Skin Remodeling with Copper Peptides
Loren Pickart PhD
Skin remodeling is a process that restores normal skin morphology after
various types of wounds, injuries, and skin damage. Development of effective
cosmetic skin remodeling is becoming an increasing focus of dermatologists and
their clients. As we age, the dermis and epidermis thins and accumulates
blemishes, lesions and imperfections. Extracellular matrix proteins such as
collagen and elastin become damaged and lose their resiliency while the
water-holding proteins and sugars diminish. The capillary network becomes less
functional which produces a “graying” of the skin, the subcutaneous fat cells
diminish in number, and fewer protective oils are secreted on the skin's
surface. These aging effects are intensified by exposure to ultraviolet rays,
irritants, allergens, and environmental toxins. The end result is a dry,
wrinkled, inelastic skin populated by unsightly lesions.
Restoration to a biologically younger skin requires two linked
processes: first, the removal of damaged proteins and aberrant skin lesions,
and second, their replacement with normal, blemish free skin. This process is
similar to the remodeling phase of wound healing in which scar tissue is
removed, slowly restoring the skin to its original state.
Many skin renewal techniques are used that produce skin remodeling but
all have drawbacks. Retinoic acid slowly remodels skin but at the price of
chronic irritation and redness. Certain peptides, melatonin, and vitamin C
increase skin collagen but skin also needs replacement of elastin,
water-holding proteoglycans, and its microcirculation must be rebuild. A class
of pentapeptides and aminopeptides, that function like TGF-beta-1, are the
latest “hot” product in cosmetic creams. Such peptides increase the skin's
extracellular matrix proteins and were extensively tested in the 1990s for
wound healing, but produced unacceptable skin thickening and scarring because
they do not adequately remove older pre-existing proteins. Lasers, chemical
peels, and dermabrasion work well only if there is a vigorous post-therapy
regenerative response from the damaged skin.
Cosmetic Skin Remodeling and Wound Healing
Children have beautiful skin because remodeling processes function
efficiently and skin damage is rapidly removed. Sadly, in adults, remodeling
slows drastically and various skin lesions may persist for years or decades.
Skin remodeling is best understood in the context of wound healing.
Cosmetic remodeling of uninjured skin appears to be a similar process since
the human body uses the same, or slightly modified, biochemically mechanisms,
over-and-over again, for closely related purposes. Many dermatological
techniques (lasers, dermabrasion, chemical peels) used for skin remodeling
actually induce a mild wounding to trigger the remodeling process.
After skin wounding, blood clotting forms a covering over the injury,
followed by the activation of a variety of anti-microbial sterilising and
tissue-destructive processes. Neutrophils infiltrate the wound area and
secrete toxic oxygen radicals to kill invading bacteria. Production of the
cytokine interleukin-1 activates an inflammatory response. Fibroblasts enter
the region and produce TGF-beta 1, a protein that induces the formation of
protective scar tissue over the wound. After this initial phase, the oxygen
radicals are neutralized and the production of interleukin-1 and TGF-beta-1 is
suppressed. Metalloproteinases and macrophages remove the scar tissue and
cellular debris. The extracellular matrix is rebuilt with new collagen,
elastin, and proteoglycans. Recent work, in the last few years, with
genetically modified mice, has also emphasized the key role of hair follicles
and their associated sebaceous glands in the production of new skin cells.
Stem cells for skin are now thought to arise from enlarged hair follicles,
primarily the follicles that produce the fine vellus hair on the human body.
Top. Mouse skin treated with one injection of saline. Bottom. Mouse skin after
one injection of GHK-Cu. Note the much larger hair follicles (colored
dark-purple) that grow larger and further down into the skin. It is from such
enlarged vellus hair follicles in humans that new stem cells are seeding into
the skin for remodeling.
the Activator of Remodeling
It now appears that a human copper peptide complex, GHK-Cu
(glycyl-l-histidyl-l-lysine:copper(II)), is the primary activator of skin
remodeling, and that remodeling is a more complex process that original
envisaged. GHK-Cu and certain copper peptide complexes, are increasingly used
in cosmetic skin and hair care products, and after clinical skin renewal
procedures; such as chemical peels, laser resurfacing, and dermabrasion, to
improve post-treatment skin recovery. GHK-Cu exerts protective and
regenerative effects on several organ systems including skin, hair follicles,
bone, gastric and intestinal linings, and the liver. Although the
understanding of the biochemical actions of GHK-Cu is still incomplete, the
situation is like a jigsaw puzzle where enough pieces have been assembled to
understand the overall picture.
