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Remodeling - The Key to Skin Beauty |
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Why Do Children have Such Beautiful Skin?
Children have the most beautiful skin. Soft, firm, elastic, and blemish-free. When children's skin is damaged, scars are usually removed with a week or two.
The reason children's skin remains so healthy is a process call "skin remodeling". It is the same process that that removes scars and damaged skin during wound repair. Damaged skin is removed and slowly replaced with normal, blemish free skin. In young children this process functions efficiently and skin damage is rapidly removed. But in adults this process slows drastically and various skin lesions may persist for years or decades.
Skin remodeling causes changes such as smoothing the skin, reducing wrinkles, the repair of sun damage, the removal of skin blemishes and imperfections, all of which give the skin a more youthful appearance.
Why Our Skin Seems to Get Older and Have More Problems as We Pass Age 45
For many years when I started my research on human aging, I collected blood samples from people between age 18 and 80. I measured changes in many factors important in blood clotting, since unexpected blood clots become much more common as we get older. I also used the blood samples to measure how well the blood supported the metabolism and survival of cells in culture. Younger blood usually worked better than blood from older individuals but this difference became more noticeable after age 45. Ultimately, this work led to the discovery of skin remodeling copper peptides. Much of the skin's loss of renewal with time appears to be due to a lower level on the copper-peptide GHK-copper in the blood.
So what we need is much more help after age 45.
As we get older, our skin becomes thinner and accumulates various blemishes, lesions and imperfections. The structural proteins are progressively damaged causing collagen and elastin to lose their resiliency. The skin’s water-holding proteins and sugars diminish, the dermis and epidermis thin, the capillary network becomes disorganized, and the subcutaneous fat cells diminish in number. These effects are further intensified by decades of exposure to ultraviolet rays, irritants, allergens, and various environmental toxins. The result is a dry, wrinkled, inelastic skin populated by unsightly lesions.
The good news is that, even though the levels of skin remodeling copper peptides decrease in the body, we can apply certain types of copper-peptides to the surface of the skin and help the skin become more like a biologically younger skin. GHK-copper was the first such copper peptide that I found and works fairly well. But in my opinion, the newer types of copper peptides that I have been developing at Skin Biology should, in time, prove to be a more effective system for helping skin act younger.
Remodeling copper peptides
are the only signal that fills all the requirements for skin remodeling.
| Requirement | Actions |
| 1. Must stop inflammatory actions in the skin | 1.1 Increase the activity
of the copper-protein antioxidant systems such as superoxide dismutase
and ceruloplasmin.
Copper-proteins are the primary antioxidants in the human body. 1.2 Suppress scar forming actions of TGF-beta. 1.3 Block skin damaging action of Interleukin 1 |
| 2. Activate removal of damaged skin | 2.1 Increase activity of metalloproteinases that remove damaged cells and proteins. |
| 3. Increase production of skin proteins | 3.1 Increase synthesis of collagen, elastin, proteoglycans |
| 4. Rebuild the skin's microcirculation | 4.1 Increase new capillary formation (angiogenesis) |
| 5. Increase production of new skin cells | 5.1 Increase the size of vellus-producing hair follicles. These produce new skin cells. |
Remodeling - Skin Removal and Replacement
Restoration to a biologically younger skin morphology requires two linked processes: (1) the removal of damaged proteins and aberrant skin lesions, and (2) their replacement with normal, blemish free skin. This process is similar to the remodeling phase of wound healing in which scar tissue is removed over several years to slowly restore the skin to its original state.
Various skin renewal methods have been developed that produce a limited type of skin restoration but all have drawbacks. Retinoic acid slowly remodels skin but at the price of chronic irritation and redness.
Chemicals such as vitamin C and melatonin increase skin collagen but skin also needs rebuilding of elastin, water-holding proteoglycans, and the blood microcirculation. Peptides (amino peptides, etc.) that are similar in action to TGF-beta 1 and fibronectin binding peptides, are the newest gimmick in the cosmetic industry (see Expensive Skin Creams). But such peptides were tested extensively for uses in wound healing but produced unacceptable skin thickening, hardening, and scarring. It is not enough to push more protein into the skin; the damaged skin components must be removed.
