Quite often, questions come from our BFT readers that convince us we have an extraordinarily inquisitive and bright readership, something for which we are very grateful. It convinces us our many uncompensated hours of research and writing and staying up past our bedtime are worth the effort.
In this case, the question stems from a post written by Dr. Lance Setterfield, a globally recognized guru in the field of microneedling and a personal friend of Drjohn and Drgeorge. It has to do with concerns that microneedling in “patients with glycation” might not be a great idea. After giving you a chance to read Dr. Setterfield’s post immediately below, we’ll provide some additional information about the phenomenon of glycation and answer our reader’s question about topical products.
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From Dr. Setterfield’s online post:
Is Microneedling Contraindicated in Patients with Glycation?
Wrinkles may worsen with microneedling in patients prone to glycation, but this is not an absolute contraindication to treatment. Glycation is due to abnormal cross-linking of collagen. Therefore, the greater the amount of new collagen that is produced via needling, (be that cosmetic or medical), the more cross-linking and worse the appearance, if it was truly due to glycation.
Glycation looks like ‘cobblestone’ which is quite different to loss of structural integrity due to sun damage. In the latter, we typically also see hyperpigmentation. Other things to consider that may ‘appear’ similar to glycation, or complicate the appearance of glycation, would be scarring (due to electrolysis or chemical peels, done repeatedly over a lengthy time), or sebaceous hyperplasia. Solar elastosis may also have a similar appearance.
Glycation is more pronounced in diabetics and influenced by diet, so any positive changes associated with needling may also be due to dietary advice given at the time of consultation. Products that contain ingredients that combat glycation, such as L-Carnosine, or Supplamine, should always be used in conjunction with microneedling. These can be applied topically or taken as a supplement. I would recommend both oral and topical in severe cases.
Remember that a normal fasting blood sugar and HgbA1c does not rule out glycation. In the early stages of metabolic disorders, the body may compensate to maintain normal readings, so the pathological process is occurring without evidence of the endpoint (abnormal blood test). In other words, the body is “working” much harder to be “normal”. Another point to consider is that readings may be set high at the lab for the benchmark for pathology so as not to have too many of the population labeled as diabetics. If one believes in prevention rather than cure, we should not be waiting for full-blown endpoint pathology, such as nerve and skin damage via glycation, to establish itself.
GLYCATION: THE SECOND MAJOR CAUSE OF SKIN DAMAGE
Everyone is aware of the damaging effect of sun exposure on the skin. Fewer are aware that the second most damaging process is glycation, which while obvious and visible in the skin, actually occurs throughout the body.
Excessive sugar, in all its forms whether natural or processed, promotes inflammation, depresses the immune system and is damaging to the skin and all internal tissues and organs. This is the result of a chemical reaction called glycation. Most people have an excess sugar intake and excess sugars initiate glycation at an increased rate.
WHAT IS GLYCATION?
In essence, glycation is the same chemical reaction, the Maillard reaction, that occurs between amino acids and sugars that gives browned foods their distinctive color and flavor. Seared steaks, pan-fried dumplings, cookies and other kinds of biscuits, breads, toasted marshmallows, and many other foods undergo this reaction – and so does our skin, albeit at a much slower rate and at much lower temperature.
The reaction is named after French chemist Louis-Camille Maillard, who first described it in 1912 while attempting to reproduce biological protein synthesis. It is a form of non-enzymatic browning which typically proceeds rapidly from around 140 to 165 °C (280 to 330 °F). The reactive carbonyl group of the sugar reacts with the nucleophilic amino group of the amino acid, forming a complex mixture of poorly characterized molecules responsible for a range of aromas and flavors. This process is accelerated in an alkaline environment. (Now, you know why a lye solution is painted onto dough to produce dark brown pretzels and pretzel bread!!)
