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Abstracts

Life Extension Magazine April 2014
Abstracts

Skin Peptides

Immediate and Long-term Clinical Benefits of a Topical Treatment for Facial Lines and Wrinkles.

Objective: To evaluate the efficacy and tolerance of a novel line treatment for periocular and perioral wrinkles. The line treatment was formulated with multiple growth factors, antioxidants, and a collagen-building peptide-ingredients that have been shown to increase collagen levels and provide long-term aesthetic benefits. To help provide immediate smoothing effects, hyaluronic acid filling spheres and a muscle contraction-inhibiting peptide were also included in the formulation. Design: Three-month, single-center, open-label, clinical study with clinical assessments at Baseline, Minutes (within 15 minutes of initial application), Month 1, and Month 3. Treatment: Subjects treated periocular and perioral wrinkles twice daily for three months with the line treatment. Participants: Thirty-seven females, 33 to 45 years of age, with mild-to-moderate, fine and coarse periocular and perioral wrinkles, were enrolled in the study. Measurements: Investigator assessments of fine and coarse periocular and perioral wrinkles, digital photography, and tolerance assessments were conducted at all visits. Subject self-assessment questionnaires were conducted within 15 minutes of initial
application and at Month 3. Results: Investigator assessments of both periocular and perioral wrinkles showed statistically significant improvements over Baseline within minutes of initial application; these positive findings continued to improve through Months 1 and 3 (all P</=0.0003). No treatment-related adverse events were reported. Conclusions: The results from this study demonstrate that this uniquely formulated line treatment was well tolerated and provided both immediate and long-term improvements in the appearance of fine and coarse wrinkles.

J Clin Aesthet Dermatol. 2009 Mar;2(3):38-43

DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein.

The signaling pathway from phosphoinositide 3-kinase to the protein kinase Akt controls organismal life-span in invertebrates and cell survival and proliferation in mammals by inhibiting the activity of members of the FOXO family of transcription factors. We show that mammalian FOXO3a also functions at the G2 to M checkpoint in the cell cycle and triggers the repair of damaged DNA. By gene array analysis, FOXO3a was found to modulate the expression of several genes that regulate the cellular response to stress at the G2-M checkpoint. The growth arrest and DNA damage response gene Gadd45a appeared to be a direct target of FOXO3a that mediates part of FOXO3a’s effects on DNA repair. These findings indicate that in mammals FOXO3a regulates the resistance of cells to stress by inducing DNA repair and thereby may also affect organismal life span.

Science. 2002 Apr 19;296(5567):530-4

Down-regulation of a forkhead transcription factor, FOXO3a, accelerates cellular senescence in human dermal fibroblasts.

The signaling pathway of insulin/insulin-like growth factor/phosphatidylinositol-3 kinase/Akt/forkhead transcription factors is known to control life span and senescence in organisms ranging from yeast to mice. The FOXO family of forkhead transcription factors, FOXO1, FOXO3a, and FOXO4, play a critical role in this signal transduction pathway. However, the impact of FOXO3a activation on life span of primary cultured human dermal fibroblasts (HDFs) is unknown. To investigate the role of FOXO3a in the regulation of cellular senescence, we prepared FOXO3a-siRNA stable HDFs. We found that the down-regulation of FOXO3a RNA and protein in HDFs induced many senescent phenotypes, including changes in cell morphology, increases in population doubling times, senescence-associated beta-galactosidase staining and the cellular reactive oxygen species, and up-regulation of p53/p21 protein expression. Our data provide evidence of the key role of FOXO3a transcription factor as a mediator of cellular senescence in HDFs, and suggest that the mechanism of senescence is conserved in HDFs.

J Gerontol A Biol Sci Med Sci. 2005 Jan;60(1):4-9

UV-induced DNA damage initiates release of MMP-1 in human skin.

