Tag Archives: skin

Cholesterol in Skin Care

Cholesterol has a negative image among many people given the unhealthy nature of dietary cholesterol. But cholesterol is made by all of our cells, and it is an important component in the skin’s barrier. Let’s quickly look at why cholesterol is successfully used in skin care products.

As the outermost layer of the epidermis, the stratum corneum serves as an important barrier. It is composed of terminally differentiated (fully matured cells), anucleated corneocytes that are derived from keratinocytes, that reside within a lipid matrix. Together, the corneocytes and lipid matrix comprise the “bricks and mortar” structure of the stratum corneum. When combined with ceramides and free fatty acids, cholesterol forms the lipid mortar between the dead corneocytes, forming a water-impermeable barrier that prevents evaporative water loss. This structure, along with other structures such as tight junctions in the epidermis, create a barrier to external insults from pathogens, allergens, and toxins. Cholesterol reaches its highest concentration in the granular layer of the epidermis, just under the stratum corneum.

Cholesterol used in topical products is usually of vegetable origin, primarily derived from squalene. It is safe and effective (when used with free fatty acids and ceramide) as a topically applied product. That is, complete mixtures of ceramide, free fatty acid, and cholesterol facilitate normal barrier function when applied topically. However, incomplete mixtures of these lipids produce abnormal lamellar bodies, the critical organelles that regulate the formation and maintenance of the skin barrier. This leads to an abnormal stratum corneum. In other words, unless you use the complete mixture of lipids; ceramide, cholesterol, and free fatty acids, the barrier function of the stratum corneum will not be optimal. This is why I formulated Neogenesis’ Barrier Renewal Cream to contain the complete set of lipids, including cholesterol, ceramide, and free fatty acids, necessary for optimally building the stratum corneum.

Many people ask, what are these three lipids; cholesterol, ceramide and free fatty acids?

Lipids are fatty, waxy, or oily compounds that are soluble in organic solvents and insoluble in polar solvents such as water. Lipids include:

  • Fats and oils (triglycerides)
  • Phospholipids
  • Waxes
  • Steroids

Lipids that are important to our discussion of skin and human cells include fats and oils (triglycerides or triacyglycerols), fatty acids, phospholipids, and cholesterol. Cholesterol and plant sterols, such as sitosterol, are high-molecular-weight alcohols with a characteristic cyclic nucleus. Fatty acids generally consist of a straight alkyl chain, terminating with a carboxyl group. Ceramides belong to the sphingolipids. Their structure consists of a hydrocarbon chain termed long-chain base, such as sphingosine or phytosphingosine. One fatty acid is linked to the ceramide. In this case, the fatty acid is not “free,” rather it is a component of the ceramide. The free fatty acids are not linked to the ceramide.

The bottom line: The biochemistry of lipids in the body, including the skin, is complex. Just remember the three lipid types that are critical to building normal barrier function, namely, cholesterol, ceramide, and free fatty acids. If you want to delve into the complexity of lipid biochemistry in the skin, a set of excellent research and review papers are found here.

Skin Microbiome: Microbes, Molecules, and Mechanisms

Human skin epidermis functions as a physical, chemical, and immune barrier against the external environment, retains internal moisture, while also providing a protective niche for its resident microbiota, known as the skin microbiome. Cooperation between the microbiota, host skin cells, and the immune system is critical for the maintenance of skin health, and a disruption to this delicate interplay, such as by pathogen invasion or a breach in the skin barrier, often leads to impaired skin function, such as eczema. Microbial metabolites and products (something I named “postbiotics” in my 2019 paper), including microbial exosomes, have been identified to mediate these interactions, particularly those involved in skin-microbe communication and defensive symbiosis, where the microbes and skin work together to ward off pathogen colonization. 

Given the small size, ubiquity, and complexity of the microbiota, scientists have had great difficulty in understanding the role of microorganisms in the health and diseases of humans. Before the germ theory of disease was accepted and bacteria were successfully cultured from human tissues, Semmelweis dramatically reduced the mortality rate of pregnant women by simply introducing hand washing in his clinic, and in the late 1800s, Lister pioneered antiseptic surgical procedures. By the early 1900s, the idea that humans are colonized by microorganisms in the hours after birth was well accepted. However, given the inability to fulfill Koch’s postulates in some dermatological diseases, the significance of the skin microbiota in health and disease remains under investigation. Understanding the microbiome’s role in health and disease requires the following:

  1. The organism must be shown to be invariably present in characteristic form and arrangement in the diseased tissue.
  2. The organism, which from its relationship to the diseased tissue appears to be responsible for the disease, must be isolated and grown in pure culture.
  3. The pure culture must be shown to induce the disease experimentally.
  4. The organism should be re-isolated from the experimentally infected subject [this postulate was added after Loeffler].

Fulfilling these criteria in Koch’s postulates is difficult if for only meeting criteria #2, where isolating and then culturing the microorganism can be very difficult. Likewise, #3 is difficult because it requires purposely infecting people. Often the criteria are fulfilled in animal models of the disease, but not humans.