Controlled skin damage (i.e., lasers, peels, dermabrasion) works well only if there is a vigorous post therapy regenerative response by the damaged skin.
The good news today is
that certain types of copper peptides possess all the necessary biochemical
actions that can, in a morphological sense, restore skin to a younger state
without causing skin irritation. Such types of copper peptides are increasingly
used in cosmetic skin care products such as Neutrogena Active Copper line
and Skin Biology's second generation copper peptides. These copper peptides
also are used to improve post-treatment skin recovery after dermatological
skin renewal procedures, such as chemical peels, laser resurfacing, and
dermabrasion. Unlike many other purported skin improvement therapies where
the "science" of the products is just not credible, the skin remodeling
actions of such types of copper peptides are documented by numerous well-controlled,
published studies from leading laboratories and universities.
The Key to Youthful Skin is Skin Remodeling
Vigorous skin renewal and skin remodeling is the key to maintaining a youthful skin. Children have wonderful skin with a high natural self regeneration and a beautiful color and texture. When a child's skin is damaged, the wounds heal rapidly and scars and skin lesions are quickly removed.
Reducing damage to your skin is not an adequate approach. You can hide from sunlight until you evolve into a mole but this will not keep your skin young and vibrant. Yes, avoiding UV light will reduce some types of skin damage as you age, but you will still end up with a pasty, grayish, lifeless, pale skin. Avoiding skin damage from ultraviolet light, allergens, detergents, damaging soaps, irritants, acne scars, airborne pollutants, chemical sunscreens and so forth but is only one part of a wider story.
As we age, a number of skin changes occur which require different types of skin care and treatments. These are four basic changes as we age.
Change 1. The rate of skin cell replacement is reduced, producing a thinner, more fragile skin. Skin is replaced every three weeks at age 20 but this increases to every nine weeks by age 50.
Change 2. Damaged protein accumulates in the skin. This damage can be the results of scars, sun damage, oxidative damage, and the cross-linking of skin proteins by sugars.
Change 3. After age 25, skin oil production starts to drop. This reduces acne but produces a dryer skin. This drop in oil production becomes more serious after age 45.
Change 4. The biosynthesis and breakdown of collagen, elastin, and the water-holding proteoglycans and GAGs exists in a dynamic balance in young healthy skin. However after age 25, the skin's production of collagen, elastin, the water-holding molecules is reduced while the breakdown of these factors is increased. This begins wrinkle formation and loss of elasticity. The problem become progressively more serious with passing years.
To understand skin renewal and remodeling, it is necessary to understand skin repair. The sequence of events producing skin renewal is very similar to the mechanisms involved in wound healing. The human body uses the same biochemical systems in many different ways.
1. Initially after skin damage or wounding, the body's damage control mechanisms serve to stop blood loss (if any), then to quickly cover the damaged skin with a layer of tough and protective scar tissue. A type of immune cell, called the neutrophil, quickly arrives in the damaged area. The neutrophils sterilize the damaged area by releasing very toxic oxygen radicals to kill bacteria. This neutrophil action is usually very brief and usually stops within a day. However, occasionally the damage is of a type that continues these neutrophil actions and the skin becomes chronically inflamed.
Also, a scar forming hormone called TGF-beta (transforming growth factor beta) is produced to stimulate scar production. Large amounts of scar-forming collagen are secreted into the damaged area. Many cosmetic companies have recently began selling skin creams with peptides said to have actions similar to TGF-beta. Such peptides were extensively tested for wound healing about 10 years ago but produced excessive skin hardening and scarring. See Are Very Expensive Skin Creams Worth the Price?
2. The tissue damage also causes the release of enzymes which, in turn, break down skin proteins into smaller fragments. Copper ions begin to accumulate within a few days and are complexed with peptides in the damaged area. If copper is deficient, then healing will be inadequate. No other metal ions are concentrated. The copper-peptides serve as chemical signals to the immune system that the skin is injured and needs repair.
3. The copper peptides then initiate the phase of healing called skin remodeling. In this phase, the scar tissue is removed and replaced with normal skin tissue.
4. As copper peptides accumulate, they act directly to protect the tissues by (1) stopping the production of, and sterilizing effects of, oxygen radicals and (2) suppressing scar formation by inhibiting the production of TGF-beta.
