Hi! Welcome to Maelove.
Today we’re talking about collagen, which is easily one of the most talked about topics in skincare. We answer, what is collagen? And maybe more importantly - What are some ingredients and products that can improve the collagen content in the skin?
The TLDR version goes like this:
Collagen is the key structural protein in our skin. In fact, collagen makes up about 3 quarters of the dry weight of the skin. Without collagen, our skin loses firmness and becomes more saggy and wrinkly.
Over time, natural aging and cumulative UV exposure degrades collagen content in the skin. Both in quantity and in quality.
Topically applied Vitamin C, retinoids and niacinamide in our opinion are currently the most proven and the best collagen boosters for the skin. And there are other ingredients like some peptides and botanicals that have also shown promise.
What is collagen (and ECM)?
We hear about collagen in many contexts, and that is because collagen is the main structural protein in your body. Collagen is part of your tendons, ligaments, cartilage, bone, blood vessels, and of course, your skin.
Collagen is referred to as a "structural protein" because it is firm and gives structure to the body. It acts like scaffolding, providing support and shape to tissues.
There are many different types of proteins in the human body, each with a specific function. Some examples include:
Structural proteins: Structural proteins are involved in the structure and function of cells and tissues. Examples include collagen and elastin which we will go into more in depth, and keratin, which is found in hair, nails, and the outer surface of your skin.
Enzymes: Enzymes are proteins that catalyze chemical reactions in the body. They are involved in a wide range of processes, including digestion, metabolism, and DNA replication.
Transport proteins: Transport proteins help to transport substances throughout the body. Examples include hemoglobin, which carries oxygen in the blood, and transferrin, which transports iron.
Hormones: Hormones can be proteins that are produced by glands or organs which are released into the bloodstream to regulate various body functions. Examples include insulin, which regulates blood sugar levels, and thyroid hormone, which regulates metabolism.
Antibodies: Antibodies are proteins that are produced by the immune system to defend against foreign substances, such as viruses and bacteria. They help to protect the body from infection and disease.
Contractile proteins: Contractile proteins are involved in muscle contraction and movement. Examples include actin and myosin, which are found in muscle tissue.
These are just some examples of the many different types of proteins that are found in the human body. Proteins are essential for the proper functioning of the body, and they play a key role in many biological processes.
Even though there are many different types of proteins, approximately one third of all the proteins in the body are collagens, and three quarters of the dry weight of your skin is collagen (Shoulders and Raines 2009). So you can see how important collagen is!
So what are all these collagen proteins in your skin doing? Basically, they are forming a scaffold and holding up the skin. That is why as you age and you lose collagen, your skin sags and you develop lines and wrinkles.
As you age, you also lose another protein called elastin which gives your skin elasticity and bounciness. Both collagen and elastin are found in the dermal layer of your skin which is the layer underneath your epidermis.
The epidermis is that visible outer layer of your skin and though you can see the lines and wrinkles from the outside, you have to go to the invisible dermal layer where collagen is located to fix the problem.
Collagen is secreted by dermal cells called fibroblasts to form something called the extracellular matrix (abbreviated as ECM). Extracellular means outside cells. The ECM is a matrix of collagen and other proteins such as elastin that are outside of cells and that form a thick scaffold around your dermal cells.
Just a reminder that ¾ ths of the dry weight of your skin is collagen! So the majority of the dry weight of your skin is this scaffold that surrounds the cells of your dermal layer.
Reproduced from Aldag et al. 2016
Different types of collagen and their functions
Now we are going to go further in depth here, and talk a little bit about collagen types in your skin, mainly because this will help you understand scientific findings related to collagen.
When we talk about collagen in reference to skin, we are mostly referring to type 1 collagen, which make up 80% of the collagen fibrils in young adult skin, and to a lesser extent, type 3 collagen which co-polymerizes with type 1 collagen to make up about 15% (Kular et al. 2014).
Type 1 and Type 3 collagen are types of collagen that can form long fibrils that provide support structure (Wang 2021). In the figure below, you can see an electron microscope image of what these collagen support structures look like (See figure from Uitto et al. 1989).
