“Breakthrough” skincare products always arrive with a big marketing splash, often including testimonials from key opinion leaders in dermatology or aesthetic medicine. Even when such august names offer their well-considered opinions, a dash of that proverbial grain of salt might be something to consider as well.
When your BFT hosts started exhibiting at medical trade shows a few years ago, we seldom met a physician who had more than cursory familiarity with the complex cellular language of human cells. The reason is simple: there are hundreds of individually identified bio-signals and trillions of cells. No wonder most practitioners had little more than passing familiarity with the topic. If we did find someone with in-depth knowledge, they were more than likely PhD level specialists in the field, not practicing physicians.
EXPERTS? MAKE SURE.
After several years of lecturing throughout North America, Europe, the Middle East, and Asia, the majority of practicing physicians still consider the field of topical bio-signals in skincare a black box. And based on numerous conversations through the years, that is true of some of the biggest names in dermatology, anti-aging medicine, plastic surgery and other medical specialties. People with busy practices can only keep up with so much – reading journals and attending specialty academic lectures takes time and effort. As prior busy practicing specialists themselves, your BFT hosts find no fault on that score with anyone.
We have covered the topic in some depth. In the past, BFT has written about the questionable and utterly non-physiologic use of single bio-signals (e.g. EGF), the differences in the secretomes of fat, bone marrow and umbilical cord derived stem cells, PRP (platelet rich plasma), the questionable ethics of using honest-to-goodness human embryonic stem cells to create skincare products without informing consumers of that fact (to wit, the CSC14 cells used to produce ingredients in Provoque come from human embryos), and the (to us) illogical use of lysed fibroblasts (NeoCutis) or lysed “parthenogenic” stem cells (LifeLine) in skincare.
Such lysed cell-derived ingredients seemed non-phsiologic to us then, and still do today. Fibroblasts are puny weaklings when it comes to secreting bio-signals, and there are no parthenogenic stem cells in human physiology, hence no proven role for them in the repair and regeneration of injured (i.e. aging) skin. That did not stop International Stem Cell Corporation from aggressively marketing LifeLine products, whose breakthrough ingredient is lysed parthenogenic stem cells. Any newly-discovered “breakthrough” ingredient is all it takes to make a compelling marketing message and launch a new product.
Success, however, is not guaranteed. International Stem Cell Corporation still managed to financially implode, even after LifeLine was introduced. BFT reviewed the LifeLine science and company fortunes several years ago.
IF AT FIRST YOU DON’T SUCCEED…
The technology in DefenAge is from the same scientist who was the Director of Research & Therapeutic Development at International Stem Cell Corporation, the developers of LifeLine.
His latest technology, Age-Repair Defensins, is the touted breakthrough ingredient in DefenAge and consists of combined alpha and beta defensins. The defensins in the product are synthetically produced.
(Just so we’re clear – nothing wrong there. Synthetically produced bio-signals are used in many products, including several we make.)
“INTERESTING” PHYSICIAN TESTIMONIALS about DEFENAGE
DefenAge is being marketed aggressively, with much of the collateral in the form of testimonials from KOLs describing clinical results and the scientific foundation of the product, sometimes (in our humble opinion) with questionable use of language.
“The key ingredient, Age-Repair Defensins®, features a stand-alone NATURAL mechanism of action, and has been named “the newest peptide on the market” and “one of the biggest breakthroughs in skin care”. These peptides are synthetically produced and target dormant Skin’s Master Stem Cells.”
“What I thought was so fascinating about DefenAge was that it was something that could simulate dormant stem cells which I had never seen in this type of delivery system before. There are many products claiming to have stem cells, but creams don’t contain living organisms in them so the idea that you could stimulate the skin to become more useful without turning on bad cells was a very exciting proposition.”
“DefenAge contains peptides. Many people have heard about peptides as they are in a variety of consumer skin care lines. However, there are different types of peptides and the ones that are unique to DefenAgeÒ are called Age-Repair DefensinsÒ. Defensins – a scientific term – are meant to defend the body and there are two kinds of defensins called Alpha and Beta defensins. DefenAge contains both of those defensins which are naturally occurring peptides that work directly to stimulate dormant LGR6 positive stem cells to create enduring new healthy cells from a pool of cells that are themselves young.”