5. The copper peptides also attract a type of immune cell called a macrophage which arrives after the neutrophils have sterilized the tissue. The macrophage begins to ingest the skin debris produced by the damage and also secrete about 20 different growth factors needed for proper skin repair. These have names such as epidermal growth factor, fibroblast growth factor, platelet-derived growth factor and so on. Regranex Gel sold by McNeil Pharmaceutical and used for wound healing contains a macrophage-released growth factor, called platelet-derived growth factor. The macrophage action also helps remove chronically-damaged, abnormal skin such as spots and lesions from sun damage.
6. The copper peptides also stimulate the production of the scar removal systems by changing the synthesis of metalloproteinases (a family of at least 14 proteins that remove damaged proteins such as damaged collagen and elastin) and antiproteases. At the same time, the copper peptides stimulate the production of new proteins such as collagen and elastin to give the skin strength and elasticity, and other proteins and molecules such as proteoglycans and glycosaminoglycans (GAGs) that bind large amounts of water to moisturize the skin. The only true skin moisturization is via these water-holding molecules. The copper peptides also stimulate angiogenesis (new capillary formation) to reestablish new blood vessels to nourish and oxygenate the newly repaired skin.
7. Skin remodeling continues for a long period. The wounded area slowly improves as scar tissue is removed or reduced. Incomplete healing causes heavy scarring but complete healing produces minimal scarring. The old damaged protein is removed and replaced with new collagen and elastin fibers. This removes scar tissue and restores skin elasticity. This mechanism can also be used to reduce wrinkles.
8. Skin renewal and hair follicles are closely linked. New skin is now
thought to arise from the hair follicles. All skin remodeling chemicals
or genes that activate skin remodeling also increase hair follicle size.
But although skin remodeling improves hair follicle health, it does not
create new follicles or grow hair in hairless areas.
| Product or Method | Causes skin remodeling | Present in wounds and human blood | Anti-inflammatory | Increases hair follicle size | Reduces TGF-beta and scar production |
| Retinoic acid (Retin-A) | Yes | Not significant | No, causes redness and irritation | Yes | No, increases TGF-beta production |
| First Generation
Skin Remodeling Copper Peptides - GHK-Copper (Procyte, Neutrogena, Simple Solution Products) |
Yes,
1. Rebuilds skin protective barrier 2. Increases collagen and elastin - more than vitamin C 3. Increases water-holding proteoglycans 4. Rebuilds blood microcirculation 5. Activates removal of damaged skin proteins and scars 6. Activates skin's main antioxidant protein - dismutase superoxide |
Yes, this is the human body's natural remodeling signal | Yes, potent anti-inflammatory,
Activates skin's main antioxidant protein - dismutase superoxide Blocks actions of of Interleukin-1, a skin damaging cytokine |
Yes | Yes, reduces TGF-beta |
| Second Generation -
Skin Remodeling Copper Peptides (Skin Biology products, being developed to find the optimal copper peptide remodeling system) |
Yes, similar to GHK-Copper
but not as well studied
Better than GHK-Copper in skin repair models |
Yes | Yes, potent anti-inflammatory,
Similar to GHK-Copper, More effective than cortisone on reducing inflammation in nickel allergy patients |
Yes | Reduces scaring but
effect on TGF beta unknown |
| Increase HEDGEHOG or Wnt Genes in mice, increase production of beta-catenin | Yes | Not applicable | Unknown | Yes | Unknown |
Skin remodeling starts with the hair follicles. The body's signal for remodeling first activates the systems that break down damaged proteins and remove damaged skin lesion. Various proteins (proteolytic enzymes) start breaking down scars and damaged tissue . Then the signals enlarge the hair follicles in the skin area to be rebuilt. New skin cells arise from the hair follicle and migrate into the surrounding skin area.
This effect was first noted about 50 years ago during World War II. It was observed, in patients with severe burns and burn scars, that if hair follicles were observed to be developing at the edge of the burned skin, then there was an excellent prognosis that the burn scar would be replaced by healthy normal skin. If the follicles were absent or very small, then healing was likely to be inadequate and the burn scars would remain.
Later, in 1985, I found that copper peptides not only stimulated healing of wounds but also increased the size of the hair follicles near the wounds. The copper peptides were not hair growth stimulators, per se, but did increase the hair follicle size and vitality.
