¹Rice University, Houston, TX, USA
²Department of Internal Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
³Baylor College of Medicine, Houston, TX USA
⁴Department of Dermatology, McGovern Medical School at University of Texas Health Science Center at Houston, Houston, TX, USA

Conflict of interest:
Rajani Katta is author of a book for the general public on dermatology, and is on an advisory board for Vichy Laboratories.
Evelyne Tantry, Ariadna Perez-Sanchez, Shelly Fu, and Shravya Potula have no conflicts of interest to declare.

Abstract:
Consumers of personal care products must be made aware of the potential pitfalls that arise from current labeling practices and regulations. For example, terms such as “hypoallergenic“, “sensitive skin“, and “baby product” lack legal definitions, and terms such as “fragrance-free“ are frequently misinterpreted. Personal care products are a general category that includes such items as cosmetics, drugs, dietary supplements, and consumer goods. This overview of current US FDA regulations of products in this category reviews pertinent regulatory policies and highlights potential consumer pitfalls when evaluating product labels. In particular, current labeling laws permit the use of language that may be incomplete, misinterpreted, or applied solely for marketing purposes. It is important that consumers understand the meaning of labeling terms, the regulations that govern them, and especially understand the potential pitfalls related to these terms.

Key Words:
personal care products, cosmetics, labeling regulations, fragrance-free, hypoallergenic, sensitive skin, baby products

Background

For consumers choosing among the wide variety of personal care products available, an understanding of current labeling laws and regulations is important. Consumers may be interested in choosing products for sensitive skin, searching for products that are suitable for children, or seeking out products that lack specific allergens. Unfortunately, current regulations limit the utility of many labeling terms to effectively inform the consumer, making it imperative that physicians counsel patients on the specifics of these terms. In this paper, we review areas where consumers may find labels confusing. For each area, we highlight potential pitfalls for consumers when choosing personal care products.

“Personal care products” are not defined by law but rather serve as a general category that can consist of cosmetics, drugs, medical devices, dietary supplements and consumer goods based on the nature of intended use.¹ Use of such products may result in allergic contact dermatitis (ACD). Data from the North American Contact Dermatitis Group (NACDG), published in 2018, found that of the top 10 allergens identified by patch testing, nine could be found in personal care products.² This included six fragrance additives and preservatives, two topical antibiotics (neomycin and bacitracin), and one chemical found in hair dyes (p-phenylenediamine). The treatment of ACD centers on allergen avoidance, and thus an understanding of labeling laws and regulations is critical.

As consumers are faced with a multitude of personal care products, physicians can help by educating them on pertinent regulations and labeling laws. It is important consumers recognize that marketing and safety of personal care products is the responsibility of the manufacturer and is not subject to premarket approval from the US Food and Drug Administration (FDA).³ “Cosmetics”, as defined by the FDA, are any articles intended to be applied to the human body for appearance-altering purposes and include moisturizers, shampoos and makeup.³ ‘Soaps’ fall into a separate category when they are mainly composed of “alkali salts of fatty acids,”⁴ although the product becomes a “cosmetic” if it contains synthetic detergents or is intended to moisturize or deodorize the body.⁴

The FDA primarily governs cosmetics and other personal care products through the Federal Food, Drug, and Cosmetic Act of 1938 (FDCA) and the Fair Packaging and Labeling Act of 1967 (FPLA).³ With these acts, Congress created broad parameters to enable effective regulation of a burgeoning industry. Since their establishment, however, these mandates have not undergone any substantial reform to accommodate the explosive growth of available personal care products.

Table 1 outlines several pertinent regulatory policies that consumers should be made cognizant of when evaluating personal care products. It is vital that consumers recognize that current labeling laws permit the use of language that may be applied solely for marketing, may be incomplete, or may be misinterpreted. Table 2 provides a brief overview of potential pitfalls for the consumer due to current labeling regulations.

Table 1: Overview of current FDA regulations of personal care products

Table 2: Potential consumer pitfalls when evaluating product labels

Skin and Hair Care Products

Potential pitfalls for consumers when evaluating skin and hair care product labels can be categorized into three broad categories. These include the potential for confusion with marketing terms, labels that are incomplete, and labels that may be misinterpreted.

