Molecular basis of retinol anti-ageing properties in naturally aged human skin in vivo.
OBJECTIVE
Retinoic acid has been shown to improve the aged-appearing skin. However, less is known about the anti-ageing effects of retinol (ROL, vitamin A), a precursor of retinoic acid, in aged human skin in vivo. This study aimed to investigate the molecular basis of ROL anti-ageing properties in naturally aged human skin in vivo.


METHODS
Sun-protected buttock skin (76 ± 6 years old, n = 12) was topically treated with 0.4% ROL and its vehicle for 7 days. The effects of topical ROL on skin epidermis and dermis were evaluated by immunohistochemistry, in situ hybridization, Northern analysis, real-time RT-PCR and Western analysis. Collagen fibrils nanoscale structure and surface topology were analysed by atomic force microscopy.


RESULTS
Topical ROL shows remarkable anti-ageing effects through three major types of skin cells: epidermal keratinocytes, dermal endothelial cells and fibroblasts. Topical ROL significantly increased epidermal thickness by stimulating keratinocytes proliferation and upregulation of c-Jun transcription factor. In addition to epidermal changes, topical ROL significantly improved dermal extracellular matrix (ECM) microenvironment; increasing dermal vascularity by stimulating endothelial cells proliferation and ECM production (type I collagen, fibronectin and elastin) by activating dermal fibroblasts. Topical ROL also stimulates TGF-β/CTGF pathway, the major regulator of ECM homeostasis, and thus enriched the deposition of ECM in aged human skin in vivo. 0.4% topical ROL achieved similar results as seen with topical retinoic acid, the biologically active form of ROL, without causing noticeable signs of retinoid side effects.


CONCLUSIONS
0.4% topical ROL shows remarkable anti-ageing effects through improvement of the homeostasis of epidermis and dermis by stimulating the proliferation of keratinocytes and endothelial cells, and activating dermal fibroblasts. These data provide evidence that 0.4% topical ROL is a promising and safe treatment to improve the naturally aged human skin.
Department of Dermatology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, MI, U.S.A.
Y
Y
Shao
Department of Dermatology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, MI, U.S.A.
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He
Department of Dermatology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, MI, U.S.A.
G J
GJ
Fisher
Department of Dermatology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, MI, U.S.A.
J J
JJ
Voorhees
Department of Dermatology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, MI, U.S.A.
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Quan
D000375:Aging / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D006801:Humans; D018625:Microscopy, Atomic Force; D012867:Skin / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014801:Vitamin A / Q000494:pharmacology*
C526317:CCN2 protein, human; D016212:Transforming Growth Factor beta; D014801:Vitamin A; D055513:Connective Tissue Growth Factor; D003094:Collagen
TGF-β; extracellular matrix; retinoid; skin ageing; vascularity