“How is this different than growth factors? Growth factors don’t actually penetrate the skin but they do send signals to turn on cells. The difference is that the cells they (growth factors) are activating are cells that have already been working for the age of the person, so they are turning on tired and fatigued cells, whereas DefenAge’s Age-Repair Defensins act upon the dormant cells that have never been turned on and are basically brand new, never been used before cells – basically very “fresh” cells.”
“Age-Repair Defensinsâ[.…]“they awaken key cells that are lying dormant, and are thus younger and healthier, rather than taxing the limited ability of currently active skin cells to affect healthy therapeutic processes.”
Huh? What does this even mean? And, where’s your proof ?
The physicians making these statements are all highly respected among their peers, so their comments carry weight and have potential to influence others to adopt the same point of view. Are these esteemed physicians making the takeaway message that “dormant”, as opposed to “fresh” cells, are otherwise doing nothing within the skin until the “Age-Repair DefesinsÒ” show up and awaken them from their slumber?
If so, we say balderdash. Even one of their physician experts appears to think so.
Miami dermatologist, skincare researcher and Founder of Skin Type Solutions, Leslie Baumann, MD, explains, ‘LGR6+ stem cells reside in the hair follicle. When the skin is wounded, immune cells release defensins which activates LGR6+ to repopulate the epidermis. A new technology using topically delivered defensins has been shown to activate these same LGR6+ stem cells. This results in rejuvenation of the epidermis through formation of new basal stem cells and new keratinocytes.’
So, it is not necessary to apply topical defensins to activate these LGF6+ cells. They “activate” on a regular basis due to intrinsic signals within the skin. If that were not the case, how would injured skin heal unless DefenAge was slathered onto it? Wouldn’t our cells just remain “dormant?” Someone should inform the other experts.
IS THE PUBLISHED STUDY REALLY WHAT IT CLAIMS? WE DON’T THINK SO.
Three oft quoted advocates for DefenAge are physicians who co-authored the debut article about it in the Journal of Drugs in Dermatology. These authors are also co-owners of the company that produces the product. Remember that grain of salt we mentioned above? Two of the five authors of the study are not owners of the company.
The study title is “Multi-Center, Double-Blind, Vehicle-Controlled Clinical Trial of an Alpha and Beta Defensin-Containing Anti-Aging Skin Care Regimen with Clinical, Histopathologic, Immunohistochemical, Photographic, and Ultrasound Evaluation”. It was published in April 2018, Vol. 17, Issue 4.
The title is not only long, we believe it is grossly misleading.
For those who wonder what the term “vehicle-controlled” means, it is the part of the study design that is intended to eliminate the placebo effect. Neither the study staff nor the study subjects knew whether or not the products a subject was using indeed contained alpha and beta defensins. That’s fine, but from what is revealed in the article, there are a number of additional variables that the study title does not mention.
The list of ingredients in the “vehicle” and “active” versions of three products tested (mask, cream, serum) differ by much more than just alpha and beta defensins. If that is the case, one wonders how such declarative conclusions concerning the efficacy of defensins can be made. A true “vehicle-controlled” study would have varied ONLY by whether or not alpha and beta defensins were in the active versions.
Ingredients in the full formula mask, that are not included in the “vehicle” mask include: Carica Papaya (Papaya) Fruit , Papain, Aloe Barbadensis Leaf Juice, Lactobacillus/Pumpkin Ferment Extract, Lactobacillus/Punica Granatum Fruit Ferment Extract, Sea Whip Extract.
Ingredients in the full formula cream, that are not included in the “vehicle” cream include: Niacinamide, Yeast Extract, Phospholipids, Alpha-Defensin 5, Beta-Defensin 3, Hyaluronic Acid, Ophiopogon Japnicus Root Extreact, Hydrolyzed Candida Saitoana Extract, Sea whip Extract, Lycium Chinense Fuit Extract, Vaccinium Angustifollium Fruit Extract, Vaccinium Marcrocarpon Fruit (Cranberry) Fruit Extract, Panthenol, Albumin, Tocopheryl Acetate, Ubiquinone, L-Alany-L-Glutamine, Leuconostoc/Radish Root Ferment Filtrate, SH Oligopeptide-1 (i.e synthetic version of epidermal growth factor.)
