Hyaluronic acid - Another Magic Health Bullet 
By Walter Sorochan

Posted May 01, 2014; update September 18, 2014; updated April 20, 2016  Disclaimer     The information provided below is intended for educational purposes only. It is not meant to either directly or indirectly give medical advice or prescribe treatment.   Work in progress.

 Update: April 20, 2016   The real picture for skin and joint health has nutrients and substances that make up the glue that keeps tissues together .... collagen.  This glue is made up of vitamin C, although other substances many also play a helper role: organic sulfur, hyaluronic acid [HA], ceramide and other helper [co-factors] nutrients.  These work together as a team and when one or more are missing, then the body responds with skin problems, joint disorders and diseases like arthritis and scurvy. 

Hyaluronic acid does not work by itself.  There are many helpers in skin health .... one of which is the lipid --- ceramide.  In conjunction with other lipids like cholesterol and fatty acids, ceramides help restore the skin's moisture and act as a natural barrier against bacteria and environmental pollution.  Although the chemistry of how both ceramides and hyaluronic acid work together is complex, the relationship appears to be a supporting one.  This initial article on hyaluronic acid [HA] began by attempting to view HA as a single item in the skin and as we all know, the body does not work that way. It would be a mistake to not be aware that ceramide works cooperatively with HA to repair skin problems.

 

Abstract:

Hyaluronic acid plays many roles in health and disease.

Most of the research about hyaluronic acid [HA] in the past 15 years has focused on skin cream applications .... where the money is. There is no effective treatment for ageing skin!  The other equally important aspects of HA have been given less priority. The exception is great interest in how HA communicates with body cells.  New information is that Hyaluronic Acid [HA] works as a secret communication system between cells, sending special signals between cells and often performing dual opposite functions in the body.

This article also reviews referenced research about what hyaluronic acid is, summarizes how it works in the body and presents some of the controversies about applying hyaluronic acid to skin and joint conditions.  This article is intended for perspective users of HA and persons with limited scientific background.

The significance of this article is that there is a 'somewhat' scientific explanation for the cause of dry itchy skin, the cause of pain in joints, the cause of inflammation and the cause of wrinkling skin.  We have only a small piece of the formula needed to fix causes of many health problems as well as relieve symptoms; like dry, itchy skin, joint stiffness and pain with HA instead of medications. Molecular size and dosage of HA to be taken is important. But hyaluronic acid by itself does not fix itchy skin and other disorders.

 

Stiff and painful joints? Or dry, itchy skin?  Then you need help.  No, not a botox injection for wrinkles, nor a knee-hip replacement for painful joints.  Instead you may want to get acquainted with a sticky sugar that helps your body work.    Try Hyaluronic Acid or HA or/and ceramide.  These might help you! This article summarizes what you should know about HA and how it may help you. 

Hyaluronic acid attracted public attention when TV reporter Connie Chung reported about how an acid starch was linked to prolong the lives of Japanese people living in a remote village in Yuzuri Hara, Japan. "Village of Long Life" program via ABCNEWS.COM, November 2, 2000. ]  A Japanese medical researcher,Dr. Komori, believes the unique local diet may hold the key local residents living a long time.   Dr. Komori believed the local grown starches stimulated the body's creation of Hyaluronic Acid (HA). These people lived on a slope where rice, the traditional staple of Japan, cannot be grown. So they eat root vegetables, fish, very little meat and low iron foods. This diet helps these people retain HA [the root vegetables provide no HA]. Passwater: HA Sardi interview 2003   Since the Connie Chung TV program, the number of commercial companies using HA as an ingredient in supplemental skin products has exploded.

Prior to 2000 the hyaluronic acid molecule was thought to be passive and simply a structural component [like a 2 x 4 in a wall].  Despite its simple structure, dramatic scientific research is now showing that HA is one of the most biologically active compounds in the human body. The new science is showing that hyaluronic acid may operate as the brains of this operation, helping to regulate how the body grows, stabilizes, and maintains structure.  What is unclear is how HA works with other substances like magnesium, zinc, vitamin D and chlorophyll to activate on/off functional switches in the body.

What is hyaluronic acid?  [ also called hyaluronate or HA ]    Hyaluronic acid is found in all tissues and body fluids of vertebrates as well as in some bacteria and is produced naturally in your body.  It is cultured and produced commercially by a fermentation process from bacteria and from animal wastes. The purist source is from bacteria.  Read more about HA HA form HA is a long chain of  two repeating like molecules [ diagram on the left], referred to as a polysaccharide.  Wiki: Hyaluronen  The term “hyaluronan” also refers to the different forms the HA molecule can take in biochemical actions; e.g, hyaluronic acid,  sodium hyaluronate and many other forms. Necas: HA review 2008

The average 70 kg (154 lb) person has roughly 15 grams of hyaluronan in the body, one-third of which is turned over [degraded and synthesized] every day. Hascall: Book 2009   Necas: HA review 2008

ha skin aging Unfortunately HA content in humans decreases as we get older, especially after age 40. Typical signs of aging are age spots, skin wrinkles, hair loss, joint pain and stiffness  and poorer eyesight.   A remarkable finding is that these visible aging signs can be reversed with oral HA supplements. Passwater: HA Sardi interview 2003   Aging is also linked to telomeres and Superoxide Dismutase or SOD, although almost none of the literature reviewed by this author made any reference to these two aging factors.

How does the body make HA?   Just how the body makes hyaluronan forms [or fragments] is not clear. But research suggests that magnesium, zinc and vitamin C are involved in the synthesis of hyaluronic acid and its by-products [although this may not be a complete list].  This should not be surprising as magnesium and zinc deficiencies are known to be associated with many of the same symptoms associated with hyaluronic acid abnormalities such as cancer, poor wound healing and symptoms of dry itchy skin. HA can help identify [test for] healthy and diseased tissues.  [HARE, Hyaluronic Acid Receptor for Endocytosis signaling].  Pandey: HA receptor HARE 2013   Other HA molecules function as off-on switches attached to different genes.

Vitamin C in combination with iron [ and other co-factors ] helps to break down HA and create a healthy turnover of fresh HA every day. Ultraviolet sunlight, viruses, illnesses and diseases like cancer can also cause rapid brake down of HA.  HA loss in the body increases after age 40, making a person look older. Passwater: HA Sardi interview2003

Functions in the body: Hyaluronic acid [HA] is present in every tissue of the body. The water-binding capacity is directly related to the molecular weight of the molecule. Up to six liters of water may be bound per gram of HA.  While most of the focus about hyaluronic acid has been on its lubricating, spacer filler, aging and skin enhancements, more recent research credits HA with more important but less understood role of communication between cells.Bucci: HA misinformation  Rossler: HA communication 2003  Yang: HA transporter 2012

It is an under-recognized regulator of special cell and tissue functions, as shown by the presence of specific receptors on all cells for HA and its fragments.

