On a macro level, water is not only the most abundant substance in our bodies, like oxygen, it is also essential to sustain life itself. Water regulates body temperature, carries oxygen and nutrients to all cells, helps convert food into energy, protects and cushions vital organs and joints and removes and detoxifies waste.

On a cellular level, the ability to maintain water homeostasis—an appropriate balance between the pressure of the intracellular environment and the extracellular environment—is essential for the cell to function optimally. In vivo analysis of cellular water is commonly done by whole-body water analysis. Total Body Water (TBW) is the sum of Intracellular Water (ICW) and Extracellular Water (ECW). Each of these values—TBW, ICW and ECW—can be calculated using bioelectric impedance analysis. This analysis will also yield a value for the phase angle (mathematically, a function of the arctangent of the ratio of reactance over resistance) which is a diagnostic measure of cellular membrane integrity.

It is well accepted that increased production of free radicals and the accumulation of their metabolic reaction products affect cell membrane integrity and the general homeostatic balance of water in tissues. The generation of reactive oxygen species (ROS), in particular hydroxyl, peroxyl and superoxide anion, can be triggered by a number of factors, including exposure to UV radiation, pollution, acute stress, chronic Cultural Stress®, climatic extremes, hypoxia, inflammation and aging.

Accordingly, The Science of Cellular Water™ looks to create environmental changes at the skin’s surface and throughout the body to promote and preserve the strength of cell membranes as the path to healthy skin and total body health.

Strategic Use of Hydrators to Promote Cellular Membrane Integrity

Cell membranes consist primarily of lipids and proteins. More particularly, the cell membrane consists of three classes of amphipathic lipids: phospholipids, glycolipids and steroids. The cell membrane also contains carbohydrates, primarily in the form of glycoproteins. These components of the cell membrane are highly susceptible to damage by free radicals—more specifically through lipid peroxidation, and protein glycation.

Diets rich in essential fatty acids, lecithin and select micro-nutrients help the body to create durable membranes that are more resistant to damage and have a strong molecular attraction for water. Topical administration of hydrophilic agents, such as Hyaluronic Acid, and hydrophobic agents, such as Linoleic Acid, have been proven to promote and preserve hydration by limiting trans-epidermal water loss. When the stratum corneum, the upper-most layer of the skin, is well hydrated it has the strength and resilience that it needs to provide healthy barrier function. When this layer is poorly hydrated, it becomes brittle, weak and more vulnerable to penetration by environmental assailants, such as pollution and pathogens that damage the integrity of the underlying vital cells.

Strategic Use of Antioxidants to Preserve Cellular Integrity

Free radicals in the body can be the products of ordinary metabolic reactions; generated in response to injury, inflammation or disease or generated in response to an external trigger, such as UV radiation, pollution or climatic extremes. Regardless of the source, free radicals are unstable reactive molecules that produce a cascade of cell damage as they aggressively “steal” electrons in order to gain chemical stability. While a certain level of free radical activity helps the body defend against pathogens and break weak or diseased cells, high levels of free radicals can damage cells that are otherwise healthy.

Because antioxidants sequentially donate electrons and thereby neutralize free radicals, internal and external administration of antioxidants is a proven strategy for reducing damage to cell membranes. Because protection from an excessive free radical load is critical to health for plants as well as animals, botanical extracts provide an almost limitless variety of antioxidant compounds.

Strategic Use of Anti-inflammatories and Stress Mediators to Preserve Cellullar Integrity

The scientific literature is also replete with studies showing the release of reactive oxygen and nitrogen intermediates (respectively, ROI and RNI) after inflammation. This inflammation is known to produce excessive extracellular water. Our strategy for optimizing cell water volume balance involves internal and topical administration of anti-inflammatory agents, including stress mediators. Given the strong correlation between stress and cellular damage, as a direct result of effect of stress-induced hyper-stimulation of the immune system, stress mediation is a critical component of inflammation management. Because stress is both a physical and emotional phenomenon, aroma-therapeutic agents that produce an overall calming effect can be strategically employed. By mediating and reducing the inflammatory processes, we can reduce oxidative stress and preserve intracellular water stores that the body can draw upon to respond to hypohydration (low overall hydration).

Because sleep is essential to preserve and restore skin’s health and healthy appearance, it is crucial to establish and maintain a healthy sleep pattern and to recognize sleep as the most significant window of opportunity for reparative intervention through topical and internal delivery of potent anti-aging ingredients.

