**8. Tarumi disease**

166 Viscoelasticity – From Theory to Biological Applications

physical properties of connective tissues.

is discussed in the following section.

deep wrinkles, as observed in Figure 12.

versican-hyaluronan (Fi-Ver-Hy) network in the dermis.

**tissues** 

**6. Diseases caused by impaired viscoelastic properties of connective** 

We discuss aging-associated diseases that result in impaired physical properties of connective tissues based on a review of genetic diseases that cause impairment in the

Marfan syndrome (MFS) is a relatively common genetic connective tissue disease. MFS is an autosomal dominant connective tissue disease that affects the aorta, lungs, ciliary zonule, muscles, and other organs. However, most phenotypes appear only in the later stages of life. The primary cause of MFS appears to be due to mutations in the microfibrillar molecule fibrillin-1, although some phenotypes observed in various organs are believed to develop from the dysregulation of TGF-beta. One explanation for the genotype-phenotype correlation is due to the aberrant activation of TGF-beta stored within microfibrils through the binding between fibrillin-1 and LTBPs (21) (Figure 4). Recent studies have highlighted the importance of proper modulation of non-canonical TGF-beta signaling (22). The role of versican in MFS is currently unknown. Interestingly, the tissue phenotype resulting from MFS shows similarities to that of aging. For instance, aneurysm, emphysema, hernia, and muscle atrophy are all common features of MFS patients and also of elderly patients. However, the correlation between MFS and aging connective tissue phenotypes is currently unknown. MFS appears to be a model for impaired viscoelasticity of human tissues, which

**7. Aging-dependent changes of versican in the dermal connective tissues** 

The dermis changes prominently with age; for example, the thickness of the dermis becomes thin and wrinkles appear. Biochemical collagen content and histological density of collagen fiber is reduced (23). We have shown that versican is a key molecule for viscoelasticity of the dermis. The amount of versican extracted from the dermis decreases with age and its GAG composition is also altered (24, 25). Therefore, as described above, we hypothesize that loss or reduction of versican, or in the HA binding ability of versican, may lead to impaired viscoelasticity of the dermis. Versican is heavily accumulated within solar elastosis, which is a hallmark of photo-aged skin and where elastic fiber components, including elastin and fibrillin-1, have accumulated (26). Clinically, photo-aged skin is not viscoelastic and shows

Using recombinant versican G1 proteins and specific antibodies, we have indicated that a loss in the HA binding affinity of versican is characteristically observed in the region of solar elastosis (27). Versican specifically loses its HA binding domain (6084) in solar elastosis, whereas the carboxyl terminal domain (2B1) remains present. Therefore, the HA binding ability of elastic fibers is lost and microfibrils in solar elastosis are unable to bind to HA (Figure 13). Therefore, loss of the HA binding region of versican disrupts the fibrillinBased on the physical properties of skin and other connective tissues, we propose "Tarumi disease" as an aging-associated, connective tissue loosening disease. Tarumi diseases are preferentially found in the elderly population, with some exceptions. Tarumi is a Japanese word that represents tissue loosening. Aging-associated loosening of connective tissue is a major pathogenesis for emphysema, aneurysm, skin wrinkles, pelvic organ, and hernias. The Tarumi diseases that we are proposing are listed in the table below (Table 1). In 2001, an interesting association between pseudoexfoliation syndrome and abdominal aortic aneurysm was reported (28). However, it should be noted that this report has not been supported by the subsequent studies on the prevalence of these conditions.

Common pathogenesis among each Tarumi disease is currently unclear. Smoking is considered to be a precipitating factor in the common pathogenesis of aortic aneurysm and chronic obstructive pulmonary disease (COPD) (29, 30). However, other factors should be investigated for the Tarumi diseases. Tarumi disease may provide a novel perspective of tissue aging in geriatrics.

Viscoelastic Properties of the Human Dermis and

Other Connective Tissues and Its Relevance to Tissue Aging and Aging–Related Disease 169

Funding for this study was provided by The Research Funding for Longevity Sciences (21- 18) from the National Center for Geriatrics and Gerontology (NCGG), Japan. We thank Hiroyuki Matsuura and Katsunori Furuta for their cooperation in this study. The authors

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Therefore, studying Tarumi disease may be a useful step toward understanding common pathogenesis among these diseases. Future directions in Tarumi disease research require pathological, biochemical, and physical studies. Methods presented in this chapter may evaluate the looseness of tissues. Furthermore, surgical intervention using a tissue filler may be a useful method to improve these diseases. Finally, the phenotypical relationship between MFS and Tarumi disease may lead to understanding their common pathogenesis.


**Table 1.** Proposed Tarumi diseases.