GHK-Cu is found in human plasma, saliva and urine. In plasma, it appears
to be bound to plasma albumin at a concentration of approximately 200 ng/ml at
age 20 which declines to 80 ng/ml by age 60 (2). GHK is a rare sequence,
existing mainly in inflammation-associated and of the extracellular matrix
proteins, such as collagen, thrombospondin, fibrin a-chain, prokininogen,
complement C1q, interleukin 4, skin collagenase, coagulation factor XI and
SPARC (3). During episodes of tissue damage, GHK is generated by proteolysis
(4). Numerous cell culture studies have found that the biologically effective
levels GHK-Cu are approximately 10exp(-9) M (5).
In vivo, GHK probably exists as a mixture of GHK and GHK-Cu. GHK has a
high binding affinity for copper (II) (pK=16.2) that is similar to albumin’s
copper (II) binding (pK=16.4). GHK can obtain copper (II) from albumin.
However, under physiological conditions only about 5% to 20% of GHK molecules
would be expected to exist as GHK-Cu complexes with copper (II) (5).
Biological actions have been reported for both GHK and GHK-Cu, although GHK is
likely to chelate available copper while, conversely, GHK-Cu may lose copper
to other binding proteins. Experiments using either molecule are actually
studying a mixture of both. Free GHK-Cu, not bound to albumin, is a fragile
molecule sensitive to carboxypeptidase actions and degrades rapidly (6).
Biochemical Actions of GHK-Cu and Skin Remodeling
GHK-Cu takes a role in many biochemical events involved in skin
remodeling (Table 1). Most surprising is that the molecule possesses a diverse
multiplicity of actions all connected with skin remodeling. These include
powerful anti-inflammatory actions that function to shut-down the initial
phase of wound sterilization and scar formation (7-10). The molecule activates
m-RNAs for both metalloproteinases that remove damaged protein and for
extracellular matrix proteins such as collagen, elastin, and proteoglycans.
(11-14) It chemoattracts tissue-repairing macrophages (15) while also
stimulating angiogenesis (7,16) and neuronal outgrowth (17,18).
When used for wound healing, GHK-Cu markedly increases the size of hair
follicles and their sebaceous glands, adjacent to the wound edge (19-20) and
analogs of GHK-Cu are marketed by ProCyte and American Crew for hair
transplantation (“Graftcyte”) and stimulation of hair growth (“Tricomin”). A
link between hair follicles and skin repair was postulated over 60 years ago
during World War II when surgeons observed that skin recovery after burn
injuries could be predicted by observing the return of hair follicles to the
wound edge. If an abundant number of dermal hair follicles were observed at
the wound edge, then scar removal followed by the re-establishment of normal
skin would occur. However, if there was a deficiency of hair follicles, then
inadequate healing would follow and scar tissue remained. This action of
GHK-Cu on hair follicles, in accord with the studies on hair follicles and
stem cells cited above (1) further strengthens evidence that GHK-Cu functions
as a remodeling signal.