Reproduced from Uitto et al. 1989
These fibrils will assemble into dense and compact bundles forming thick, regular fibers. These bundles connect to each other at various points due to interlacing, and these bundles increase in size the deeper you go in the dermis (Thakur et al. 2008).
These fibrils are anchored to the basement membrane located between the dermis and epidermis, and then cells and macromolecules can anchor themselves to this collagen fibril scaffold. This is how collagen gives your skin its shape and also organizes the various components of the dermis.
The basement membrane that is in between your dermis and your epidermis is mostly made up of Type 4 collagen which forms networks (sheets) rather than long fibrils (van der Rest and Garrone 1991, Bosman and Stamenkovic 2003).
Type 5 and Type 6 collagens may also be found in the dermis and may play roles in cell migration and matrix assembly, while Type 7 collagen is a predominant component of anchoring fibrils between the Type 4 collagen in the basement membrane and the upper dermis (Uitto et al. 1989).
So, what we commonly call collagen is actually collagen fibers. Think of this as the finished product.
To be more precise, what is made by fibroblasts is procollagen. Procollagen is where it all starts.
What the heck is procollagen? So when you hear “pro-something” in a biology context it usually means a precursor, a building block, to that something. Like - you can say eggs are pro-omelet. Because Omelet is made from eggs. Likewise, collagen is made from procollagen.
You might see Procollagen also referred to as collagen peptides. That’s because collagen is protein, and peptides are fragments of protein.
Procollagen looks like a loose, single strand string.
As a next step, Enzymes take these loose strands of procollagen and braid them into collagen molecules. A finished collagen molecule is 3 procollagen strands braided together in a form called triple-helix. And once the braiding is done the ends are neatly trimmed off.
Once we have a bunch of collagen molecules, they can be crosslinked together to form what’s called “fibrils”. And then when you bundle a bunch of collagen fibrils together you get collagen fibers.
And here is a picture taken from skin of a younger person between 18 and 29. This image is showing a cross-sectional slice.
Reproduced from Varani et al. 2006
Here, the swarm of black dots are collagen fibers sliced in cross section and the black lines are collagen fibers cut along the length. And the purple stuff is the fibroblast, the maker of procollagen.
BTW - this is not the natural color fibroblasts. They were colored to refine the image so we can more easily tell which is which.
So we just went over the collagen building process: Procollagen to collagen molecules to fibrils to fibers. You want healthy, intact, strong collagen fibers because healthy collagen fibers give firmness to the skin and prevent sagging.
To have a lot of healthy collagen fibers you need three things:
1) You need lots of procollagen, which is the building block for collagen fibers.
2) And then you need enzymes to “fold” all the procollagen into thick and strong collagen fibrils.
3) And finally, you want to prevent the deterioration of these collagen fibers. Broken up, unraveled collagen fibers don’t do you any good.
Elastin and glycosaminoglycans (GAGs)
And this is a good place to mention another protein that’s also critical for maintaining beautiful skin. It’s called elastin. Elastin doesn’t get anywhere as many mentions as collagen, but it’s really important for our skin so it’s worth covering briefly here.
Elastin is a protein - like collagen - and elastin is responsible for providing elasticity and resilience to the skin, which allows it to stretch and move while retaining its shape. Think of elastin like lycra in your jeans.
It is a stretchy protein that forms a randomly oriented, interconnected fiber network that can rapidly recoil after being mechanically stretched. Though elastin content in normal adult skin is only about 2-4% of its dry weight, it is important for skin’s elasticity and stretchiness (Uitto et al. 1989).
Fibroblasts play a role in production of both collagen and elastin. So generally speaking, what’s good for collagen production is also good for elastin production.
This is what elastin fibers look like under electron microscope. It’s like stretchy netting. If you think of collagen like the sticks in an Erector set that kids play with, then elastin is like the rubber bands that hold the parts together so they can flex and move.
Reproduced from Uitto et al. 1989
In addition to collagen and elastin, the third component of the ECM is the glycosaminoglycan/proteoglycan macromolecules that account for 0.1-0.3% of the dry weight of the dermis (Thakur et al. 2008).