Marketing Terms

As many labeling terms lack FDA definitions, they can essentially mean anything a manufacturer decides. The term “hypoallergenic”, for example, is not regulated by law. Therefore, although the term is commonly used in marketing a product, it does not inform consumers about the actual safety of a product.

Similarly, there are no legal standards for qualifying a product as a “baby product.” This may lead to consumer concerns about certain ingredients, as in 2013 when Johnson & Johnson was pressured by consumers to remove formaldehyde and 1,4-dioxane from about 100 of its baby products.⁵ According to the NACDG, formaldehyde is the fourth most common allergen in cosmetics.²

One study evaluated the use of marketing terms on products. Researchers found that out of 187 cosmetic products, 89% “contained at least 1 contact allergen, 63% 2 or more, and 11% 5 or more” despite being marketed as “hypoallergenic”, “dermatologist recommended/tested”, “fragrance free”, or “paraben free.”⁶

The lack of regulation involving personal care products marketed and sold as “hypoallergenic”, “baby product”, “natural,” “for sensitive skin”, and other terms is further discussed in Table 3.

Table 3: Marketing terms and regulations

Incomplete Labels

“Free of” Labels

The growing trend among consumers to purchase “free of ” ingredient cosmetics, as evident by growing sales and market shares of these products, has prompted cosmetic companies to address these factors when marketing their products.⁷

While these labels are technically correct, they often do not highlight information that patients would find useful. For example, the words “paraben-free” are often highlighted on product labels. However, for those who are prone to ACD, the words “free of methylisothiazolinone” (MI) would be more useful. The NACDG publishes a Significance-Prevalence Index Number (SPIN) ranking, which is a weighted calculation that incorporates both clinical relevance and prevalence of an allergen.² MI had the highest SPIN rating of all allergens tested. It has been banned by the European Commission from use in leave-on products, although it is still used in the US. By contrast, parabens were ranked 48th and had the lowest prevalence of positivity of any major preservative on the North American market. In 2019, the American Contact Dermatitis Society announced that because “[parabens] are rarely problematic as contact allergens, [parabens] have been designated (non) allergen of the year.”⁸

“Active” Ingredients Listed Separately From Inactive Ingredients

For consumers with ACD, knowledge of all ingredients found in a product is critical. Thus, consumers must be aware that certain product categories separate active ingredients from inactive ingredients. Consumers choosing sunscreens, eyedrops, and over-the-counter medications must be informed to seek out information on both active and inactive ingredients, as sections are separated in these product categories.

Labels That May Be Misinterpreted

Fragrance additives are one of the top causes of ACD,² but avoidance can be challenging for patients. While product labels may use the terms “fragrance-free” and “unscented”, these terms are frequently misinterpreted by consumers.

• Although the term “fragrance-free” might suggest that a product does not contain any fragrance additives, that is not correct. The FDA defines fragrance as “any natural or synthetic substance or substances used solely to impart an odor to a cosmetic product.” According to that definition, if a fragrance additive is used for another function, then it may legally be included in a fragrance-free product.⁹ Examples are benzyl alcohol, which may be used as a preservative, and rose oil, which may be used as a moisturizing ingredient.
• Unscented products may contain masking fragrances.

Sunscreens

Sunscreen labels are also a common source of confusion among consumers, including the sun protection factor (SPF) value. The SPF is defined as the ratio of the amount of ultraviolet (UV) energy required to produce erythema on skin protected by sunscreen, to the amount of energy required to produce erythema on unprotected skin. Contrary to popular belief, an increased magnitude of SPF value above SPF 30 offers minimal increase of protection from UV rays. Specifically, SPF 30 shields the skin from 97% of UV rays and SPF 50 shields 98%.¹⁰

Importantly, SPF values only specify protection against UVB radiation, responsible for sunburns.¹¹ The SPF value does not provide information on protection from UVA rays, which damage the deeper layers of the skin and contribute to skin cancer.¹²