Table 1. Actions of GHK-Cu on Skin Remodeling
1. Suppression of initial oxidative sterisation, inflammation, and scar
Blocks ferritin channels that release ferric ions
Stops iron induced tissue oxidation
Suppresses TGF-beta production by fibroblasts
Stops production of scar forming proteins
Concentrates copper (II) ion in wound area
Activates Cu, Zn Superoxide Dismutase
Blocks cell damaging actions of interleukin-1
Stops post-wounding cellular damage
2. Removal of damaged molecules and cellular debris
Stimulating production of M-RNA, and synthesis of, metalloproteinases and
Remove damaged collagen and elastin Reduce blemishes and scars while smoothing
11 to 14
3. Repair Phase - Scar tissue and cellular debris removed and replaced with
Stimulating production of M-RNA, and synthesis of, collagen, elastin, and
Rebuilding of extracellular matrix proteins,
Increases elasticity, firmness, and water-holding properties of skin
11 to 14
Chemoattractant for capillary cells and induction of angiogenesis
Rebuilding of the skin's microcirculation,
increase youthful “glow”
Chemoattractant for macrophages that remove debris and release cellular growth
Enhances repair processes
Promotes nerve outgrowth
Restores innervation of damaged skin
Markedly increases hair follicle size
Follicles produce stem cells that produce new skin cells
Newer, younger-looking skin
Repairs and tightens skin barrier
Restores protective actions of skin
Reduces water loss,
More resistance to entry of viruses and bacteria
Skin Repair and Remodeling
Initially GHK-Cu was studied as a factor that increased the survival of
many types of cell cultures and organ cultures. The first in vivo effect that
I observed in 1984 was an acceleration of wound healing in a variety of animal
models (21). In 1985, I started a company, ProCyte Corporation, to develop
GHK-Cu into products for human use. A few examples of healing actions include:
the healing of pad wounds in dogs (22), more rapid wound closure and
production of granulation tissue (23). Healing with GHK-Cu works best with
light bandaging. Wet bandages nullified the effects (22). In immunosuppressed
rats, healing is impaired and collagen synthesis is 23% of that in normal
rats. GHK-Cu more than tripled collagen synthesis in these rats, raising it to
77% of normal; restoring normal wound healing (24). In punch biopsy wounds in
pigs, intradermal injections of GHK-Cu produced highly localized patterns of
healing. Thus, in animal or human studies, it is possible to test several
potential formulations on a given test subject (25). A GHK-Cu cream used after
Moh’s surgery increased wound healing and skin re-epithelialisation (26). An
open study of wounds in 60 patients in 1987 with diabetic and venous stasis
ulcers gave evidence of rapid healing (27). This study used high
concentrations of GHK-Cu and very low concentrations of anti-microbial agents.
This apparently successful GHK-Cu formulation was never used in later clinical
studies, which did not achieve therapeutic goals in FDA controlled trials.
The first suggestion that GHK-Cu was a remodeling agent came from
studies that indicated that both collagen synthesis and breakdown were
stimulated by GHK-Cu. In 1987, I also found, that the application of skin
creams containing GHK-Cu, increased the thickness of the epidermis and dermis,
increased skin elasticity, reduced wrinkles, and resulted in a removal of skin
imperfections such as blotchiness and sun damage marks, while producing a
significant increase in subcutaneous fat cells (28). But this observation was
not pursued until recently. Finally, between 1998 and 2002, more extensive
human studies solidified these observations. Abulghani et al reported GHK-Cu
was more effective in stimulating new collagen development than vitamin C,
retinoic acid, or melatonin (29). Appa et al reported that in eight weeks, a
GHK-containing liquid foundation improved epidermal thickness, increased skin
elasticity, and improved skin appearance (30). Leyden et al found, in another
eight week study, such creams to reduce visible signs of photodamage and
increased skin density in eight weeks on facial skin (31) and also in a
further, placebo-controlled study (71 females, 12 weeks) found that
GHK-Cu-containing face creams reduced wrinkles and fine lines while increasing
skin elasticity, density and thickness while another placebo-controlled study
(41 females, 12 weeks) found that a GHK-Cu containing eye cream reduced
wrinkles and fine lines and improved eye appearance (32). Cosmetic products
that contain GHK-Cu include lines such as Visibly Firm by Neutrogena and Neova
by ProCyte. We expect more products using GHK-Cu to be marketed in the future
since ProCyte's patent on cosmetic uses of GHK-Cu expires in May 2004.
Skin of 51 year old woman. Left - before treatment. Right - after three weeks
of treatment with GHK-Cu.