The most common glycosaminoglycans (GAGs) in the skin are hyaluronic acid and dermatan sulfate, with chondroiton 4-sulfate and chondroitin-6 sulfate found in smaller amounts. GAGs are polysaccharides but can be linked to a protein core, and when so, are called proteoglycans. GAGs and proteoglycans can bind a volume of water in the dermis up to 1,000 times the size of the molecule itself! (Thakur et al. 2008). These play a role in maintaining skin hydration and turgor as well as transport of water-soluble nutritional material in the ECM.
In addition to collagen and elastin, fibroblasts also secrete GAGs and proteoglycans. Hence, again, generally speaking, what’s good for collagen production is often also good for production of these hygroscopic GAGs.
How aging affects ECM
In aging, your dermal fibroblasts produce less and less collagen.
For example, Varani et al. 2006 found that fibroblasts from older skin produced two thirds less Type 1 procollagen than those from younger skin. (Varani et al. 2006, see figure).
Reproduced from Varani et al. 2006
Further, as you age, even the collagen that you do have left gets more degraded and broken up and so it isn’t in an intact form.
In addition to collagen, you may hear about the protein elastin, which decreases with age. Going back to an image we saw earlier of collagen and fibroblast from younger skin, when compared against older skin, it is noticeable that in older skin, collagen fibers are sparse and spotty. You don’t see that extensive netting made up of collagen fibers anymore.
Reproduced from Varani et al. 2006
Fibroblasts are attached and anchored to the collagen fibers. Like a rock climber holding onto a cliff with all his limbs. Fibroblasts need that mechanical tension of being physically anchored to collagen fibers to optimally function and produce procollagen. However, in older skin like in the figure B, as collagen deteriorates the fibroblasts become unmoored. Basically fibroblasts just float around in older skin.
This lack of anchoring also makes the fibroblast produce less procollagen as explained in this illustration from Varani and colleagues.
Reproduced from Varani et al. 2006
The fibroblasts in this illustration are blue. And in younger skin the fibroblasts are tethered to collagen fibers, in the old it’s unmoored and this causes less procollagen synthesis.
So, it’s a vicious cycle. As you get older not only you start making less collagen but less collagen today leads to reduced collagen production tomorrow. And it just keeps getting worse exponentially.
MMP and collagenases
So - Why is collagen less able to stay intact as we age? What causes collagen to break down as we get older?
The culprit in this case is enzymes called matrix metalloproteinases or MMPs. And to be more precise, it’s uncontrolled overactivity of MMPs that lead to breakdown of collagen. MMPs are a type of protease, which means they are proteins that can break down other proteins.
In younger skin, the activities of MMPs are well controlled. MMPs are NOT bad for you. They’re actually quite essential for maintaining our health because MMPs are used for wound healing - for basically purging damaged skin so new skin can grow. Think of MMPs like wrecking crews that have to come in and knock down walls when you do house remodeling.
MMPs that break down collagen can also be referred to as collagenases which are a subset of MMPs (MMP-1, 8, 13). Other MMPs are involved in the degradation of other ECM proteins, such as elastin and proteoglycans. Further, MMPs often are nonspecific and can break down many different components of the ECM (Bosman and Stamenkovic, 2003).
Electron microscopy images of dermal fibroblasts young and old: Varani et al. 2006
MMPs are regulated by a number of different mechanisms, including the action of other enzymes, hormones, and growth factors.
In older skin, like any other part of the body, things don’t work as well as they should and MMPs go a little haywire. In older skin, the amounts of MMPs become overly elevated - there are more MMPs than needed - and excess MMPs turn on us and start to attack the healthy collagen and break them up. Specifically, levels of MMPs, including MMP-1 (interstitial collagenase), MMP-9 (gelatinase- molecular weight 92 kDa) and MMP-2 (gelatinase- molecular weight 72 kDa) were found to be elevated by 40, 52 and 82 percent respectively in the 80 + -year-old group as compared to the 18 – 29-year-old group (Thakur et al. 2008).
Why does this happen? Well, it could be an immune system gone awry. Your mast cells which are immune cells that handle inflammation and MMP secretion, become more activated by innate mechanisms (rather than allergic reactions which is what mast cells are known for in the young) (Thakur et al. 2008).