While Koch’s postulates are valuable in helping to understand infectious diseases, the concept is reductionistic. That is, diseases are multifactorial. Koch’s postulates will look for one pathogen involved in the disease, while the disease may involve not only other pathogens, but also other health aspects of the host such as environmental exposures and one’s health status. My point is that any disease, including infectious diseases, are multifactorial. Exploring one of many factors will not be predictive of transmission or of outcomes. For example, if we look at acne, P. acnes is one factor in the disorder. And P. acnes exists in different forms, with a distinctly different phenotype in the acneic lesion versus the normal areas of skin. Further, bacteriophage are involved. These are viruses that infect bacteria, in this case, infecting P. acnes. The P. Acnes variants in the acneic lesion areas of the skin don’t contain an immune system called CRISPR. Therefore, these bacteria become infected with bacteriophage and harbor these inflammatory viruses. This is one of the reasons why we believe the NeoGenesis product called MB-1 is helpful to acneic skin. MB-1 contains skin identical bacteria that possess the CRISPR system and are likely killing the inflammatory bacteriophage. So the MB-1 helps to populate the skin with symbiotic bacteria, out competing inflammatory bacteria, and also introduces CRISPR containing bacteria that kill the inflammatory bacteriophage. Considering MB-1, it’s like showing the opposite of Koch’s postulates. The organisms we use to make MB-1 are present in normal skin (1), and the bacteria in MB-1 seem to be responsible for reducing the disorder when applied to the affected area of skin (2). However, 3 and 4 of Koch’s “opposite postulates” are difficult to perform. We’d have to isolate the MB-1 bacteria from the skin, culture them, and then apply the cultured bacteria to acneic skin, showing the cultured MB-1 bacteria reduce the acneic lesion. This is the sort of difficult work that scientists are currently performing to understand infectious diseases.

There are new techniques being employed, such as genomics (Next Generation Sequencing), so that the genetic fingerprint of pathogens can be used to identify what is or has been present in the infected tissue. For example, bacteria that once populated the area of skin under investigation but have now died and are no longer present, often leave a genetic fingerprint of their past colonization. This technique alone has brought a wealth of information about skin disease. I’ll have more to say about the skin’s microbiome in future posts. We understand much about it, and I’ll share some of the complexities in the weeks to come.

Glycation: What Is It, and How Do We Prevent It?

There’s a big difference between glycation and glycosylation. Glycation is unhealthy, glycosylation is predominantly beneficial.

Glycosylation refers to an enzyme-mediated modification that alters protein function, for example, extending their life span by protecting against denaturation or proteolytic degradation. Glycosylation can also enhance a protein’s interactions with other proteins. By contrast, glycation refers to a monosaccharide (usually glucose) attaching nonenzymatically to the amino group of a protein. In other words, the enzymatic cross-linking of carbohydrates to other organic molecules, such as proteins, is called glycosylation and is an important post-translational modifications of proteins, essential for human cell signaling and metabolism. Glycation is different than glycosylation. Less commonly known is the non-enzymatic and less specific reaction called the Maillard reaction, after its discoverer Louis-Camille Maillard. This is the reaction that underlies the browning of bread. The Maillard reaction takes place in multiple steps, leading to the irreversible formation of advanced glycation end products (AGEs). In the early steps of the reaction, the sugars can react irreversibly with amino acid residues of peptides or proteins to form protein adducts or protein crosslinks. Initially this step of glycation affects the interactions of collagen with cells and extracellular matrix components. However, the most damaging effects of glycation are caused by the formation of glucose-mediated intermolecular cross-links. The cross-linking decreases the critical flexibility and permeability of the tissues and reduces cellular turnover. Advanced glycation end products form and bind to long-lived proteins in the skin, cross-linking them, damaging their structure, deforming their fibers. Many proteins in the skin, including collagen, can be long lived. That is, these long lived proteins don’t turnover for years, sometimes decades. As such, they are susceptible to damage, including through glycation. This glycation of collagen in the skin, noticeable as browning skin, likely means glycation of the collagen is happening in other parts of the body, including the cardiovascular system.

In the last step, when oxidation is involved, the products are called advanced glycation end products (AGEs). AGEs are formed through four pathways: (1) the Maillard reaction, (2) sugars auto-oxidation pathway, (3) lipid peroxidation pathway, and (4) polyols pathway. Glucose is converted into fructose via the polyol pathway (based on aldo-keto reductase enzymes), which accelerates the production of AGEs. The formation of AGEs is a slow process that occurs physiologically in vivo, with higher accumulation of AGEs in tissues with slow renewal rates, such as the skin’s long lived proteins. AGE levels are increased in patients due to increased production, but they are also increased due to impaired excretion. In conditions such as metabolic and oxidative stress, AGE accumulates more rapidly. New, non-invasive assessment techniques of AGE are now available. The measurement is made using skin autofluorescence.

Not only is the skin autofluorescence (SAF) a measure of AGE in the skin, but the value determined in the skin is highly correlated with that in other parts of the body. That is, the measurement of AGE accumulation in the skin can serve as a biomarker for disease states other than those in the skin, including cardiovascular disease and diabetes mellitus. Chronic kidney disease has also been recently shown to correlate with SAF. As I have said previously, the health of the skin is an important biomarker for the health of many other organs in the body.

Not surprisingly, an environmental factor that is likely to have a profound effects on AGE accumulation is diet. Studies have shown that breastfed infants, consuming few AGEs, had lower SAF intensities than formula-fed infants, a diet rich in AGEs. Meat consumption is also associated with higher AGEs, where lower SAF values have been observed for vegetarians in hemodialysis patients.

In addition to environmental factors, herditary factors are likely to contribute a small amount to the observed AGE phenotypes as measured by SAF.  Studies of twin and sibling pairs have implicated heredity as partly responsible for lens and skin fluorescence variations.

So what can we do? Reducing our consumption of sugars and simple carbohydrates is one obvious prophylactic measure. Another is reducing one’s consumption of meat, and eating a diet rich in vegetables. And, because environmental (dietary) AGEs promote inflammatory mediators, leading to tissue injury, restriction of dietary AGEs will suppress these effects. This is true in the skin, as well as throughout the body. Further, because metabolic state, and oxidation are important to driving the formation of AGEs, in addition to healthy lifestyle and dietary practices, one can use a course of topically applied skin care products to promote better metabolism, increased anti-oxidative capacity, and a renormalization of the extracellular matrix (ECM) in order to better prevent glycation and the formation of cross-linking and AGEs in the skin. Important to a skin care routine to prevent and remediate AGEs is the inclusion of NeoGenesis’ S2RM technology to prevent and remediate damage to the ECM and to provide a wide variety of antioxidants.

