Suboptimal hydration remodels metabolism, promotes degenerative diseases, and shortens life
Michele D. Allen, … , Manfred Boehm, Natalia I. Dmitrieva
Michele D. Allen, … , Manfred Boehm, Natalia I. Dmitrieva
Published September 5, 2019
Citation Information: JCI Insight. 2019;4(17):e130949. https://doi.org/10.1172/jci.insight.130949.
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Research Article Aging

Suboptimal hydration remodels metabolism, promotes degenerative diseases, and shortens life

Abstract

With increased life expectancy worldwide, there is an urgent need for improving preventive measures that delay the development of age-related degenerative diseases. Here, we report evidence from mouse and human studies that this goal can be achieved by maintaining optimal hydration throughout life. We demonstrate that restricting the amount of drinking water shortens mouse lifespan with no major warning signs up to 14 months of life, followed by sharp deterioration. Mechanistically, water restriction yields stable metabolism remodeling toward metabolic water production with greater food intake and energy expenditure, an elevation of markers of inflammation and coagulation, accelerated decline of neuromuscular coordination, renal glomerular injury, and the development of cardiac fibrosis. In humans, analysis of data from the Atherosclerosis Risk in Communities (ARIC) study revealed that hydration level, assessed at middle age by serum sodium concentration, is associated with markers of coagulation and inflammation and predicts the development of many age-related degenerative diseases 24 years later. The analysis estimates that improving hydration throughout life may greatly decrease the prevalence of degenerative diseases, with the most profound effect on dementia, heart failure (HF), and chronic lung disease (CLD), translating to the development of these diseases in 3 million fewer people in the United States alone.

Authors

Michele D. Allen, Danielle A. Springer, Maurice B. Burg, Manfred Boehm, Natalia I. Dmitrieva

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Figure 2

Effects of mild chronic water restriction on renal water conservation mechanisms and markers of inflammation and coagulation.

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Effects of mild chronic water restriction on renal water conservation me...
(A–E) One-year water restriction does not worsen renal water conservation ability and remodels metabolism toward metabolic water formation. Mice were exposed to water restriction for 1 year and then provided with free access to water for 1 month. Efficiency of water balance regulation was assessed by exposing water-restricted (WR) mice and control mice (CT) to a short period of limited water availability performed in metabolic cages. Mice were given gel food containing 43% of water for 5 days, followed by a reduction to 30% water. No additional water was provided. (A) Time courses of food and water consumption and of weight changes. Top row: Both chronically WR mice and CT mice are losing weight with WR group at slightly lower rate. (P < 0.0001, test for the slopes difference). Middle and bottom rows: Upon reduction of water availability, CT mice decrease whereas WR mice increase food intake. (B) Despite decreased water consumption, WR mice increase urine volume indicating a fast switch of metabolism to metabolic water production. (C) Increased urine osmolality shows preserved kidney concentrating ability. (D) WR mice increase osmolar excretion consistent with metabolic water production from excess of consumed food. (E) Similar water content in feces indicates that this water preservation mechanism is not changed in WR mice. (F) Blood pressure (BP) measurements. Left panel: WR mice have lower BP (mean ± SEM). *P < 0.05 by unpaired, 2-tailed t test. Right panel: Analysis of correlation between BP and weight. All measurements for both groups and all time points are combined (n = 27). Significant correlation indicates that weight rather than water restriction determines BP variability (Pearson’s correlation coefficient = 0.65, P = 0.0002). (G) WR mice demonstrate faster glucose clearance in glucose tolerance test performed at age 16 months (mean ± SEM; Control: n = 5; WR: n = 4). **P < 0.01; *P < 0.05 by unpaired, 2-tailed t test. See Supplemental Figure 2 for mouse weights. (H) Increased levels of markers of inflammation and coagulation in chronically WR mice. Levels of vWF and D-Dimer are slightly elevated in WR mice at age 5 months. Quantification by densitometry (mean ± SEM). *P < 0.05; **P < 0.01 by unpaired, 2-tailed t test. See Supplemental Figure 3 for Western blot images. (I) Plasma IL-6 level increases faster with age in WR mice (mean ± SEM). *P < 0.05 by unpaired, 2-tailed t test.