Mast cells are not bad – they help clear bacterial infections and so are crucial to your health. However, they can also lead to inflammation related skin aging and allergic responses such as atopic dermatitis. As you age, you lose cellular integrity and you generate more reactive oxygenated species ROS. (Remember that UV exposure can also lead to ROS generation)
These ROS are, if you remember, like bullets that rip through your skin tissue and destroy collagen, elastin and DNA. In the case of intrinsic aging, ROS are generated in the process of oxidative phosphorylation and this leads to mitochondrial damage.
The cell damage from ROS leads to production of prostaglandins and leukotrienes, part of your immune system. This will then lead to inflammation via mast cell activation, and the release of histamine and other inflammatory molecules which recruit more immune cells such as antigen presenting cells and lymphocytes that release MMPs.
Mast cells also release MMPs. They also release more prostaglandins and leukotrienes to promote even more inflammation and you guessed it, even more MMPs. Stress and exposure to electromagnetic fields can also increase mast cell number and hasten skin aging. Overall, this over-the-top mast cell inflammation response leads to degraded collagen and elastin and skin aging in allergic and inflammatory disorders, with photoaging and with intrinsic skin aging (Thakur et al. 2008).
UV exposure will also increase these MMPs even in young people - and this is part of the mechanism by which UV exposure leads to premature wrinkles.
MMPs will break down collagen, elastin and GAGs. It doesn’t help that fibroblasts from older adults secrete less of every other component of the ECM as well in the first place, including elastin and GAGs.
In one study, fibroblasts were cultured from persons of various ages and resultant fibroblast cultures were assessed for the levels of elastin mRNA. While levels from fibroblasts obtained from fetal skin was comparable to that of a 45 year old, in the 61 year old, elastin mRNA levels were only at 12 percent of the mean of the other three strains (Thakur et al. 2008).
The picture with elastin is slightly more complicated than with collagen however, as photoaging seemingly has the opposite effect as intrinsic aging in that UV exposure triggers fibroblasts to make excessive amounts of elastin. While this might seem like a good thing, the elastin that is secreted in this manner does not form functional elastic fibers. Think Zombies or mutants – this type of elastin may be up and running but it just isn’t right.
Instead, this UV-induced elastin forms aberrant elastotic material that leads to a condition called solar elastosis which manifests as yellow, thickened, coarsely wrinkled skin as in the image below.
Solar elastosis (Source: DermNet)
Interestingly, treatments like retinoids that enhance dermal collagen can lead to replacement of the elastotic material leading to repair of the condition (Uitto et al. 1989). Hence, increasing collagen affect other positive changes on other components of the ECM, such as elastin.
Further, as aging progresses dermal fibroblasts also secrete less hyaluronic acid and other GAGs, which erodes the water retaining capacity of the skin, further resulting in a dried and wrinkled appearance in aged skin (Thakur et al. 2008). Hence, another aim of stimulating fibroblasts beyond increasing collagen synthesis is the increase in GAGs. Retinoids which increase collagen also increase GAGs.
3 ways to boost collagen
Let's now focus on how you can boost levels of collagen to help return your skin to its more vibrant state (remember that boosting collagen can also lead to boosts in elastin and GAGs as well).
There are three basic strategies to increase collagen:
(1) First is to stimulate fibroblasts in your dermis to secrete more Type 1 and Type 3 procollagen which you can think of as the raw material that forms collagen.
(2) Second is to boost the enzymatic processes that take all the procollagen and fold them into collagen molecules, which then go on to form collagen fibrils and then collagen fibers.
For firmer skin you need assembled collagen fibers and not just a lot of procollagen, so you have to fuel the process of taking a bunch of procollagen and folding and assembling them into collagen fibers. This processing is done by enzymes which use Vitamin C as a cofactor (Shoulder and Raines 2009).
(3) Third, is to preserve the collagen you already have. And we can do this by inhibiting the MMP enzymes - to prevent collagen fibers from getting broken up and degraded.
Ingredients that can boost collagen
So first, let’s start with the ingredient Vitamin C. Vitamin C is sort of a superstar ingredient in skincare and like many things, Vitamin C levels decrease in your skin as you age irrespective of diet.