The skin became tighter and denser with more collagen (bright areas).
Development of Improved Skin Remodeling Copper Peptides.
The first generation products designed around GHK-Copper performed well
in many controlled tests, however, the products failed in FDA clinical trials
on the healing of very difficult-to-heal human wounds (as have many other
approaches). The actions of GHK-Cu are limited by its fragility and tendency
toward breakdown and also its lack of adhesion to the skin surface.
Therefore, in 1994, I started Skin Biology to develop improved second
generation, skin regenerative/remodeling, copper peptides with enhanced
potency, breakdown resistance, and high adherence to skin. We isolated peptide
fragments from soy protein digests that possessed the desired qualities when
chelated to copper (II). Such peptides have a very low antigenicity and long
history of safe use in cosmetic products. In veterinary studies, creams made
from these new copper complexes produced rapid and scar-free healing in dogs
after spaying operations, and in young horses after leg-straightening
operations. This allowed the dogs to be returned to their owners in four days
instead of the usual five, while the foals were returned in five days instead
of seven. Howard Maibach and colleagues (UCSF) tested these new copper
peptides in four small, placebo-controlled human studies. They found that
creams made from these new copper complexes produced significantly faster skin
healing and reduced redness and inflammation after mild skin injuries brought
on by tape stripping (33) , acetone burns (removal of skin lipids) (34),
24-hour detergent irritation (35) , and nickel allergy inflammation (36).
Current Research on Remodeling Copper
Scarless Healing – Our current research at Skin Biology is opening an
approach to scarless or nearly-scarless healing of surgical incisions. GHK-Cu
markedly reduces scarring after surgery if injected (an aqueous solution of 1
mg/ml) down the incision line. However, the second generation copper peptides
appear to be superior for such uses. In veterinary studies, the application of
2nd generation copper peptides in creams immediately after surgery produced
rapid and scarless healing in dogs after spaying operations and in young
horses after leg-straightening operations. This allowed the dogs to be
returned to their owners in four days instead of the usual five, while the
foals were returned in five days instead of seven. For such uses, the
incisions should be left open to air or only lightly covered with gauze.
Occlusive dressing and wet bandages nullify the positive effect.
Post-Procedure Treatments - Both GHK-Cu and the second generation copper
peptides function well to improve the recovery of skin after procedures such
as deep peels, laser resurfacing, and dermabrasion. ProCyte Corporation
markets their “Cu-3” line for such uses. If the skin is treated with copper
peptides within two hours after the procedure, post-treatment redness and
inflammation is avoided without the use of corticosteroids. Skin rebuilding is
hastened while scars and infections are greatly lessened. At Skin Biology, we
are developing a water based product, called CP Serum, that works especially
well for these uses. This product is often followed by either emu oil or
squalane which act as moisturizers and as penetrating agents that push more
copper peptide into the skin.
Removal of Skin Lesions - The second generation copper peptides work
well for the removal of skin lesions. Our research finds that most skin
imperfections (hypertrophic scars, pitted scars, skin tags, moles, actinic
keratosis) can be removed or greatly reduced by repeated daily use of hydroxy
acids to loosen and dissolve the lesions followed by strong copper peptides to
aid skin regeneration. Hydroxy acids such as 2% salicylic acid (pH=3.2) or 14%
glycolic acid (pH=3.9) are effective with copper peptides but obtaining a
cosmetically satisfying result may require several months of applications. The
use of stronger hydroxy acids, followed by the application of copper peptides
greatly speeds the removal of lesions and scars, but can be very irritating if
not expertly applied. For example, to remove moles, 70% glycolic acid is
applied for 6 minutes, washed off, then the strong copper peptides are applied
to the moles. Two to three days of this procedure often removes moles
Safety of Copper Peptides
Numerous safety tests of skin regenerative copper peptides have failed
to find any toxicity problem. Extremely small amounts penetrate the skin and
no rise in blood copper has ever been found in animals or humans treated with
copper peptides. Further reassurance as to the safety of copperceuticals is
that in nutritional studies, increased supplementation with copper has been
reported to increase DHEA levels (37), raise brain enkephalins (38), reduce
carcinogenesis and cancer growth (39-41), reduce the development of
cardiovascular disease (42), reduces the markers of osteoporosis (43), reduce
rheumatoid arthritis (39), improve immune function (44), reduce protein
glycation (45) and deleterious peroxidation of fats and red blood cells (46),
reduce brain developmental defects in offspring (47), and increase
anti-oxidant defenses by activation of superoxide dismutase (48). Indeed, many
researchers have noted that copper supplementation appears to counter many of
the degenerative diseases of aging.