Ingredients in the full formula serum, that are not included in the “vehicle” serum include: Niacinamide, Sinorhizobium Meliloti Ferment Filtrate, Phospholipids, Alpha-Defensin 5, Beta-Defensin 3, Palmitoyl Tripeptide-38 (a peptide also known as MatixylTM synthe’6TM which “evens out skin relief and smooths wrinkles”) Sodium Hyaluronate, Arabidopsis Thaliana Extract, Sea Whip Extract, Ergothioneine, SH Oligopeptide-1 (i.e. synthetic version of epidermal growth factor), Tocopheryl Acetate, Ubiquinone, Leuconstoc/Radish Root Ferment Filtrate, Albumin, L-Alanyl-L-Glutamine, Cetyl Hydroxyethylcellulose, Lecithin, Hydroxypropyl Cyclodextrin.
Far from being an apples-to-apples comparison of the same product with and without alpha and beta defensins, the full ingredient products contain numerous additional active ingredients with peer-reviewed proof of efficacy in improving the appearance of aging skin. The products we developed contain many of the same active ingredients.
So, what is it that accounts for the skin changes reported? The defensins, as the study title implies, or the several other active ingredients that can be found in many other high-quality cosmeceuticals? Or maybe it’s all of them.
This is NOT a “vehicle controlled” trial. If the intention is to prove the benefits of alpha and beta defensins in skincare, this study does no such thing.
LET’S LOOK AT WHAT THE PUBLISHED LITERATURE SAYS
Dynamics of Lgr6+ Progenitor Cells in the Hair Follicle, Sebaceous Gland, and Interfollicular Epidermis. Stem Cell Reports. 2015 Nov 10; 5(5): 843–855.
“We show that these Lgr6+ (leucine-rich repeat-containing G protein-coupled receptor 6) cells constitute long-term self-renewing populations within each compartment in adult skin.”
Lgr6 Marks Stem Cells in the Hair Follicle That Generate All Cell Lineages of the Skin. Science 12 Mar 2010: Vol. 327, Issue 5971, pp. 1385-1389
“Mammalian epidermis consists of three self-renewing compartments: the hair follicle, the sebaceous gland, and the interfollicular epidermis. [….]Prenatal Lgr6+ cells established the hair follicle, sebaceous gland, and interfollicular epidermis. [….] Adult Lgr6+ cells executed long-term wound repair, including the formation of new hair follicles.”
Transplantation of the LGR6+ epithelial stem cell into full-thickness cutaneous wounds results in enhanced healing, nascent hair follicle development, and augmentation of angiogenic analytes. Plast Reconstr Surg. 2014 Mar;133(3):579-90.
“Stimulation of the follicular bulge LGR5+ and LGR6+ stem cells with the gut-derived human alpha defensin 5 results in decreased bacterial presence, enhanced wound healing, and hair growth from tissues devoid of adnexal structures.”
SO, WHAT DO WE LEARN FROM THESE ARTICLES?
It is well established that there are skin stem cells located in the hair follicles, sebaceous glands, and between follicles within the epidermis. These cells are required for skin healing to occur throughout life, meaning they are far from “dormant”. They are on duty continuously, ready to respond to appropriate signals. Alpha defensins can be the signal. Nothing is said about from where these defensins must originate in order to stimulate stem cell activity.
Topical alpha defensins can promote healing when applied to full-thickness cutaneous (skin) wounds. The alpha defensins can be synthetic and created in a laboratory. In our day-to-day lives, however, the defensins that promote healing are secreted from nearby local white cells (PMN – polymorphonuclear neutrophils) that arrive at sites of injury, and incidentally do so at the bidding of the bone marrow stem cells that migrate to the injury to orchestrate the symphony of healing.
Defensins are of several types, the most common being alpha and beta, As a general rule, one can consider alpha defensins to be predominant within the gut, and beta defensins as being predominant in and on the skin.
Alpha defensins are gut peptides involved with innate immunity and regulation of microbial balance in the intestine i.e. they make sure “good” bacteria predominate in the intestinal tract. Alpha defensins are also exceptionally strong neutrophil attractors, which is the sine quo non for INFLAMMATION. Their effect is so potent, they are used as inflammatory markers and correlate highly with atherosclerosis, coronary artery disease and even acne.
Since alpha defensins are pro-inflammatory, which is pro-aging by definition, their application to skin seems like a questionable strategy, especially if done on a regular basis. The following quote is particularly compelling in making the case that alpha-defensins are pro-inflammatory.