If you have followed Maelove for a while, you will have read our newsletter on this ingredient. Vitamin C is one of the main antioxidants in your skin and the decline in Vitamin C in your skin leaves you with less protection against UV and free radical damage. Another implication of this is that less collagen is synthesized in your skin.
Vitamin C is a required cofactor for enzymes that allow procollagen peptides to form the triple helix conformation seen in collagen fibrils. Further, the presence of ascorbic acid spurs the synthesis of type 1 and type 3 procollagen peptides (Uitto et al. 1989). Hence, a decrease in ascorbic acid in the skin with age can contribute to the decline in collagen.
The good news is that studies suggest topical application of Vitamin C serums can partially reverse this trend, with application leading to (1) increase in fibroblast secretion of procollagen types 1 and 3 (2) increase in the levels and functioning of enzymes involved in folding collagen into long fibrils and (3) inhibition of the secretion of MMPs leading to less collagen degradation (Nusgens et al. 2001)
Specifically, Nusgens and colleagues found that Vitamin C upregulated mRNA production of Type 1 and 3 procollagens by increasing transcription of the genes and stabilizing the transcripts (Nusgens et al. 2001).
Vitamin C is used as a cofactor for enzymes necessary to cleave and fold the collagen polypeptides into a triple helical shape that then forms the collagen fibers. Nusgens and colleagues also found that synthesis of these enzymes increased with topical Vitamin C (Nusgens et al. 2001).
Finally, Nusgens and colleagues found that topical Vitamin C also inhibited the synthesis of collagenase 1, an MMP involved in collagen degradation (Nusgens et al. 2001,Pullar et al. 2017).
Skin benefits have been demonstrated in placebo-controlled studies of intrinsically aged skin in postmenopausal women (Nusgens et al. 2001) as well as photo-damaged skin (Traikovitch 1999) with improvements also noted in skin appearance for fine wrinkling, tactile roughness, coarse rhytids, skin laxity/tone, and sallowness/yellowing.
Retinoids (Vitamin A and Vitamin A derivatives)
Retinoids are Vitamin A itself or Vitamin A derivatives. Irrespective of the retinoid you use, if it is effective as in the case of retinol, retinal, or tretinoin, then it all gets converted into retinoic acid inside the skin cell where it has its effects. So all retinoids work via retinoic acid receptors.
If you are interested in anti-aging, you will definitely want a retinoid in your skincare regime. Retinoids will get into the nucleus of your skin cells and kick off a host of processes that include stimulating keratinocytes so that your epidermis thickens, increasing endothelial proliferation so that you will have better dermal vascularity and improved blood flow to the skin, and lastly of course, our topic of the day, increasing collagen production (Shao et al. 2017).
In this figure, reproduced from Shao and colleagues’ 2017 study, you can see these changes taking place at the microstructural level.
Reproduced from Shao et al. 2017
The dark staining is for fibroblasts that are positive for procollagen type 1. Shao and colleagues found that with retinoid treatment there was a three fold increase in fibroblasts that stained positive for procollagen for Type 1 collagen. On the right are arrows pointing to these positive fibroblasts and they were particularly prominent at the epidermal dermal junction.
Shao and colleagues also found that application of retinoids resulted in a four fold increase in elastin, which is shown in the red stain.
Reproduced from Shao et al. 2017
You can also see in the following figure that not only is collagen content increased with retinoid treatment, but also more collagen is preserved and intact. This is likely due to inhibition of MMPs by retinoids. You can see how collagen fibers look more intact and in the 3-dimensional image the collagen fibers are interconnected with each other with more cohesive, smoother surfaces.
Compare the images on the left column versus those on the right. Quantified, there was a 48% difference between the control and retinoid groups.
Reproduced from Shao et al. 2017
These benefits have been replicated in other high quality studies. For example, this figure from another paper, this time by Kong and colleagues from a 2015 study showed increases in gene expression for Type 1 and Type 3 procollagen with retinol and retinoic acid compared to vehicle treatment.