Marketing claims on sunscreens are also of significant concern.¹³ Many commonly used claims are neither approved nor regulated by the FDA, including claims such as “dermatologist recommended.”¹³ Unregulated claims are rampant among sunscreens and advertisements, and sunscreens with more than six of these claims have been associated with increased popularity among consumers.¹³

Another area of concern relates to GRASE products (generally recognized as safe and effective). While GRASE ingredients are regulated by the FDA, some sunscreens are sold in the form of products that are not considered GRASE, including powders, wipes, towelettes, and insect repellants.²⁶ These product forms have not been extensively studied for their safety and sun protection efficacy.²⁶

Insect Repellents

Governed by the Environmental Protection Agency (EPA), insect repellents may be required to list active ingredients, but the “EPA does not require a complete declaration of ‘inactive or inert’ ingredients” nor a list of “the identities of inert ingredients on product labels.”²⁷ The label is only required to list the percent composition of inert ingredients.

Furthermore, because only active ingredients require registration for safety and effectiveness, scented inactive ingredients may present concerns for patients with fragrance sensitivity. Case reports documenting insect repellent contact dermatitis have identified various botanical and fragrance chemical ingredients, such as citronellol, lemon oil, eucalyptus oil, and neem oil.²⁸

Hair Dyes

P-paraphenylenediamine (PPDA) is a common allergen, with the latest data placing it as the 10th most frequent allergen in North America.² Exposure is primarily via permanent hair dyes.

Although hair dyes in retail stores must list this ingredient, consumers face some challenges. First, unlike other products such as sunscreen, active hair dye ingredients are not required to be highlighted on the label. In fact, active ingredients are typically found as just one ingredient in a long list of chemical names. Second, products that are not intended for retail sale are exempt from ingredient declaration. Products used at a hair salon, therefore, may be exempt from providing ingredients.

In terms of product safety, consumers should realize that FDA approval is not required for hair dyes with PPDA. Regulations divide hair dyes into two categories: coal-tar hair dye (CTHD) and plant or mineral sourced hair dye. Although PPDA is not a coal-tar by-product, it falls into this category. Under FDA regulations there is no need for approval for any of the CTHD.²⁹ Even more worrisome, the FDA cannot take action against a CTHD even if “it is or contains a poisonous or deleterious ingredient that may make it harmful to consumers,” as long as the manufacturer includes a caution statement.²⁹ The only exception is for dyes used in eyelash and eyebrow coloring.

Conclusion

Of the 100+ pages of the FDCA, only two pages discuss cosmetics and personal care product safety. In fact, there is a heavy reliance on safety reporting by manufacturers. Current information from the FDA consists of voluntary ingredient and establishment reporting from companies, along with reports of serious adverse events provided by consumers. Recently, however, there have been efforts to amend the FDCA through the introduction of the Safe Cosmetics and Personal Care Products Act of 2019 and the Personal Care Products Safety Act of 2019. The passage of either bill would increase the regulation of cosmetic labeling and allow the FDA to suspend and even recall the sale of products that cause “adverse health reactions.”^30,31

Given the current limitations of federal labeling and safety regulations, it is the responsibility of the consumer to be informed of current regulations and to learn how to accurately evaluate and interpret the information found on personal care product labels.

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¹McGovern Medical School at The University of Texas Health Sciences Center at Houston, Houston, TX, USA
²Baylor College of Medicine, Houston, TX, USA
³Katta Dermatology, Bellaire, TX, USA
⁴Rice University, Houston, TX, USA

Conflict of interest:
Rajani Katta is the author of a book for the general public on diet and dermatology and has been an advisory board member for Vichy Laboratories. Ariadna Perez Sanchez and Evelyne Tantry have no conflicts to declare for this work.