Formulating Copper Peptides into Products
When formulating copper-peptide products, great care must be taken to
minimize interactions with the ionic copper. Other ingredients of creams,
lotions, and solutions may interact with the ionic copper and neutralize the
positive copper-peptide actions and, in some cases, generate copper-complexes
that inhibit cell replication.
Some companies have sell cosmetic skin products using copper complexes
such as EDTA-copper but many complexes of copper with chelating molecules
inhibit fibroblast function and skin repair (49). All products should be
carefully tested in actual human skin repair tests. Also, not all copper
peptide complexes are skin regenerative. Only products based on GHK-Cu or the
newer complexes from Skin Biology are supported by credible, published
evidence of efficacy.
1. Oshima H., Rochat A., Kedzia C., Kobayashi K., and Barrandon Y.
Morphogenesis and renewal of hair follicles from adult multipotent stem cells.
Cell, 2001; 104:233-45.
2. Pickart, L. A tripepeptide in human serum that promotes the growth of
hepatoma cells and the survival of normal hepatocytes, Ph.D. thesis, Univ. of
California, San Francisco, 1973
3. Maquart F.X., Simeon A., Pasco S., Monboisse J.C., [Regulation of
cell activity by the extracellular matrix: the concept of matrikines] French.
J Soc Biol. 1999;193:423-8
4. Lane T.F., Iruela-Arispe M., Johnson R.S., Sage E.H. SPARC is the
source of copper-binding peptides that stimulate angiogenesis. J Cell Biol
1994; 125: 929-943
5. Pickart L. Iamin: A human growth factor with multiple wound-healing
properties. In: Biology of Copper Complexes(edit Sorenson J.R., Humana Press,
Clifton, New Jersey, 1985) pp.273-282
6. Schlesinger D., Pickart L., Thaler M.M. Growth modulating serum
tripeptide is glycyl-histidyl-lysine. Experientia 1977; 33: 324-325
7. Pickart L., Downey D., Lovejoy S., Weinstein B.
Gly-l-his-l-lys:copper(II) – A human plasma factor with superoxide
dismutase-like and wound-healing properties, In: Superoxide and Superoxide
Dismutase (Edit Rotilio, Elsevier, 1986) pp.555-558
8. Miller D.M., DeSilva D., Pickart L., Aust S.D. Effects of
glycyl-histidyl-lysyl chelated Cu(II) on ferritin dependent lipid
peroxidation. Adv Exp Med Biol 1990; 264: 79-84
9. Vinci C., Caltabiano V., Santoro A.M., Rabuazzo A.M., Buscema M.,
Purrello R., Rizzarelli E. Copper addition prevents the inhibitory effects of
interleukin 1-beta on rat pancreatic islets. Diabetologia. 1995; 38:39-45
10. McCormack MC, Nowak KC, Koch RJ. The effect of copper tripeptide and
tretinoin on growth factor production in a serum-free fibroblast model. Arch
Facial Plast Surg 2001; 3:28-32
11. Maquart F.X., Pickart L., Laurent M., Gillery P., Monboisse J.C.,
Borel J.P. Stimulation of collagen synthesis in fibroblast cultures by the
tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. FEBS Lett. 238;
12. Simeon A., Monier F. Emonard H., Gillery P., Birembaut P.. Hornebeck
W., Maquart F.X. Expression and activation of matrix metalloproteinases in
wounds: modulation by the tripeptide-copper complex
glycyl-L-histidyl-L-lysine-Cu2+. J Invest Dermatol 1999; 12:957-964.