Investigating a Combined Strategy for Resolving Common Skin Concerns and Deducing Signs of Aging

Clinical testing of a combined strategy designed to maximize skin health and improve its appearance through external and internal administration of the “recipe” demonstrated significant improvement in the integrity of cell membranes, as measured through phase angle testing. In addition, changes in clinical indications of the following skin conditions demonstrated positive resolution: acne, genetic aging, cellulite, environmental aging, persistent redness, hormonal aging, pseudo-folliculitis and imbalanced oil production.

Promoting and protecting the ability of cells to hold vital intracellular water through a treatment strategy relying on internal and external skincare formulas containing a combination of antioxidants, anti-inflammatories and hydrators can quickly and effectively resolve common skin concerns and reduce the signs of aging.

Murad Skincare is your exclusive source for targeted products and comprehensive regimens that transform
skin’s health and appearance through The Science of Cellular Water™

Because adult skin with acne is less resilient to accelerated aging, optimal health and appearance can only be achieved by addressing acne with a system that strengthens, restores and protects vulnerable epidermal and dermal components of the skin.

Accelerated Skin Aging
Acute and chronic stress lead to hyperstimulation of the nervous and endocrine system. Visible symptoms of skin aging, such as fine lines and wrinkles, are some very prominent clinical manifestations of accumulated stress damage. Prevalence of more serious symptoms of aging in all adults and early onset of skin aging, are both trending upward along a track parallel with increasing levels of Cultural Stress® — i.e. the pervasive, cumulative stress of modern living with over-taxed schedules; conflicting demands and lack of downtime. The primary biological mechanism through which Cultural Stress accelerates the degeneration of the skin is the broad systemic increase in free radical load. The generalized oxidative stress exacerbates the loss of cell and connective tissue integrity caused by glycation and UV damage. In addition, skin aging may be accelerated by over-processing which induces dehydration and impairs the barrier function. This often results in a cycle of inflammation triggered by bacterial incursions through the weakened barrier.

Acne
Skin that has experienced stress induced damage and premature aging, is also vulnerable to the consequences of infection with the P. acnes bacteria. In addition, the same stress-induced glandular hyperstimulation that accelerates skin aging frequently triggers the pilosebaceous acne cycle. Owing to fragile condition of aging skin, some modalities established for treatment of acne in stronger, more resilient skin, may not be appropriate as they may further damage aging skin.

Cumulative Effect of Acne in Aging Skin—Symptoms of Water Loss
Both the adult acne cycle and loss of epidermal and dermal integrity are directly related to intracellular and connective tissue water loss — the ultimate pathway of aging as predicted by The Science of Cellular Water.™ Adverse changes to the skin are apparent as: a range of acne lesions; redness and inflammation; more pronounced fine lines and wrinkles; lack of elasticity, contractility and architectural regularity; dryness and rough texture.

A proprietary, multi-functional treatment strategy for resolving adult acne and reversing aging can reduce acne breakouts while re-establishing collagen, lipid and moisture levels typical of young, smooth skin.

Investigating an Anti-Acne & Anti-Aging Strategy
Because existing therapies—primarily designed to treat acne as a single concern—do not effectively address the presentation of acne in aging skin, research was undertaken with the intent of creating a comprehensive approach to address acne breakouts while diminishing the appearance of fine lines and wrinkles. The therapeutic strategy employed a three-step, twice-daily regimen that delivered a multi-active acne treatment, a compound anti-aging treatment and an advanced barrier protection complex.

• Reduces concentration of P. acnes bacteria in the skin by up to 97% in just one week

• Number of blemishes was reduced
• Appearance of fine lines and wrinkles was reduced
• Suppleness was improved
• Appearance of pores was minimized
• Firmness was improved
• Dryness was improved

By arresting the acne cycle and restoring dermal and epidermal integrity, both cellular and connective tissue water was restored. This restoration was apparent as: a decrease in redness and inflammation; a significant improvement in elasticity, contractility and architectural regularity and a significant mediation of dryness and rough texture.

A patented, proprietary, multi-functional treatment strategy for resolving adult acne and reversing aging reduces acne breakouts while improving all main visual aspects of premature skin aging.

