The physical, chemical, and biological behavior of macromolecules in biological tissues depends on the content and binding energy with water molecules. Proteins and other macromolecules in living tissue are functional provided that they contain water molecules as an integral part. Biological macromolecules are inactive in the absence of bound water. The changes in bound water and free water ratios have been associated with age-related and protein-conformational diseases and have an important role in time-dependent processes in biological tissues [1
]. The content of tightly bound water in biological tissues decreases with advanced age [1
]. Nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC) are methods that can determine the state of water. NMR and differential thermal analysis (DTA) studies demonstrated variation in water binding energy from tightly bound water molecules to loosely bound water molecules depending on the changes of moisture content in a polymer material. Commonly, three regions of proton molecular mobility represented by relaxation times can be observed using NMR. The relaxation time of free water is much higher if compared with the relaxation time of tightly bound water molecules. Otsuka and co-authors [4
] suggested the application of near-infrared spectroscopy to study states of water. Absorbance spectra in the frequency range of 4500–5500 cm−1
were resolved into three peaks, which correspond to water molecules with different hydrogen bond states.
The behavior of unfrozen water below the equilibrium free water freezing temperature has been discussed by Wolfe and co-authors [5
]. Free water freezes at 0 °C, but freezing point depression can be observed for loosely bound water molecules absorbed by polymers. Wolfe et al. suggested that the binding energy of water molecules depends on the distance from the hydrophilic surface or hydrophilic functional groups of macromolecules, and higher water freezing point depression is related to higher energy of interaction with the surface or macromolecule. The tightly bound unfreezable water molecules in the first and second molecular layers next to the surface are less mobile than the water molecules that are at a higher distance from the surface [5
It has been concluded that water in close contact with macromolecules is no longer liquid but somewhat structured [8
]. Bound water also controls the conformational changes in biological macromolecules.
The effect of living tissue plasticization by water on tissue stiffness is typically neglected in the current state of the art. The aim of this paper is to review mechanisms that demonstrate how changes in bound water content can lead to changes in tissue stiffness, promoting the aging process and triggering related pathologies.
3. Conclusions and Future Perspectives
Strong dependence on a patient’s age allows us to conclude that current methods of treatment of age-related diseases have to be verified, as well for application in the treatment of COVID-19. Thus, COVID-19 is unique and differs from previous epidemics by the fact that children are very rarely infected by novel coronavirus (Figure 3
). COVID-19 virus particles interact with stiffer cell surfaces in old people, and, in cardiovascular diseases, platelets interact with stiffer arterial wall surfaces in old people. In both cases, stiffer substrate leads to a much more severe disease because, in both cases, the tissue surface adhesion and permeability increases. It is well known that children have the highest level of tissue hydration that decreases with advanced age and that tissue stiffness increases with aging. The hospitalization rate is very low for children having soft tissue and the hospitalization rate is high for the older population with hard tissue. Hence, there is an urgent need for the development of de-stiffening therapies.
Changes in water status lead to the change in extracellular matrix stiffness. The age-related decrease in tightly bound water content due to reduction of binding forces between water molecules and biological macromolecules results in the development of age-related and protein-conformational diseases due to an increase in tissue stiffness and permeability. It has been recently demonstrated that the ratio of extracellular water/intracellular water increases with advanced age and especially accelerates after the age of 70 years; a high value of this ratio is a major risk indicator for all-cause mortality.
The role of bound water in biological processes is underestimated in the current state of the art. It is evident that taking into account the effect of bound water on protein conformations and stability can facilitate understanding mechanisms of biophysical processes in age-related diseases and protein-conformational diseases. It is more correct to say that bound water is essential to life than to say that liquid water is essential to life.
Release of tightly bound water triggers glycation reactions that have a very important role in the aging process. Correlation between arterial stiffness and tightly bound water mobility can be expected. An increase in arterial stiffness is commonly accompanied by a decrease in glycocalyx coverage.
The relationship of bound water with tissue stiffness has scarcely been studied for the time being and can be suggested for in-depth study in future.
Biochemical glycation reactions and biophysical changes in hydration status are equally important in the development of physiological processes during aging. The possibility to regulate the hydration status of extracellular matrix could help in the development of new, more effective therapeutics for treatment of age-related and protein-conformational diseases.
NF-κB activation was associated with matrix stiffening and the development of age-related diseases. Rho GTPases control cell proliferation and cytoskeleton remodeling, and the inhibition of RhoA/ROCK inhibits stress fiber formation and has the potential to decrease the stiffness of extracellular matrix and, in such a way, to treat a wide number of pathologies. In order to understand Rho GTPase inhibitors’ functional properties more clearly, it would be reasonable—in parallel with tissue stiffness—to study changes in the content of tightly bound water using nuclear magnetic resonance.
Polyphenols, omega-3 fatty acids, vitamins D, E, C and K2, and statins have been suggested as de-stiffening agents. Research on tightly bound water’s role in de-stiffening is still in its infancy and needs a lot more attention. This review is focused on the role of dehydration and stiffness development in aging tissues. Evidently, other processes—for example, those involved in water–salt metabolism—have an important role in aging, and they could be discussed in special reviews.