In this edition, we look at the marketplace and try to make sense of products containing cytokines and growth factors derived from human stem cells. How do they add up in term of the science we laid out in parts 1-4. Is it possible to actually know what is in such products? Is it important to know?
Let’s start with a quick peek at a commercial product that publishes on its website a list of cytokines in its skin care product. This particular one is based on adipose-derived stem cells, which we dealt with extensively in part 4 of this series.
Now let’s take these cytokines and put them on our “cytokine balance” to get a picture of the inflammatory vs. anti-inflammatory potential. As you can see, it is heavily tilted to the inflammatory side of the scale. In fact, only one anti-inflammatory cytokine is even mentioned. And they are quite accurate in their descriptions of the functions, e.g. GM-CSGF “activates neutrophils, eosinophils, and monocytes”. Those are the acutely inflammatory white cells we have talked about.
Now, we don’t know whether they actually measured these cytokines or just looked in the adipose stem cell literature. Although we did see in some forums where people said they contacted the company and these were actually measured. I’d like to leave them a little wiggle room.
Recall from our earlier discussions that what stem cells in culture actually express is not a constant, but depends on many factors. We talked extensively about age of donor, tissue site of origin, what you feed the cells in the lab, and the many other variables (and deliberate manipulations) that come into play. So the best way to really know is to measure them. In fact, this chart is my favorite, because it sums this up simple and clearly:
In our own work, we do not simply grow MSC’s in culture and farm them for cytokines. Although we know from their tissue of origin and many published reports in the literature what we would probably get. We talk to the cells in their own language to get them to alter their output of the cytokines we know are the most important. Important for what? For healing wounds? No. That will not surprise those of you who read back in part 2 about the differences between wound healing as a paradigm, and skin rejuvenation as a goal.
Here is a modest proposal. Just like there are “Nutrition Facts” labels on foods, why not “Cytokine Facts” labels on skin care products derived from stem cell technology. Let’s make it easy for people to see what is actually in a product, so they can make good purchasing decisions for themselves. This will make it much easier to do meaningful comparisons between products.
At left: example of a net anti-inflammatory cytokine facts label.
At right: example of a net inflammatory cytokine facts label.
The non-benign consequences of inflammation.
Is there going to be a prize awarded for the first one to guess which product on the market has that amazingly inflammatory profile?
A little googling is all it takes to figure out what product. LOL. You do know that the live-in magpies at EDS are going to go all apoplectic over this. I would guess they shut down any thread where the topic is even brought up. They can’t take the truth! Thanks for this landmark review on the subject.
Does this mean you will be publishing a “Cytokine Facts” label for AnteAge soon? Or is that the AnteAge label up above since it said it is from marrow? Thanks!
I see 22 inflammory cytokines and 12 anti-inflammatory cytokines listed on the mock Nutrition Label above; I see 12 inflammatory cytokines ‘starred’ and 11 anti-inflammatory cytokines ‘starred’. Please explain/clarify the 2:1 ratio of anti-inflammatory to inflammatory cytikines listed. on that label.
Kath, this is a work-in-progress post, and we planned to update these illustrations before calling it final. They are meant to be mockups;conceptual, not definitive. Although we did use the examples in the text.
There will probably be another series to follow, stepping back and examining the more general topic of inflammation in skin care. How many products out there rely on acute inflammation to “diminish fine lines” which actually results from inflammatory cells and resulting fluid infiltrates? And is “chronic smoldering inflammation” (CSI) resulting from continued use of these products, how is that anti-aging? Or is it in fact pro-aging, in the same sense that CSI leads to atherosclerosis, kidney failure, osteoarthritis, and other disorders associated with aging? We are now ion the process of gathering evidence that the latter may well be the case.
I just found your site and have been enjoying it immensely. I appreciate your honest and unbiased approach to skin care products. How do you feel about PRP or platelet rich plasma? Where your own blood is drawn, spun down and the platelet rich plasma is then activated with calcium gluconate and either injected with a syringe or used topically with micro-needling on the skin. Do you feel the platelet derived growth factors and cytokines may be more or less inflammatory than fat derived? Thank you for your response.