Technology
Murad Anti-Aging Acne system is a comprehensive regimen designed to rapidly resolve adult acne breakouts while reducing signs of aging. Pore congestion is relieved and blemishes are reduced by a multi-active acne fighting system. Kombucha Collagen Defense™ optimizes both the quality and the quantity of collagen to restore smoothness to aging skin. An advanced barrier protection complex, featuring sunscreens certified to meet the rigorous international PA++ standard for strong UVA protection, shields fragile skin from sun damage. The result is healthy, acne-free skin with youthful looking fullness.

Environmental exposure to physical and chemical stressors significantly contributes to
premature skin aging by stimulating the formation of cell damaging molecules. This damage
can be counteracted and prevented by enhancing the ability of cells to defend themselves,
stimulating collagen production and inhibiting unwanted pigmentation.

Assault on skin by environmental factors causes a cascade of destructive chemical changes that lead to
DNA damage, inflammation, cell membrane and connective tissue damage and, ultimately, to cellular
water loss. The Science of Cellular Water™ tells us that loss of cellular water compromises cells’
function and leads to premature aging.

Environmentally induced changes to the skin include:

• Abnormal pigmentation caused by damage to, and irregular activity of, melanocytes
• Fine lines, deep wrinkles and loss of elasticity caused by decreases in fibroblast proliferation
  and collagen synthesis as well as degradation of the skin’s collagen framework
• Dullness, dryness and rough texture induced by damage to the skin barrier
• Elastosis, the breakdown of elastic tissue visible as yellowish nodules
• Damage to DNA that can trigger skin cancers

The skin naturally relies on antioxidants to protect itself from environmental damage. Because Vitamin C—the
most plentiful antioxidant in the body—is depleted as it protects skin, it must be replenished. Topical
application allows targeted application to areas in need of protection.

Vitamin C is necessary for skin health and healthy appearance because it:

• Is essential for the synthesis of new collagen
• Preserves collagen by down-regulating the enzymes responsible for collagen degradation
• Improves epidermal barrier function by stimulating sphingolipid production and preventing water loss
• Inhibits TNF-a (tumor necrosis factor-alpha) and several pro-inflammatory agents

Because chemical instability is inherent to antioxidants, including Ascorbic Acid, only topical Vitamin C
compounds with established stability and efficacy such as Tetrahexyldecyl Ascorbate, Sodium Ascorbyl
Phosphate, and Chitosan and Ascorbic Acid retain the integrity necessary to deliver optimal benefits.

Resilient-C™ Complex may have cytoprotective abilities against environmental aggressors and may support
repair of premature aging caused by environmental exposure.

Resilient-C Complex™ combines three stable and potent forms of Vitamin C that work synergistically to provide
both immediate and long lasting protection against oxidative damage while addressing clinical (visual) aspects of
environmentally skin aging.

Tetrahexyldecyl Ascorbate (THDA; Figure 1) is a long acting lipophilic (oil-soluble) Vitamin C derivative proven in multiple in vitro studies to: Have a cytoprotective, antioxidant effect when exposed to: a) oxidizing agents; b) UVB radiation—DNA damage was suppressed; c) UVA radiation—higher cell survival rate was achieved Decrease synthesis of p53 to 10% indicating that cellular resistance to UVB damage increased up to 90% Significantly increase cell proliferation and collagen production while significantly decreasing skin matrix metalloprotinasses (e.g., MMP-2 and MMP-9) production Inhibit irregular melanin production, reducing melanogenesis by more than 80%, indicating potent anti-pigmentation activity Have a significant, stable, radical-reducing activity for up to 40 hours Sodium Ascorbyl Phosphate (SAP; Figure 2) is a well studied, hydrophilic (water-soluble) Vitamin C derivative that is converted into free Ascorbic Acid by enzymatic degradation in the skin which allows it to: Scavenge and destroy aggressive oxidizing agents (e.g. hydroperoxides and lipoperoxides) Work with lipophilic Tocopheryl Acetate (Vitamin E) to form an excellent antioxidant system Improve skin elasticity by promoting collagen I and collagen III synthesis in fibroblasts Suppress hyperpigmentation of skin and decompose melanin Reduce UVA light induced sebum (squalene) oxidation to suppress inflammation Chitosan Ascorbate (CA; composed of Chitosan and Ascorbic Acid; Figure 3) is a water-soluble, high-molecular-weight polyelectrolyte composed of Ascorbic Acid and Polyglucosamin shown in multiple in vitro tests to: Increase collagen production by 62% (in the culture of human dermal fibroblasts) Provide powerful antioxidant protection (proven by Malondialdehyde Assay, Cytochrome C Reduction Assay and Dichlorofluorescein Reduction Assay) Inhibit collagenase (type I) to suppress collagen degradation

The ability of Resilient-C Complex to optimize skin health is enhanced by successfully combining Resilient-C
Complex with Tocopheryl Acetate and other cell protective actives such as Ectoin and Myrtle Extract.