EFFECTS OF THE MAILLARD REACTION ON HUMAN PHYSIOLOGY
The Maillard reaction is involved in diseases in the human body including diabetic complications, pulmonary fibrosis, neurodegeneration, eye diseases, and atherosclerosis (“hardening” of the arteries.) The eyes are particularly susceptible to injury from AGEs. In the cornea, the accumulation of AGEs is associated with thickened corneal stroma, corneal edema, and morphological changes. In the lens, Maillard chemistry has been studied extensively in the context of cataract formation. Glycation may lead to destabilization of the vitreous gel structure within the eye via unnecessary cross-linking between collagen fibrils. This process is more strongly observed within diabetic patients. Within the retina, the accumulation of AGEs has also been observed at a higher level among patients with age-related macular degeneration (AMD).
With these examples of the negative effects of glucose chemically reacting with proteins and lipids in the delicate tissues of the eye, it is easy to understand that the same chemical reaction can cause damage in other tissues, including the collagen and elastin within the skin.
THE DOWNSIDE OF OXYGEN AND SUGAR – “CAN’T LIVE WITH ‘EM, CAN’T LIVE WITHOUT ‘EM”
The human body depends on fuel and oxygen to provide the energy that powers our physiology. Mitochondria powers up every cell in our body using glucose, fatty acids, and oxygen. But it comes with a price. Sugar is the most damaging compound to mitochondria
As glycation progresses, this leads to mitochondrial energy production that slows down, along with increased oxidative stress. Eventually, damaged mitochondria can stop functioning, accelerating the aging process both inside and outside the body.
Glycation takes its toll slowly. It “gums up” proteins, deactivates enzymes, triggers unhealthy, cellular signaling and damages DNA = AGEing you.
The two tissues in our skin that make our skin look youthful and springy are elastin and collagen. These are the proteins in the skin most affected by glycation, creating discolored, weak and hardened tissues leading to wrinkles, sagging skin and a loss of radiance. Glycation is a natural process in the human body. Because most everything that we eat converts to glucose in order to utilized as mitochondrial “fuel”, diet modification is important in the management of the rate and scale of glycation. Foods with high concentrations of sugar contribute to the rate of glycation. This is even more of a concern when it comes to fructose, which contributes to glycation at a rate 10 times as fast as glucose. Avoiding foods with fructose (think how ubiquitous corn derived fructose is in processed foods) should be a priority. Food with high concentrations of sugar should be a small part of one’s diet.
STATEGIES TO REDUCE GLYCATION
Avoid Excess Carbohydrate Intake. Such as whole wheat bread, white potatoes, white rice, pasta, and all grains. Excess healthy carbs are also a contributor to glycation.
Avoid High Temperature Cooking (think crispy, blackened foods). Steaming, stewing and poaching are the cooking methods rather than frying, direct-fire grilling and high-temperature roasting.
Add Antioxidant Rich Foods: Make every plate and anti-inflammatory meal. Choose all veggies, nuts, seeds, low-sugar fruits such as raspberries, blackberries, kiwi, healthy fats such as avocados, macadamia nut oil, and healthy proteins such as whole pastured eggs,
DIET, TARGETED SUPPLEMENTS, AND SKINCARE INGREDIENTS TO COPE WITH GLYCATION
Carnosine. Carnosine helps prevent cellular glycation. This nutrient is a potent free-radical scavenger and anti-glycating agent that inhibits AGEs formation and its cross-linked proteins. Take carnosine with fat for bio-availability.
Benfotiamine. This nutrient (a lipid-soluble form of thiamine, vitamin B1) can boost your body’s cellular levels of vitamin B1, which is an essential component in clearing the dangerous debris left behind due to glycation.
Curcumin. Curcumin is the active component in the spice turmeric. Curcumin is an antioxidant, powerful anti-inflammatory, antimicrobial, anticancer, memory-enhancing, life-extending, and Curcumin uniquely protects against AGE-induced diabetic complications.
Tomato Paste. Research shows that simple tomato paste strongly inhibited the formation of AGEs in the glycation process.
Resveratrol. Resveratrol has the ability to reduce oxidative stress along with its highly protective cellular effect.
Rosemary. The use of the herb rosemary will help reduce the formation of AGEs.
Alpha Lipoic Acid. Alpha Lipoic Acid possesses unique properties that specifically slow mitochondrial dysfunction and reversing mitochondrial damage by preventing the release of damaging oxidants.
