These articles suggest that CPs both activate epithelial stem cells and may slow aging throughout the body.

1. Arch Dermatol Res. 2009 Apr;301(4):301-6.
Copper-GHK increases integrin expression and p63 positivity by keratinocytes.
Kang YA, Choi HR, Na JI, Huh CH, Kim MJ, Youn SW, Kim KH, Park KC.
Department of Dermatology, Seoul National University College of Medicine, Yeongeon-dong, Jongno-gu, Seoul, Republic of Korea.

Glycyl-L-histidyl-L-lysyl (GHK) possesses a high affinity for copper(II) ions, with which it spontaneously forms a complex (copper-GHK). It is well known that copper-GHK plays a physiological role in the process of wound healing and tissue repair by stimulating collagen synthesis in fibroblasts. This study was conducted to investigate the effects of copper-GHK on keratinocytes. Proliferative effects were analyzed and hematoxylin and eosin staining and immunohistochemistry were conducted to evaluate the effects of copper-GHK in skin equivalent (SE) models. In addition, western blotting was performed. In monolayer cultured keratinocytes, copper-GHK increased the proliferation of keratinocytes. When the SE models were evaluated, basal cells became cuboidal when copper-GHK was added. Immunohistochemical analysis revealed that copper-GHK increased proliferating cell nuclear antigen (PCNA) and p63 positivity. Furthermore, the expression of integrin alpha6 and beta1 increased in SE models, and these results were confirmed by Western blotting. The results of this study indicate that treatment with copper-GHK may increase the proliferative potential of basal keratinocytes by modulating the expression of integrins, p63 and PCNA. In addition, increased levels of p63, a putative stem cell marker of the skin, suggests that copper-GHK promotes the survival of basal stem cells in the skin.

2. Cell Stem Cell. 2009 Jul 2;5(1):64-75.
TAp63 prevents premature aging by promoting adult stem cell maintenance.
Su X, Paris M, Gi YJ, Tsai KY, Cho MS, Lin YL, Biernaskie JA, Sinha S, Prives C, Pevny LH, Miller FD, Flores ER.
Department of Molecular and Cellular Oncology, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

The cellular mechanisms that regulate the maintenance of adult tissue stem cells are still largely unknown. We show here that the p53 family member, TAp63, is essential for maintenance of epidermal and dermal precursors and that, in its absence, these precursors senesce and skin ages prematurely. Specifically, we have developed a TAp63 conditional knockout mouse and used it to ablate TAp63 in the germline (TAp63(-/-)) or in K14-expressing cells in the basal layer of the epidermis (TAp63(fl/fl);K14cre+). TAp63(-/-) mice age prematurely and develop blisters, skin ulcerations, senescence of hair follicle-associated dermal and epidermal cells, and decreased hair morphogenesis. These phenotypes are likely due to loss of TAp63 in dermal and epidermal precursors since both cell types show defective proliferation, early senescence, and genomic instability. These data indicate that TAp63 serves to maintain adult skin stem cells by regulating cellular senescence and genomic stability, thereby preventing premature tissue aging.

3. Cell Cycle. 2006 Feb;5(3):260-5.
p63: a new link between senescence and aging.
Keyes WM, Mills AA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.

Cellular senescence is a distinctive form of cell cycle arrest that has been suggested to modulate the processes of tumor suppression and aging. Though a detailed understanding of the cellular machinery regulating this process is emerging, a more thorough understanding of the key players linking senescence to organismal aging is needed. The recent discovery that loss of the p53-related protein p63 induces cellular senescence and causes features of accelerated aging provides further evidence that cellular senescence is intimately linked with organismal aging, and identifies p63 as a key regulator of both of these processes.

4. Genes Dev. 2005 Sep 1;19(17):1986-99.
p63 deficiency activates a program of cellular senescence and leads to accelerated aging.
Keyes WM, Wu Y, Vogel H, Guo X, Lowe SW, Mills AA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

The p53 tumor suppressor plays a key role in organismal aging. A cellular mechanism postulated to drive the aging process is cellular senescence, mediated in part by p53. Although senescent cells accumulate in elderly individuals, most studies have relied on correlating in vitro senescence assays with in vivo phenotypes of aging. Here, using two different mouse models in which the p53-related protein p63 is compromised, we demonstrate that cellular senescence and organismal aging are intimately linked and that these processes are mediated by p63 loss. We found that p63(+/-) mice have a shortened life span and display features of accelerated aging. Both germline and somatically induced p63 deficiency activates widespread cellular senescence with enhanced expression of senescent markers SA-beta-gal, PML, and p16(INK4a). Using an inducible tissue-specific p63 conditional model, we further show that p63 deficiency induces cellular senescence and causes accelerated aging phenotypes in the adult. Our results thus suggest a causative link between cellular senescence and aging in vivo, and demonstrate that p63 deficiency accelerates this process.

This message has been edited. Last edited by: Dr. Pickart,

Hi Dr.Pickart, Is there any future plan for skin biology,to produce Cps for oral ingestion or as dermal patches.As you suggested in your earlier post.

All I can say is "Sign me up for Auto-Delivery" if supplements are waiting in the wings...

Wouldn't that be fantastic! Sorry if I sound stupid, but would some be in our system if we are applying it to our skin?

Hi Dr Pickart,

what about sublingual Cu-GKL instead. Its more practical delivery system bypasses intestinal wall and degradation like vitamin B-12?.

Otherwise entercoated capsules are better for protecting the very fragile peptides from enzymatic cleavage in the saliva.

We are thinking about putting the GHK-Cu in liposomes that target the lymphatic system to avoid damage in the intestines.