Ectoin is derived from bacteria that grow in extreme conditions (high UV radiation, high temperature, dryness
and salinity). Recent in vitro studies reported multiple cell protection properties of Ectoin including: a)
preservation of Langerhans’ cells under UV-induced stress and b) accelerating protection of human keratinocytes
in culture exposed to UV-irradiation, heat and other physical and chemical stress determinants by stimulating HSP
(heat-shock-protein) expression while optimizing cell viability. Ectoin also improves skin moisture maintenance
and reduces trans-epidermal water loss.

Myrtle Extract helps protect cells (e.g. fibroblasts) from senescence and degradation by stimulating the
synthesis of a class of proteins (SIRT-1) that can act to boost cell vitality and intercellular communication.

In a clinical context, using Resilient-C Complex in a topical formula with complementary actives improves skin’s
barrier function, moisture, luminosity, elasticity, tone and texture while reducing the number and depth of fine
lines and wrinkles.

Resilient-C Complex is a potent antioxidant complex with cytoprotective capabilities that prevents and treats
premature skin aging caused by harmful environmental factors.

Because sleep is essential to preserve and restore skin's health and healthy appearance, it is crucial to establish and maintain a healthy sleep pattern and to recognize sleep as the most significant window of opportunity for reparative intervention through topical and internal delivery of potent anti-aging ingredients.

Theoretical explanations connecting loss of sleep to disease processes include the theory that the loss of cellular and tissue repair time results in multiple homeostatic imbalances that have a significant adverse impact on all systems. The consequences of sleep induced imbalances on the skin include:

• Elevated secretion of cortisol which can cause: inhibition of protein synthesis (including collagen production in skin); increased water loss and suppression of the immune system
  
  
• Decreased secretion of the human growth hormone (hGH) which has negative impact on cell proliferation and tissue repair
  
  
• Increased disturbances in skin barrier homeostasis, damage to stratum corneum integrity, inhibition of synthesis of epidermal lipids and delayed barrier recovery

The end result of these adverse impacts is intracellular and connective tissue water loss – the ultimate pathway of aging as predicted by The Science of Cellular Water.™ Adverse skin changes are apparent: more pronounced fine lines and wrinkles; lack of elasticity, contractility and architectural regularity; sallow tone, under-eye dark circles and puffiness; dryness and

Repair Enhancing Matrix (REM) was developed to work during sleep to encourage faster and more complete skin repair while providing antioxidant protection to shield cells from further damage. To that end, the agents in the REM formula specifically act to relax skin tension, reduce wrinkle depth, improve collagen synthesis and enhance elasticity.

Both topical and internal versions of Repair Enhancing Matrix (REM) contain 3 potent agents:

In order to investigate the anti-aging potential of REM, topical and internal formulas combining REM with other agents were created. Both formulas included ingredients that encourage the onset of a fundamental resting state conducive to significant cellular renewal. The paired agent was Melatonin, the principle hormone produced by the pineal gland to help regulate the body's sleep-wake cycle, mental alertness and body temperature.

Because natural Melatonin production decreases with age and exposure to high levels of artificial light, insufficient levels of Melatonin often contribute to insomnia and poor sleep quality. Accordingly, Melatonin supplementation as a therapeutic modality for inducing and regularizing sleep is well established. Melatonin was selected as the featured additive in these formulas because of its efficacy as a soporific, its freedom from significant counter-indications and its powerful antioxidant activity.

On a cellular level, the investigation reveals a recovery of optimal intracellular and connective tissue water content. Visually, healthy skin color is reestablished, texture is refined, skin is firmer, more voluminous and the number and depth of fine lines and wrinkles are reduced.

Because sleep is essential to preserve and restore skin's health and healthy appearance, it is crucial to establish and maintain a healthy sleep pattern and to recognize sleep as the most significant window of opportunity for reparative intervention through topical and internal delivery of potent anti-aging ingredients.