Wow, we apologize for missing this question which was posed in 2013. It certainly remains timely, maybe more so now than before since PRP has grown so popular over the years, for a number of indications including facial microneedling. Some readers may be familiar with the so-called “Vampire Facial” which was popularized long ago when Kim Kardashian underwent the procedure on her family’s reality show. The terms was copyrighted by an enterprising physician who was quick to file lawsuits against anyone who used the term without paying him a royalty. Not sure where that business plan is at present, or what the risk is of using his coined term, so we’ll stick to PRP microneedling. So we’re complete in telling the PRP story, which includes many other indications that just facial rejuvenation, check out the references at the end of this post.
The alpha granules contained within platelets are chock-full of cytokines and growth factors including IL-1b, IL-1ra, IL-4, IL-6, IL-8, IL-12, IL-13, IL-17, INF-γ, TNF-α, MCP-1, MIP-1a, RANTES, bFGF, PDGF, and VEGF. Newer studies additionally report the presence of IL-2, IL-5, IL-7, IL-9, IL-10, IL-15 G-CSF, GM-CSF, Eotaxin, CXCL10 chemokine (IP-10), and MIP 1b. Chock-full, indeed.
Our opinion remains that PRP incites a significant pro-inflammatory response when used in conjunction with microneedling, and that this may be something to avoid, especially in individuals prone to hyperpigmentation or fibrosis. On an occasional basis, most people should tolerate PRP without problem or difficulty. We remain convinced, however, that PRP may not be worth the extra expense which adds several hundred dollars to the cost of microneedling. Our preferred approach is use of topical products that contain pro-healing anti-inflammatory growth factors and cytokines, something we have offered for years. First and foremost should be the avoidance of topical substances that contain “non-native” substances on freshly microneedled skin. The reduced barrier function, which lasts for several hours can permit otherwise innocuous substances to gain entrance into the skin, potentially inciting nasty allergic reactions that can lead to months-long granulomatous dermatitis. We have seen the worst cases following application of “snail derived” products. Few people realize that there is a 60-70% cross reactivity between snails and dust mite allergens. Certainly, anyone allergic to dust mites should avoid “snail” products like the plague. Just saying…
Cytokine, chemokine, and growth factor profile of platelet-rich plasma. Platelets. 2016 Jul;27(5):467-71
Current knowledge and perspectives for the use of platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) in oral and maxillofacial surgery part 2: Bone graft, implant and reconstructive surgery. Curr Pharm Biotechnol. 2012 Jun;13(7):1231-56.
Sports medicine and platelet-rich plasma: nonsurgical therapy. Clin Podiatr Med Surg. 2015 Jan;32(1):99-107.
Platelet-rich plasma, the ultimate secret for youthful skin elixir and hair growth triggering J Cosmet Dermatol. 2018 Jun;17(3):423-430
Platelet-Rich Plasma (PRP) in Orthopedic Sports Medicine. Am J Orthop (Belle Mead NJ). 2016 Jul-Aug;45(5):290-326.
Current clinical applications of platelet-rich plasma in various gynecological disorders: An appraisal of theory and practice
Clin Exp Reprod Med. 2018 Jun; 45(2): 67–74.
How long are the stem cells active for in the cream? I was reading they only have a short term lifespan, is this correct? Thank you. Anna
Anna, there are no cells in the cream. The products contain the cytokines and growth factors made by human stem cells grown under special conditions in the lab. These are proteins, which are wrapped in natural lipid envelopes to preserve them and keep them functional. Stem cells exert their magic using the signaling biochemicals, you you get the benefits without needing live cell transplants (as long as you apply twice a day).
I can definitely vouch for their magic. I’m on my third duo of the Anteage MD formulations. I’m 54 and got carded the other day. Thank you, doctors, and please never, ever stop making your products!