Destruction of collagen is a hallmark of photoaging. The major enzyme responsible for collagen 1 digestion, matrix metalloproteinase-1 (MMP-1), is induced by exposure to sunlight. To study the molecular trigger for this induction, human skin was ultraviolet-B (UVB)-irradiated and treated with liposome-encapsulated DNA repair enzymes. The photolyase-mediated DNA repair of epidermal UV damage was associated with a reduction of MMP-1 mRNA and protein expression in both the epidermal and dermal compartments of the skin. The role of the epidermal cells in MMP-1 induction in the fibroblasts was examined when human epidermal keratinocytes were irradiated with UVB and their media were transferred to unirradiated human dermal fibroblasts. Transfer of media from irradiated keratinocytes to unirradiated fibroblasts enhanced MMP-1 mRNA and protein. Thus, UV damage to keratinocytes of the epidermis may participate in the destruction of collagen in the dermis by release of soluble mediators that signal fibroblasts to release MMP-1. The MMP-1 induction was reduced when the keratinocytes were treated with DNA repair enzymes T4 endonuclease V or UV endonuclease prior to transfer of the media to fibroblasts. This implies that UVB, which deposits most of its energy on the chromatin of the epidermal keratinocytes and to a lesser extent in the upper dermis, has a significant role in photoaging. DNA damage in the keratinocytes initiates one of the signals for MMP-1 release, and enhancing DNA repair can reduce MMP-1 expression in human skin cells and tissue.

Exp Dermatol. 2008 Dec;17(12):1037-44

Matrix-degrading metalloproteinases in photoaging.

UV radiation from the sun impacts skin health adversely through complex, multiple molecular pathways. Premature skin aging (photoaging) is among the most widely appreciated harmful effects of chronic exposure to solar UV radiation. Extensive damage to the dermal connective tissue is a hallmark of photoaged skin. Disruption of the normal architecture of skin connective tissue impairs skin function and causes it to look aged. UV irradiation induces expression of certain members of the matrix metalloproteinase (MMP) family, which degrade collagen and other extracellular matrix proteins that comprise the dermal connective tissue. Although the critical role of MMPs in photoaging is undeniable, important questions remain. This article summarizes our current understanding of the role of MMPs in the photoaging process and presents new data that (1) describe the expression and regulation by UV irradiation of all members of the MMP family in human skin in vivo and (2) quantify the relative contributions of epidermis and dermis to the expression of UV irradiation-induced MMPs in human skin in vivo.

J Investig Dermatol Symp Proc. 2009 Aug;14(1):20-4

Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation.

Reduced synthesis of collagen types I and III is characteristic of chronologically aged skin. The present report provides evidence that both cellular fibroblast aging and defective mechanical stimulation in the aged tissue contribute to reduced collagen synthesis. The reduction in collagen synthesis due to fibroblast aging was demonstrated by a lower in vitro production of type I procollagen by dermal fibroblasts isolated from skin of young (18 to 29 years) versus old (80+ years) individuals (82 +/- 16 versus 56 +/- 8 ng/ml; P < 0.05). A reduction in mechanical stimulation in chronologically aged skin was inferred from morphological, ultrastructural, and fluorescence microscopic studies. These studies, comparing dermal sections from young and old individuals, demonstrated a greater percentage of the cell surface attached to collagen fibers (78 +/- 6 versus 58 +/- 8%; P < 0.01) and more extensive cell spreading (1.0 +/- 0.3 vs. 0.5 +/- 0.3; P < 0.05) in young skin compared with old skin. These features are consistent with a lower level of mechanical stimulation on the cells in old versus young skin. Based on the findings presented here, we conclude that reduced collagen synthesis in chronologically aged skin reflects at least two different underlying mechanisms: cellular fibroblast aging and a lower level of mechanical stimulation.

Am J Pathol. 2006 Jun;168(6):1861-8

LOXL as a target to increase the elastin content in adult skin: a dill extract induces the LOXL gene expression.