The combination of Repair Enhancing Matrix (REM), Melatonin and other multifunctional agents does enhance the nightly skin repair process by producing clinically distinct, anti-aging benefits while optimizing and regularizing sleep.

REM, the night-specific Repair Enhancing Matrix™ makes the most of skin's restorative hours. This patent pending formula adds depth and power to skin's natural sleep repair cycle and dramatically reduces the signs of aging with ingredients that have been shown to improve collagen production. Repair Enhancing Matrix accelerates skin barrier recovery and protects barrier homeostasis while enhancing the penetration of other ingredients. REM infuses skin with powerful anti-inflammatory and photoprotective agents while promoting skin epithelization- the collagen synthesis needed for firmer, stronger, younger-looking skin.

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

Specific hormonal disturbances that become manifest during perimenopause, menopause and postmenopause have a significant and perceptible impact on the aging process. Clinical manifestations of these disturbances in the skin include development of fine lines and wrinkles, dryness, textural irregularities, loss of luminosity and brightness, reduced elasticity and firmness, and an increase in acne breakouts. The negative dermal and epidermal consequences associated with the hormonal aging syndrome can be successfully addressed through application of formulas with multifunctional actives specific to the evolution of hormonal skin aging on both the cellular and macroscopic levels.

Beyond the commonly recognized gross clinical manifestations of the menopause phase of hormonal aging syndrome (such as vasomotor episodes—"hot flashes," night sweats, sleeping disturbances, severe tiredness, stiff joints, body pain, headaches, urogenital symptoms, mood changes and lower self-esteem), hormonal aging has an influence on both skin development and composition that begins subtly but becomes quite profound over time.

Hormone receptors specific to estrogens and other hormones have been detected throughout the skin in keratinocytes, fibroblasts, sebaceous glands, hair follicles, sweat glands and blood vessels. These receptors are sites where hormones are received and bind to cellular structures—a process that stimulates a specific cellular response, for example, production of collagen. Because of the role hormones play in triggering these skin building responses, adequate levels of hormones are required to maintain the skin's structural integrity and functional capacity. In clinical terms, as a result of diminishing levels of estrogen, women experience symptoms of skin aging that become more pronounced as the hormonal aging syndrome moves toward menopause. Hormonal aging is associated with:

• Skin dehydration (dryness and roughness) caused by a decrease in the capacity of the stratum corneum to retain water as well as a reduction in levels of mucopolysaccharides and hyalouronic acid in the dermis and epidermis
• Decreased epidermal cell adhesions, migration and differentiation
• Decrease in size, number and activity of sebaceous glands
• Flattening of the dermal-epidermal junction
• Degradation of collagen, elastic tissue, dermal matrix ( i.e., glycosaminoglycans, proteoglycans) and fibroblasts in the dermis, with consequent loss of elasticity and distensibility, accompanied by a progressive deepening of facial creases and wrinkling
• Manifestations of hyperandrogenism (excessive secretion of male hormones) such as acne breakouts and hirsutism (excessive growth of facial or body hair)
• Poor wound healing
• Overall thinning of the skin, resulting in pronounced transparency and fragility
• Loss of subcutaneous fat, resulting in less resiliency and less cushioning against assault

The histological and clinical changes seen in skin as a result of the hormonally aging syndrome are predicted and explained by The Science of Cellular Water,™ Dr. Howard Murad's hypothesis of aging. Dr. Murad's theory looks at the impact of the hormonal aging syndrome on hydration at the macro and micro level for markers of skin health. In the stratum corneum, hormonal depletion causes skin barrier disruption and an increase in transepidermal water loss (TEWL). In deeper layers of skin, hormonal depletion can be seen as the root cause of cell membrane and connective tissue deterioration. This deterioration increases cellular water loss which can be detected by visual and tactile evaluation as signs of aging.

A unique combination of select phytoestrogens with multifunctional ingredients that possess robust hydrating and nourishing properties may prevent and reverse signs of hormonal skin aging by reestablishing moisture level, lipids and cellular profile typical of young skin.

A unique proprietary blend of phytoestrogens with multifunctional ingredients, which possess robust hydrating and nourishing properties, induces clinically significant improvements in all main visual aspects of hormonally aging skin.