Abstract:
There is growing awareness of the complex link between nutrition and skin. In the last few decades, our understanding of this link has grown significantly with research findings from multiple laboratory, animal, and human studies. From the impact of diet on clinical features of aging skin, to documentation of the biochemical and histologic changes that occur, our understanding of this link continues to expand and evolve. In this paper, we review the research on the impact of diet on skin aging. A number of long-term observational population studies have documented that healthier diets are linked to fewer signs of skin aging. Animal and laboratory studies have elucidated the biochemical processes that play a large role in the development of these clinical findings. A number of studies have also reported on the role of specific dietary compounds in impacting these processes, whether by combating or potentiating these forces. This body of research serves as guidance in recommending nutritional strategies that can combat the skin aging forces of oxidation, inflammation, and glycation.

Key Words:
antioxidants, anti-wrinkle diet, glycation, inflammation, nutrition, oxidation, skin aging

Introduction

The clinical features of skin aging are well documented and a common question in clinical practice is whether dietary choices have any impact on these features. Based on research ranging from long-term human population to intervention studies, laboratory investigations, and animal studies, a diverse body of data links diet to skin aging.

This research provides significant guidance when discussing nutritional strategies that can promote healthy skin aging. Skin aging is particularly impacted by the processes of oxidation, inflammation and glycation. For each, dietary choices can play a large role in modifying these forces. Specifically, certain dietary patterns, foods, nutrients, and compounds have the ability to either potentiate or combat these processes.

It is well documented that certain populations differ in the rate of development of skin aging. Multiple large scale studies have reported that in those with healthier dietary patterns, fewer fine lines and wrinkles are seen,^1,2 while other population studies have documented fewer pigmentary changes³ and less skin atrophy and dryness.⁴ In one study of over 500 non-diabetic subjects, it was found that as blood glucose levels increased, perceived age increased.⁵

In researching the role of nutrition, researchers have focused on different avenues of study. Population studies, human interventional studies (both long-term and short-term), animal studies, and laboratory studies have all been used to investigate the role of dietary patterns, foods, nutrients, and/or dietary compounds. Population research now focuses on the study of dietary patterns,⁶ due to the complexity of long-term dietary effects. Human interventional studies have detailed both the beneficial and harmful effects of specific foods, nutrients, or compounds. Animal and laboratory studies have provided data on the biochemical and histologic effects of dietary compounds. Taken together, this body of research supports a strong, complex relationship between diet and skin aging. Importantly, this research identifies a number of areas where dietary modification may promote an improvement in the parameters of skin aging.

The Pathophysiology of Skin Aging

Skin aging is a highly complex process. Our current understanding of this process, while not complete, has indicated that the intricate and intertwined processes of oxidation, inflammation, and glycation play major roles. Each of these is highly impacted by diet.

Ultraviolet radiation (UVR) is the major contributor to extrinsic skin aging, and the impact of UVR on the skin has been well described. UVR is responsible for multiple direct effects on the skin, as well as numerous downstream effects. UVR may produce direct DNA damage via induction of DNA photoproducts.⁷ It also results in oxidative stress, with a resultant increase in free radical production, especially reactive oxygen species (ROS).⁸ These cause additional DNA damage⁹ as well as damage to both structural (collagen and elastin) and enzymatic proteins. Effects on lipids include peroxidation of cell membrane lipids.¹⁰

Metabolic processes, pollution, smoking, and other factors also contribute to oxidative stress. Due to constant exposure, the body’s defense mechanisms are designed to withstand the damaging effects of free radicals. Endogenous enzyme systems include superoxide dismutase, glutathione peroxidase, catalase, and others. The epidermis and dermis also contain antioxidant defenses, including vitamin C, vitamin E, carotenoids, selenium, and others.^11,12 While these are important components of the body’s endogenous defense systems, they require constant replenishment from dietary sources. and others. The epidermis and dermis also contain antioxidant defenses, including vitamin C, vitamin E, carotenoids, selenium, and others.^11,12 While these are important components of the body’s endogenous defense systems, they require constant replenishment from dietary sources.