HA fetus
Fukaya: HA blog

The amount of HA in cells, dependent on molecular weight size, is linked to numerous complex functions: Bucci: HA misinformation 2004 Laurent: HA binding properties 1992   Manasa: Review HA 2012  Hascall: Book 2009   Necas: HA review 2008 Wiki: Hyaluronen  Paraskevi: HA breakdown & cancer 2013  Papakonstantinou: HA skin aging 2013  Petrella: HA joint pain 2002   Rossler: HA communication 2003   Schlesinger: Low Mol wt HA cream 2013

    9dot5a   reduces nerve impulses and nerve sensitivity associated with pain.
    9dot5a   has an anti-inflammatory effect.
    9dot5a   facilitates biochemical processes in many tissues and organs of the body, such as the brain, heart, liver, skin, synovial fluid in joints, cartilage, eyes and developing embryos.
    9dot5a   attaches to collagen and elastin to form cartilage.
    9dot5a   lubricates movable joints and muscles.
    9dot5a   increases supplies of joint-lubricating synovial fluid.
    9dot5a   acts as a shock absorber in joints.
    9dot5a   signals for other cells within the body to respond. [Hyaluronan also acts as a signaling molecule by interacting with cell surface receptors and regulating cell proliferation, migration, and differentiation.]
    9dot5a   helps deliver nutrients to and carry toxins from cells that do not have a blood supply, such as those found in cartilage.
    9dot5a   encourages water retention in other bodily tissues.
    9dot5a   moisturizes and binds water to the skin.
    9dot5a   prevents tissue dehydration.
    9dot5a   fill fluid in space between cells.
    9dot5a   holds cells together.
    9dot5a   helps to heal the body.
    9dot5a   helps relieve pain.
    9dot5a   prevents scarring
    9dot5a   serves as a barrier against disease
    9dot5a   promotes a youthful appearance.
    9dot5a   enhance transport of drugs via HA-human growth hormone complex

Hyaluronan has been recognized in clinical medicine for some time. A concentrated solution of hyaluronan (10 mg/ml) has been used in ophthalmic surgery. Hyaluronan  helps to diagnose disease and various inflammatory conditions, e.g., rheumatoid arthritis, cancer. Accumulation of hyaluronan in the intestine is linked to numerous diseases and dysfunction in various organs.  So the question arises .... could hyaluronic acid help you?  That depends on the dosage and size of the molecular weight of HA used.  The illustration below tries to explain this phenomenon:

HA size function
Fukaya: HA blog


Source:  Cells signaling to each other

Medicine is just  beginning to seriously recognize the possibilities of applying hyaluronic acid to immunology and health.  Ruffell HA & immune system 2009   A specific HA molecule size [length] can send a signal to match with another receptor of same size.  Such active HA signaling is linked to healthy people and those with various diseases. Diabetes is a case in point.  A special HA form in sugar metabolism signals an insulin related HA size to a matching size receptacle in another cell so that blood sugar [glucose] can enter it.  When there is not enough HA for the pancreas to synthesize enough insulin to act, then sugar accumulates in the blood stream [high blood sugar] and a form of diabetes results.  Or diabetes may also result when the cells of the body, deficient in HA, do not respond properly to the insulin that is produced. Thus, HA works in a dual manner in sugar metabolism.  Researcher Galeanoa and others support the idea that HA may be most helpful in controlling blood sugar in diabetes. Galeanoa: HA wound healing diabetes 2011  Dasu: Diabetes & receptor activation 2010  Mahadevan: HA increased in diabetic rats 1996  Mine: HA conc diabetes 2006   Tabak: Diabetes & Mg 2013   However, there are a few wrinkles to work out in the application of HA to help diabetics.

As mentioned above, skin HA accounts for most of 50% of total body HA. The HA content of the dermis is significantly higher than that of the epidermis, while papillary dermis has much greater levels of HA than reticular dermis. HA in the dermis regulates water balance, osmotic pressure and ion flow and functions as a sieve, excluding certain molecules, enhancing the extracellular domain of cell surfaces and stabilizes skin structures by electrostatic interactions. Unfortunately, exogenous HA is cleared from the dermis and is rapidly degraded.  Papakonstantinou: HA skin aging 2013

It also follows that the water-binding capacity is directly related to the molecular weight of the HA molecule. Up to six liters of water may be bound per gram of HA. [ 1,000 times its HA molecular weight in water. The HA molecule acts like a cellular sponge. Manasa: Review HA 2012    Brown: HA skin absortion 1999

Metabolism of Hyaluronic acid: The metabolic functions of HA are not fully understood. HA has many dual functions that are complex and varied.   It is naturally synthesized by a class of integral membrane proteins called hyaluronan synthases, and degraded by a family of enzymes called hyaluronidases.  Necas: HA review 2008 For example,  some cells, such as chondrocytes in cartilages, actively synthesize [make] and break down [catabolize] hyaluronan throughout the lifetime of the tissue.  It is interesting to note that HA also has contradictory dual functions in the inflammatory process. Abundant HA promotes inflammation in the early phase of tissue repair, then suppresses inflammation.  Wiki: Hyaluronen  Maharjan: HA molecular wt effect 2011 The dual action of HA is also found in cancer.  Paraskevi: HA breakdown & cancer 2013

HA is naturally produced [ 1 million molecular weight Dalton ], a few grams a day and some is degraded and excreted through the liver. Vitamin C in combination with iron helps to break down HA and creates a healthy turnover of fresh HA every day.

Although hyaluronic acid is produced in the body in a natural manner, over time, the synthesis of HA diminishes. The half-life of Hyaluronic Acid in the cartilage is 2-3 weeks, and only one day or less in the skin. When the decline in hyaluronic acid synthesis begins to happen, one may experience joint discomfort, wrinkles and a tendency to get sick frequently.  Manasa: Review HA 2012 Necas: HA review 2008 Papakonstantinou: HA skin aging 2013  Without adequate amounts of HA, the joints will become stiff, brittle and deteriorate. "Tissues in joints, such as the lining cells of the joint capsule of the knee, synthesize hyaluronan and release it into the synovial fluid.  It has been estimated that almost one-third of the total hyaluronan in the human body is metabolically removed and replaced during an average day."  Hascall: HA metabolism

HA filaments: We would be remise in not mentioning the impact that the breakdown of HA has on the body.  The long chain of HA breaks down often into HA smaller chains of filaments.  Such filaments are unstable and form free radicals.  Ingesting anti-oxidants is important in clearing these free radical filaments from the body.

HA has a dynamic turnover rate in the human body.  The half-life of hyaluronan in tissues ranges from less than one to several days. Hascall: Book 2009  Fraser: HA functions 1997   The remainder enters the general circulation and is removed from blood, with a half-life of 2–5 minutes.  Wiki: Hyaluronen  Necas: HA review 2008,  less than a day in the skin and 1 to 3 weeks in the cartilage.  HA is degraded into fragments of varying size by the enzymes  hyaluronidases (HYAL).  Papakonstantinou: HA skin aging 2013

Bioavailability: While there are animal studies alluding that HA is absorbed in small amounts, we do not have accountable research to validate that HA is absorbed from the human digestive system in appreciable amount.  Balogh: Hi HA oral intake 2008  Saranraj: HA review 2013  Schauss: HA absorption into body 2004

HA Co-Factors: These are nutrients that help hyaluronic acid do its work in the body.  Mentioned by numerous researchers [as referenced below] are the following: sulfur, iron, zinc, magnesium, calcium, selenium, protein amino acids and vitamins A, and C.  Vitamin D, iodine, chlorophyll, and silica should not be discounted!  A coordinated and independent research on HA co-factors is most wanting!  The nutrients are found in foods that we eat.

Foods rich in HA  There is no direct research to support claims that food contains hyaluronic acid; except for trace amounts in meat.  Hyaluronic Acid (HA) is not in the diet in any appreciable amounts. Manasa: Review HA 2012  However, there is a link between HA, magnesium, zinc and diseases and health.

