Signal peptides are also known as Matricin or Matrikine peptides and specifically refer to collagen or extracellular matrix (ECM) fragments which improve wrinkles and skin hydration by signaling fibroblasts to increase the production of collagen, elastin, glycosaminoglycans (GAGs) such as hyaluronic acid, and other components of the ECM including proteoglycans, fibronectin and laminin (Errante et al. 2020, Gorouhi and Maibach 2009).

Matrixyl 3000 is a patented combination of two signal peptides (pal-GHK and pal-GQPR, aka palmitoyl tripeptide-7 and palmitoyl tripeptide-1) which have known synergy with one another as first demonstrated in in-vitro studies with dermal fibroblasts (fibroblasts secrete collagen, elastin, and other ECM components in the dermal layer of the skin) (US patent 2004/0132667 A1). In these studies, the combination of pal-GHK and pal-GQPR was more effective at stimulating collagen type 1, fibronectin and hyaluronic acid than either peptide alone.

Subsequent placebo controlled clinical studies in both men and women showed that a cream containing Matrixyl 3000 significantly decreased wrinkle depth and volume as well as skin roughness. In the first clinical study in older women, Matrixyl 3000 cream was applied on half the face versus placebo on the other half for crow’s feet wrinkles. With Matrixyl 3000, they found a significant 23.3% decrease in wrinkle volume, a 19.9% decrease in wrinkle depth and 16% decrease in roughness compared to baseline but no benefit with placebo. In the second clinical study in older men, Matrixyl 3000 cream gel was applied on half the face versus placebo on the other half on crow’s feet wrinkles. With Matrixyl 3000, they found a significant 17.1% decrease in wrinkle volume and 10.2% decrease in wrinkle depth and 8.4% decrease in roughness compared to baseline but no benefit with placebo (Sederma Matrixyl 3000).

A final clinical study was conducted to image changes of the papillary dermis. As described in a follow-up US patent 2012/164488, Sederma conducted a double-blind, placebo-controlled clinical study in 28 women who applied Matrixyl 3000 on half the face and placebo on the other half for 2 months and found an improvement in dermal density and reduced fragmentation in the collagen fibers of the dermis with Matrixyl 3000 compared to placebo (Sederma Matrixyl 3000).

On their own, pal-GHK and pal-GQPR also represent two of the best studied signal peptides. As characteristic of signal peptides, GHK and GQPR are fragments of proteins found naturally in the human body that are involved in ECM remodeling particularly during wound healing. GHK is a fragment of the alpha 2 chain of type I collagen while GQPR is a fragment of immunoglobin G. By linking each of these peptides to a palmitoyl group (and hence the pal-), these peptides become lipophilic. In other words, being lipophilic, they can cross the stratum corneum, the waterproof outer layer of the skin barrier, and can be absorbed into the deeper layers of the skin where they have their action.

GHK was first isolated from human plasma in 1973 (Pickart and Thaler 1973) and its wound repair properties were first observed in 1985 by Maquart and colleagues who found GHK was a potent activator of ECM synthesis and remodeling (Maquart et al. 1999). GHK has been found since then to have multiple biological actions improving tissue repair in skin, lung connective tissue, boney tissue, liver, and stomach lining. It has a wide range of effects on gene expression (Pickart and Margolina 2018). When damage activates proteolytic enzymes, GHK is released into the site of injury. GHK can stimulate skin dermal fibroblasts to produce growth factors and increase collagen synthesis and epidermal basal cells increasing integrins and p63 expression (Pickart and Margolina 2018, Lintner 2002).

GHK content is highest in the young with plasma levels at about ~200ng/ml at age 20 which declines to ~80ng/ml at age 60. This natural decline with aging may in part explain why adding peptides back to the skin can reverse signs of aging. GHK has been used in anti-aging and cosmetic products in humans for decades without any adverse effects and so has an established safety record (Pickart and Margolina 2018). Even without co-formulation with pal-GQPR, pal-GHK can increase collagen and GAG synthesis as well as improve collagen repair (Sederma Matrixyl 3000).

There is some misinformation on the web that states signal peptides such as GHK that are involved in wound healing have negative effects such as increasing inflammation because they mimic wounds. This is untrue as GHK has proven anti-inflammatory and antioxidant activity. GHK has anti-inflammatory benefits by reducing TNF-alpha induced secretion of proinflammatory cytokine IL-6 in dermal fibroblasts, and GHK is an efficient antioxidant, inactivating damaging free radical by-products of lipid peroxidation (Pickart et al. 2015, Pickart and Margolina 2018).

Pal-GQPR has also been studied and used separately from pal-GHK for many years in both skin and eye creams. GQPR is a fragment of immunoglobin G which is immunomodulatory. As skin ages, there is an increase in inflammatory cytokine IL-6, which may contribute to chronic inflammation in the aging process. The putative mechanism by which Pal-GQPR works is by reducing IL-6 secretion by keratinocytes. However, like GHK, GQPR changes the expression of multiple genes and so it has a broad effect on fibroblast activity that goes beyond anti-inflammatory action. Studies by Sederma show that pal-GQPR and pal-GHK activate complementary genes explaining the synergy between the two peptides (Sederma Matrixyl 3000).