Photooxidative stress also activates several inflammatory pathways and contributes to chronic inflammation, which impacts the clinical and molecular features of aging^13,14 as well as the promotion of skin tumorigenesis.¹⁵ Activation of these pathways ultimately acts to increase the expression of several matrix metalloproteinases (MMPs).^13,14,16

MMPs encompass a number of different enzymes, including collagenases. Along with elastases, these act to remodel the extracellular matrix (ECM), with resulting fragmentation of the collagen and elastin fibers that provide structural support and elasticity to the skin. UVR also results in the reduced expression of tissue inhibitor of MMPs (TIMPs), which ordinarily would act to inhibit ECM destruction.¹⁷

Several other inflammatory pathways are activated by oxidative stress, including pathways which promote the release of a number of inflammatory cytokines and prostaglandins. The induction of pro-inflammatory genes leads to the release of inflammatory mediators from keratinocytes, fibroblasts, white blood cells, and others, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha. These further contribute to the effects of chronic inflammation.

Glycation is another factor that accelerates aging of the skin. Glycation is distinct from photoaging, but is closely intertwined. Glycation refers to the non-enzymatic process whereby sugar molecules covalently bond to proteins, lipids, or nucleic acids. The resulting products are known as advanced glycation end products (AGEs) or glycotoxins. AGEs are a heterogeneous group of molecules, with the prevalent AGE in the human body, including the skin, being carboxymethyl lysine (CML).

Glycation is an important factor in atherosclerosis,¹⁸ renal disease,¹⁹ diabetic complications, and other conditions. It plays an important role in skin aging as well. The accumulation of AGEs within the skin results in typical structural and functional changes that are colloquially known as sugar sag.²⁰

AGEs have a large impact on the collagen and elastin fibers that maintain the structural framework of the skin and provide resilience and elasticity. Glycation results in intermolecular collagen cross-linking, resulting in increased stiffness and vulnerability to mechanical stimuli.²¹ In addition, cross-linked collagen cannot be repaired as well. Collagen is highly susceptible to glycation, in part due to its long half-life, and may undergo up to a 50% increase in glycation over a lifetime.²² Glycation is closely related to oxidation and inflammation as well. Glycation increases reactive oxygen species (ROS), further accelerating oxidative damage. Additionally, AGEs may bind to specialized cellular surface receptors called receptor for AGEs (RAGEs). When activated, RAGE triggers several cellular signaling pathways.²³ These further promote inflammation and altered cytokine expression.

Nutritional Strategies to Target Key Processes in Skin Aging

Research has demonstrated that dietary components have the ability to impact each of these skin aging processes. The skin is commonly referred to as the largest organ of the body, and as such plays a substantial role in its defense. The skin barrier and its concomitant complex immune defenses play a significant role in protection against UVR, physical impact, temperature variations, irritants, allergens, microbes, and other factors. In fact, it can be said that our skin is under siege every minute of every day. Because of these constant threats, the skin barrier has many intricate built-in defense and repair mechanisms.

Dietary factors have the ability to either support these mechanisms or impair them. In other words, certain dietary patterns, foods, nutrients, and compounds have the potential to either accelerate or combat skin aging.

Oxidation

Antioxidants (AOs) are a key feature of the body’s defense against free radicals. They may act to neutralize ROS or may upregulate genes encoding for enzymes that neutralize ROS. The cutaneous impact of dietary AOs has been demonstrated in multiple studies. Several animal studies, for example, have documented that oral AOs including vitamin C,²⁴ vitamin E,²⁴ beta-carotene,²⁵ selenium,²⁶ and others play important roles in skin photoprotection.²⁷

Human interventional studies have documented these benefits as well. In one randomized controlled trial, daily tomato paste ingestion for 10 weeks resulted in improved minimal erythema doses,²⁸ while another study documented histologic improvement.²⁹ Other human intervention studies have reported benefits from dietary AOs including green tea polyphenols, cocoa flavanols, pomegranate, and others.³⁰ As detailed in an extensive review, the documented clinical, histologic, and biochemical benefits of dietary AOs have included reductions in erythema, DNA damage, markers of inflammation, extracellular matrix damage, and others.³⁰

While single nutrients (such as vitamins, minerals, and phytonutrients) may serve as AOs, a key point is that one food may provide multiple AOs. One research study evaluated the total AO capacity of over 3100 foods and found that the categories of “spices and herbs” and “herbal/traditional plant medicine” contained the most AO-rich products analyzed in the study.³¹ Berries, fruits, and vegetables also included many common foods and beverages with medium-to-high AO values.³¹

While dietary AOs may be beneficial, high-dose AO supplements have not shown benefit. In fact, some have demonstrated harm, as outlined in a later section.

