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 1

Mild lifelong water restriction shortens mouse lifespan accompanied by metabolic remodeling toward increased food intake and energy expenditure.

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Mild lifelong water restriction shortens mouse lifespan accompanied by m...
Mice were water restricted throughout their entire lives by feeding them with gel food made from 30% of water and 70% of dry food without access to any additional water. (A and B) Water restriction results in chronic decrease in hydration level. (A) Water-restricted (WR) mice have elevated urine osmolality. (B) WR mice have elevated hematocrit. (C–F) Aging of WR mice is accompanied by a sharp decrease in weight during the last several weeks of life. (C) Control and WR mice grow at the same rate during the first year of life. (D) Representative growth curves showing sharp weight decrease of WR mice. (E) WR mice stop gaining weight at an earlier age. Data are plotted as age at maximum weight (mean ± SEM).**P < 0.01 by unpaired, 2-tailed t test. (F) Weight change during the last 2 months of life (mean ± SEM. ***P < 0.001 by unpaired, 2-tailed t test. (G) Representative pictures. WR mice are shown after they lost weight. They looked similar to control mice before the weight loss started. (H) WR mice have shortened life span. Left panel: the Kaplan-Meier survival curves (P = 0.029, log-ranked Kaplan-Meier survival analysis). Right panel: average life span (t test, unpaired 2-tailed, P = 0.039; Control: n = 11, WR: n = 6). (I) Attenuation of weight gain followed by weight loss is caused by decrease in body fat mass. Body composition analysis: fat-to-lean mass ratio (mean ± SEM, *P < 0.05 relative to water restriction by unpaired, 2-tailed t test). See Supplemental Figure 1 for fat and lean mass. (J–M) Water restriction increases energy expenditure. (J) WR mice consume more food. Daily food consumed per mouse is plotted as mean (of 30 days) ± SEM. *P < 0.001 relative to water restriction by unpaired, 2-tailed t test). (K) Estimation of energy expenditure by calculations of energy balance (TEEbal): caloric intake minus change in body energy stores. See Methods for details. WR mice have increased TEEbal through whole period of water restriction. (L and M) Characterization of energy expenditure by measurement of gas exchange and heat production in calorimetric chambers. (L) Higher heat production in WR mice is consistent with increased energy expenditure detected by energy balance calculations shown on panel K (mean ± SEM, n = 6). *P < 0.05; **P < 0.01 by unpaired, 2-tailed t test). (M) Respiratory exchange rate (RER) decreases in WR mice after 13 months of water restriction consistent with higher proportion of metabolic utilization of lipids.