I had a mole removed via CO2 laser 2 weeks ago. Can the AnteAge Microneedling solution be used on fresh, pink skin to help with healing, decreased redness and scar proliferation? If it’s beneficial, how often should it be applied along with the AnteAge Serum?
Indeed it can, Joel. I would just use it twice daily just before AnteAge serum. Increases the dose of anti-inflammatory, anti-scarring TGF-B3.
I noticed your point that a mix of cytokines should have a net anti-inflammatory profile. But is it more desirable for a cytokine cocktail to contain only anti-inflammatory signals, or to contain some inflammatory signals as well?
G,another great question. Yes, some inflammatory cytokines are acceptable along with anti-inflammatory ones in a cocktail of regenerative signaling molecules. Any human cell-derived medium contains some of each – it is the net balance that counts. Inflammatory cytokines may be helpful to kick things off (e.g. for wound healing in diabetics) but you want to quickly transition from inflammatory to anti-inflammatory (the so-called regenerative phase of wound healing). If you stay in inflammatory you will get scars, rigid fibroblasts, poor cross linking on collagen fibers, high levels of proteases, all of which accelerates the appearance of aging rather than being anti-aging. Aging itself can be linked to a progressive inability to mount a good anti-inflammatory healing process. Of of this also brings up our nagging question – WHY WOULD YOU PUT INFLAMMATORY SUBSTANCES ON SKIN HEALING AFTER LASER, RF, MICRONEEDLING, DERMABRASION, HYDRAFACIALS, AND OTHER AESTHETIC PROCEDURES? Makes no sense to us. Just puts you back into rapid aging mode which diminishes the end result.
I appreciate your reply. I understand that it is important for the body to produce some inflammatory cytokines, however I’m still confused as to why inflammatory cytokines are beneficial in topical products.
Since our bodies make enough inflammatory signals when needed, and since it is anti-inflammatory signals that adults desire more of, why not apply purely anti-inflammatory cytokines to the skin? Would this cause a cytokine ‘imbalance’? Or is it impossible to isolate purely anti-inflammatory signals from the medium? Or, do we include some ‘bad’ cytokines in skin care products because they can actually produce greater anti-inflammatory effects than ‘good’ cytokines alone?
Please help me understand.
Again, great questions. It’s because stem cells produce both, under different circumstances. And because, as you guessed, sometimes you can make inflammatory cytokines work in your favor if balanced by anti-inflammatory ones. As a example, there are molecules called MMPs that dissolve old proteins, which is good because because you can then clean up debris from dead cells. But too many of them and you get tissue4 breakdown, thinning skin, and aging. But if you balance with lots of TIMP’s, which inhibit those guys, you get a net benefit.
I am 37 year old and starting to see signs of aging that I hadn’t before. Bad behavior in my teens and 20s are probably the big culprits. Time to ditch the Estée Lauder and get real results. I have been reading your blog for weeks now, and the science presented has steered me away from purchasing an EGF (Bioeffect), and instead I’m look into anti-inflammatory cytokine skincare, namely, Anteage. I also see there is an Anteage MD, which is not available for purchase online. Should I try to access the MD, or will the plain Anteage create results? Thank you for creating visibility for the consumer in an otherwise murky industry!
AnteAGE is very good and our first product. The MD versions does contain more of certain ingredients, most notably additional human bone marrow stem cell conditioned media, It was created to enter the physician dispensed market and has proved valuable not only as an anti-aging system but in helping promote recovery following energy-based aesthetic treatments such as fractional laser, radio frequency and microneedling. If you contact us with your home town, we can steer you to a practice where you can buy AnteAGE MD.
Hi there! I I find the science behind your products to be fascinating and have a few questions about the role of TGF-beta in the aging process as well as the different variations of it.