Skin Derived Adipose Mesenchymal Stem Cells and Their Secretome in Wound Healing and Skin Aging

Adipose-derived stem cell secretome has been successfully used for treatment of various diseases, e.g., multiple sclerosis, rheumatoid arthritis, osteoarthritis, fistulae, diabetes mellitus, autoimmunity, and cardiovascular diseases, but also in skin aging, skin diseases, and wound healing. Let’s focus on the skin wound healing and aging.

Skin derived adipose mesenchymal stem cell (AMSC) secretome is a key component in the S2RM technology used by NeoGenesis in many of its skin care products. These mesenchymal stem cells are found in the hypodermis and dermis of intact, normal skin. Secretome is the complete set of molecules released by the AMSCs, the same set of molecules that the AMSCs in the skin normally release to help maintain and heal the skin. Secretome is what we call “stem cell released molecules (SRM)” at NeoGenesis. All the molecules released by the stem cell. And the “2” is present because we use the SRM from two types of skin derived stem cells, hence S2RM. So what we’re using at NeoGenesis is the complete set of all stem cell released molecules from two types of skin-derived stem cells, including the AMSCs. The other stem cell type used in the S2RM are fibroblasts derived from the skin. Fibroblasts are progenitor cells that are distinct from mesenchymal stem cells. Here’s a quick look at why this skin-identical ingredient, S2RM, is so useful in skin care. We’ll focus on the AMSC component of the S2RM. In another post, I’ll describe the many benefits of the fibroblast secretome. The approach we use at NeoGenesis is what I call, “Stem cell therapy without the cells,” a methodology that uses the many molecule types released from skin resident stem cells to renormalize the skin’s physiology.

The skin is physical barrier against physical, chemical, and biological damage. It is normally self-repairing, and protects against dehydration and thermal, pathogenic, chemical, and physical stress. Repairing physical damage in the skin is a dynamic process involving five overlapping stages of homeostasis, inflammation, proliferation, re-epithelization, and fibrosis. In clinical practice, AMSCs are usually administered as part of fractionated adipose tissue i.e., as part of enzymatically isolated stromal vascular fraction (SVF or cellular SVF), mechanically isolated SVF (tissue SVF), or as lipograft. AMSCs, as part of the full thickness skin grafts, have been used by physicians in their practices beginning in 1875 when Hungarian-born Scottish-trained surgeon John Reissberg Wolfe first developed the technique.

Let’s explore some of the mechanisms by which AMSCs exert their maintenance and repair of the skin. The mechanisms are complicated, and I’ll give you a glimpse into the many proteins and pathways that underly how AMSCs work in the skin. I’ve published on the immune modulating actions of AMSCs, and those of you interested in those aspects of AMSCs can read the paper as a free, open-access PubMed listed journal article. While the detailed pathways I write about below may not be important to those of you who are not scientists, what’s of value is to recognize the many pathways and many molecules types that are involved in maintaining and healing the skin. Products using one or a few peptides or proteins for example, will have minimal effect in bringing the skin to a healthy physiological state. In contradistinction, products that contain the many molecule types, such as S2RM, needed to maintain and heal the skin, will bring safe and efficacious results.

As part of their secretome, AMSCs secrete four key growth factors that promote re-epithelization: EGF, FGF-2, IGF-1, and TGF-β. These proteins induce the mechanisms underlying tissue repair including cell migration, proliferation, and differentiation as well as angiogenesis, extracellular matrix production, and inflammation resolution. Studies have found that co-treatment of AMSCs and AMSCs secretome increases the proliferation of dermal keratinocytes and fibroblast in the skin, and the maturation of fibroblasts through, at least partially, the upregulation of microRNA. Other studies have found that AMSC secretome prevents flap necrosis (cell death) after skin flap transplantation by increasing proliferation and secretion of IL-6. Another study found that AMSC secretome enhances skin flap recovery by reducing inflammation and apoptosis. AMSC secretome also prolongs the survival of vascularized composite allografts after transplantation by immune modulation, downregulating CD4+ T and Th1 cells and upregulating Tr1 and Treg cells. This paper exemplifies that the use of AMSCs secretome is an important new approach in reconstructive and plastic surgery. This is the all-important regulation of the immune system that is necessary for wound healing as described in my recent paper.

Key to tissue repair is the mitigation of inflammation. In addition to secreted immunomodulatory proteins by AMSCs, it is possible to modulate inflammatory pathways by microRNA in the AMSC secretome. Studies have found that AMSC secretome contains miR-21, which increases migration and proliferation of HaCaT (keratinocytes) cells by enhancing the matrix metalloproteinase 9 (MMP-9) expression in the PI3K/AKT pathway, thereby increasing wound healing. Also, miR-19b from AMSC secretome enhances wound healing by regulating the TGF-β pathway through targeting chemokine C-C motif ligand 1 (CCL1) by modulating the CCL1/TGF-β signaling axis. Delving more into these mechanistic pathways, TGF-β secreted by AMSCs has been found to act synergistically with growth differentiation factor 11 (GDF11) to reverse keratinocytes aging and trigger skin rejuvenation. Enhanced re-epithelialization, collagen remodeling, angiogenesis, and vessel maturation leading to improved wound healing were also found in diabetic mice treated with engineered AMSC secretome containing miR-21-5p. In digging deeper into these pathways, keratinocyte proliferation and migration and accelerated wound healing were induced through the Wnt/β-catenin signaling pathway in vitro, confirming earlier results where AMSC secretome was found to improve wound healing also through the Wnt/β-catenin pathway. AMSC secretome can also be used in alleviating atopic dermatitis.