Foods are linked to HA by way of magnesium, sulfur and zinc and include:

    9dot5a   Meats: Since hyaluronic acid is found in the connective tissues of animals, it is also assumed that eating the connective tissues of animals and fowl [chicken soup] will provide the body with hyaluronic acid. There is no direct documented research to back up these claims; although these observations are linked to HA studies.
    9dot5a   Root Vegetables: There are claims that certain root vegetables promote the synthesis of HA in the body. Mentioned have been magnesium rich potatoes, carrots, sweet potatoes, horse radish, carrots, beets nd parsnips.
    9dot5a   Green vegetables: like asparagus, green lettuce, parsley, broccoli, green peas. spinach, green beans, broccoli, and cauliflower.
    9dot5a   Fruits: linked to magnesium include papaya, mangos, grape seeds, cranberry, cherries ,avocados, apples, bananas, strawberries, tomatoes, pineapples, oranges, melons, peaches and pears.
    9dot5a   Legumes:  such as kidney beans, pinto beans, black-eyed peas and lentils are rich in magnesium.
    9dot5a   Seeds: nuts, pumpkin seeds, almonds, walnuts, flax seeds are rich in magnesium.
    9dot5a   Other: Magnesium liked Echinacea, green tea, bilberry, quercetin, fish oil, yeast, whole grains or brown rice, soy temeh and miso, yogurt.

So while foods themselves do not contain hyaluronic acid, they are presumed to somehow cause the body to increase the amount of HA in the body.   Zinc is also linked to HA. Low levels of hyaluronic acid have also been found in individuals with low zinc levels. Manasa: Review HA 2012   Although revealing information on all of this food source-HA connection is somewhat suspect and mysterious, it might be explained as a co-factor.  We need immediate research about HA co-factors!

It is important to fix the cause as well as treat the symptoms of the cause!  As mentioned previously, it is the molecular weight of secreting HA that must match the receptor cell size in order for the HA to enter cells in the top skin layer. Then the HA can begin to do its work.  If you get a cream with the wrong HA molecular weight, or lacking it altogether, then that cream will not relieve dry, itchy skin. The research is unclear as to whether ingesting supplement HA capsules will stimulate already existing HA in the cells and, in turn, trigger other HA cells to synthesize more HA or whether the new capsule HA activates the synthesis of more HA.  There is also some concern about the amount, and necessity of additives [ as listed on commercial label products ]  that may have adverse effects on the body co-factors.    Wich: HA additives 2013

Skin Health   The skin is the largest organ in the body. As previously pointed out, hyaluronic acid plays a critical role in skin health.  The editor of PLOS Journal Kaya: HA restoring skin in 1 month 2006  and the diagram illustrating skin layers help to understand this role:

Skin layers: "The skin consists of three main layers. The outermost layer is the epidermis. It is the thickness of a sheet of paper and forms a barrier that prevents the body losing water or infectious agents entering it. The cells in the epidermis are mainly keratinocytes [ protective barrier cells ]. These specialized skin cells are continually produced at the base of the epidermis. From there, they move toward the skin's surface where they are shed.

The middle layer is the dermis. It is about ten times thicker than the epidermis and contains the blood vessels that feed the skin, nerves, sebaceous glands, and hair follicles. The final 'fatty tissue' layer in the diagram, also referred to as the subcutaneous layer, contains sweat glands, some hair follicles, blood vessels and fat tissue. The dermis contains collagen fibers that support the skin and elastin fibers that provide flexibility. Human skin begins to age in early adulthood. By the time a person is 80 years old, their epidermis may be half its original thickness because of decreased keratinocyte proliferation. The dermis also thins, and loss of collagen and elastin fibers means that the skin becomes less elastic. The gradual loss of epidermis and dermis—skin atrophy—is clinically important because aging skin is more fragile and heals slower than young skin and is also prone to ulceration.

No one knows why skin atrophy occurs, but it is becoming more common as people live longer, and there is no effective treatment for it. [ A few scientists speculate that crop soils using fossil fertilizers are disabling plants from absorbing sulfur from the soil, causing an inorganic sulfur deficiency in most humans. ]  One characteristic of atrophic skin is that, compared to normal skin, it contains less hyaluronate (also called hyaluronan and hyaluronic acid) — a large carbohydrate component of the extracellular matrix, the material that surrounds cells. It also contains less CD44, a cell-surface protein that interacts with hyaluronate. This interaction can stimulate cell proliferation and migration."

itchiness3 Liquiori's study in 1997 initially established that hyaluronan is absorbed from the surface of the skin and passes rapidly through the epidermis.   Liguori Double-blind study HA 1997   Other studies have confirmed Liquiori's findings.  Brown: HA skin absortion 1999   Farwick: HA LowMW & ageing 2008  Fukyama skin HA   Manasa: Review HA 2012  Passwater: HA Sardi interview 2003  Yang: HA transporter 2012  The main proteins in maintaining skin health are collagen [synthesized from vitamin C] and elastin.  But skin health deteriorates when collagen breaks down.  "A primary cause of the degeneration of collagen is the decrease in hydrated HA [ and also lack of vitamin C ], which supports collagen. Another contributing cause of dry skin is the breakdown of chlorinated water, although there is no research linking this to HA.  Skin moisture is very important. Putting moisturizers on the skin surface helps, but this is like using a small Band-Aid on a large cut. Replenishing skin HA is much more important than moisturizers. Drinking plenty of fluids also helps keep the HA hydrated. HA helps keep the collagen intact and smoothes out the skin to prevent wrinkling." Passwater: HA Sardi interview 2003  The real power of HA would be to form a permanent, protective layer on the skin!

Collagen and organic sulfur give the skin its firmness but it is HA that nourishes and hydrates the collagen.  HA acts as a space-filler in dermal layers between skin cells on a long term basis; enhancing soft, smooth and elastic skin.

"Nutritional supplement and beauty products contain ultra-high concentrations of hyaluronic acid in order to provide intensive moisture for aged skin that suffers from the dryness and wrinkles. When applied to the skin HA can penetrate the skin surface and replenish the natural levels already present. Like hyaluronic acid produced in the body, skin applications of hyaluronic acid used in this form are thought to moisturize from the dermis to the epidermis from deeper layers of the skin to the outer layer." Manasa: Review HA 2012  Pavicic: HA creams effectiveness 2011

Key question:  What is the Dalton molecular weight of HA that helps HA to be absorbed into the skin?   Researchers Farwick: HA LowMW & ageing 2008  Kaya: HA restoring skin in 1 month 2006  Maharjan: HA molecular wt effect 2011  Pavicic: HA creams effectiveness 201  Schlesinger: Low Mol wt HA cream 2013  have found that Low Molecular Weight HA [LMWHA] provides better penetration abilities than larger sized HA [HMWHA].

Restoring Joints: Medical doctors are marketing hip and knee joint replacements as well as HA injections to ease pain and discomfort in joints.  These approaches are controversial in many instances due to vested interests tainting their own practices, research and information. Petrella: HA joint pain 2002  Medical doctors neglect to consider that organic sulfur may be missing from the American diet, thereby causing joint inflammation and pain. ]  When your joints get stiff and painful, try organic sulfur supplement flakes and also try stretching and exercising them; thereby activating the synthesis of more hyaluronic acid to relieve the symptoms in a few minutes.  Both 'tries' work!

