovarik et al, 2021) and with less than 2L/d usual total water intake in healthy young men (Stookey et al, 2023). Higher concentrations of intracellular solute allow cells to tolerate chronic hypertonic stress by creating an osmotic gradient that favors retaining water inside the cells.
Patients with chronic hypertonicity due to uncontrolled diabetes are known to develop suppressed thirst. Healthy athletes (Casa et al, 2000) and individuals exposed to heat (Rosinger et al, 2022) are known to experience 'involuntary dehydration' or incomplete rehydration after dehydration, when given ad-libitum fluids and allowed to drink following thirst. Thirst is significantly reduced in older adults (Phillips et al, 1984). It is plausible that decreased thirst is a function of intracellular osmolyte accumulation, resulting from altered metabolism in response to chronic hypertonicity.
In older adults, reduced thirst is attributed to higher baseline extracellular osmolality and higher osmotic set-point for thirst sensation (Kenney \& Chiu, 2001). In older people, reduced thirst or faster thirst satiation after drinking water is related to a larger drop in activation of the anterior midcingulate cortex (aMCC) in the brain (Farrell et al, 2008).
With respect to young adults, while evidence indicates that 'involuntary dehydration' depends on cations lost or excreted from the intracellular and/or extracellular space (Nose et al, 1988), roles for osmolytes other than cations remain to be explored. There are gaps in the clinical literature regarding effects of chronic extracellular hypertonicity on osmoadaptation, shifted osmoreceptor set-point, suppressed thirst, and hydration biomarkers.
Chronic extracellular hypertonicity and suppressed thirst are conceivable in daily life, because people frequently consume foods and fluids that are more concentrated than blood (beverage osmolality \>280 mmol/kg). Most commercially available beverages including milk and juice have an osmolality above 300 mmol/kg.
Given that adaptation to chronic hypertonicity carries metabolic cost (Pena-Villalobos et al, 2016) and favors chronic disease risk factors in healthy young adults (Stookey et al, 2023), including micronutrient (e.g. Zn) excretion (Zorbas et al, 1993; Zorbas et al, 1995), oxidative stress, protein breakdown, and altered immune function, low thirst in young adults may not be a reliable guide for water intake - if thirst is 'suppressed' as opposed to 'satiated'. On the contrary, low thirst in young adults may signal chronic suboptimal cell hydration and unmet need for hypotonic water.
Hypotheses
Holding constant usual intake of food and other beverages and physical activity levels over 10 weeks, this study hypothesizes that participants who are randomly assigned to drink water to dilute afternoon urine to USPG\<1.013 daily (PWI of about 20 mL/kg or 500 mL 3x/d in Spring and Autumn; 4x/d in Summer) for 4 weeks will have a:
Primary outcome
• significantly greater increase in the mean overnight water restricted thirst rating between Week 5 and Week 10 compared to participants assigned to the control group.
Secondary outcomes
* significantly greater decrease between Week 5 and Week 10 in the acute decrease in regional cerebral blood flow seen by functional MRI in brain regions of interest (S1/M1, prefrontal cortex, anterior midcingulate cortex, premotor cortex, and superior temporal gyrus) from maximum thirst after overnight water restriction to immediately following 500 mL drinking water, compared to the control group.
* significantly different metabolomic profile in Week 10, with greater shift away from the aestivation- and Warburg-like patterns, including significantly greater reduction in protein breakdown between Week 5 and Week 10, compared to the control group.
* significantly greater decrease in urine excretion of zinc between Week 5 and Week 10, compared to the control group.