We would need to get in only about 75 mgs of GHK-CU three times a week. This is based on systemic wound healing in studies on pigs.

Hi Dr.Pickart,
would Cu-GKL taken internally help with chronic inflammation ,secondary to hyper-Autonomic-sympathetic nervous system activity due to familial phaeochromocytoma( very high level of IL-6 48 ng/dl; normal is < 12 ng/dl).

GHK-Cu has huge anti-inflammatory actions.

It also increases protein P63 which many feel might the the best biochemical candidate for the "Fountain of Youth" factor.

These articles suggest that CPs both activate epithelial stem cells and may slow aging throughout the body.



1. Arch Dermatol Res. 2009 Apr;301(4):301-6.
Copper-GHK increases integrin expression and p63 positivity by keratinocytes.
Kang YA, Choi HR, Na JI, Huh CH, Kim MJ, Youn SW, Kim KH, Park KC.
Department of Dermatology, Seoul National University College of Medicine, Yeongeon-dong, Jongno-gu, Seoul, Republic of Korea.

Glycyl-L-histidyl-L-lysyl (GHK) possesses a high affinity for copper(II) ions, with which it spontaneously forms a complex (copper-GHK). It is well known that copper-GHK plays a physiological role in the process of wound healing and tissue repair by stimulating collagen synthesis in fibroblasts. This study was conducted to investigate the effects of copper-GHK on keratinocytes. Proliferative effects were analyzed and hematoxylin and eosin staining and immunohistochemistry were conducted to evaluate the effects of copper-GHK in skin equivalent (SE) models. In addition, western blotting was performed. In monolayer cultured keratinocytes, copper-GHK increased the proliferation of keratinocytes. When the SE models were evaluated, basal cells became cuboidal when copper-GHK was added. Immunohistochemical analysis revealed that copper-GHK increased proliferating cell nuclear antigen (PCNA) and p63 positivity. Furthermore, the expression of integrin alpha6 and beta1 increased in SE models, and these results were confirmed by Western blotting. The results of this study indicate that treatment with copper-GHK may increase the proliferative potential of basal keratinocytes by modulating the expression of integrins, p63 and PCNA. In addition, increased levels of p63, a putative stem cell marker of the skin, suggests that copper-GHK promotes the survival of basal stem cells in the skin.

2. Cell Stem Cell. 2009 Jul 2;5(1):64-75.
TAp63 prevents premature aging by promoting adult stem cell maintenance.
Su X, Paris M, Gi YJ, Tsai KY, Cho MS, Lin YL, Biernaskie JA, Sinha S, Prives C, Pevny LH, Miller FD, Flores ER.
Department of Molecular and Cellular Oncology, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

The cellular mechanisms that regulate the maintenance of adult tissue stem cells are still largely unknown. We show here that the p53 family member, TAp63, is essential for maintenance of epidermal and dermal precursors and that, in its absence, these precursors senesce and skin ages prematurely. Specifically, we have developed a TAp63 conditional knockout mouse and used it to ablate TAp63 in the germline (TAp63(-/-)) or in K14-expressing cells in the basal layer of the epidermis (TAp63(fl/fl);K14cre+). TAp63(-/-) mice age prematurely and develop blisters, skin ulcerations, senescence of hair follicle-associated dermal and epidermal cells, and decreased hair morphogenesis. These phenotypes are likely due to loss of TAp63 in dermal and epidermal precursors since both cell types show defective proliferation, early senescence, and genomic instability. These data indicate that TAp63 serves to maintain adult skin stem cells by regulating cellular senescence and genomic stability, thereby preventing premature tissue aging.

3. Cell Cycle. 2006 Feb;5(3):260-5.
p63: a new link between senescence and aging.
Keyes WM, Mills AA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.

Cellular senescence is a distinctive form of cell cycle arrest that has been suggested to modulate the processes of tumor suppression and aging. Though a detailed understanding of the cellular machinery regulating this process is emerging, a more thorough understanding of the key players linking senescence to organismal aging is needed. The recent discovery that loss of the p53-related protein p63 induces cellular senescence and causes features of accelerated aging provides further evidence that cellular senescence is intimately linked with organismal aging, and identifies p63 as a key regulator of both of these processes.

4. Cell Stem Cell. 2009 Jul 2;5(1):1-2.

SKP-ing TAp63: stem cell depletion, senescence, and premature aging.
Beaudry VG, Attardi LD.
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

The p53 family member p63 comprises multiple isoforms and is critical for stratified epithelial development. In this issue of Cell Stem Cell, by generating isoform-specific knockout mice, Su et al. (2009) reveal pivotal roles for TAp63 in the maintenance of dermal and epidermal precursors, genomic stability, and organismal longevity.


5. Cell. 2007 May 4;129(3):523-36.Click here to read Links
p63 Is essential for the proliferative potential of stem cells in stratified epithelia.
Senoo M, Pinto F, Crum CP, McKeon F.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

The distinguishing feature of adult stem cells is their extraordinary capacity to divide prior to the onset of senescence. While stratified epithelia such as skin, prostate, and breast are highly regenerative and account disproportionately for human cancers, genes essential for the proliferative capacity of their stem cells remain unknown. Here we analyze p63, a gene whose deletion in mice results in the catastrophic loss of all stratified epithelia. We demonstrate that p63 is strongly expressed in epithelial cells with high clonogenic and proliferative capacity and that stem cells lacking p63 undergo a premature proliferative rundown. Additionally, we show that p63 is dispensable for both the commitment and differentiation of these stem cells during tissue morphogenesis. Together, these data identify p63 as a key, lineage-specific determinant of the proliferative capacity in stem cells of stratified epithelia.

This message has been edited. Last edited by: Dr. Pickart,