Advanced glycation end products (AGE) in human chronic skin wounds. Histol Histopathol. 2014 Feb;29(2):251-8.
The matricellular protein galectin-3 (Gal-3) is upregulated in excisional skin repair in rats where it has been shown to modulate the inflammatory phase of repair. Recent research into kidney pathology has implicated Gal-3 as a receptor for advanced glycation end products (AGE), resulting in the binding and clearance of these molecules. AGEs are thought to contribute to defective skin repair in diabetic patients as well as a result of the normal aging process. However, the distribution and localization of Gal-3 and AGEs has never been performed in human chronic skin wound tissue. Using immunohistochemistry, the localization of Gal-3 and AGEs in tissue isolated from chronic wounds and non-involved skin from the same patient was investigated. Of the 16 patients from which tissue was isolated, 13 had type II diabetes, one had type I diabetes and 2 patients without diabetes were also examined. In non-involved dermis, Gal-3 was detected strongly in the epidermis and in the vasculature. However, at the wound edge and in the wound bed, the level of Gal-3 labelling was greatly reduced in both the epidermis and vasculature. Labelling of serial sections for Gal-3 and AGE demonstrated that where Gal-3 immunoreactivity is reduced in the epidermis and vasculature, there is a concomitant increase in the level of AGE staining. Interestingly, similar labelling patterns were evident in diabetic and non-diabetic patients. The results from our study demonstrate an inverse correlation between Gal-3 and AGEs localization, suggesting that Gal-3 may protect against accumulation of AGEs in wound healing.
Effect of advanced glycation end products on gene expression profiles of human dermal fibroblasts. Biogerontology. 2008 Jun;9(3):177.
The Maillard reaction and its end products, AGE-s (Advanced Glycation End products) are rightly considered as one of the important mechanisms of post-translational tissue modifications with aging. We studied the effect of two AGE-products prepared by the glycation of lysozyme and of BSA, on the expression profile of a large number of genes potentially involved in the above-mentioned effects of AGE-s. The two AGE-products were added to human skin fibroblasts and gene expression profiles investigated using microarrays. Among the large number of genes monitored the expression of 16 genes was modified by each AGE-preparations, half of them only by both of them. Out of these 16 genes, 12 were more strongly affected, again not all the same for both preparations. Both of them upregulated MMP and serpin-expression and downregulated some of the collagen-chain coding genes, as well as the cadherin- and fibronectin genes. The BSA-AGE preparation downregulated 10 of the 12 genes strongly affected, only the serpin-1 and MMP-9 genes were upregulated. The lysozyme-AGE preparation upregulated selectively the genes coding for acid phosphatase (ACP), integrin chain alpha5 (ITGA5) and thrombospondin (THBS) which were unaffected by the BSA-AGE preparation. It was shown previously that the lysozyme-AGE strongly increased the rate of proliferation and also cell death, much more than the BSA-AGE preparation. These differences between these two AGE-preparations tested suggest the possibility of different receptor-mediated transmission pathways activated by these two preparations. Most of the gene-expression modifications are in agreement with biological effects of Maillard products, especially interference with normal tissue structure and increased tissue destruction.
Evaluation of tissue accumulation levels of advanced glycation end products by skin autofluorescence: A novel marker of vascular complications in high-risk patients for cardiovascular disease. Int J Cardiol. 2015 Apr 15;185:263-8.
A non-enzymatic reaction between reducing sugars and the amino groups of proteins, lipids and nucleic acids is known as the “Maillard reaction”. The reactions have progressed in a normal aging process and at an accelerated rate under hyperglycemic, inflammatory, and/or oxidative stress conditions, thus leading to the formation and accumulation of advanced glycation end products (AGEs). Cross-linking modification of organic matrix proteins such as collagen by AGEs not only leads to an increase in vascular and myocardial stiffness, but also deteriorates structural integrity and physiological function of multiple organ systems. Furthermore, there is a growing body of evidence that interaction of AGEs with a cell surface receptor RAGE elicits oxidative stress generation and subsequently evokes inflammatory, thrombogenic and fibrotic reactions, thereby being involved in the development and progression of various age- or diabetes-related disorders, including cardiovascular disease (CVD), Alzheimer’s disease, osteoporosis, cancer growth and metastasis. Skin AGE levels measured in biopsy specimens are associated with the development and progression of diabetic microangiopathy. Recently, accumulation levels of AGEs in the skin can be measured non-invasively by autofluorescence. Accumulating evidence has suggested that skin autofluorescence (SAF) is correlated with the presence and severity of vascular complications of diabetes and could predict future cardiovascular events and death in patients with diabetes. This review summarizes the pathophysiological role of tissue accumulation levels of AGEs in vascular damage in high-risk patients, especially focusing on the association between SAF and cardiorenal disorder.