In recent years, it has been established that genetic modifications in mice that stimulate skin remodeling also increase hair follicle size (Fuchs 1998). Genes such as sonic hedgehog (Sato et al 2001, Nanba et al 2003, Oro et al 2003. Mill eta al 2003), catinin (Huelsken 2001, Van Mater et al 2003), Wnt (Stenn 2001) and Noggin (Botchkarev 2001) all enhance hair follicles then produce remodeling.
Top Figure. Hair follicle
before remodeling signal.
Middle Figure. The remodeling
signal increases the size of the hair follicles.
Bottom Figure. The enlarged
hair follicle begins to produce new skin cells that migrate into the surrounding
skin and rebuild the skin.
The
application of copper-peptide complexes to the skin's surface creates an
environment that helps the skin tighten its barrier and increase its collagen
and elastin density. The photo on the left is an ultrasound scan of the
skin of a women aged 59 before treatment with the a cream containing peptide-copper
complexes. On the right is the same skin after one month of treatment with
the complexes. The white-yellow colored areas are the ultrasonic reflections
from skin that is more dense because of closer cellular binding and increased
amounts of collagen and elastin. This effect is opposite to the usual thinning
and loosening of skin during aging.
This skin regeneration can be enhanced by also using (1)
exfoliating agents such as alpha hydroxy acids, beta-hydroxy acids, and
retinoic acid or by (2) methods that mildly damage skin such as laser re-surfacing
or chemical peels. This is followed by a natural rebuilding of the skin
that removes imperfections, rebuilds collagen and elastin fibers that tighten
skin, and increases the amount of glycosamoinoglycans, the moisture-holding
proteins that give skin its firmness.
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How Skin Remodeling Copper Peptides Reverse Aging Effects Left Diagram: At age 20, your skin is thick, collagen and elastin strands are free and elastic (green), there is a rich blood supply through the skin (red and blue), and thick layer of subcutaneous fat cells (round balls). Center Diagram: By age 50, your skin thins and accumulates numerous small lesions, collagen and elastin fibers are broken and cross-linked, the skin's blood supply is diminished, and the layer of fat cells narrows. This produces wrinkles, sagging, and a less protective skin. Right Diagram: Skin remodeling copper peptides help reverse many effects of aging. They help remove minor skin lesions, re-thicken your skin, collagen and elastin are rebuilt, the skin's blood supply is improved, and subcutaneous fat is increased. This produces a skin biology more like young skin again. |
Metalloproteinase Activation to Remove Damaged Protein and Skin Lesions
Skin remodeling is the process that removes damaged proteins from the skin so that they can be replaced with new healthy protein. Proteins accumulate damage from many causes - sun damage, cross-linking by sugars, free radical injuries and so on. The metalloproteinases, a family of at least 14 proteins, act in the skin to remove damaged proteins such as damaged collagen and elastin.
Remodeling copper-peptide complexes are potent activators of metalloproteinases (Alain et al 1999). The old damaged protein is removed and replaced with new collagen and elastin fibers. This removes scar tissue and restores skin elasticity and reduces wrinkles. The activation of such proteins may explain the potent scar reduction properties of strong copper peptide creams. (For more information, see Chapter 6 of this website and www.scar-reduction.com.)
There is much confusion
on the role of metalloproteinases on skin health. Some dermatologists are
of the opinion that their effect is totally negative, but in reality metalloproteinases
are part of the system that removes old and damaged proteins from the skin.
The critical factor is the balance of protein production to metalloproteinase
activation.