Studies have found that an in vivo model of atopic dermatitis after AMSC secretome injection exhibited reduced clinical score, decreased level of inflammatory cytokines, serum IgE and blood eosinophil counts and CD86+ and CD206+ cells in skin lesions, as well as diminished infiltration of mast cells. Moreover, it has been shown that levels of inflammatory cytokines such as IL-4, IL-23, and IL-31 were reduced. Recently, Shin et al. found that not only the levels of these cytokines are reduced after AMSC secretome treatment in atopic dermatitis, but also IL-5, IL-13, TNF-α, IFN-γ, IL-17, and TSLP were reduced. The study also demonstrated that AMSC secretome restored expression of genes responsible for lipid metabolism, including ceramides, the cell cycle, a normal inflammatory response, as well as improving the skin barrier.

Furthermore, AMSCs and their secretome can be used in skin rejuvenation and wrinkle reduction, partly by stimulating collagen synthesis and regulating the proliferation and migration of dermal fibroblasts. You can think of wrinkles as a type of wound. Other studies have demonstrated the protective function of AMSCs secretome on dermal fibroblasts and keratinocytes against UVB-induced photoaging. They found reduced skin cellular senescence was observed in the group given AMSC secretome after UVB irradiation. Moreover, treatment with AMSCs secretome improved collagen I, collagen III, elastin, and TIMP-1 expression. AMSC secretome treatment was also able to upregulate the antioxidant response element (ARE), thus preventing and remediating damage to lipids, proteins, and DNA in the skin. 

These examples provide a glimpse into the complexity of maintaining and healing the skin, and exemplify why carefully formulated products that contain a multitude of skin-identical proteins, such as the S2RM in NeoGenesis products, are critical to providing a natural, safe, and efficacious means for skin care.

Why Skin Appearance Matters

People judge other’s traits based on facial appearance, and these inferences guide social interactions and avoidance. Facial skin blemishes and smoothness influence trait impression.

Healthy skin is beautiful skin, and that matters in a number of ways. I’ve frequently discussed how healthy skin, without chronic inflammation, is a means to better control systemic inflammation. That is, inflammation in the skin translates to inflammation in the body. Reducing inflammation in the skin, even in just the outer layer, the skin’s epidermis, results in reduced systemic inflammation.

Healthy skin is also important for other reasons, including our social interactions. People rapidly judge others based on the appearance of skin, especially facial skin. Studying ancient cultures, one can find beliefs that the face is a window to a person’s true nature. In Western culture, Kaspar Lavater (1800), a Swiss pastor, is given much credit for spreading the ideas of physiognomy, the “art” of reading personality in faces. Lavater said, “Whether they are or are not sensible of it, all men are daily influenced by physiognomy.” Unfortunately, when making social attributions from faces, people are making too much out of too little information. 

In a study from 2018 of skin smoothness and skin blemishes, scientists found these skin states to be critical for how people judge other’s traits. Across ratings of trustworthiness, competence, maturity, attractiveness, and health, the negative influence of skin blemishes was stronger and more consistent than the positive influence of skin smoothness. Further, the presence of skin blemishes diminished the positive effect of skin smoothness on attractiveness ratings. In sum, both facial skin blemishes and facial skin smoothness influence trait impression, but the negative effect of blemished skin is larger and more salient than the positive effect of smooth skin. To be clear, results of their study found that faces with skin blemishes were seen as less trustworthy, competent, mature, attractive, and healthy compared to the unmanipulated version of the faces. Results for the smoothed faces were less clear-cut.

Caring for your skin, therefore, is not only important for maintaining the health of the body’s largest organ and a huge component of your immune system, but also for one’s social interactions and psychological health. Be very careful of what products you use on your skin, eat a plant-forward diet to provide the nutrients your skin requires to be healthy, exercise, and expose your skin to only moderate amounts of sunlight – small amounts are beneficial. Healthier skin will result. Considering products used on the face, the positive effects of exercise on the skin can be mimicked by injecting IL-15 into the skin. The positive effects of a low dose of IL-15 can likely be derived from NeoGenesis Recovery, which contains the IL-15 cytokine in its S2RM technology, a natural and balanced mix of many skin-identical proteins, sourced from skin resident adipose mesenchymal stem cells. This is one of many benefits using S2RM technology in NeoGenesis products.

The Reductionist Pharma Mindset in Start-Up Skincare Companies – Purveyors of Magic Bullets

The recent spate of start-up skincare companies featuring technologies that rely on one one magical ingredient belie the complexities of the skin’s physiology – When will they ever learn about “Systems Therapeutics for Physiological Renormalization”?

Some recent examples of magic bullets being funded by venture capital and brought to the market by their marketing puppets include: the long-available and widely used ingredient called, phytosphingosine; a peptide du jour called OS-01 Peptide; another peptide du jour with the tradename, LIPOXERASE. I could go on, but these are a few examples that popped up on my radar over the weekend. Let’s be clear, the mindset of these private equity funded skin care companies is to develop skin care products in the same manner as drug companies. That mindset is reductionist, meaning that they feature one ingredient as a “cure all.” But making drugs that cure a disease is a bad business model – if it’s cured, the customer goes away and money is lost. The reductionist strategy is why most drugs don’t work, and most have serious negative side-effects. I wrote a book about this. Pharma knows it. Often the key is to develop one ingredient for which a patent can be attained. It doesn’t matter if the patented ingredient really works, it just matters that a patent is in place. Once the patent is granted, no one else can use the ingredient for about 15-20 years. This makes for great marketing hype in the USA. A new patented ingredient will spread like wild fire through the corporate media circles, and having heard the corporate media hype thousands of times over, many will believe the nonsense. These companies will make money, because with private equity behind them, they’ve got the money to hire the Mad Men. Private equity is a huge negative for healthcare. It doesn’t matter that the new patented or “patent-pending” (anyone can say this) product doesn’t work well, media hype will say that it does and people will buy it. Private equity makes money, your skin will whither.