Reverse ageing: Sardi claims that visible aging signs can be reversed with oral HA supplements.  Passwater: HA Sardi interview 2003  Newspaper reporter Zinko discloses the questionable claims made by the company Solazyme about its "Algenist" anti-aging skin cream. Zinko: anti-aging cream 2011  Saranraj points out that there is no evidence to support the claim that taking it by mouth or applying it to the skin can prevent changes associated with aging. Saranraj: HA review 2013

Restore eyesight: Oral HA refills the eyes, it slightly lengthens the front-to-back length of the eye. This means the focus point of the eyes is altered. Therefore, farsighted people who take oral HA supplements may find their vision improving without glasses. Since all adults become a bit farsighted with advancing age, HA has enormous possibilities to help people postpone using glasses to read.  Passwater: HA Sardi interview 2003

Dosage:  HA is available in four forms: liquid injectable, oral capsule, oral liquid and skin cream. Whether HA taken works or not is related to percentage of total supporting ingredients, molecular size and dosage. Schlesinger: Low Mol wt HA cream 2013  Bucci: HA misinformation 2004  Oral dosage should be 150 mg per day, with possibly a loading dose for one month of 300 mg per day. More HA is not always better. HA in an injectable form ranges from 3 million to 6 million daltons molecular weight, while some oral forms are as low as about 1,500 to 3,000 daltons. A Dalton is a unit of mass equal to the mass of a single hydrogen atom.  Smaller molecular weight forms of HA are more easily absorbed in the intestines.   Passwater: HA Sardi interview 2003  The problem of dosage and molecular weight is further complicated by research studies that often fail to fully describe the nature of the HA they use. Bucci's review of 2004 also points out the practice of commercial companies borrowing information from irrelevant studies and putting this misleading information on their labels. Bucci: HA misinformation 2004 Consult a knowledgeable doctor prior to usage.

Test to Detect HA:  There is NO inexpensive test for hyaluronic acid in body tissues.  Since hyaluronic acid is found in all human tissues, one would assume that it would be easy to test for it in the blood or urine. HA is a bench-marker identifying many cancer types, hepatic fibrosis and other disorders as well well-being. But there is no recognized simple test to identify the amount of HA in the blood or urine.  Reason: HA has a very simple, conserved composition and is freely found in all animals that have a developed immune response; HA is not immunogenic. Therefore, there are no antibodies that specifically recognize HA, and traditional immunohistochemical methods of detection of HA are not possible. Fortunately, a very specific and tightly binding protein, the hyaluronan binding protein (HABP), which is composed of the HA binding domain with the link module from aggrecan, was isolated and adapted as an HA probe. dela Motte: staining HA 2011    HABP is now widely employed for specific but expensive detection of HA.

Buying HA:  Hyaluronic acid is cultured and produced commercially by a fermentation process from bacteria and from animal wastes. The purist source is from bacteria. But even the purity assumption may be misleading as using HA from traditional streptococcal origin may cause an inflammatory response in some individuals; as the human body can recognize streptococcus and many of its cell components as a pathogen.  Klingenberg, director of Novoenzymes Biopharma, claims that the safest and purest form of commercial HA available is his company's product hyasis.  Klingenberg: HA production 2013

What distinguishes one form of HA from another is its molecular weight, solubility, dosage, purity, additives like co-factors and cost.  Benefits [ of different sorts ] are reported from the use of all the oral HA products.  Passwater: HA Sardi interview 2003   But is the benefit one of fixing the cause or relieving a symptom?  This is where the information and research gets confusing!  Most companies marketing HA do not have independent research backing up the quality of their products, nor that their products are truly effective in promoting wellbeing. The marketers do not disclose the essential consumer information [ supplemental ingredients or formularies ] that consumers need to make informed decisions on first contact.

Although there has been an explosion of commercial companies inserting HA into their skin and aging products since 2000, most of these companies have lacked good research studies to support their product claims.  Most of the information about the affect commercial skin creams and lotions have on the skin is misleading and lacks documented research. Most of these creams do not contain HA. Bucci: HA misinformation 2004  Bucci's review of 2004, pointing out the practice of commercial companies borrowing HA information from irrelevant research studies and putting this misleading information on their labels is still true in 2014.

Numerous researcher-authors have pointed out that: "Those marketing anti-ageing products do not fully understand what they is selling. Collagen products promoted for joint health simply aren’t going to produce the results that HA does.  Go into a health food store today and ask about hyaluronic acid. They haven’t a clue what you are talking about. There are so many natural products claiming "anti-aging" benefits that it is often confusing."  Passwater: HA Sardi interview2003 Berneburg: fiction about cosmetics 2008   Bucci: HA misinformation 2004  Schlesinger: Low Mol wt HA cream 2013  Zinko: anti-aging cream 2011

Best HA supplements:  Many supplements contain ingredients other than hyaluronic acid.  Some of the ingredients or additives may cause health problems. Here is a web-site by Wich that recommends purest HA supplements with fewest additives: Wich: HA best supplements 2013   The list of Wich supplements is not complete nor validated.  Buyer beware!

Side effects from taking oral HA supplements:  There should be almost no chance of side-effects from taking HA if it matches the chemical molecular weight already occurring naturally in the body.  Manasa: Review HA 2012  Passwater: HA Sardi interview 2003

"Sardi: Yes, there are, though they are not common. First, understand that oral HA causes water to gel up, like Jell-O in the refrigerator. Now if a person were to be dehydrated, or be taking extra doses of a diuretic, he or she might experience a whopping headache due to a rise in blood pressure. This actually happened to a woman who inadvertently doubled up on her water pills and had a hypertensive crisis while taking oral HA. Fortunately, the problem subsided. Patients with high blood pressure on diuretics should be aware and take lower doses of HA, let’s say no more than 150 mg per day, and they must remember to drink water. Many hypertensive patients take oral HA supplements and report no problems. One of the pieces of advice I [William Sardi] offer in my book is to not to forget to drink water. HA plus H2O is the way it all works. Then there are cancer patients who have lymphedema, a condition in which the lymph glands are filled with HA degraded by the tumor and the HA has blocked the drainage from the lymph glands. This results in swelling in the legs. Oral HA would be contraindicated in cancer patients with lymphedema. Probably, oral HA should be avoided by patients with rheumatoid arthritis, which comprises less than 5% of the cases of arthritis. The classic symptoms of morning stiffness in a rheumatoid arthritis patient are caused by an autoimmune reaction degrading HA during sleep. Upon awakening, the rheumatoid patients find their joints are rigid because they are filled with excessive amounts of degraded HA. Once physical activity and the circulation gets moving, the stiffness disappears." Passwater: HA Sardi interview 2003

This would be a lot of information to digest were it not for other extraneous factors that may also impact on how well hyaluronic acid works.  There is speculation that the bad bacteria in the large intestine may also play a role in immunity, skin health and related body disorders.  But the research is weak and at best suggests linkage of colon bacteria to HA.  For example, it is not at all unusual to see skin issues associated withsmall intestinal bacterial overgrowth [SIBO].

