Looking Older

Abstract

Background-Skin appearance is a primary indicator of age. During the last decade, substantial progress has been made towards understanding underlying mechanisms of human skin aging. This understanding provides the basis for current use and new development of anti-aging treatments. Objective-To present state of the art knowledge pertaining to mechanisms involved in skin aging, with specific focus on the dermal collagen matrix. Results-A major feature of aged skin is fragmentation of the dermal collagen matrix. Fragmentation results from actions of specific enzymes (matrix metalloproteinases), and impairs the structural integrity of the dermis. Fibroblasts that produce and organize the collagen matrix cannot attach to fragmented collagen. Loss of attachment prevents fibroblasts from receiving mechanical information from their support and they collapse. Stretch is critical for normal balanced production of collagen and collagen-degrading enzymes. In aged skin, collapsed fibroblasts produce low levels of collagen and high levels of collagen-degrading enzymes. This imbalance advances the aging process, in a self-perpetuating, never-ending deleterious cycle. Clinically-proven anti-aging treatments such as topical retinoic acid, CO 2 laser resurfacing, and intradermal injection of crosslinked hyaluronic acid stimulate production of new undamaged collagen. Attachment of fibroblasts to this new collagen allows stretch, which in turn balances collagen production/degradation and thereby slows the aging process. Conclusion-Collagen fragmentation is responsible for loss of structural integrity and impairment of fibroblast function in aged human skin. Treatments that stimulate production of new, nonfragmented collagen should provide substantial improvement to the appearance and health of aged skin.

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

“…These enlarged fibroblasts produce increased levels of collagen and CTGF/CCN2. Interestingly, we recently reported that reduced fibroblast size/mechanical force also up‐regulates matrix metalloproteinase‐1 expression and thus causes collagen fibril fragmentation (Qin et al ., 2014), as observed in aged human skin in vivo (Fisher et al ., 2008, 2009). These data combined with our current findings provide a foundation for our understanding the cellular and molecular basis of age‐related loss of collagen production and increased collagen fragmentation in aged human skin.…”

“…During aging, the dermal ECM undergoes progressive fragmentation that impairs fibroblast attachment with consequent reduction of size (Varani et al ., 2004; Fisher et al ., 2008, 2009; Quan et al ., 2013a). In aged skin, reduced size of fibroblasts is accompanied by their decreased production of key ECM components, such as type I collagen, fibronectin, and connective tissue growth factor (CTGF/CCN2) (Varani et al ., 2004, 2006; Fisher et al ., 2008; Quan et al ., 2010).…”

“…In aged skin, reduced size of fibroblasts is accompanied by their decreased production of key ECM components, such as type I collagen, fibronectin, and connective tissue growth factor (CTGF/CCN2) (Varani et al ., 2004, 2006; Fisher et al ., 2008; Quan et al ., 2010). …”

Oxidative Stress and Human Skin Connective Tissue Aging

“…In this state, the ECM microenvironment is unable to provide sufficient mechanical stability to maintain normal cell spreading/mechanical force [7,20,27]. Therefore, age-related fragmentation of the collagen fibrils deleteriously alters fibroblast size/mechanical tension and function associated with skin connective tissue aging [7,27,28]. Reduced fibroblasts size stimulates intracellular ROS generation.…”

“…At molecular levels, naturally aged and photoaged skin share common features of skin aging-thin and fragmented collagen [5]. Biochemical and histological studies have revealed that aged human skin is primarily characterized by a loss of collagen and damaged/disorganized collagen fibrils [6,7]. Alterations of the dermal connective tissue collagen impair the skin's structural and mechanical integrity, and eventually result in old-looking skin, such as thin, fragile, and wrinkled skin.…”