Balance of skin protein synthesis to metalloproteinase
activity |
When this occurs |
Resultant effect on skin |
| Heavy production of skin proteins and TGF beta but little metalloproteinase activity | Early stages of healing or after use of TGF beta or peptides (such as RGD-type) that only stimulate skin protein production | Gives rapid closure of wounds to stop bleeding and prevent bacteria infection but also develops heavy scars |
| Production of skin proteins plus metalloproteinase activation | Later stages of healing and skin remodeling - bioactive copper peptides stimulate this effect | Slowly removes scars and other skin blemishes, produces a biologically younger skin |
| Low production of skin
proteins
but high metalloproteinase activation |
Persons in poor health, after radiation and thermal burns, diabetic complications, inadequate blood circulation | Skin ulcers and bedsores |

| Left Graphic - Stage
1
When skin is wounded, blood vessels are cut. Blood pours out and forms a protective clot that seals the wound |
Center Graphic - Stage
2
The blood clot is then filled with stronger collagen that forms a protective and tough scar over the injury. Copper peptide begin to arrive and cause collagen contraction to close the wound. |
Right Graphic - Stage
3
Copper peptides activate the scar removal mechanisms and rebuilds the skin's collagen, elastin, and blood circulation. |
Vitamin A/Retinol helps to remove wrinkles mainly by reducing collagen/elastin degradation. A protein complex called AP-1 produces the enzymes that break apart and degrade collagen and elastin, the major structural materials in skin. While a balance of biosynthesis and breakdown is essential for healthy skin, as we age, the balance is shifted toward excessive breakdown and harmful biochemical changes.
The application to the skin of retinol (normal vitamin A - also called vitamin A alcohol) or retinoic acid (vitamin A acid) helps restore a more normal (younger) balance between the skin's structural protein biosynthesis and breakdown, and also keeps a normal balance between healthy and dying skin cells. The applied vitamin A binds to receptors in the skin which then transfer genetic instructions from DNA to the cell's protein producing machinery which restores the characteristic proteins needed for healthy skin cells.
Creams with Retinol, in general, work very well for people over age 45.
Retinol can cause increased acne in person from 18 to 25. Paradoxically,
retinol creams can often stop severe chronic cystic acne in some people
between 25 and 40. When using retinol creams it is best to start slow and
work up to increased amounts of cream.
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Renova |
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Reduces acne |
May cause acne |
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of small wrinkles |
Combination treatments use skin remodeling products after more vigorous procedures such as laser re-surfacing, dermabrasion, chemical peels, and surgical techniques such as facelifts. The basic idea is that the laser re-surfacing, dermabrasion, or chemical peel removes some of the older or damaged skin and the remodeling peptides help rebuild the skin after these procedures.
Many of these methods are actually very old. The basic concept is that, after very damaging skin injuries, the body mounts a strong skin regenerative response that can heal poorly-healing wounds and, if the circumstances are propitious, actually improve skin quality. For thousands of years, physicians used hot hot irons on non healing wounds. Although this produced scarring, there would be a sufficient healing response to seal the wound. A variant method to heal wounds was "scarification" whereby a surgeon would cut scars into a poorly-healing wound. This would often induce enough healing to seal the wound although the scars remained.
Within the last few years, dermatologists using lasers to burn off skin lesions, found that often this resulted in a significant regeneration of the skin and a younger-looking appearance. Improvements in these techniques have given rise to the "laser re-surfacing" technique of regenerating skin.
The concept of using hydroxy acids or fruit acids is very old. Cleopatra wrote the book "Beautification" in which she described the use of fruit acids to renew and beautify the skin. The book was an ancient "best-seller" for 200 years. Today, we use similar acids, the AHAs (alpha hydroxy acids) and the BHAs (beta hydroxy acids) to speed skin turnover, remove skin lesions, and restore the skin firmness, elasticity, and internal moisture-holding properties.
However, you can't go to the cosmetic companies for help. The cosmetic companies have never made a significant contribution to skin and hair health. But about every 18 months they announce new "breakthrough, miracle" products but none ever last. All significant advances in skin and hair health have arisen from university researchers, private dermatologists, estheticians, cosmetologists and pharmaceutical companies.
The cosmetic companies
focus on producing safe, innocuous products. On the positive side, cosmetics
companies do produce excellent color cosmetics but this is not skin health.