Unresolved controversy:  "Hope triggers hype!"  Many are tempted to use topical skin hyaluronic acid in the form of gels, serums and so forth with the hope that they can reverse skin aging, and relieve joint pain and dry skin.  Independent researcher Todorov Todorov: Review HA skin care  has done a superb review of HA providing effective skin surface moisturizing, either alone or in combination with other moisturizing ingredients.  His comments are worth noting:

"However, there is a controversy whether concentrated HA formulas should be used as a moisturizer in dry climate. When air humidity is very low, HA may preferentially pull water from the skin rather than from the air, thus producing the opposite effect. The optimal use of HA as a moisturizer needs further research. But can topical HA go beyond moisturizing? Can it penetrate into the dermis and help rebuild the skin matrix? Generally, large molecules do not penetrate the skin or do so in very small amounts. Most likely, medium-to-large size HA molecules (perhaps with molecular weight above 20,000 Da) won't penetrate sufficiently to have an impact on the skin matrix. However, small size HA (5,000 - 20,000 Da) may penetrate into the dermis in significant amounts. However, this may not necessarily be a good thing. Assuming small size HA molecules penetrate into the dermis, they are likely to trigger some elements of the wound healing response (as we discussed above), such as immune activation, inflammation, cell division, blood vessel growth, new skin matrix synthesis and so forth. The net effect might be either matrix degradation and accelerated skin aging or matrix remodeling and improved skin texture. Studies are required to answer this question." Todorov: Review HA skin care

The good, the bad and the ugly of HA:

The significance of this article is that you now have another scientific explanation for the cause of dry itchy skin, the cause of pain in joints, the cause of inflammation, the cause of wrinkling skin as well as some auto-immune disorders, diabetes and cancer.  Rilla: Sugar conc & HA 2013 The explanations are not perfect but better than just saying that "dry skin is caused by aging and lack of skin moisture, so cover your skin with a cream and your itchiness will go away!"  HA has many dual functions that are complex and confusing.   Lets not overlook that certain levels of HA may be an important contributing factor in causing cancer, diabetes and auto-immune disorders.  Small HA fragments are thought to occur at inflammation sites and be active in inducing inflammation.  Pandey: HA receptor HARE 2013   Knowing the cause gives you an honest rational basis to fix causes of health problems instead of relieving symptoms.  The HA explanations are not all inclusive and, as pointed out by Sardi, Todorov and others, still need further research, but you now don't need to cover up your dry itchy skin with a cream that doesn't really work!  [ After all, the skin is living tissue that has skin pores that need to breath and covering the skin with cream plugs up these pores! ]  There is another option and that is to do something about what is causing the problem.

The good aspect of HA:  As the reader should surmise from reading this article, there are more unasked questions than answers!  There is some good research going on; especially HA signaling between cells and the dual functions of HA. The larger HA is far more effective at low doses because it has more HA-binding sites per molecule than the larger kDa HA dose. The results indicate that mammalian HA responds exclusively and very selectively to a narrow range of HA sizes, from 40 to 400 kDa (i.e. from mid-range sHA to mid-range iHA.

The bad side is that the HA research lacks priority, focus and coordination on an international level. Scientists are beginning to understand how HA really works and how it might be used to more effectively improve symptomatic disorders like dry, itchy skin.   A major need is for new sources of highly pure and safe HA, like Bacillus subtilis.  The production of HA is an issue that has been undergoing closer and closer examination in the last few decades. The major research flaw is investigating HA or ceramide exclusively as a separate entity and not in a co-factorial relationship.

Related to using a better HA source is the need for the world to define an international nomenclature standard to define and designate the broad size ranges of HA found physiologically. Literature terms or HA size are not uniform or consistent, and some reports use identical terms (e.g. small) for different sizes. Pandey: HA receptor HARE 2013   For example, some reports designate 500 kDa HA as low molecular weight HA (LMW-HA), whereas others consider the same size to be HMWHA.” Pandey: HA receptor HARE 2013  Lack of such a standard is greatly responsible for mis-interpretation of research articles and controversy.  Furthermore, the HA research community has a unique responsibility to make complex HA research more understandable to "common folk" with average science background [as this article attempts to do!].

The ugly is that there is a lot of misinformation and hype about HA, commercial creams and joint replacements.  Researchers are working with drug companies to transport drugs via HA into the body .... instead of researchers independently working to effectively regenerate damaged and aging skin.  Making matters worse, our own government, largely through ineptitude of the Federal Food and Drug Administration, has abandoned protecting American citizens in not fostering much needed HA research.

Meanwhile what do we do?

    1. Consult with an informed healer before using any form of HA.
    2. Continue to become better informed about HA as research and knowledge are exploding exponentially every year. New research is continuously posted on the internet and you need to update.
    3. Get HA indirectly by eating whole food complex foods, especially root vegetables and fruits rich in vitamins A, C, D, magnesium, iodine and zinc.  Your body functions best when you give it good nutrition from the inside.
    4. Consider the possibility that your skin may need HA, ceramide, organic sulfur and other co-factors. Skin creams may be better absorbed than oral supplements, but the research on all of this is shaky!
    5. Be cautious in using commercial products that make unsupported claims. Investigate where the product is made, its purity, molecular weight, percentage of total ingredients and dosage. Check out HA supplements with fewest additives.
    6. Contact your political representatives and besiege them to support better labeling and to provide more independent research funding for HA and ceramide.

Your feedback is most appreciated: E-mail to: Author Walter Sorochan

To return to: web-site main page

References: 

Ainbinder Denize and Elka Touitou, "Nanotechnologies in Skin Antiaging Treatment," TKO Science. Ainbinder: antiaging skin treatment [ Authors have vested interest in cosmetic products ]

[ Alguronic acid is said to contain anti-aging properties superior to other beauty creams on the market.  Alguronic acid is not affected by enzymes that break down hyaluronic acid and even stunts the growth of those enzymes.  Alguronic acid, company officials maintain, is superior to hyaluronic acid, a substance in the skin that helps to retain moisture (and is found in many moisturizers).FDA does not support  these claims ]

Balough Lajos, Andras Polyak, Domokos Mathe, Reka Kiraly, Juliana Thuroczy, Marian Terez, Gyozo Janoki, Yaoting Ting, Luke R. Bucci and Alexander G. Schauss, "Absorption, Uptake and Tissue Affinity of High-Molecular-Weight Hyaluronan after Oral Administration in Rats and Dogs," J. Agric. Food Chem. 2008, 56, 10582–10593.   Balogh: Hi HA oral intake 2008

"This report presents the first evidence for uptake and distribution to connective tissues of orally administered, high-molecular weight HA.  Most HA being ingested by consumers is in a high-molecular-weight form around 1 million daltons (1 MDa). The labeling process for HA that yielded the highest efficiency was as follows: 9 mg of HA in 900 μL of distilled water, 30 μL of 10-3 M calcium glucoheptonate, 1.1 mL of 2.2 GBq 99mTcpertechnetate solution, and 100 μL of 1 mg/mL SnCl2 in 1.0 M HCl, pH 4.0. This mixture was incubated at 50 °C for 90 min with gentle stirring."

Barnes L., et al, "Inhibition of Putative Hyalurosome Platform in Keratinocytes as a Mechanism for Corticosteroid-Induced Epidermal Atrophy," J Invest Dermatol. December 6, 2012, doi: 10.1038/jid.2012.439.   Barnes: HA Affect skin 2012   "The molecular size of HA fragments of intermediary size (HAFi) appeared essential for its biological activity in the epidermis. According to our in vivo and in vitro mouse models, the suitable size for such a biological activity in epidermis ranges between 50 and 400 kDa."