So when will these people learn about “Systems Therapeutics for Physiological Renormalization“? The skin has a very complex physiology. And when you have a skin disease, the changes in physiology are complex. The disease is not about one pathway in the skin changing, and then using one ingredient to fix the pathway. Rather, disease is complex and involves many pathways, and a systems therapeutic that targets multiple pathways underlying the disease is required to significantly ameliorate the disease. That means many molecule types are delivered to the skin to renormalize the physiology, affecting all or many of the pathways underlying the disease, and to bring the skin back to a non-diseased state. This is the approach we use at NeoGenesis, the skincare company that I co-founded. We use a multitude of molecules, most of which are skin-identical, to renormalize the skin’s physiology. Those skin identical ingredients include the S2RM molecules – a collection of many molecule types that are released from adult stem cells derived from human skin. These molecules are an example of endogenous skin identical ingredients, because they are molecules produced by cells in the skin. We also use exogenous skin identical ingredients, such as Vitamin C, A, and E and essential fatty acids, that are derived from a healthy diet. These are all skin identical ingredients because they are normally found in the skin and man evolved to naturally use these ingredients, whether they are made in the skin or acquired through diet. Choosing a myriad of healthy ingredients with which man co-evolved is how I formulate our products at NeoGenesis. It’s not about one magical ingredient, it’s about a collection of healthy ingredients.

Why NeoGenesis Doesn’t Lyophyilize (Freeze Dry) Or Ultracentrifuge Our Secretome/Exosome S2RM – Fresh is Better

Some ignorant, non-scientist, physicians who are retired and lost their medical license for incompetence are pushing some marketing hype about lyophilized exosomes for skin care. Let’s see why this lyophilization technology is for the convenience of the company, and to the detriment of the secretome/exosome product. If left in their natural state, the way NeoGenesis does in its products, exosomes are highly stable and maintain their natural penetration abilities. So good are exosomes at penetrating barriers that they are now being used for drug delivery.

Have you ever had freeze-dried food? It’s not very good. But it is convenient. Hiking, camping, or traveling through outer space, freeze-dried food is convenient. You won’t find it served at your local three-star Michelin Guide rated restaurant (I double checked the menu of my local 3 star Michelin restaurant and found no freeze-dried food on the menu). The texture and taste is off. Exosomes, when they’re freeze-dried, called lyophilized in the industry, suffer a similar fate as the freeze-dried food. Their texture and function is degraded, but it sure is convenient for the company – it’s a means to easily and cheaply store the exosomes. Put the lyophilized exosomes in a jar, store them in your company’s closet for decades, and then suspend them in water for use. Or ship them across country to unsuspecting customers because shipping powdered exosomes is cheaper and easier than shipping fresh exosomes. This is what AnteAge is doing. Making freeze-dried, powdered exosomes. What should we expect from a company founded and run by two physicians, John Sanderson, who lost his medical license for repeated incompetence and sexual abuse of his patients, and George Taylor, a retired medic living in Florida. George Taylor’s life work as a practicing anesthesiologist was standing around watching patients sleep as other physicians performed operations on the patient. Hardly a life of science, and a profession that had to have bored him silly. And I do mean silly. Just look at the silly BS he promotes. Laughable, and reminiscent of his days in the OR with too much laughing gas (nitrous oxide). Neither are scientists, nor have they ever published any scientific papers. They do have, however, a history of business fraud as I wrote about in another blog.

First, what are exosomes? About 20 years after the discovery of liposomes, scientists discovered similar lipid vesicles form naturally in living organisms. These include membrane-contained nanosized extracellular vesicles (EVs), secreted from cells as part of their normal process. This is a natural means by which cells in our body communicate with one another, and maintain and heal our tissues. We’ve known for many years that exosomes secreted by cells in the skin are important for the skin’s natural processes. Based on the origin and size of the EVs, as well as on the current understanding of their biogenesis, the vesicles are grouped as follows: exosomes (diameter ∼30–150 nm); microvesicles (100 nm–1 μm); and apoptotic bodies (50 nm–5 μm). So the exosomes we’re talking about are nanospheres, 30-150 nm in diameter, composed of a lipid bilayer and containing a cargo of proteins and microRNA, with proteins and other molecules tethered to the outside or embedded into the lipid bilayer structure.  Despite the evident similarities to liposomes, exosomes exhibit certain advantages, which make them a preferable drug delivery vehicle. As a result, in the last few years, exosomes have become preferable over lipid nanoparticles as prospective drug carriers.

Let’s look at why exosomes, which I described in my peer-reviewed book chapter in 2016, are degraded during these harsh freeze-drying procedures. Both the proteins in the exosome and on the surface of the exosome can be damaged during the lyophilization process of the exosome. Yes, even the proteins inside the exosome can be damaged by lyophilization. Damaged proteins can cause many health problems. You don’t want to be using a freeze-dried product with damaged proteins! The exosome surface proteome, termed the surfaceome, serves as the main communication hub between an exosome and the extravesicular environment (Wollscheid et al., 2009). For exosomes, the molecules on the surface of the exosome impart many functional qualities, such as penetration through barriers, targeting, and gain of entry into target cells. I discuss some of this in a recent blog. As a surface component, this compartment of proteins on the exosome often reveals the first signs of distress and disruption, and is of substantial interest to the scientific community for diagnostic and therapeutic development of exosomes, and especially enabling the exosomes as a therapeutic-delivery vehicle. We can say the same for surface glycoconjugates on the exosomes, which play important roles in exosome biogenesis, release, targeting, and uptake by cells. These important functional qualities ascribed to the glycans on the exosome’s surface can be disrupted by lyophilization. In other words, the exosome’s surface has been denuded by lyophilization, resulting in all those functions imparted by the surface proteins and glycans being lost. It’s like stripping the surface components off of a truck, such as its tires, so that the truck can no longer deliver its cargo to the destination. Its also like stripping the handles off the truck’s cargo door, so that the cargo can’t be delivered even if it did arrive. I could go on, but enough of the analogies.

