A Role for Estrogen in Skin Aging and Dermal Biomechanics

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Abstract

The skin is the body’s primary defense against the external environment, preventing infection and desiccation. Therefore, alterations to skin homeostasis, for example with skin aging, increase susceptibility to skin disease and injury. Skin biological aging is uniquely influenced by a combination of intrinsic and extrinsic (primarily photoaging) factors, with differential effects on skin structure and function. Interestingly, skin architecture rapidly changes following menopause, as a direct result of reduced circulating 17-estradiol. The traditional clinical benefit of estrogens is supported by recent experimental data, where 17- estradiol supplementation prevents age-related decline in the skin’s structural and mechanical properties. However, the off-target effects of 17-estradiol continue to challenge therapeutic application. Here we discuss how aging alters the physiological and structural properties of the dermal extracellular matrix, and explore how estrogen receptor-targeted therapies may restore the mechanical defects associated with skin aging.




1. Introduction


Almost all animals undergo intrinsic biological aging as they advance in chronological age. Environmental pressures in the natural world mean that prolonged aging is, however, limited to only a handful of species that inhabit protected environments (Kirkwood, 2002). Indeed, with modern medicine and technological progression, human lifespan (relative to body mass) has significantly surpassed that of other animals. Advanced age (chronological or biological) is not without consequence, as cellular degradation directly enhances the risk of pathology (Niccoli and Partridge, 2012). An ever-expanding elderly population is driving the increased incidence of age-related disease, with mounting socioeconomic pressure (Howdon and Rice, 2018). The skin is our most visible organ, providing a window into age-associated structural and functional changes occurring throughout the body. This review will explore the current understanding of the structural, functional, and biomechanical changes that accompany skin aging, and highlight the important protective effects of estrogen against skin aging.




2. Skin – The Body’s Largest Organ

3. Skin Ageing

4. Dermal Structure and Function

5. Biomechanical and Physiological Consequences of Dermal Ageing

6. Estrogen is a Major Regulating Factor in Skin Ageing




7. Conclusion


Skin aging is a complex, multifactorial process influenced by both intrinsic and extrinsic factors. As the body’s primary defense barrier, age-related structural and functional skin changes heighten susceptibility to infection, wounding, and disease. The loss of structural integrity associated with aging is underpinned by the remodeling of the ECM. Fragmentation of collagen and elastin lead to enhanced tissue stiffness, reduced elasticity, and skin thinning. These structural and functional changes are the result of increased oxidative stress, inflammation, and glucose-mediated cross-linking. Interestingly, 17β-estradiol deficiency is a key contributor to skin aging, where both menopause and experimental ovariectomy lead to accelerated degradation of the dermal matrix. Although exogenous 17β-estradiol can protect skin from altered biomechanical properties following menopause, its use in the clinic remains controversial. On the contrary, SERMs are able to exert positive estrogenic effects without increasing tumorigenic potential, and thus may offer a viable option to prevent age-associated deterioration in skin function.
 
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Figure 1. Structural changes that occur in intrinsic and extrinsic skin ageing. Intrinsically aged skin is characterised by epidermal and dermal thinning, fine lines, fewer cells, and reduced blood flow. By contrast, photoaged skin is thicker with deeper wrinkles and hyperpigmentation but still shows reduced dermal thickness compared to young skin. Dilation of blood vessels, inflammatory cell infiltration and build-up of elastic material (elastosis) are also features of photoaging. Both intrinsic and extrinsic ageing causes a reduction in Langerhans cells (LCs), loss of rete ridges at the dermal-epidermal junction (DEJ), accumulation of senescent cells reduced skin hydration (fewer glycosaminoglycans, GAGs) and AGE-related cross-linking of matrix fibres. Moreover, enhanced production of matrix metalloproteinases (MMPs) leads to degradation of collagen, elastin and elaunin. AGE = advanced glycation end-products.
Screenshot (4912).png
 
Figure 2. Age-related changes in the skin extracellular matrix and their structural consequences. A) Ultraviolet (UV) A rays penetrate deeper into the skin than UVB, causing substantial damage to aged skin due to reduced antioxidant mechanisms. B) Ultraviolet radiation (UVR) induces reactive oxygen species (ROS) and matrix metalloproteinases (MMPs) via AP-1 and NF-κB to cause collagen and elastin fragmentation. Collagen degradation reduces mechanical tension in fibroblasts, which stimulates MMP production and downregulates TGF-β to promote further matrix degradation. Accumulation of advanced glycation end products (AGEs), as a result of hyperglycaemia and natural ageing, leads to cross-linking of collagen to increase tissue stiffness. Cross-linking of elastin reduces skin recoil and promotes sagging, while loss of glycosaminoglycans (GAGs) decreases skin hydration. Red arrows = decreased. Green arrows = increased.
Screenshot (4913).png
 
Figure 3. Estrogen and selective estrogen receptor modulators (SERMs) protect against skin aging following menopause. Without estrogen (17β-estradiol), post-menopausal the skin undergoes rapid intrinsic and extrinsic aging resulting in wrinkles, skin thinning, and deterioration of the extracellular matrix. Treatment with estrogen or SERMs protects against skin aging by preventing degradation of collagen, elastin, and glycosaminoglycans (GAGs), shielding against ultraviolet radiation and severe elastosis, and slowing advanced glycation end-product (AGE) cross-linking of matrix fibers. Post-menopausal skin treated with estrogen is, therefore, thicker than naturally aged skin, with more hydration, higher elasticity, and less wrinkling. Up arrows = increased. Down arrows = decreased.
Screenshot (4914).png
 
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