Berneburg M, Trelles M, Friguet B, Ogden S, Esrefoglu M, Kaya G, et al., "How best to halt and/or revert UV-induced skin ageing: strategies, facts and fiction," Exp Dermatol. 2008;17:228–40. Berneburg: fiction about cosmetics 2008

Brown Tracey J., Daine Alcorn and J Robert E Fraser, "Absorption of Hyaluronan Applied to the Surface of Intact Skin," Journal of Investigative Dermatology, 1999, 113, 740–746; doi:10.1046/j.1523-1747.1999.00745.  Brown: HA skin absortion 1999   [ Hyaluronan is absorbed from the surface of the skin and passes rapidly through epidermis. Hyaluronan absorption demonstrated by the recovery of polymers of molecular size 360–400 kDa from both blood and skin. "This study establishes that hyaluronan is absorbed from the surface of the skin and passes rapidly through epidermis, which may allow associated drugs to be carried in relatively high concentration at least as far as the deeper layers of the dermis." ]

Bucci Luke R., and Amy A. Turpin, " Will the real hyaluronan please stand up?" JOURNAL OF APPLIED NUTRITION, VOLUME 54, NUMBER 1, 2004.   Bucci: HA misinformation 2004

Consumer Guide to Oral Hyaluronic Acid Supplements "Bill Sardi interview: The lower molecular weight HA is absorbed quicker, before stomach acid can degrade it, while the heavier weight HA supplements are broken down by stomach acid and enzymes and enter the circulation as fragments of HA. All HA supplements are orally absorbed."

Dasu Mohan R. , Sridevi Devaraj, Samuel Park, and Ishwarlal Jialal, "Increased Toll-Like Receptor (TLR) Activation and TLR Ligands in Recently Diagnosed Type 2 Diabetic Subjects," Diabetes Care April 2010, vol. 33 no. 4 861-868.  Dasu: Diabetes & receptor activation 2010

"Levels of glucose, A1C, FFAs, and HOMA-IR were significantly higher in type 2 diabetic subjects than in control subjects. In this study, we provided key evidence for increased monocyte TLR2 and TLR4 expression, activation, cofactor expression, ligands, and downstream signaling contributing to systemic inflammation seen in type 2 diabetic subjects. Our observations significantly add to the emerging role of TLRs in atherosclerosis and diabetes."

dela Motte Carol A. and Judith A. Drazba, "Viewing Hyaluronan," J Histochem Cytochem March 2011, vol. 59 no. 3 252-257.   dela Motte: staining HA 2011 [ Imaging Contributes to Imagining New Roles for This Amazing Matrix Polymer] This article discusses the conditions and considerations that the authors’ lab and others have developed for optimal HA staining in many tissues and cell types.

Farwick M., P. Lersch, G. Strutz, "Low Molecular Weight Hyaluronic Acid: Its Effects on Epidermal Gene Expression and Skin Ageing," SOFW-Journal, November 2008. | 134 |   Farwick: HA LowMW & ageing 2008    "The in-vivo effects of different LMW HA molecules (50 kDa, 130 kDa and 300 kDa) were compared in an eight-week placebo controlled study with an O/W cream containing 0.1% Na-salt of the HA derivatives. 12 female volunteers, aged 30-60 years, applied the cream two times ily for 60 days. HA offers not only beneficial effects to the skin but also that these effects can be controlled by varying the molecular size. It was found that LMW HA provides better penetration abilities than larger sized HA. These data show for the first time that topical application of LMW HA improves skin functioning and provides anti-aging effects which could be achieved by strengthening its penetration abilities based on decreasing the molecular size."

FASEB [ Federation of American Societies for Experimental Biology  ], A. G. Schauss, L. G. Balogh, A. G. Polyak, D. G. Mathe, R. G. Kiraly and G. G. Janoki, "Absorption, distribution and excretion of 99mtechnetium labeled hyaluronan after single oral doses in rats and beagle dogs," American Institute for Biosocial and Medical Research, Inc and National Institute for Health, 2004.   [The results demonstrate that HA is absorbed and distributed to organs and joints after a single oral administration.] FASEB HA absorbed 2004

Fraser J. R. E., T. C. Laurent2 and U. B. G. Laurent, "Hyaluronan: its nature, distribution, functions and turnover," Journal of Internal Medicine, July 1997, Volume 242, Issue 1, pages 27–33.   Fraser: HA functions 1997

Fukaya, "Hyaluronic acid of around 100 thousand dalton (molecular weight)" 2013 Fukaya: HA blog

Medication for after steriod use: "Dr. Fukaya's Skin Repair Lotion (also known as Hyaluprotect in Japan) is made with Hyaluronic Acid of 50000 to 110000 molecular weight, which is proven to effectively hold back the side effects of Topical Steroids such as atrophic skin (skin thinning) and rosacea. " It's presently unknown how a Hyaluronic Acid of middle molecular weight affects skin during this period as there have been no conclusive scientific reports yet. [Advertisement] Fukyama skin HA

Galeanoa Mariarosaria and others, "Systemic administration of high-molecular weight hyaluronan stimulates wound healing in genetically diabetic mice," Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. July 2011, Volume 1812, Issue 7, Pages 752–759.   Galeanoa: HA wound healing diabetes 2011

Goldfaden Gary, "Delay Skin Aging with Cutting-Edge Topical DNA Technology," Life Extension Magazine, August 2011.   Goldfaden: skin aging delay 2011  Relationship of ageing, skin, HA and telomeres. "A combination of two key ingredients, teprenone and caprylic acid, has been clinically demonstrated to extend skin cell life span and maintain moisture to promote youthful looking skin.

HA Active ingredients:  hyaluronic acid ( intermediary size, 50-100 thousand Da ), additives for preservation : Phenoxyethanol, Iodopropynyl, ButylcarbamateO, Hydroxypropyl-b-Cyclodextrin. "Chemistry in Necas: The uronic acid and aminosugar in the disaccharide are d-glucuronic acid and d-N-acetylglucosamine, and are linked together through alternating beta-1,4 and beta-1,3 glycosidic bonds."

HA Ingredients: [incomplete list] Many commercial brands of Hyaluronic acid may contain more than just the acid itself. For example, silica or silicon dioxide are often added to prevent caking, magnesium stearate or stearic acid for easier manufacturing, hypromellose (hydroxypropyl methylcellulose) as an emulsifier or thickener, and titanium dioxide for whitening.  This is not a complete list!

HA terminology: CD44, the primary cell surface receptor for HA, is present at varying levels on the majority of cells.  CD44 = cell surface glycoprotein; CDC37 = intracellular HA-binding protein; Da = dalton; DNA = deoxynucleotid acid; ECM = extracellular matrix; EM = electron microscopy; GHAP = glial hyaluronate-binding protein; GIT = gastrointestinal tract; HA = hyaluronic acid; HARE = hyaluronic acid receptor for endocytosis; HAS1, HAS2, and HAS3 = types of hyaluronan synthases 1, 2 and 3; IHABP = intracellular HA-binding protein; IMP = integral membrane protein; IL-1 = interleukine 1; LM = light microscopy; LYVE-1 = lymphatic vessel endocytic receptor; MRHD = maximum recommended human dose; NS = normal saline; OA = osteoarthrosis; P-32 = protein-32; RHAMM = receptor for hyaluronic acid mediated mobility; RHAMM/IHABP = receptor for hyaluronic acid mediated mobility/intracellular HA-binding protein; TDLo = toxic dose low; TIMP-1 = tissue inhibitor of matrix metalloproteiness 1;TNF-α = tumor necrosis factor alpha; TSG-6 = tumor necrosis factor-α-stimulated gene-6; t1/2 = half-life; UDP = uridine diphosphate  Necas: HA review 2008

Hascall Vincent C. and Torvard Laurent, "Metabolism of Hyaluronan," Index of /science/hyaluronan/HA01, January 06, 2011.  Hascall: HA metabolism

Hascall Vince and Jeffrey D Esko, Chapter 15 Hyaluronan, Essentials of Glycobiology. 2nd edition 2009.   Hascall: Book 2009 [turnover of hyaluronan in most tissues is rapid] This chapter describes the structure and metabolism of the nonsulfated glycosamino-glycan hyaluronan and how its chemical attributes contribute to its highly diverse and versatile biological functions.