| Breakthrough Products | Source of Technology |
| Skin Renewal | |
| Retin-A | Kligman, University (Univ. Pennsylvania) |
| Differin | Pharmaceutical (Galderma) |
| Hydroxy Acids | Van
Scott and Yu University (Temple Univ.), then
Neostrata, a company they founded |
| Copper-Peptides for Tissue Regeneration | Pickart, University (UCSF
and Univ. Washington) and
Pharmaceuticals (Procyte and Skin Biology) |
| Alpha Lipoic Acid | Perricone (Yale and Michigan State) |
| Skin Ulcer Healing (PDGF) | University (Univ. Washington)
and
Pharmaceuticals (Chiron and Johnson & Johnson) |
| Hair Regrowth | |
| Minoxidil (Rogaine) | Pharmaceutical (Upjohn & Pharmacia) |
| Propecia | Pharmaceutical (Merck) |
| Tricomin | Pickart, University (UCSF)
and
Pharmaceutical (Procyte) |
| Hair Transplantation | |
| Surgery | Private Dermatologist - Norman Orenreich |
| Product improve transplant
"take" -
Graftcyte |
Pickart, University (UCSF and Univ. Washington) and Pharmaceutical (Procyte) |
| Clinical techniques | |
| Laser Resurfacing | Private-practice dermatologists |
| Chemical Peels | Private-practice dermatologists, estheticians, and cosmetologists |
| Dermabrasion | Private-practice dermatologists, estheticians, and cosmetologists |
During our analyses of skin-care cosmetic products from other companies, we often detect chemicals such as coloring agents and other organic chemicals that are not listed on the ingredient list because they are under 1% in concentration.
Cosmetic companies teach complicated skin layering techniques requiring several types of cosmetic products. Such layering techniques work well for painting cars and houses but have no beneficial effect on skin health.
Cosmetic products that contain collagen, elastin, or DNA have no effect of the skin's production of collagen and elastin and have no effect on the skin's firmness or elasticity, and also have no effect on the rate of skin renewal. They only serve to attract water to the surface of the skin (the worst possible effect would be if the bovine collagen and elastin in cosmetics gave you the prions that cause Mad Cow Disease ). Only collagen and elastin that is produced within the skin helps improve skin firmness and elasticity.
Cosmetic moisturizers do not moisturize the skin, but only block the normal loss of water from the skin's surface. For very dry skin that has excessive water loss, these products can be helpful for a time. But they also hydrate (wet) and loosen the skin's protective outer proteins and degrade the protective qualities of these proteins. The only true skin moisturization is via the skin's internal synthesis of new proteoglycans and glycosaminoglycans (GAGs) which hold water in the skin.
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Copper-Peptides | Retinoic acid
(Retin-A, Renova) |
Vitamin C |
| Reducing wrinkles | Yes, two recent
unpublished studies |
Several positive studies published | Minor improvements |
| Skin color tone | Very good tone "glow" | Often reddish, leathery appearance | Fair tone |
| New collagen | Yes, significant in 70% of users in one month | Yes, significant in 40% of users in one month | Yes, significant in 50% of users in one month |
| New elastin | Yes | Yes | Minor improvement |
| Increase water-holding proteoglycans and glycosaminoglycans | Yes | Yes | No |
| Repair skin barrier | Yes | No, actually degrades skin barrier | No |
| Improve capillary circulation | Yes | Yes | No |
| Activate metalloproteinases to remove damaged proteins | Yes | No, Actually increases production of scar forming factor TGF-beta | No |
| Causes irritation | No | Yes, strong irritant | No |
| Anti-inflammatory | Yes | No | No |
| Anti-oxidant | Yes, activates superoxide dismutase in skin | No | Yes, vitamin C acts as anti-oxidant |
| Used for clinical skin repair? | Yes, for wound healing and dermatological skin repair | Yes, for skin renewal and anti-acne | No, effects are too minor |
A clinical study which compared the effect on the skin's production of collagen after using creams containing copper-peptides, vitamin C, or retinoic acid (retin-A) was published by researchers in the Dermatology Department at UMDNJ - Robert Wood Johnson Medical School (Abulghani et al 1998). Twenty volunteers applied the various creams to their thighs daily for one month. New collagen production was determined by studying skin biopsy samples using immunohistological techniques.
The study found, that after one month, copper-peptides had the most significant effect on collagen production. Significant increases in collagen production were found in 70% of the persons treated with copper-peptide creams, 50% of the persons treated with the vitamin C cream, and 40% of the persons treated with retinoic acid.
Significant wrinkle reduction is still difficult. Many products are sold for the reduction of wrinkles but effects are temporary. Keep in mind that a piece of tape on your skin for a day will produce a temporary wrinkle reduction. There have been several successful studies on significant reduction of major wrinkles with retinoic acid. Procyte and Neutrogena have announced successful studies on wrinkle reduction with copper-peptides. There are no published studies on significant wrinkle reduction with vitamin C despite heavy sales of the product for seven years.