Noninvasive measurement of advanced glycation end-products in the facial skin: New data for skin aging studies. J Cosmet Sci. 2017 May/Jun;68(3):195-204.
Using skin autofluorescence (SAF) as a marker of advanced glycation end-products (AGEs) has been extensively studied in the last decade since the introduction of the noninvasive in vivo measurement technique. Data have shown the level of skin AGEs increases with chronological age in healthy human beings, and this increase is substantially higher in age-matched diabetic patients. In skin research, glycation with the accompanying accumulation of skin AGEs has been regarded as one of the primary skin aging mechanisms that contribute to skin wrinkling and the loss of skin elasticity. To date, the totality of SAF data reported in literature has been obtained from measurements on the arm, and noninvasive measurement of facial skin AGE accumulation would add great value to skin aging research. In this study, we report the levels of facial and forearm skin AGEs in 239 men and women of 21-65 year of age. Significantly lower levels of AGEs were detected in the facial skin than in the forearm skin from the young Caucasian groups, and the difference was much larger for men than for women. The rate of change in skin AGE level over age was found to be about 50% higher in men than in women, which further highlights the gender difference. A statistically significant correlation between the levels of skin AGE and facial wrinkling was also observed. The facial skinAGE data may provide new insight into skin aging research.
Skin autofluorescence predicts cardio-renal outcome in type 1 diabetes: a longitudinal study. Cardiovasc Diabetol. 2016 Sep 1;15(1):127.
BACKGROUND: We aimed to analyze the relationships between skin autofluorescence (SAF) and incident macrovascular events and renal impairment after 4 years of follow-up in patients with type 1 diabetes (T1D).
METHODS: Two hundred and forty-three patients (51.2 ± 16.7 years old) with T1D participated. SAF was measured by AGE-Reader-TM at inclusion. Macrovascular events (MVE), estimated glomerular filtration rate (eGFR) and urinary albumin excretion rate (AER) were recorded then and 4 years later. Multivariate logistic regression was used to analyze the relationships between SAF and incident MVE and renal profile 4 years later.
RESULTS: Patients with incident MVE had a higher SAF (p = 0.003). SAF predicted incident MVE after adjustment for age, sex, body mass index, tobacco, diabetes duration, hypertension, HbA1c, AER, eGFR (OR 4.84 [95 % CI 1.31-17.89], p = 0.018). However, this relation was no longer significant after adjustment for history of MVE. An inverse relation was found between SAF and incident eGFR (p = 0.0001). Patients with incident eGFR <60 ml/min/1.73 m(2) had a SAF higher than patients with normal eGFR. After adjustment for the previous criteria, SAF remained associated with the risk of impaired incident eGFR (OR 7.42 [95 % CI 1.59-34.65], p = 0.018). No relation was found between SAF and increased AER 4 years later.
CONCLUSIONS: SAF predicts MVE in patients with T1D, adjusted for cardiovascular risk factors but the most powerful predictive factor remains history of MVE. SAF also predicts eGFR impairment, adjusted for initial AER and renal function. SAF could be a useful non-invasive tool for estimating risk of cardiovascular or renal impairment in patients with T1D.
Accumulation of Advanced Glycation Endproducts and Subclinical Inflammation in Deep Tissues of Adult Patients With and Without Diabetes. Can J Diabetes. 2018 Jan 10
OBJECTIVES: Advanced glycation endproducts (AGEs) play a key role in the development of foot complications in people with diabetes. Skin autofluorescence (AF) might noninvasively determine tissue accumulation of AGEs. This study evaluated the association between skin AF and AGE contents in the deep tissues of those with diabetes and the further consequences of such contents.