The lysyl oxidases lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) are responsible for elastin cross-linking. It was shown recently that LOXL is essential for the elastic fibres homeostasis and for their maintenance at adult age. We first determined whether or not elastin, LOX and LOXL are less expressed during adulthood. The LOX and LOXL mRNA level, quantified by real-time reverse transcriptase-polymerase chain reaction decreased in adult skin fibroblasts compared with fibroblasts from children. In contrast, the elastin mRNA level remains stable at all ages. The goal of this study was to induce elastogenesis at the adult age. Therefore, both enzymes, and in particular LOXL, of which expression is the most affected by age, could be targeted to induce elastogenesis in adult skin. We screened a library of about 1000 active ingredients to find activators capable to stimulate specifically the LOXL gene expression in adult dermal fibroblasts. The positive effect of selected active ingredients was confirmed on fibroblasts grown on monolayers and on dermal and skin equivalent cultures. One extract, obtained from dill (LYS’LASTINE V, Engelhard, Lyon, France), stimulates the LOXL gene expression in dermal equivalents (+64% increase in the LOXL mRNA level when compared with control). At the same time, the elastin detection is increased in dermal equivalents and under the dermal-epidermal junction of skin equivalents, without increase of the elastin mRNA. In conclusion, LOXL can be considered as a new target to reinduce elastogenesis. Its stimulation by a dill extract is correlated with increased elastin detection, suggesting an increase in elastogenesis efficiency.

Exp Dermatol. 2006 Aug;15(8):574-81

Elastic fiber and microvascular abnormalities in aging skin.

In summary, the aging process in skin has at least two major manifestations: elastic fiber abnormalities involving degradation and assembly, and microvascular wall alterations of widening and atrophy depending upon the functional state of the veil cell. The abnormalities of the elastic fiber network most likely correlate with the increasing cutaneous laxity associated with aging. The microvascular abnormalities are not easily related to any specific clinical feature of aging skin. The finding of identical abnormalities in the skin of juvenile diabetics strengthens this hypothesis, as well as suggesting that these alterations are accelerated in diabetic patients. Diabetic skin might be another model system for studying cutaneous aging.

Dermatol Clin. 1986 Jul;4(3):391-405

A novel anti-ageing mechanism for retinol: induction of dermal elastin synthesis and elastin fibre formation.

Dermal elastic fibres are extracellular matrix protein complexes produced by fibroblasts and involved in skin elasticity. Elastin fibres decrease with age as a result of reduced synthesis and increased degradation, resulting in skin sagging and reduced skin elasticity. In this study, we show that retinol (ROL), known to enhance dermal collagen production, is also enhancing elastin fibre formation. ROL induced elastin gene expression and elastin fibre formation in cultured human dermal fibroblasts. Topical treatment of cultured human skin explants with a low dose (0.04%) of ROL increased mRNA and protein levels of tropoelastin and of fibrillin-1, an elastin accessory protein, as documented by QPCR and immunohistochemistry staining. Luna staining confirmed the increased elastin fibre network in the ROL-treated skin explants, as compared with untreated controls. These data demonstrate that ROL exerts its anti-ageing benefits not only via enhanced epidermal proliferation and increased collagen production, but also through an increase in elastin production and assembly.

Int J Cosmet Sci. 2011 Feb;33(1):62-9

Fibulin-2 and fibulin-5 cooperatively function to form the internal elastic lamina and protect from vascular injury.

OBJECTIVE: Recent findings on the role of fibulin-5 (Fbln5) have provided substantial progress in understanding the molecular mechanism of elastic fiber assembly in vitro. However, little is known about differential roles of fibulins in the elastogenesis of blood vessels. Here, we generated double knockout mice for Fbln5 and Fbln2 (termed DKO) and examined the role of fibulins-2 and -5 in development and injury response of the blood vessel wall. METHODS AND RESULTS: Fibulin-2 is distinctly located in the subendothelial matrix, whereas fibulin-5 is observed throughout the vessel wall. All of the elastic laminae, including the internal elastic lamina (IEL), were severely disorganized in DKO mice, which was not observed in single knockout mice for Fbln2 or Fbln5. Furthermore, DKO vessels displayed upregulation of vascular adhesion molecules, tissue factor expression, and thrombus formation with marked dilation and thinning of the vessel wall after carotid artery ligation-injury. CONCLUSIONS: Fibulin-2 and fibulin-5 cooperatively function to form the IEL during postnatal development by directing the assembly of elastic fibers, and are responsible for maintenance of the adult vessel wall after injury. The DKO mouse will serve as a unique animal model to test the effect of vessel integrity during various pathological insults.

Arterioscler Thromb Vasc Biol. 2010 Jan;30(1):68-74