Discher and co-authors reported in 2005 that cells respond to the rigidity of their planar substrate [9]. It has been further demonstrated that cellular processes in the three-dimensional matrix respond differently to microenvironment stiffness and, for example, in hyaluronic acid hydrogels, the differentiation behavior of human mesenchymal stem cells (hMSCs) depends on cellular traction. High degrees of cell spreading on stiffer surfaces favored osteogenesis, and lower degrees of cell spreading on softer surfaces favored adipogenesis [10]. Protein-conformational diseases and age-related diseases are associated with increasing tissue stiffness with increasing age [1,11,12]. Arterial stiffness was associated, not only with cardiovascular diseases, but also with neurodegenerative diseases, cognitive impairment, and vascular dementia [13,14,15]. Thus, the prevention of tissue stiffening is a therapeutic approach with the clinical potential to attenuate disease, which has been discussed in a recent review by Lampi and Reinhart-King [11]. It has also been suggested that antihypertensive drugs can decrease vascular stiffness and reduce the occurrence of cognitive impairment [15]. Increased extracellular matrix (ECM) stiffness was related to cancer, cardiovascular disease, diabetes, and other pathologies. ECM provides biomechanical cues that direct cell growth, migration, differentiation, and survival [16].

It is important to take into account that mechanical properties depend on the content and state of water bound to biological macromolecules [2,3]. The binding energy of water molecules to biological macromolecules decreases with aging, and tightly bound water transforms into loosely bound and free water. Tightly bound water is a plasticizer and the decrease in its content results in an increase in tissue stiffness. The decrease in bound water fraction in the extracellular matrix with advanced age was correlated with the loss of mechanical properties of the cortical bone in female and male BALB/c mice [17]. Strength and toughness of hydrated human bone decreases with decrease of bound water content, indicating the risk of fracture [18]. In bone, the quantity of water bound to collagen decreases with age [19]. Total body water (TBW) and intracellular water (ICW) decrease with age, but elderly individuals with higher ICW content have higher muscle strength and better functional performance [20]. An increase in the extracellular water (ECW) to ICW ratio in the upper legs determined using segmental bioelectrical impedance spectroscopy was associated with a decrease in muscle strength in older individuals [21]. Kim and co-authors demonstrated that high ECW/ICW ratio is a major risk indicator for all-cause mortality and cardiovascular diseases. A correlation between ECW/ICW with inflammation and pulse wave velocity was reported [22]. ECW/ICW also has been reported as a prognostic factor for survival in metastatic cancer [23]. A decrease in the ICW content with age proceeds with a higher rate than in the ECW content. Increase in ECW/ICW ratio accelerates after the age of 70 years [24].

Thus, it is very important to prevent or retard the transformation of intracellular tightly bound water into extracellular loosely bound and free water in order to mitigate an increase in tissue stiffness.

It has been shown that tissue stiffness increases as a result of tissue crosslinking by advanced glycation end products (AGEs). Dehydration and glycation may be considered as subsequent steps during the aging process [3,25]. A decrease in bound water content and increase in AGEs during aging were reported in the cortical bones of rats [26]. The accumulation of AGEs and reduction of water content in the ovine intervertebral disc was also observed [27]. Crosslinking of elastin and collagen by AGEs was associated with stiffening of the arterial wall with aging [12,16] and AGE cross-link breakers can be suggested as “de-stiffening” drugs [28,29].

A number of AGE inhibitors that are effective in decreasing AGE accumulation in tissues have been proposed, such as aminoguanidine, pyridoxamine, aspirin, ALT-711 (alagebrium), thiamine, tenilsetam (antidementia drug), and others [30,31,32,33,34,35,36].

It is very important that children have an extremely low rate of hospitalization presented by the U.S. Department of Health and Human Services in Figure 3. This fact demonstrates that people with soft tissues have a low chance of becoming ill with both age-related diseases and COVID-19.

It has been also reported that obesity as an underlying condition was observed in 48.3% COVID-19 patients. It was earlier demonstrated that obesity results in increased arterial stiffness [121].