The bottom line is that fresh secretome/exosome preparations are much more functional and efficacious than are lyophilized (freeze-dried) and ultracentrifuged exosome preparations, because that harsh freeze-drying process or centrifugation process damages proteins (and other molecule types) on the surface of the exosome as well as inside the exosome. Although it is more expensive and time consuming to work with fresh secretome/exosome preparations, companies, such as NeoGenesis and Skin Medica, who go through the pains and expense to prepare fresh sectretome/exosomes, offer a much more safe (this is a peer-reviewed, PubMed listed scientific study on the safety of the NeoGenesis secretome/exosome technology) and efficacious product than those who do the quick and dirty, inexpensive freeze-drying methodology.

“Systems Therapeutic for Physiological Renormalization,” A Paradigm Shift in Skin Care

As Dr. Thomas Kuhn, a former physics professor at Harvard and Berkeley, taught in his book, The Structure of Scientific Revolutions, scientific fields undergo periodic “paradigm shifts” rather than progressing in a linear and continuous way, and that these paradigm shifts lead to new approaches in understanding what scientists would never have considered valid before. Such a paradigm shift is now underway for drugs and therapeutics, specifically for skin care, and has been described as “Systems Therapeutics for Physiological Renormalization.” Until now, the paradigm for drug and therapeutic development has been an ineffective reductionistic approach, where a small molecules was developed to target one pathway in an attempt to remedy the diseases or condition. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, long believed to be the oracle for teaching pharmacology to physicians and other practitioners, taught that “the small molecule had to specifically hit its target, and only its one target.” That is, their misguided approach is to develop a drug or a product that specifically hits one target, and only one target, and that is thought to be the best way for drug or skin care product development. It’s nonsense. This doesn’t work well because all diseases and conditions of the skin involve multiple pathways at multiple levels in the tissue, and therefore multiple molecules, not just one, are required to renormalize the multiple pathways in the diseased tissue to ameliorate the disease or condition.

Examples in skin care of this reductionist approach are to offer products that focus on one antioxidant, namely Vitamin C, as a cure all. You’ll see many products on the market that prominently feature Vitamin C, and only Vitamin C, as their active antioxidant ingredient. Sometimes the product has C and E, and only C and E. Your body’s cells naturally produce many powerful antioxidants, such as melatonin, alpha lipoic acid, superoxide dismutase, and glutathione. The foods you eat supply other antioxidants, such as vitamins C, ergotheoneine, carotenoids, and vitamin E. Many antioxidants, including these and others, naturally work together in the antioxidant cascade. It’s not just about Vitamin C. Too much Vitamin C can actually be oxidative and potentially damaging, and inhibit other normal biochemical pathways in the body. The evidence is not clear about the damaging effects, but too much is suboptimal. Rather, it’s about a combination of different types of antioxidants used together. Just as nature intended. This is clear, you need a wide variety of antioxidants, not just vitamin C. It’s similar to when you eat a wide variety of fruits and vegetables, with all those different colors due to the different kinds antioxidants and other molecules they contain. All of those different molecule types are required to keep us healthy. And many of those colorful molecules will be pumped into the skin from the blood supply, feeding the skin from the inside-out. When formulated properly and applied topically to the skin, most of those molecules can feed the skin from the outside-in.

Most diseases and conditions involve many perturbed pathways, and a product that targets only one of these many pathways is a product doomed to failure or suboptimal therapeutic effect. As an example, such is the case for well over 50% of the FDA-approved drugs on the market today, they don’t work. The drugs that don’t work include many cancer drugs, that are toxic and only cause harm. While this problem has received media attention, the world’s largest lobby, the medical-industrial complex, drowns out these reports by saturating the media with drug propaganda. This way of thinking permeates social media, and many skin care products will tout their favorite ingredient in a reductionist manner. That is, they tout one ingredient as a cure all. EGF products are an example of this nonsense. They promote one growth factor out of hundreds that used in the skin’s biochemical pathways. EGF alone will puff up the face like a balloon, causing depilation (loss of hair). It’s not healthy.

This problem of reductionism only became worse when physicians, such as Francis Collins, ushered in genomic fashionistaism, teaching that the small molecules should not only hit just one target, but that the target should be at the level of the genome. As Dr. Stephen Rappaport, Ph.D. at Berkeley teaches us, over 90% of diseases are caused by our exposome and mutations in the genome are not the underlying cause. Yet, Collins in all of his ignorance, called for genetically sequencing everyone, carrying your genetic sequence on a card that can be read by physicians, such that the physician can then treat you based on the information contained on your “genomics card.” Another physician, Leroy Hood, was quoted as saying, ” your entire genome and medical history will be on a credit card. You just put it in there [a computer] and a physician will instantly know what he’s dealing with.” Besides irrational thought underlying Collin’s call for a “genome card,” fraud was in his calling to make such ignorant claims. Publishing five fraudulent paper on genomics. When found out, Collins said, “the significance and the scope of the fabrication in this circumstance, of which I had not the slightest idea, began to be very apparent.” In other words, Collins had no idea what was going on in his lab, and was attaching his name to “scientific papers” of which he had nothing to do with. This is called “ghostwriting,” where physicians put their names on “scientific papers” yet have had nothing to do with the study. The practice is rampant for practitioners, i.e. physicians. Leading other physicians astray, who control over 95% of biological research spending in the US given that physicians control the National Institutes of Health, Collins would cause biological research in the USA to be highly biased towards looking for diseases in all the wrong places – the genome. This mentality of looking for disease in all the wrong places has hit skin care and the beauty industry. At Neogenesis, I formulate products that are based on the “systems therapeutics for physiological renormalization” approach, where our core technology, S2RM Technology, is compromised of hundreds of proteins native to healthy, young skin, that can be returned to aged and/or damaged skin through simple topical application. And, the molecules in S2RM are used in combination with other skin identical ingredients, such as Vitamin C, Vitamin E, ergotheoneine, carotenoids, SOD, urea, squalane, ceramide, etc, to renormalize the skin’s physiology. It’s a natural, efficacious, and safe approach to skin care. All of the ingredients in the products are carefully chosen to not induce inflammation or an allergic response.