13. Simeon A., Wegrowski Y., Bontemps Y., Maquart F.X. Expression of
glycosaminoglycans and small proteoglycans in wounds: modulation by the
tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+). J Invest
Dermatol. 2000; 115:962-968.
14. Simeon A., Emonard H., Hornebeck W., Maquart F.X. The
tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ stimulates matrix
metalloproteinase-2 expression by fibroblast cultures. Life Sci. 2000;
15. Zetter B.R., Rasmussen N., Brown L. Methods of Laboratory
Investigation: An In Vivo Assay for Chemoattractant Activity, Lab Invest 1985;
16. Raju K.S., Alessandri G., Gullino P.M. Characterization of a
chemoattractant for endothelium induced by angiogenesis effectors. Cancer Res
17. Sensenbrenner M., Jaros G.G., Moonen G., Mandel P., Effects of
synthetic tripeptide on the differentiation of dissociated cerebral hemisphere
nerve cells in culture. Neurobiology 1975; 5:207-13
18. Lindner G., Grosse G., Halle W., Henklein Uber die Wirkung eines
synthetischen Tripeptids auf in vitro kultiviertes Nervengewebe (The effect of
a synthetic tripeptide nervous tissue cultured in vitro). Z Mikrosk Anat
Forsch 1979; 93: 820-828
19. Pickart L. US Patents 5,177,061; 5,214,032; 5,550,183; 5,120,831
20. Uno H., Kurata S. Chemical agents and peptides affect hair growth. J
Invest Dermatol 1993; 101: 143S-147S
21. Pickart L., US Patents 4,665,054; 4,760,051; 4,810,693; 4,877,770;
22. Swaim S.F., Vaughn D.M., Kincaid S.A., Morrison N.E., Murray S.S.,
Woodhead M.A., Hoffman C.E., Wright J.C., Kammerman J.R. Effect of locally
injected medications on healing of pad wounds in dogs. Am J Vet Res 1996; 57:
23. Downey D., Larrabee W.F., Voci V., Pickart L. Acceleration of wound
healing using gycyl-histidyl-lysine copper (II) Surg Forum 1985; 25: 573-575
24. Ehrlich H.P., Symposium on Collagen and Skin Repair, Reims, Sept.
25. Counts, D., Hill, E., Turner-Beatty, M., Grotewiel M., Fosha-Thomas
S., Pickart L. Effect of Iamin on full thickness wound healing. Fed Am Soc Exp
Biol 1992; A1636
26. Fish F.S., Katz I., Hien N.R., Briden M.E., Johnson J.A., Patt, L.
Evaluation of glycyl-l-histidyl-l-lysine copper complex in acute wound
healing. Wounds 1991; 3: 171-177
27. Aupaix F., Maquart F.X., Salagnac L., Pickart L., Gillery P., Borel
J.P., Kalis B., Effects of the tripeptide glycyl-histidyl-lysine on healing.