METHODS: Between September 2014 and September 2015, we studied 33 patients, with and without diabetes, who had received lower-limb amputations. Skin AF was measured. Artery, nerve and skin were harvested during surgery. AGE contents were quantified using high-performance liquid chromatography mass spectrometry and were located by immunohistochemistry staining. Inflammatory cells were also located by immunohistochemistry, immunofluorescence and scanning electron microscopy.
RESULTS: Values of skin AF and AGE contents in artery, nerve and skin in patients with diabetes were higher than those in healthy patients. Skin AF was strongly affected by AGE contents in these tissues. AGE contents in various tissues were strongly correlated with each other. Differing AGEs were deposited in similar manners in the same tissues and were accompanied by inflammatory cells.
CONCLUSIONS: AGE contents were strongly correlated with each other and were accompanied by inflammatory cells. Skin AF measurement could provide information about the systemic accumulation of AGEs.
Advanced Glycation End-products are associated with Physical Activity and Physical Functioning in the older population. J Gerontol A Biol Sci Med Sci. 2018 Apr 28.
BACKGROUND: Decline in physical activity and functioning is commonly observed in the older population and might be associated with biomarkers such as Advanced Glycation End-products (AGEs). AGEs contribute to age-related decline in the function of cells and tissues in normal aging and have been found to be associated with motor function decline. The aim of this study is to investigate the association between the levels of AGEs, as assessed by skin autofluorescence, and the amount of physical activity and loss of physical functioning in older participants.
METHODS: Cross-sectional data of 5,624 participants aged 65 years and older from the Lifelines cohort study was used. Linear regression analyses were utilized to study associations between skin autofluorescence/AGE-levels (AGE reader), the number of physically active days (SQUASH), and physical functioning (RAND-36), respectively. A logistic regression analysis was used to study associations between AGE-levels and the compliance with the Dutch physical activity guidelines (SQUASH).
CONCLUSIONS: This study indicates that high AGE levels may be a contributing factor as well as a biomarker for lower levels of physical activity and functioning in the older population.
Accumulation of advanced glycation end products is associated with macrovascular events and glycemic control with microvascular complications in Type 2 diabetes mellitus. Diabet Med. 2018 Apr 23.
AIM: The United Kingdom Prospective Diabetes Study (UKPDS) study showed that glycemic control (HbA1c ) can predict vascular complications in Type 2 diabetes mellitus. The Diabetes Control and Complications Trial (DCCT) study showed that accumulation of advanced glycation end products (AGEs) from skin biopsies predicts vascular complications in Type 1 diabetes. Previously, we showed that tissue AGEs can be measured non-invasively using skin autofluorescence (SAF). The aim of this study was to compare the predictive value of HbA1c and SAF for new macrovascular events and microvascular complications in people with Type 2 diabetes.
METHODS: A prospective cohort study of 563 participants, median age 64 years [interquartile range (IQR) 57-72], diabetes duration of 13 years, from five Dutch hospitals was performed.
RESULTS: After a median follow-up of 5.1 (IQR 4.3-5.9) years, 79 (15%) participants had died and 49 (9%) were lost to follow-up. Some 133 (26%) developed a microvascular complication and 189 (37%) a macrovascular event. Tertiles of HbA1c were significantly associated with development of microvascular complications (log rank P = 0.022), but not with macrovascular events. Tertiles of SAF were significantly associated with macrovascular events (log rank P = 0.003). Cox regression analysis showed SAF was associated with macrovascular events: crude hazard ratio (HR) 1.53 (P < 0.001) per unit increase, HR 1.28 (P = 0.03) after correction for UKPDS score. HbA1c was predictive for microvascular complications: crude HR 1.20 (P = 0.004), HR 1.20 (P = 0.004) after correction for UKPDS score.
CONCLUSION: This study shows that tissue accumulation of AGEs, assessed by SAF, is associated with development of macrovascular events in people with Type 2 diabetes, whereas HbA1c is associated with the development of microvascular complications.