“Human neutrophil-derived alpha-defensins (HNPs) are proven capable of enhancing phagocytosis by mouse macrophages. HNP1-3 have been reported to increase the production of tumor necrosis factor (TNF) and IL-1, while decreasing the production of IL-10 by monocytes. Increased levels of proinflammatory factors (e.g., IL-1, TNF, histamine and prostaglandin D2) and suppressed levels of IL-10 at the site of microbial infection are likely to amplify local inflammatory responses.”
Some of our readers may recognize tumor necrosis factor (TNF) and interleukin 1 (IL-1) as two of the most pro-inflammatoroy bio-signals in existence. And because interleukin 10 (IL-10) has pronounced anti-inflammatory potency, the sum total effect of alpha-defensins is decidedly pro-inflammatory. That is fine if robust inflammation is needed to heal an acute wound; increased delivery of oxygen and nutrients is beneficial in such circumstances. But what about when used as an anti-aging ingredient in one’s daily skincare regimen? Is chronic smouldering inflammation something to be actively pursued?
Regular BFT readers are well aware that we consider any effort to induce inflammation as an anti-aging strategy to be irrational and counterproductive. Inflammation is aging by definition. Period. As we have written in BFT many times, subclinical inflammation has an edematous component, which can contribute to plumper skin with reduced appearance of fine lines. But, at what price if smouldering inflammation is slowly damaging tissues?
The physiologic role of alpha defensins is to help maintain healthy gut flora.
The following references provide additional evidence as to the pro-inflammatory nature of alpha-defensins. Of particular interest is the association of alph-defensins in acne, making the deliberate use in facial skincare potentially ill-advised.
Alpha-Defensin: link between inflammation and atherosclerosis. Atherosclerosis. 2007 Oct;194(2):452-7
“The deposition of alpha-defensin in the skin is a strong independent predictor of CAD in men. These results suggest a link between neutrophil activation and progression of atherosclerosis and provide a novel approach to assessment of risk factors for CAD (coronary artery disease).” (Note: the article looked at alpha-defensin withint the skin in CAD patients; not from topical application.)
Enteric α-defensins on the verge of intestinal immune tolerance and inflammation. Semin Cell Dev Biol. 2018 Jan 29.
“The gut is the biggest immune organ in the body that encloses commensal microbiota which aids in food digestion. Paneth cells, positioned at the frontline of host-microbiota interphase, can modulate the composition of microbiota. Paneth cells achieve this via the delivery of microbicidal substances, among which enteric α-defensins play the primary role. If microbiota is dysregulated, it can impact the function of the local mucosal immune system.”
Increased alpha-defensin expression is associated with risk of coronary heart disease: a feasible predictive inflammatory biomarker of coronary heart disease in hyperlipidemia patients. Lipids Health Dis. 2016 Jul 18;15:117
“Polymorphonuclear neutrophils play a pivotal role in inflammation and atherogenesis. Human neutrophil peptides (HNPs) or alpha (α)-defensins are cysteine-rich cation polypeptides that are produced and released from activated polymorphonuclear neutrophil granules during septic inflammation and acute coronary vascular disorders. HNPs cause endothelial cell dysfunction during early atherogenesis.”
Expression of human neutrophil proteins in acne vulgaris. J Eur Acad Dermatol Venereol. 2010 Jan;24(1):32-7
“Our current study demonstrates the novel observation that a recently identified antimicrobial peptide, HNP 1-3, is expressed in neutrophils of acne inflammation but not in uninvolved skin of these patients. These results suggest that HNP 1-3 may contribute to the development of inflammatory lesions of acne.”
Beta-defensins are an important family of cationic antimicrobial peptides which greatly enhance the resistance of epithelial surfaces, including skin, to microbial colonization. In contrast to alpha defensins, beta defensins are anti-inflammatory
Identification of a cell-penetrating peptide domain from human beta-defensin 3 and characterization of its anti-inflammatory activity. Int J Nanomedicine. 2015; 10: 5423–5434.
“hBD3-3 has the ability to be used as a carrier, and suggest a potential approach to effectively treat inflammatory diseases.”
The Effects of Human Beta-Defensins on Skin Cells in vitro. Dermatology. 2017;233(2-3):155-163.
“Beta defensins exert biological effects on skin cells that are potentially beneficial in wound healing.”