The reductionist and genomic bias continues today and has been taken to such an absurd level that almost every gene studied has been linked to a disease. Further upsetting those who believe that mutations in the genome underlie disease, is that mutations in the genome don’t happen just by chance, but are driven by environmental influences. Basically, one’s health status is not only influenced by your current environment acting at the protein level of your body, but also by what your ancestors experienced in their environments acting on their genetics and epigenetics. So what you do in life, including your diet, directly effects your health and can cause most diseases, but also will have consequences to your children and their children. As such, when what one has experienced in life disrupts their physiology, mostly acting at the protein level of the body, the resulting disease can be treated by renormalizing the physiology. This means, renormalizing the protein (and other molecules such as lipids) content of the afflicted tissues. As Dr. Daniel Nomura, Ph.D,, professor at Berkeley, has written, “Many diseases, including cancer and monogenic diseases, are often caused by specific proteins that are abnormally degraded and lost from the cell.”

As an example of the therapeutic benefit of this “systems therapeutic for physiological renormalization” approach, our group has demonstrated its efficacy in the skin for a number of conditions, including radiation dermatitis in cancer patients. The approach was also shown by Maguire and colleagues to be effective in protecting the nervous system from neurodegenerative diseases in an experimental animal model. The safety of this technology has been demonstrated, and the mechanism of action partially described. The approach has also been discussed in an interview of Dr. Greg Maguire by Dr. Tom Kleyman of the Physiological Society. Dr. Maguire has also recently described in a journal publication, Human Vaccines and Immunotherapeutics, how the “systems therapeutics for physiological renormalization” approach may help to make safer and more efficacious vaccines, helping to better prevent the spread of the disease. I’ll be speaking about this an upcoming talk at the 8th Annual Vaccines Research & Development congress in Nov. 2023. The point here is that this strategy of using a systems therapeutic (many types of molecules) to bring about physiological renormalization (restoring normal protein content, for example) can work for all tissues and for all kinds of diseases and conditions, including those of the skin. Remember, it’s the proteins (plural!), stupid. Not the genome, not just one molecules.

Stay tuned, there is much more to come, including our approach in treating immune and autoimmune conditions, including of the skin, as I began to describe in my 2021 paper.

Eczema on the Rise: What to Do.

Atopic dermatitis (AD), an inflammatory skin condition is a form of eczema. Eczema refers to a group of conditions that cause inflamed skin. There are many types of eczema. Atopic dermatitis is the most common type. Recent studies of AD have found that both structural abnormalities of the skin and immune dysregulation play important roles in the pathophysiology of the disease.  Impairment of epidermal barrier function, for example, owing to deficiency in the structural protein filaggrin, can promote inflammation and infiltration of immune cells, such as T cells. And, as we age, immune cells, such as macrophages, become more inflammatory because of a loss of certain calcium pumps within the mitochondria (mCa2+). Specifically, mCa2+ uptake capacity in macrophages drops significantly with age. This amplifies Ca2+ signaling in the cytosol of the macrophage and promotes NF-κB activation, rendering the macrophages prone to chronic low-grade inflammatory output at baseline and hyper-inflammatory when stimulated. This means if you have interrupted skin barrier, and a trigger penetrates and presents in the skin, older people will likely have an exaggerated, pro-inflammatory macrophage response that elicits an inflammatory cascade. While this phenomenon increases with age, many people with inflammatory skin conditions can experience this too. While macrophages are necessary for normal skin function, the inflammatory types are not. One way to reset macrophage types from an inflammatory state to an anti-inflammatory, pro-repair state is the use of skin derived mesenchymal stem cell secretome (stem cell released molecules). This so-called S2RM technology is available in Neogenesis Recovery. Our studies have found Recovery to work well to quell the inflammation associated with psoriasis and AD.

Therefore, optimal management of AD requires a multifaceted approach to heal and protect the skin barrier and address the complex immunopathogenesis of the disease. Other types of eczema include contact dermatitis, nummular eczema, and dyshidrotic eczema. People often say atopic dermatitis when referring to any one of these conditions. Although eczema involves an immune response, it is not considered an autoimmune condition because eczema is not self-triggered, rather it is induced by environmental factors. However, once chronic inflammation is induced, tissue breakdown from the inflammation can elicit an autoimmune response and become self-sustaining. That is, inflammation induces tissue breakdown that causes sterile inflammation, which then leads to further tissue breakdown. And the cycle continues. At this point, if the environmental trigger is stopped, an autoimmune response may continue from the damage signals emanating from the structural breakdown of the epidermis. This process is called inflammaging. People with AD have a higher prevalence and incidence of autoimmune conditions compared to the general population. BTW, the epidemiological terms, prevalence is about what’s out there, while incidence tells you what’s new.

In 2000, the American Academy of Dermatology (AAD) warned Americans: eczema was on the rise. In the warning, the group of dermatologists said that the rate of atopic dermatitis, a form of eczema, had nearly tripled since 1970. This provides evidence that the disease is a consequence of environment and not hereditary-genetics. At the time, it was estimated that nearly 6 percent of all Americans had the condition that can cause itchy, red, and scaly skin. Today, the National Eczema Foundation estimates that at least 10 percent of Americans have eczema, and that one in ten people will have eczema in their lifetime. I want to stress that this is an inflammatory disease where the skin’s innate and adaptive immune systems have gone awry. Immune cells are abnormally activated and may be found in parts of the skin, the epidermis, where they are not normally resident as happens in a similar disease called psoriasis. Itch (pruritis) is associated with neuroinflammation of the skin’s, part of the neuro‐immuno‐cutaneous (NIC) system. The skin’s microbiome will also be altered, a dysbiosis occurs where Staphylococcus aureus proliferates in overabundance. And remember, as I always stress, inflammation in the skin means inflammation in the body.