Skin aging is a continuous, multifaceted process. Intrinsic, or genetic, aging normally begins in our mid-20s. Deoxyribonucleic acid, DNA, controls how quickly the naturally occurring functional decline in aging skin unfolds. Extrinsic, or environmental, aging commences with the skin's first exposure to its main causes such as UV rays, pollution, trauma and unhealthy lifestyle, including poor nutrition, cigarette smoke, alcohol consumption and stress, among others. Visual consequences of skin aging appear gradually but incessantly. Skin becomes thin, transparent, loose, dry and rough. Over a lifetime, fine lines and wrinkles, irregular pigmentation, uneven complexion, redness and telangiectasia develop. Multifunctional ingredients, like Durian Cell Reform, are necessary for intensive topical prevention and reversal of visible skin aging.

The unique polysaccharide, lipid and sulfur-rich fractions of Durian combine to create optimized cell water homeostasis following natural cell turnover initiated by alpha hydroxy acids.

Skin aging is a consequence of many simultaneous and unrelenting events.

In the epidermis, corneocytes do not desquamate as frequently and the skin barrier function is easily compromised. At the same time, cell proliferation decreases, senescence keratinocytes accumulate mutations (cell damage) and start to significantly vary in size and shape. The epidermis becomes thinner and the dermal-epidermal junction flattens, hindering the communication and nutrient transfer between the layers.

In the dermis, atrophy, or loss of dermal thickness, and gradual destruction of the dermal fibers' network progress due to a decline in the number of fibroblasts, collagen and elastin synthesis slows and fibers appear more disorganized. Biochemical changes in collagen and elastin, including a decrease in the ground substance, consisting of glycosaminoglycans, proteoglycans and mucopolysaccharides, lead to increased skin rigidity. Reduction in the vascular network affects supply of water and nutrients to the skin.

Overall, repetitive oxidative stress, caused by free radical activity, weakens antioxidant defense systems and DNA repair capacities in the skin with consequent accumulation of damaged cellular lipids and proteins and lack of healthy skin constituents. Increased levels of pro-inflammatory cytokines caused by oxidative stress contribute to cell membrane and connective tissue damage. The end result a rapid decline of water content within skin cells and connective tissue as proven by The Cellular Water Principle®.

The Durian plant contains an abundance of flavonoid antioxidants as well as numerous compounds containing a chemical element that is essential to cell membrane health—Sulfur. Sulfur donors are critical to protect the cell membrane and provide vital nutrients used by the body to produce free radical fighting antioxidants. Over 100 sulfur-containing ingredients have been identified in Durian. These components act with minerals (Copper, Manganese and Potassium) and vitamins (Vitamin C, Niacin and Vitamin B-6) found in the Durian plant to bolster cell membrane integrity, provide protection from free radicals and other environmental stressors and aid in maintaining cellular water balance.

Analytical studies done by leading plant lipid, polysaccharide and antioxidant chemists supplemented by over twenty years of clinical research by Dr. Murad with hydroxy acids are combined in Durian Cell Reform to optimize cellular water homeostasis. Durian Cell Reform contains the same key components that provide the Durian fruit, and now our cells, with the immense health benefits of homeostatic cellular water balance.

Durian Cell Reform™ is a proprietary blend of Durian Extract and Glycolic Acid that forms synergistic cell turnover and active ingredient delivery system. The Durian seed contains numerous fatty acids notably, palmitic, oleic and linoleic acids, as well as other valuable fruit acids, including malic acid. Durian Cell Reform enhances the activity of these ingredients by adding clinically proven amounts of Glycolic Acid. This combination increases the rate of natural cell turnover while exposing new cells for enhanced penetration of Age Reform Intensives active ingredients; UGL Complex, Glucosamine, Hyaluronic Microspheres, Dried Plum Extract and Vitamin C, as well as the intensive hydro-protection of Durian's active ingredients, trehalose and polygalacturonic acid.

Provide your cells with the foundation for a lifetime of healthy, beautiful skin.

Skin health is preserved by optimal biological responses to a variety of antagonists. Synergistc action of repair mechanisms (e.g. keratinocytes or fibroblast proliferation, collagen production, restitution of dermal matrix, etc.) and immune defense system is necessary for optimal biological response. Skin aging is characterized by a decline in the ability to respond to and defend against UV rays, pollution, poor nutrition, cigarette smoking, alcohol consumption, stress, and other degrading factors.