Inflammation

Many research studies have delineated the role of diet in modifying the inflammatory process. For example, some phytochemicals may specifically interrupt the inflammatory pathway that activates nuclear factor-kappa beta (NF-KB), including turmeric, cloves, ginger, garlic, and others.³² This pathway impacts MMPs and collagen remodeling, and in fact researchers were able to demonstrate that compounds from garlic in a mouse model inhibited UVB-induced wrinkle formation. This was accomplished via the modulation of NF-KB, with a resulting decrease of MMPs and collagen fiber destruction.³³

Multiple studies have described the impact of dietary patterns, foods, nutrients, and compounds on inflammatory biomarkers. One review article³⁴ specifically examined research on dietary patterns affecting high sensitivity C-reactive protein (hsCRP), a marker of inflammation with demonstrated predictive value for coronary heart disease.³⁵ Multiple dietary patterns had some evidence of impact, including the Dietary Approaches to Stop Hypertension (DASH) and similar diets.³⁴

The effects of specific foods and nutrients were described in one summary analysis in which researchers looked at over 1900 studies. These evaluated the effects of foods and nutrients on six major biomarkers of inflammation. If a nutrient increased levels of IL-1B, IL-6, TNF-alpha, or CRP, or decreased levels of IL-4 or IL-10, it was considered pro-inflammatory.³⁶ Using these results, researchers developed a dietary inflammatory index that highlights anti-inflammatory foods. Some of the strongest effects were seen with foods including turmeric, green/black tea, ginger, garlic, and onion, as well as with macronutrients and micronutrients including fiber, magnesium, vitamin D, and omega-3 fatty acids.³⁶ Highly anti-inflammatory phytonutrients included flavones, isoflavones, beta-carotene, and flavonols.

The Gut Microbiome

The gut-skin axis is an area of intense research, due to the impact of the gut microbiome on inflammation and skin barrier function,^37-39 as well as features of skin aging.^40,41 While more research is needed to delineate these impacts, the gut microbiome is considered an important factor in inflammation. Diet serves as the foundation for healthy gut flora, particularly a focus on fiber-rich foods, which beneficially support the growth of good gut microbes.^42-44 Fermented and cultured foods, with beneficial live microbes, may also play a role,⁴⁵ while prebiotic and probiotic supplementation research is ongoing to determine potential efficacy as well as dosing strategies.

Foods that Impact MMPS

Collagenase and elastase play important roles in ECM remodeling, thereby contributing to loss of skin elasticity, wrinkling, and sagging. Some foods and nutrients are able to block the activity of collagenase, such as green tea, white tea, and pomegranate,⁴⁶ while inhibition of elastases was also seen with ginger⁴⁷ and spices such as turmeric, cinnamon, and nutmeg.⁴⁸ Foods with anti-inflammatory capabilities, by blocking inflammatory pathways, may also ultimately result in lower levels of MMPs, as with curcumin,⁴⁹ omega-3 fatty acids,⁵⁰ and garlic.³³

Glycation

The accumulation of AGEs within the body arises from two main sources. The first is via endogenous production in the presence of hyperglycemia. The second is via the ingestion of foods that contain preformed AGEs, also known as dietary AGEs.

Therefore, nutritional strategies to limit AGE-induced tissue damage focus on three main areas. The first is a focus on patterns, foods, and compounds that limit hyperglycemia. The second is a focus on foods and compounds that limit the biochemical processes of glycation. The third is limited ingestion of dietary AGEs. Additional strategies, as outlined previously, include a diet rich in antioxidants and anti-inflammatory foods, as these processes are closely intertwined with glycation.