Exposure to tailpipe emissions is a big factor in eczema. Diisocyanates from auto exhausts show temporospatial and epidemiological association with AD while also inducing eczematous dysbiosis. As the authors of this study correctly point out, “The prominent AD paradigm is that the disease has a multifactorial pathology, but with frequent reference to genetic predispositions causing defects in barrier and/or inflammatory pathways. However, the stark post-industrialization increase in AD prevalence strongly suggests that environmental factors must play a substantive role.” In other words, eczema is another environmental disease – forget the genetics-hereditary hype.

What to do? Cleanse the skin daily with a gentle cleanser. No harsh alcohol cleanser or those with strong surfactants such as sodium lauryl sulfate (SLS). In this way you’ll remove those environmental toxins, antigens, allergens, and haptens that can trigger the inflammatory response. Use something mild like NeoGenesis Cleanser, or a similar mild cleanser. Be very careful to choose products without harsh chemicals that degrade the barrier and have allergic triggers. BTW, I’ve formulated a new cleanser for eczema and other inflammatory skin conditions that is currently in testing. More about this in future posts. I also have a new topical probiotic (yes, it’s really possible to do this) that I’ve formulated, also in testing. It remediates the dysbiosis associated with eczema. And because barrier function is perturbed in these conditions, using a product to restore the function of the stratum corneum and its barrier function is very important. This helps to prevent those environmental triggers from penetrating into the skin and inducing an immune response. Using a product, such as Neogenesis Barrier Renewal Cream, can help to rebuild the skin’s natural barrier function, preventing those triggers from entering the skin.

I have a trio of products that I’ve formulated for these skin conditions, and I’ll have more to say in the months ahead about how well they are working. The formulas are backed by decades of research, and while early results are promising, it will be interesting to see for what conditions they work best in real world studies. Stay tuned.

Procell Microneedling Device Injures Dermis and Epidermis, Inducing Adverse Events in its Users

I was recently asked to review a cosmetic microneedling device white paper, meaning not a peer-review publications, rather an internal document generated by a company for sales purposes, from a company in Texas called Procell. As I’ve reported previously in peer-reviewed, PubMed listed papers, microneedling is a deep wounding procedure that activates the innate and adaptive immune systems and induces a wounded-proliferative state in the skin that is inflammatory and possibly pro-oncogenic. Sadly, this company, with its medical director (Mitchel Schwartz), who has no peer-reviewed publications and is paying for this study, is selling this product online and apparently making illegal sales to estheticians in states where microneedling procedures performed on others by estheticians is illegal.

The study in question here was performed by a physician in Canada who has no peer-reviewed publications, and the study, and the physician performing the study, were paid by Procell. The Procell device uses an array of needles that are 250 micrometers in length, with the thickness of the needles not reported. The device is run over the face such that these needles are puncturing holes in the epidermis and dermis at high rates, thus injuring both the epidermis and dermis.

The study design and the results are indicative of an inexperienced practitioner performing a study. First, the author states, “This study is a prospective, evaluator-blinded, single-site study, involving up to 30
subjects comparing clinical benefits after a treatment series versus baseline.” The claim of “evaluator-blinded” is ridiculous. Each subject serves as her own control, with photos being taken before and after treatment, and its easy for the evaluator to know who they are analyzing. Then they have a section called, “3.5 Randomization of Subjects.’ There is no randomization of the subjects. All are given the treatment. Next they say that “Photographic assessments will be conducted by a blinded expect evaluator.” I think they meant “expert” instead of “expect.” Although I think “expect evaluator” is the better descriptor, I’ll give them the benefit of the doubt. Regardless, the evaluator can easily identify each patient through their photos, and know what picture has been captured before and after the procedure. This is all just gobbledygook, and is either a consequence of ineptitude and/or fraud.

There are no results presented in the paper, only a conclusion. Yes, that’s right. No results are presented. What they do present in their “Safety Analysis” is a set on incongruous statements about how one patient was injured. Here’s what they reported in their “Safety Analysis”:

8.0 Safety Analysis
8.1 Safety Results:
To assess safety, all subjects were evaluated for adverse events during treatment and at all follow up visits. There was one event reported during the study duration.
The subject reported a “break out” along her jawline, which was evaluated by the
Primary Investigator. The effects were mild and transient in nature. The event was
coded as “possibly related to the procedure”. Upon further investigation and follow up
by the Primary Investigator, the subject was determined to have a baseline condition,
which should have eliminated her from study inclusion. The Investigator’s notes and
letter to file are included in the dataset for reference. All other subjects treated were
evaluated and no other events were reported.

My comment: (here they’re saying one of the patients had an adverse reaction)

9.0 Deviations from CIP
Based on the Primary Investigator’s assessment of the subject who has a possible
related event, he has concluded that this subject should not have been included in the
study based on her underlying clinical condition of inflammatory rosacea.

My comment: (here they’re saying the physician screwed up and shouldn’t have included this patient in the study)

10.0. CONCLUSION
During the study, all subjects tolerated the treatment well demonstrating only mild
erythema which was aniticpated [sic]. Improvement in the overall aesthetic appearance of
the skin was reported across all independent evaluators. Based on the results of this
study the ProCell .25mm Microchanneling system is safe to be used across all skin
types and can offer improvement in overall skin appearance as reported by both
patient and Independent evaluators.

My Comment: (here they contradict themselves, saying that the procedure is good for all skin types)

Here’s an image from the study so you can see for yourself:

Combine this inflammatory-proliferative, injurious procedure with the bone marrow mesenchymal stem cell cytokines that they sell, and one has set themselves up for adverse events, possibly long-term. There are skin conditions for which microneedling, when not performed repeatedly, is beneficial and the benefits out way the risks. Acne scarring and other types of scars can be an example. To quell the inflammation associated with the procedure and to set the immune system into a anti-inflammatory, pro-repair state, use the S2RM technology, found to be safe and efficacious, contained in Neogenesis Recovery.