Clinical and biochemical correlations. J. Invest. Derm., 94, 390, 1990 (abst)
28. Pickart L. US Patents 5,135,913; 5,348,943
29. Abulghani A.A., Shirin S., Morales-Tapia S., Sherr A., Solodkina G.,
Robertson M., Gottlieb A.B. Studies of the effects of topical vitamin C, a
copper binding cream, and melatonin cream as compared with tretinon on the
ultrastructure of normal skin, J. Invest. Derm., 1998; 110: 686 (abst)
30. Appa Y. Stephens T., Barkovic S. Finkey M.B. A clinical evaluation
of a copper-peptide containing liquid foundation and concealer designed for
improving skin condition. Abstract P66, Amer. Acad. Derm. Meeting, February
31. Leyden J.J., Stephens T., Finkey M.B., Barkovic S. Skin care
benefits of copper peptide creams. Amer Acad Derm 2002; February, Abstract P68
32. Leyden J.J., Stephens T., Finkey M.B., Barkovic S. Skin care
benefits of copper-peptide-containing eyes creams. Amer Acad Derm , February
2002 Abstract P69
33. Zhai H., Poblete N., Maibach H.J. Stripped skin model to predict
irritation potential of topical agents in vivo in man. Inter J Dermatol 1998;
34. Zhai H., Leow Y.H., Maibach H.R., Human barrier recovery after acute
acetone perturbation: an irritant dermatitis model. Clin Exp Derm, 1998: 23:
35. Zhai H., Leow Y.H., Maibach H.R., Sodium lauryl sulfate damaged skin
in vivo in man: a water barrier repair model. Skin Res Tech, 1998: 4: 24-27
36. Zhai H., Chang Y.C., Singh M., Maibach H.J. In vivo nickel contact
dermatitis: human model for topical therapeutics. Contact Dermatitis 1999; 40:
37. Klevay l.M., Christopherson D.M. Copper deficiency halves serum
dehydroepiandrosterone in rats. J Trace Elem Med Biol 2000; 14:143-5
38. Bhathena S.J., Recant L., Voyles N.R., Timmers K.I., Reiser S.,
Smith J.C., Powell A.S. Decreased plasma enkephalins in copper deficiency in
man. Am J Clin Nutr 1986; 43: 42-46
39. Sorenson JR. Copper complexes offer a physiological approach to
treatment of chronic diseases. Prog Med Chem. 1989;26:437-568.
40. Davis C.D., Johnson W.T. Dietary copper affects azoxymethane-induced
intestinal tumor formation and protein kinase C isozyme protein and mRNA
expression in colon of rats. J Nutr. 2002; 132:1018-1025.
41. Narayanan V.S., Fitch C.A., Levenson C.W. Tumor suppressor protein
p53 mRNA and subcellular localization are altered by changes in cellular
copper in human Hep G2 cells. J Nutr 2001;131:1427-32
42. Allen K.G.D. Ischemic heart disease and dietary copper – Towards and
unifying hypothesis. Nutrition 1993; 9: 189-199
43. Baker, A., Harvey L., Majask-Newman G., Fairweather-Tait S., Flynn
A., Cashman K. Effect of dietary copper intakes on biochemical markers of bone
metabolism in healthy adult males. Eur J Clin Nutr 1999; 53:408-412
44. Percival S.S. Copper and immunity. Am J Clin Nutr 1998; 67:
45. Saari, J.T., Bode A.N., Dahlen G.W. Defects of copper deficiency on
rats are modified by dietary treatments that affect glycation. 1995; 125:
46. Rock E., Mazur A., O'Conner J.M., Bonham M.P., Rayssiuguier, Strain
J.J. The effect of copper supplementation on red blood cell oxidizability and
plasma antioxidants in middle-aged healthy volunteers. Free Rad Biol Med 2000;
47. Lonnerdal B., Copper nutrition during infancy and childhood. Am J
Clin Nutr 1998; 67: 1046S-1053S
48. Harris E.D., Copper as a cofactor and regulator of copper,zinc
superoxide dismutase. J Nutr, 1992; 122: 636-40)
49. Pickart, L., Lovejoy S. Biological effects and the mechanism of
action of the plasma copper-binding growth factor glycyl-l-histidyl-l-lysine.
Methods Enzymol 1987; 147:314-328
50. For more extended references, see
Interview with Loren Pickart PhD
- Mr. Pickart, am I right that you were
the first scientist who started research on Copper-Peptides and there was
nothing known about them before?
- I would not say that proteins associated with copper were completely
unknown. Chemists had been investigating the ability of copper to make
complexes with some peptides. And there is a lot of research on copper and
enzyme superoxide dismutase. But this molecule, the model of which I'm holding
now (Seen Here), was unknown to scientists.
It all happened in 1970s when I was working at the University of
California at San Francisco. It was time of great belief in medicine. Many
scientists wanted to do big things, such as fighting cancer. I decided to find
the way to reverse human aging.
We worked with blood cells and discovered that young cells contained
some Copper-Peptide complex. We found out, that old cells lasted longer if we
supplied them with this peptide complex. But it took us 15 years to understand
how they work. Now we know that Copper-Peptides work as a restorative signal
in skin, bones, and hair follicles. And it is possible that they work the same
way in other tissues.