During the aging process, immune function declines dramatically, adversely affecting the skin's ability to repair and defend itself. Advances in biotechnology have led to the discovery of peptides (bio-peptides, analogues of natural peptides) formulated to enhance intercellular communication, optimize skin immunity and stimulate the growth factors that regulate skin cell proliferation and dermal matrix remodeling.

Immuno-Skin Complex™ may assist in modulating the signs of advanced skin aging by stimulating skin immunity and up-regulating proliferative growth factors and cell proliferation.

The human immune system is not a single system, but instead a complex constellation of responses to attacks from outside the body. It has many facets, a number of which constantly adapt to optimize the biological defenses necessary to prevent infection, disease and other unwanted invasions. The skin is a critical outpost of the immune system because it provides control of local immune processes and influences systemic immunity. Both Langerhans cells and keratinocytes within the skin are able to trigger a bodywide immunologic response.

The skin is affected by a variety of negative factors that can weaken its immune system and may ultimately adversely affect systemic immunity. These factors include pathogens, toxic substances, trauma, UV exposure, poor nutrition, prolonged stress and many other aspects of an unhealthy lifestyle, all of which damage healthy skin, increasing the incidences of skin disorders and age-related changes.

The skin's epidermis is primarily composed of keratinocytes and specialized immune cells called Langerhans cells. Both the Langerhans cells (antigen-presenting cells) and the keratinocytes are involved in the immunological processes. The Langerhans cells are the primary immunological cells within the epidermis and are counterparts to the macrophages located in the dermis, providing dermal immunological function. The Langerhans cells play a vital role in sustaining skin integrity by recognizing aggressors and providing defensive and regulating functions.

Keratinocytes are also immunocompetent skin cells and play an irreplaceable role in modulating skin immune responses. Keratinocytes have been shown to promote T-cell lines (white blood cells) and subsequently enhance antibody production. Keratinocytes provide this important immune response through cellular signals produced by cytokines. Cytokines are a group of proteins and peptides that mediate intercellular communication. These signaling chemicals include interleukins, monokines, interferons, EGF (epidermal growth factor), FGF (fibroblast growth factor), TGFa (transforming growth factor alpha) and numerous others.

When skin is assaulted, immunocompetent skin cells are triggered to defend and repair skin damage. The skin is flooded with a complex of cytokines and growth factors, which function as Messenger molecules to stimulate cellular proliferation and restore normal skin function.

However, as we age and expose our skin to adverse external factors, our immune system's ability to create messenger molecules that send a distress signal in response to ongoing assaults and challenges declines. Therefore, topically applied immunostimulating compounds such as bio-peptides and other bioactive ingredients can provide a new therapeutic defense for immunocompromised skin against age-related changes.

The objective of the investigative studies was to evaluate the immunostimulating and dermal matrix enhancing properties of the proprietary Immuno-Skin Complex™ comprised of highly active bio-peptide sequences
Leu-Gln-Gly-Glu-Glu-Ser-Asn-Asp-Arg or L-Glu-Hist to:
(1) Help strengthen the skin's immune modulating properties against external and internal factors and
(2) Upregulate the production of specialized growth factors essential to cellular proliferation and tissue remodeling.

Keratinocytes were cultivated in vitro for several days and baseline measurements of EGF (epidermal growth factor) and KGF (keratinocyte growth factor) were evaluated. The commercial ELISA (enzyme-linked immunosorbent assay) test systems were used to measure the quantity of growth factors and interleukins. The PCR (polymerase chain reaction) was used to measure gene expression. The number of mRNA copies started to increase within 10-15 minutes after the introduction of the bio-peptide sequence Leu-Gln-Gly-Glu-Glu-Ser-Asn-Asp-Arg in cell culture. Keratinocyte cultures exposed to the bio-peptide increased the expression of keratinocyte growth factor (KGF) and epidermal growth factor (EGF).

Immunostimulant activity of bio-peptide sequence L-Glu-Hist was tested in vitro on murine splenocytes and human lymphocytes population. The cell proliferation was followed by measuring indicators of DNA synthesis. For both types of tested cells, L-Glu-Hist significantly amplified DNA synthesis and cell proliferation. Cytostimulating properties of the L-Glu-Hist were tested on human fibroblast cultures. Results confirmed significant stimulating abilities of L-Glu-Hist on artificially aged fibroblasts.

Immuno-Skin Complex™ induced the synthesis of specialized growth factors and cytokines in vitro, which demonstrates its potential to enhance skin immunity, facilitate cellular proliferation and subsequent tissue rejuvenation.