Ishijima, M. et al., "Intra-articular hyaluronic acid injection versus oral non-steroidal anti-inflammatory drug for the treatment of knee osteoarthritis: a multi-center, randomized, open-label, non-inferiority trial," Arthritis Res Ther. Jan 21, 2014; 16(1): R18.  Ishijima: knee osteoarthritis 2014   [ The aim of this study was to clarify the efficacy and safety of early-phase IA-HA in comparison to those of NSAIDs for patients with knee OA. ]

Ito, Asaka., "The Effects of a Hyaluronan Lotion with a Molecular Weight of around 50 - 110 kDa on the Aged Atrophic Skin," Journal of Cosmetics, Dermatological Sciences and Applications, 2014, 4, 150-155. doi: 10.4236/jcdsa..43021.   Ito: HA lotion on human skin 2014  Ito: Fukaya HA lotion on human skin HTML 2014

"ABSTRACT: Background: Hyaluronic acids act upon keratinocytes via CD44 receptors and regulate proliferation and differentiation. Some cosmetic hyaluronan lotions manufactured based upon the fact are nowadays available. Aims: To evaluate a cosmetic hyaluronan lotion (Dr. Fukaya’s skin repair lotion or Hyaluprotect) from the viewpoint of anti-aging effects and to consider its mechanism. Patients/Methods: In ten healthy volunteers at the age over 60, immunohistochemical research of the biopsied skin was performed before and after the application of the hyaluronan lotion for two weeks. Results: Expression of PCNA in the lower epidermis increased in 8 of 10 subjects. Filaggrin expression of the upper epidermis increased in 6 subjects. 11βHSD1 decreased in 5 subjects and 11βHSD2 increased in 5 subjects. Conclusions: The proliferative and differentiative effects of the hyaluronan lotion upon keratinocytes were confirmed immunohistologically. There is a possibility that hyaluronic acids work through the regulation of corticosteroids by 11βHSD1 and 11βHSD2."

Kaya G et al, "Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism," PLoS Med. December 2006; 3(12):e493.  Kaya: HA restoring skin in 1 month 2006

"Chronic cutaneous insufficiency/fragility syndrome named ‘‘dermatoporosis.’’    The skin consists of three main layers. [Excellent description of skin layers. ] Our observations have defined 50,000–400,000 Da HAF as reagents capable of inducing a proliferative response in mouse and human skin. Clinically, topical HAFi application resulted in epidermal hyperplasia with restoration to normal thickness of atrophic human skin as early as 1 mo after initiation of treatment. This effect was accompanied by significant clinical improvement."

Klingenberg Hans Ole, "Finding an Alternate Source: Bacillus Subtilis in the Production of Hyaluronic Acid," Novozymes Biopharma, December 23, 2013   Klingenberg: HA production 2013 "This article discusses the alternative sources of Hyaluronic Acid – Bacillus subtilis – and the production technique for a safe and consistent HA for use in large scale formulations."

Laurent TC and Frazer Jre, "Hyaluronan," FASEB JOURNAL, April, 1992, Volume: 6 Issue: 7 Pages: 2397-2404.  Laurent: HA binding properties 1992

Lewis Aled and others, "Diabetic nephropathy,inflammation, hyaluronan and interstitial fibrosis," Histol Histopathol, 2008, 23: 731-739.   Lewis: HA & diabetes 2008 The aim of the current study was to quantify both inflammatory infiltrate and the expression and organization of hyaluronan in renal biopsies of patients with diabetic nephropathy.

Liguori V., and others, "Double-blind, randomized clinical study comparing hyaluronic acid cream to placebo in patients treated with radio-therapy, Radiother Oncol, 1997, 42(2) 155-161. Liguori Double-blind study HA 1997 ["CONCLUSION: The prophylactic use of a cream with hyaluronic acid is shown to reduce the incidence of high grade radio-epithelitis, suggesting an interesting role of the hyaluronic acid cream as supportive treatment to improve compliance and quality of life in patients undergoing radiation therapy."]

Mahadevan P,m R.G. Larkins, J. R. E. Fraser, A. J. Fosang and M. E. Dunlop, "Increased hyaluronon production in the glomeruli from diabetic rats: a link bewteen glucose-induced prostaglandin production and reduced suphated proteoglycan," Diabetologia 1995, 38: 298-305.   Mahadevan: HA increased in diabetic rats 1996    It is concluded that increased prostaglandin production secondary to high glucose environment can lead to an increased glomerular hyaluronan synthesis. This can substantially affect the levels of sulphated glycosaminoglycans in the extracellular matrix. We propose that these effects provide a possible link between the initial biochemical consequences of hyperglycaemia and later structural changes seen in the glomerulus in diabetes.

Maharjan Anu S., Darrell Pilling, Richard H. Gomer, "High and Low Molecular Weight Hyaluronic Acid Differentially Regulate Human Fibrocyte Differentiation," Journal Pone, October 11, 2011.   Maharjan: HA molecular wt effect 2011   [ " We found that 300 µg/ml HMWHA potentiates fibrocyte differentiation and 300 µg/ml LMWHA inhibits fibrocyte differentiation. These HA concentrations are similar to what has been observed in tissues, and the HA concentrations used in other studies.  There is still no known mechanism to explain how a simple repeating disaccharide of varying length has opposing effects on a same type of cell."]

Manasa M, Sridevi V., Chandana Lakshmi M.V.V, and Dedeepya J., “ A Review on Hyaluronic Acid,” Int. J. Res. Chem. Environ. Vol.2 Issue 4 Oct. 2012(6-11).   Manasa: Review HA 2012   This paper reviews on properties, production, routes of injection, sources and applications of hyaluronic acid. When applied to the skin HA can penetrate the skin surface and replenish the natural levels already present. Like hyaluronic acid produced in the body, hyaluronic acid used in this form moisturizes from the dermis to the epidermis from deeper layers of the skin to the outer layer.

Mine S., Okada Y, Kawahara C, Tabata T, and Tanaka Y., "Serum hyaluronan concentration as a marker of angiopathy in patients with diabetes mellitus," Endocr J. December 2006; 53(6):761-6. Epub 2006 Sep 12.  Mine: HA conc diabetes 2006  [The aim of this study was to determine the correlation between serum HA concentrations and diabetic angiopathy. "Serum HA levels were significantly (P<0.05) higher in diabetic patients (83.6 +/- 5.6 ng/ml, mean +/- SEM) than in normal subjects (41.7 +/- 12 ng/ml)." ]

Necas J., L. Bartosikova1, P. Brauner, J. Kolar, "Hyaluronic acid (hyaluronan): a review," Veterinarni Medicina, 53, 2008 (8): 397–411 Review Article.  Necas: HA review 2008 [ This review describes metabolisms, different physiological and pathological functions, basic pharmacological properties, and the clinical use of hyaluronic acid.  "Chemistry: The uronic acid and aminosugar in the disaccharide are d-glucuronic acid and d-N-acetylglucosamine, and are linked together through alternating beta-1,4 and beta-1,3 glycosidic bonds." ]