Source: Kong et al. 2015
Overall, all these changes translate into measurable decreases in fine lines and wrinkles and result in a firmer, smoother, more bouncy skin. These changes are dramatic. For example, Kong et al. found up to 39% reduction in eye area wrinkles and 64% reduction in cheek area wrinkles after 12 weeks of treatment with 0.1% retinol.
Source: Kong et al. 2015
There has been a large number of studies that demonstrate the effectiveness of retinoids in improving the conditions of both naturally aged and photo-damaged skin. It improves elastin and GAG levels as well as collagen levels. That’s why retinoids are your dermatologist's favorite anti-aging ingredient.
So which retinoid should you use? We recommend either Retinol or Retinaldehyde. They're both available without prescription.
If you have a prescription retinoid, you may be using tretinoin under the brand name Retin-A. At Maelove, our favorite is Retinaldehyde also known as retinal with an A. It’s as potent as prescription retinoid like tretinoin but you can get it without a prescription, and it’s also less irritating than tretinoin.
Niacinamide (Vitamin B3)
You might have heard that niacinamide is amazing for strengthening the skin barrier. Here is how that works:
Once absorbed into the skin, niacinamide gets converted into nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate - usually abbreviated as NAD and NADP.
Similar to Vitamin C, the levels of NAD and NADP in the skin naturally decline with aging. These cofactors are critical for cell metabolism, and so as the levels drop, your cells are less able to synthesize the lipids and proteins that help form the skin barrier resulting in dry, scaly skin.
Topical supplementation with niacinamide has been shown to raise NAD and NADP levels in the skin, and lead to an increased synthesis of these lipids and proteins to help fortify the skin barrier and increase the ability of the skin to retain its integrity maintaining moisture and suppleness.
Now these lipids include ceramides, free fatty acids and cholesterol, while proteins that increase in production include keratin, filaggrin, involucrin and you guessed it, collagen. This leads to improved fine lines and wrinkles as well as improved skin texture (Matts et al 2002)
A study conducted by Oblong and colleagues and published in 2002 found that fibroblasts from aged skin, when supplemented with niacinamide, started producing 54% more procollagen (Matts et al. 2002). That’s literally turning back the clock.
So, niacinamide is another do-it-all ingredient, much like Vitamin C and Retinoids.
What skincare products to look for to boost collagen
Our 3 favorite ingredients for boosting collagen are Vitamin C, retinoids and niacinamide.
In terms of products you’d actually buy. We recommend Vitamin C serums that come in 10% ascorbic acid concentration or higher. Ideally also formulated with other antioxidants like Vitamin E and Ferulic Acid in a pH 3.5 or lower.
We’re really big fans of retinaldehyde for the reasons I mentioned earlier. It’s really potent but relatively very mild in terms of irritation. Serums or creams are both fine. I’d go for a minimum retinaldehyde concentration of 0.05%.
And Niacinamide serums or creams in concentration of 5% or higher.
There are some other ingredients that show evidence of boosting collagen. These are generally less proven so we’d just mention briefly in this video. But we'll cover them more in-depth in the future.
Hydroxy acids seem to indirectly spur collagen production by basically purging the dead skin cells at the skin surface and stimulating new cell growth deeper below.
There are certain peptides that show promise. You may have heard of Matrixyl peptides, or copper tripeptide-1. These peptides have some supporting research to suggest they may help boost collagen, which we will cover in more depth in a future video.
And there are some botanicals that show promise. Bakuchiol is one of them. Bakuchiol is not a Vitamin A or retinoid, but it seems to work like retinoid in the skin.
And one more thing to mention here is oral supplementation of collagen. Hydrolyzed collagens have in multiple randomized, double-blind trials shown positive results - compared to placebo - for skin hydration, elasticity, and wrinkles). We’ll make a longer video on this specific topic as there are some nuances to explore.
That's it! Thanks for reading. Don't forget to check out our other newsletters.
This writeup was lead-authored by our senior scientist, Sunbin Song, PhD. Sunbin graduated from MIT with a degree in Biology before receiving a doctorate in neuroscience from Georgetown and becoming a research scientist at the NIH. When Sunbin isn't busy researching the brain, she loves to explore how we can best nurture our body, mind and spirit to live more joyful lives.
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