I recently came across an article on the UCSD website describing how TGF-beta is responsible for loss of facial fat in skin. This is a topic of great interest to me because I feel that ceasing this process is a strangely overlooked component of anti-aging. I’ve linked the article as well as the abstract to the study in question below. I am curious what you think of this research, and how the traditional distinction between the inflammatory TGF-beta 1 and 2 and the anti-inflammatory TGF-beta 3 might come into play. The summaries I browsed didn’t seem to differentiate between different types of TGF-beta when making this conclusion, but I’d love to hear your take on this as scientists.
Additionally I found a study exploring the relationship between TGF-beta and elastin production in Caucasian vs. African-American skin. From what I saw it seems to suggest that higher levels of TGF-beta 1 (what I thought was a no-no) contribute to greater levels of elasticity in African-American skin. What do you make of this correlation? I have linked the abstract to this research below as well.
Lack of detail with regards to TGF-beta isoforms in the articles you cite makes commenting somewhat challenging. There is enough literature, however, linking lipoatrophy of the face to inflammatory processes to incriminate the pro-inflammatory TGF isoforms, the likely culprit being TGF-beta 1. That said, a recognized major modulator of TGF-beta 1 function is TGF-beta 3, making it of possible benefit although changes may occur in such a “slow motion” fashion that visible changes may evade casual notice. As you may have noticed from reading other comments and posts on BFT, we are great fans of TGF-beta 3 and include it in several of our product formulations.
Physiological facial lipoatrophy is associated with a normal course of ageing. The most common locations of adipose tissue loss in the course of facial lipoatrophy are cheeks, temples and the preauricular, orbital or perioral region. A significant decrease in fat volume in cheeks, temples and orbits starts to be visible at the age of 20, however changes in contour of the face begin to be noticeable roughly at the age of 30.
The fat distribution is one of the decisive factors which have an impact on the appearance of young and old looking face. With the ageing, the adipocyte tissue of the periorbital, frontal, temporal and perioral region and cheeks, undergoes atrophy whereas the hypertrophy is seen in the submandibular region, mandibular arch, nasolabial fold, mentolabial fold and infraorbital area. The facial fat pads also modify their shape and location due to facial skeleton changes. As a result of the bone resorption process, orbital entrance areas become wider, the jaw moves back and the frontal process decreases its thickness. The mandibular angle becomes more obtuse and the height and length of its corpus decrease. The loss of bone support in these locations causes the indentation of soft tissues. In consequence, the face loses its full young oval shape and facial contours become more prominent.
The article below helps.
Acquired facial lipoatrophy: pathogenesis and therapeutic options Postepy Dermatol Alergol. 2015 Apr; 32(2): 127–133.
The most common causes of facial lipoatrophy connected with chronic disease are the lipoatrophy due to antiretroviral therapy for HIV infection and the lipoatrophy as a consequence of connective tissue diseases associated with panniculitis (inflammation of the fat pads.)
Panniculitis of the face is a rare manifestation of connective tissue diseases such as lupus erythematosus and localized scleroderma. The lipoatrophy in the course of connective tissue diseases is usually preceded by the inflammatory, painful phase and may cause a deep contour loss of facial tissues.
Currently, no specific treatment for facial lipoatrophy is known. In the case of lipoatrophy associated with connective tissue disease the point of great importance is early prevention of the atrophy of the adipose tissue by the early diagnosis and management of the disorder in an acute phase to avoid scarring and atrophic lesions. Established changes such as necrosis and subsequent loss of adipose tissue are irreversible.
The standard first-line therapy of lupus erythematosus profundus consists of antimalarial agents, such as chloroquine, hydroxychloroquine and quinacrine. Besides having anti-inflammatory and immunosuppressive effects resulting from inhibition of lysosomal proteases, suppression of the mechanisms involved in presentation of the antigens, inhibition of lymphocyte T stimulation and prostaglandin synthesis and blocking a pro-inflammatory cytokine cascade, antimalarials also give partial protection against UV radiation, which may be beneficial for patients with coexisting hypersensitivity to sunlight.