- So they work as growth factors?
- Not exactly. Let us look at wound healing. After damage, there are
mostly destructive and sterilizing processes involving free radicals. Then
cells begin to release transforming growth factor TGF-beta-1 that stimulates
scar formation. But damaged tissue also releases Copper-Peptides. At some
point their concentration reaches the level where they suppress TGF-beta-1
production and block oxidation.
- I have read that free radicals could be a restorative signal and
because of this too much antioxidants might delay wound healing.
I believe in good oxidation. You can accelerate wound healing by
applying oxidizing agents first and Copper-Peptides second.
- In your article you are saying that Copper-Peptides work as
antioxidants and anti-inflammatory agents; they also inhibit scar formation,
stimulate angiogenesis, attract macrophages to wound, stimulate hair
follicles, speed up both collagen destruction and new collagen synthesis...
Yes, that's correct. They remodel skin, you may say that they turn off
destruction and turn on reparation.
- It is hard to believe that one molecule can be so powerful.
We hardly could believe it too. But numerous other laboratories all over
the world extended our observations. French scientists found that
Copper-Peptides stimulate nerve growth, scientists from National Cancer
Institution researched angiogenesis, scientists from Utah investigated
antioxidant capacity of this molecule and so on.
- We keep talking about medical use, but now they are used in
Yes, initially we developed these products for medical use, but
physicians don't like trying new inventions; they prefer well-known remedies.
Besides, the procedure of drug approval is ridiculously complicated in USA. It
takes years and you have to spend a fortune. It is much easier to get approval
for cosmetic products, and women love to explore new cosmetics. I can assure
you, that many cosmetic products already contain the medicine of the future,
because their developers do not want to bother with drug approval. But I agree
that unlike drugs, cosmetic products should be perfectly safe. We tested
Copper-Peptides and didn't find any toxicity, any side effects. They are safe,
and they are meant to be safe, because they are found in human body and they
don't modify any physiological processes in skin. They protect skin and give
the signal to restoration. Don't you think it is perfect role for cosmetic
- You mean that there is no risk of scar formation or inflammation
even if people use high concentrated products?
On the contrary, Copper-Peptides prevent scars and inflammation. Some
women using our products report disappearance of stretch marks and scars. We
have very good testimonials, especially from middle-aged women. Usually they
buy one or two products for start, then come back for more, and then start to
recommend them to all their friends and relatives. Their praises keep us
going. (Read Their Testimonials Here)
- It seems that your product affects the skin physiology after all.
But FDA still requires cosmetic products to be inert in skin.
There are no such things as inert cosmetic ingredients. All substances
that we put on our skin, such as Vaseline and other emollients (even plain
water) affect skin in some way. And people in FDA understand this. They also
understand that modern people want cosmetics to improve skin, to make it
better. I have no doubt that the definition of cosmetics will be changed soon.
- Today many cosmetic companies make
cosmetics using your Copper-Peptides. Do you believe they use efficient
concentrations of Copper-Peptides?
Unfortunately many cosmetic companies just don't care. They want a
popular ingredient on the label and that is all. But some companies make very
good products and spend a fortune on testing. It is not only a matter of
concentration, it is important to know how Copper-Peptides will behave in a
complex mixture, and how a technical process will affect them. That is why
dermatological testing of finished products is so important.
- It seems for majority of cosmetic manufacturers it is still easier
to make fake claims rather than develop potent cosmetic products?
Unfortunately it is true. But this situation is changing now. The more
great cosmetic products come to the market, the closer the future in which
only efficient cosmetics will be profitable.
- As I understand, your company does a very little manufacturing, and
your main occupation now is still science of reversal of skin aging. But don't
you ever dream to be famous with your own cosmetic line?
Yes, I have been thinking about this a lot. But I prefer to be a
scientist. Manufacturing and promotion of new cosmetics is a tough business.
I'm 65 years old and I want to enjoy life.