Expression of the peptide antibiotics human beta defensin-1 and human beta defensin-2 in normal human skin. J Invest Dermatol. 2001 Jul;117(1):106-11.
“The localization of human beta defensins to the outer layer of the skin is consistent with the hypothesis that human beta defensins play an essential part in cutaneous innate immunity.”
Human β-defensin-3 increases the expression of interleukin-37 through CCR6 in human keratinocytes. J Dermatol Sci. 2015 Jan;77(1):46-53
“Interleukin (IL)-37, a new member of the IL-1 family, is characterized as a fundamental inhibitor of innate immunity: it dampens the production of proinflammatory cytokines, protects against inflammatory and autoimmune diseases, and plays a potent immunosuppressive role in the pathogenesis of psoriasis.”
Defensins: “Simple” antimicrobial peptides or broad-spectrum molecules? Cytokine Growth Factor Rev. 2015 Jun;26(3):361-70.
“While human α-defensins are mostly expressed by neutrophils, β-defensins are secreted by epithelial cells of the skin and mucosae. Besides their anti-microbial activity, accumulating data emerged in the past decade indicating that defensins have extended functions in human physio(patho)logy. Indeed, defensins appeared as modulators of the adaptive immune system and angiogenesis, key mediators of wound healing and determinant players in male fertility.”
Identification of a cell-penetrating peptide domain from human beta-defensin 3 and characterization of its anti-inflammatory activity. Int J Nanomedicine. 2015 Aug 26;10:5423-34
Human beta-defensins (hBDs) are crucial factors of intrinsic immunity that function in the immunologic response to a variety of invading enveloped viruses, bacteria, and fungi. hBDs can cause membrane depolarization and cell lysis due to their highly cationic nature. These molecules participate in antimicrobial defenses and the control of adaptive and innate immunity in every mammalian species and are produced by various cell types. [….] Our findings indicate that hBD3-3 may be conjugated with drugs of interest to ensure their proper translocation to sites, such as the cytoplasm or nucleus, as hBD3-3 has the ability to be used as a carrier, and suggest a potential approach to effectively treat inflammatory diseases.
BEWARE: USE OF DEFENAGE WITH MICRONEEDLING CAN BE PROBLEMATIC.
One of the physician testimonials touting DefenAge compared the benefits of PRP (platelet rich plasma) and DefensAge when used in conjunction with microneedling of the face. In the study, PRP was used at time of needling on half of the patients and DefenAge applied 48 hours after treatment on the other half of patients. The reported result was DefenAge patients had superior aesthetic outcomes. Without going into the specifics of that trial, we feel obliged to caution BFT readers to NOT use DefenAge at or near the time of microneedling treatment. Be sure to wait the 48 hours if interested in seeing how, and if, DefenAge can enhance results. The reason for this has to do with the presence of several types of silicone in the ingredient list of DefenAge
The ingredient deck of DefenAge is below. Please note it contains several kinds of silicones (in bold), something proven to be a potential inciting ingredient for granulomatous dermatitis. The enhanced penetration that microneedling creates, can allow such foreign substances to gain entrance into the skin with potential ill effects.
Water (Aqua), Cyclopentasiloxane, Glycerin, Niacinamide, Sinorhizobium Meliloti Ferment Filtrate, Dimethicone, Polysorbate 20, Dimethicone/Vinyl Dimethicone Crosspolymer, Lauryl PEG-9 Polydimethylsiloxyethyl Dimethicone, Ammonium Acryloyldimethyltaurate/ VP Copolymer, Phospholipids, Alpha-Defensin 5, Beta-Defensin 3, Palmitoyl Tripeptide-38, Sodium Hyaluronate, Arabidopsis Thaliana Extract, Sea Whip Extract, Ergothioneine, Helianthus Annuus (Sunflower) Seed Oil, Rosmarinus Offinalis (Rosemary) Leaf Extract, SH Oligopeptide-1, Tocopheryl Acetate, Ubiquinone, Leuconostoc/Radish Root Ferment Filtrate, Albumin, Gelatin, L-Alanyl-L-Glutamine, Caprylic/Capric Triglyceride, Cetyl Hydroxyethylcellulose, Lecithin, Hydroxypropyl Cyclodextrin, Phytic Acid, Phenoxyethanol, Caprylyl Glycol, Ethylhexylglycerin, Hexylene Glycol, Sodium Chloride.