Pandey Madhu S., Bruce A. Baggenstoss, Jennifer Washburn, Edward N. Harris, and Paul H. Weige, "The Hyaluronan Receptor for Endocytosis (HARE) Activates NF-κB-mediated Gene Expression in Response to 40–400-kDa, but Not Smaller or Larger, Hyaluronans," J Biol Chem. May 17, 2013; 288(20): 14068–14079.   Pandey: HA receptor HARE 2013

Papakonstantinou Eleni, Michael Roth, and George Karakiulakis, "Hyaluronic acid: A key molecule in skin aging," Dermatoendocrinol. July 1, 2012; 4(3): 253–258.  Papakonstantinou: HA skin aging 2013  [ This review presents in brief recent knowledge in HA biology and function and focuses on its involvement in skin aging. "The size of HA appears to be of critical importance for its various functions. HA of high molecular size, usually in excess of 1,000 kDa, is present in intact tissues and is antiangiogenic and immunosuppressive, whereas smaller polymers of HA are distress signals and potent inducers of inflammation and angiogenesis." ]

Passwater Richard,  “Oral Hyaluronic Acid: Anti-aging, Skin, Joints and Healing An interview with Bill Sardi, Whole Foods- April, 2003.   Passwater: HA Sardi interview 2003

Paraskevi Heldin, Kaustuv Basu, Berit Olofsson, Helena Porsch, Inna Kozlova and Kaoru Kahata, "Deregulation of hyaluronan synthesis, degradation and binding promotes breast cancer," J Biochem, 2013, 154 (5): 395-408. Paraskevi: HA breakdown & cancer 2013

Pavicic T et al., "Efficacy of cream-based novel formulations of hyaluronic acid of different molecular weights in anti-wrinkle treatment," J Drugs Dermatol., September 10, 2011, (9):990-1000.   Pavicic: HA creams effectiveness 2011  "CONCLUSION: Topical application of all 0.1% HA formulations used in this study led to significant improvement in skin hydration and elasticity. Application of low-molecular-weight (LMW) HA was associated with significant reduction of wrinkle depth"

Petrella RJ, DiSilvestro MD, Hildebrand C., "Effects of Hyaluronate sodium on pain and physical functioning in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled clinical trial," Arch Intern Med., February 11, 2002 ;162(3):292-8.   Petrella: HA joint pain 2002  [ For resting pain relief, hyaluronate sodium seems to be as effective as NSAIDs. Further, for pain with physical activity and functional performance, hyaluronate sodium may be superior to placebo alone or NSAIDs alone.]

Rilla K., S. Oikari, T. A. Jokela, J. M. T. Hyttinen, R. Karna, R. H. Tammi, M. I. Tammi., " Hyaluronan Synthase 1 (HAS1) Requires Higher Cellular UDP-GlcNAc Concentration than HAS2 and HAS3," Journal of Biological Chemistry, 2013; 288 (8): 5973 DOI: 10.1074/jbc.M112.443879  Cell sugar concentrations affect hyaluronan production and cancer growth. Rilla: Sugar conc & HA 2013

Rossler A, and Hinghofer-Szalkay H., "Hyaluronan fragments: an information-carrying system?" Horm Metab Res 2003 Feb; 35(2):67-68.   Rossler: HA communication 2003

Ruffell Brian and Pauline Johnson, "The regulation and function of hyaluranan binding by CD44 in the immune system," Glycoforum, January 7, 2009.   Ruffell HA & immune system 2009 [ CD44 can have a dual role in immunity ]

Ruff Kevin J, "Eggshell membrane: A possible new natural therapeutic for joint and connective tissue disorders. Results from two open-label human clinical studies," Clin Interv Aging, June9, 2009, 4: 235–240.  Ruff: Egg shell HA relieves pain 2009 [ Significant proportions of patients treated with Natural Eggshell Membrane (NEM] had pain relief. ]

Saranraj P. and M.A. Naidu, "Hyaluronic Acid Production and its Applications - A Review," International Journal of Pharmaceutical & Biological Archives, 2013; 4(5): 853 - 859.   Saranraj: HA review 2013  {"There is also a lot of interest in using hyaluronic acid to prevent the effects of aging. In fact, hyaluronic acid has been promoted as a "fountain of youth." However, there is no evidence to support the claim that taking it by mouth or applying it to the skin can prevent changes associated with aging."]

Schauss Alex. G., L. G. Balogh, A. G. Polyak, D. G. Mathe, R. G. Kiraly and G. G. Janoki, "Is High Molecular Weight Hyaluronic Acid Absorbed?" April 18, 2004, Paper presented to American Institute for Biosocial and Medical Research, Inc and National Institute for Health. Schauss: HA absorption 2004   [ (FASEB, 2004). A. G. Schauss, L. G. Balogh, A. G. Polyak, D. G. Mathe, R. G. Kiraly and G. G. Janoki.] This study examined the absorption, excretion and distribution of High Molecular Weight HA from bacterial fermentation in organs and joints after a single oral administration in Wistar rats and Beagle dogs..  Uptake of HA into the bloodstream (5% of an oral dose) was found, and scintigraphy found uptake of labeled HA into joints. Schauss: HA absorption into body 2004  Schuass: HA report 2008

Schlesinger Todd E., et al., "Efficacy and Tolerability of Low Molecular Weight Hyaluronic Acid Sodium Salt 0.2% Cream in Rosacea," J Clin Aesthet Dermatol v.5(10); October 2012. PMC3486775   Schlesinger: Low Mol wt HA cream 2013 [ Schlesinger has vested interest in funding and as consultant for Innocutis Holdings.  This study evaluated the efficacy and tolerability of hyaluronic acid sodium salt gel 0.2% in the treatment of facial seborrheic dermatitis. ]

Smith MM1, Ghosh P., "The synthesis of hyaluronic acid by human synovial fibroblasts is influenced by the nature of the hyaluronate in the extracellular environment," Rheumatol Int. 1987;7(3):113-22.  Smith: HA synthesis in humans 1987

Tabak, Alan J., "Magnesium-Rich Foods Reduce Diabetes Risk", The Harvard Crimson, January 21, 2004; Website: March 11, 2013.  Tabak: Diabetes & Mg 2013    [Eating foods rich in magnesium can reduce the risk of type two diabetes onset, according to two studies by Harvard researchers.]

Todorov G., "Hyaluronic acid: Skin matrix health is not just about proteins," SmartSkinCare, 2014. Todorov: Review HA skin care [  Todarov has vested interest in Smart care Products ]

Wich Dan, "Hyaluronic acid supplements with the fewest additives," October 7, 2013.  Wich: HA best supplements 2013   [ Best recommended HA supplements ]

Wikipedia, "Hyaluronen."  Wiki: Hyaluronen

Yang Jeong-A and others, "Transdermal delivery of hyaluronic acid & Human growth hormone conjugate," Biomaterials, May 25, 2012.  Yang: HA transporter 2012

"Pharmakinetic [PK] analysis of topically applied HAehGH conjugate revealed the effective delivery of HAehGH conjugate through the skin into the blood stream."

Zinko Carolyne , "Algenist uses Solazyme microalgae for anti-aging," SFGate, March 25, 2011.   Zinko: anti-aging cream 2011

Yoshimura Masafumi, and others, "Effect of a chicken comb extract-containing supplement on subclinical joint pain in collegiate soccer players," EXPERIMENTAL AND THERAPEUTIC MEDICINE 2012, 3: 457-462.  Yoshimura: HA releves soccer pain 2012 [ HA may be implicated in the favorable effect of the chicken comb extract [CCE] supplement by suppressing inflammation of the affected joints, thereby relieving joint pain. ]