Dr. Howard Murad, the world renowned dermatologist who revolutionized the world of professional esthetics with Alpha-Hydroxy Acids introduces a new, groundbreaking way to fight skin aging — Immuno-Skin Complex.™

Immuno-Skin Complex™ is comprised of immune modulators that help boost the skin's defenses to fight the signs of future skin aging and next generation peptides to repair existing damage. Immuno-Skin Complex™ helps stimulate the skin's own immune response system to defend against the contributing factors of skin aging.

This latest innovation from Dr. Murad, found exclusively in Murad® Professional products, is an outgrowth of his continuing research into the way in which cellular water loss and the resulting connective tissue degradation are responsible for the skin damage we attribute to aging. This research into The Cellular Water Principle® is the foundation for every product developed by Murad.

Wrinkles are just one of several signs of skin aging that affect individuals over their lifetime. Fortunately, the visible signs of skin aging can be prevented and in many cases reversed.

Skin aging is a complex subject with numerous theories proposed to explain its dynamics and mechanism. The two most widely accepted causes of skin aging are internal factors and external factors, herein referred to as genetic skin aging and environmental skin aging.

Genetic skin aging is determined by our predisposition and is characterized by changes within the skin occurring over time. Environmental skin aging is caused by sun exposure, cigarette smoking, alcohol consumption, poor nutrition, stress, pollution and gravity. Although distinct in definition, our skin is generally affected by both genetic and environmental factors.

In aging skin, the most profound changes occur within the structure of the dermis, evidenced by collagen and elastin degradation, decreased production of naturally occurring carbohydrates (glycosaminoglycans and polysaccharides) and cellular water loss.

The loss of structural collagen and elastin proteins causes skin to lose its firm, wrinkle-free appearance and ability to snap back into place. The naturally occurring carbohydrates which contribute to skin density, volume and essential hydration also diminish with the aging process. What's more, dead surface skin cells do not desquamate as frequently leading to cellular retention.

Conclusively, wrinkles are one of the several clinical signs of genetic and environmental skin aging. Other age-related signs include dyschromias (age spots), epidermal thinning, loss of elasticity and barrier dysfunction.

Replicating the constituents of healthy skin may assist in the reversal of age-related changes associated with genetic and environmental skin aging.

The data concludes Murad Intensive Wrinkle Reducer significantly reduced the appearance of fine lines and wrinkles, improved skin tone, hydration and texture over an eight-week period.

Clinical Assessment of Intensive Wrinkle Reducer:

• Skin firmness increased up to 40% within ten minutes
• Skin tone improved up to 25% after eight weeks
• Skin hydration increased up to 37% after eight weeks
• Fine lines and wrinkles decreased up to 45% after eight weeks

* Data on file. Individual results may vary. Eleven subjects participated and all completed the study. No subject dropped out due to adverse reactions to the product.

Photographic Assessment of Intensive Wrinkle Reducer

GlycoNutrient Complex is a water-soluble, bioengineered aggregate of Glycosaminoglycans, Glucosamine, marine-derived Polysaccharides, Linoleic Acid and Glycolic Acid, which have been shown to activate epidermal cells resulting in increased cellular turnover and proliferation. Clinical studies demonstrate the complex provides epidermal resurfacing without irritation while significantly increasing skin firmness. Intensive Wrinkle Reducer also includes a Lipo-Amino Acid containing Cinnamon Extract to improve skin imperfections revealing clearer, more radiant skin. In addition, this exclusive formula contains antioxidants, water-binding humectants, lipids and skin protectants that improve barrier function and protection against future skin damage.

Intensive Wrinkle Reducer® is a daily skin regenerating treatment scientifically proven to dramatically diminish the visible signs of skin aging.

A breakthrough in anti-aging technology, Intensive Wrinkle Reducer contains the GlycoNutrient Complex. This revolutionary complex has been clinically proven to regenerate the skin's appearance, thereby providing skin resurfacing without irritation while increasing skin firmness. This targeted, fast acting formula begins to work in just 10 minutes with more dramatic results with continuous use.

The breakthrough technology of Intensive Wrinkle Reducer delivers a potent synergy of age defying ingredients providing both immediate and long-term results. Daily use will dramatically diminish the appearance of fine lines and wrinkles and reveal firmer, smoother and more even-toned skin.