Copyright
1998-2008 by Dr. Loren Pickart. All rights reserved. No reproduction without
written permission.
Abulghani el al 1998 - Abulghani, Shirin, Morales-Tapia, Sherr, Solodkina, Robertson, and Gottlieb, J. Invest. Derm. 110(4), page 686, 1998.
Alain et al 1999 - Alain, Monier, Emonard, Gillery, Birembaut, Homebeck and Maquart, Expression and activation of matrix metalloproteinases in wounds: Modulation by the tripeptide-copper complex glycyl-l-histidyl-l-lysine-cu2+, J. Invest. Dermat. 112: 957-964.
Dial 1990 - Dial, WF (1990)
Use of AHAs adds new dimensions to chemical peeling. Cosmetic
Dermatology 32-34).
Kligman, AM 1989 - Guidelines for the use of topical tretinoin (Retin-A) for photoaged skin. Journal of the American Academy of Dermatology 21:650-654
Olsen EA et al 1992 - J Am Acad Dermatol 26:215-224
Olsen et al 1997 - Tretinoin emollient cream for photodamaged skin: Results of 48-week, multicenter, double-blind studies, Journal of the American Academy of Dermatology, August 1997
Perricone and Dinardo 1996 - Dermatol Surg 1996;22: 435-437
Pruijn FB, Schoonen WG, Joenje H, Inactivation of mitochondrial metabolism by hyperoxia-induced oxidative stress. Ann N Y Acad Sci 663: 453-455 (Nov 21 1992)
Shalita, A 1990 - Retin-A for wrinkles: daily use preferred. Skin Allergy News:21:1
Stiller et al 1996 - Stiller, MJ et al. (1996) Topical 8% glycolic acid and 8% lactic acid creams for the treatment of photodamaged skin. Archives of Dermatology 132:631-636).
Van Scott and Yu 1989 - Van Scott, EJ and RJ Yu, Alpha hydroxy acids: procedures for its use in clinical practice, Cutis 43:222-228, 1989.
Weinstein GD et al 1991 - Arch Dermatol 1991;127:659-665
Weiss, JS et al. 1988 - Topical tretinoin improves photoaged skin. Journal of the American Medical Association. 259:527-532
Role of Sonic hedgehog signaling in epithelial and mesenchymal development of hair follicles in an organ culture of embryonic mouse, Nanba D, Nakanishi Y, Hieda Y., Dev Growth Differ. 2003 Jun;45(3):231-9
Transient activation of beta -catenin signaling in cutaneous keratinocyte is sufficient to trigger the active growth phase of the hair cycle in mice, Van Mater D, Kolligs FT, Dlugosz AA, Fearon ER., Genes Dev. 2003 May 15;17(10):1219-24
Hair cycle regulation of Hedgehog signal reception., Oro AE, Higgins K., Dev Biol. 2003 Mar 15;255(2):238-48,
Establishment of cadherin-based intercellular junctions in the dermal papilla of the developing hair follicle., Nanba D, Nakanishi Y, Hieda Y., Anat Rec. 2003 Feb 1,270A(2):97-102
Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development., Mill P, Mo R, Fu H, Grachtchouk M, Kim PC, Dlugosz AA, Hui CC., Genes Dev. 2003 Jan 15;17(2):282-94
Effect of adenovirus-mediated expression of Sonic hedgehog gene on hair regrowth in mice with chemotherapy-induced alopecia., Sato N, Leopold PL, Crystal RG., J Natl Cancer Inst. 2001 Dec 19:93(24):1858-64
Noggin is required for induction of the hair follicle growth phase in postnatal skin., Botchkarev VA, Botchkareva NV, Nakamura M, Huber 0, Funa K, Lauster R, Paus R Gilchrest BA., FASEB J. 2001 Oct; 15(12):2205-14
beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin., Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W., Cell. 2001 May 18;105(4):533-45
Controls of hair follicle cycling, Stenn KS, Paus R, Physiol Rev. 2001 Jan:81(1):449-494
Beauty
is skin deep: the fascinating biology of the epidermis and its appendages.,
Fuchs E., Harvey Lect. 1998-99:94:47-77