Limiting Hyperglycemia

Improving glycemic control is a key strategy in limiting AGE production. In one experimental study, improved glycemic control in human volunteers over a 4-month period resulted in significantly decreased new collagen glycation.⁵⁰ In fact, a key tenet of an anti-wrinkle diet is diabetes prevention. A full review of dietary strategies to limit hyperglycemia is beyond the scope of this review, and readers are referred to comprehensive reviews on this subject.⁵¹

Strategies supported by research include a low glycemic load diet, which focuses on low glycemic index foods as well as portion sizes.^52,53 Food groups and components with demonstrated benefits include fiber, monounsaturated fatty acids, fruits, vegetables, and others.⁵¹ Eating order (with protein consumed earlier)⁵⁴ and vinegar consumption with a meal⁵⁵ have also demonstrated benefits. Specific foods that have shown promise include garlic, onions,⁵⁶ nuts,⁵⁷ turmeric,⁵⁸ cinnamon,⁴⁸ fenugreek,⁵⁹ and a number of other spices.⁶⁰

Foods and Compounds that Limit Glycation

A number of dietary compounds have demonstrated the ability to inhibit AGE biosynthesis.⁶¹ Some limit glycation via their antioxidant properties, while others act via other mechanisms, such as trapping reactive intermediate compounds.^61-63

In laboratory studies, anti-glycation properties have been demonstrated by foods such as cinnamon,⁶⁴ garlic,⁶⁵ rosemary,⁶⁶ yerba mate,⁶⁷ and tomato paste⁶⁸. One laboratory study evaluating multiple foods demonstrated significant anti-glycation activity by ginger, cumin, cinnamon, black pepper, and green tea.⁶⁹ Phytonutrients exhibiting beneficial effects include the flavonoids luteolin, quercetin, and rutin,⁷⁰ as well as the phenolic acids ferulic acid, chlorogenic acid, vanillic acid, and others⁷¹. In animal studies, curcumin has inhibited collagen cross-linking,⁷² while green tea extracts have reduced AGE formation⁷³ and inhibited collagen cross-linking⁷⁴.

In a laboratory study specifically evaluating the anti-glycation potential of polyphenols in herbs and spices, the most potent spices were cloves, allspice, and cinnamon, while potent herbs included sage, marjoram, tarragon, and rosemary.⁷⁵ The researchers noted that level of inhibition correlated with total phenolic content. Similar findings were seen in a study evaluating spices used in European cuisine, with strong activity by star anise, cinnamon, allspice, cloves, and oregano.⁷⁶

Strategies to Reduce Dietary AGEs

Dietary strategies to limit ingestion of preformed AGEs focus on three main areas. These include the type of food, cooking method, and use of ingredients that modify AGE production.

Meat products, high in fat and protein, contain some of the highest levels of dietary AGEs, and are particularly prone to developing new AGEs during cooking.⁷⁷ High-fat cheeses are also relatively high in AGEs. In contrast, carbohydrate-rich fruits, vegetables, and whole grains contain low levels.

Cooking methods have a marked impact on AGE production. Dry heat methods such as grilling, roasting, and frying can increase AGE levels by 10 to 100 times.⁷⁷ Reduction strategies include moist cooking methods such as steaming and boiling, as well as cooking for lower temperatures and for shorter times. It is noteworthy that even with cooking, foods such as fruits, vegetables, and whole grains remain relatively low in AGEs. The exception is for carbohydrate-rich foods that are also high in fat, such as biscuits.

An additional strategy is the use of ingredients such as lemon juice and vinegar prior to cooking, as these reduce the amount of AGEs ultimately produced.⁷⁷

The Role of Nutrient Supplementation

A common question in patient care centers on the use of dietary supplements, more specifically, given the link between dietary compounds and the biochemical processes that impact skin aging, is if there is a benefit to consuming supplementation either in addition to, or in place of, dietary consumption?

While a review of supplements is beyond the scope of this article, a few points must be emphasized. At this time, there is very limited evidence for benefit of nutrient supplementation beyond the treatment of deficiency states. Indeed, there is significant evidence of potential harm from some supplements.

The primary role of supplementation has always been, and continues to be, in the treatment of deficiency. Although research from deficient-state conditions is often used to justify supplementation in general, evidence is lacking for this approach.

As one example, biotin deficiency leading to hair loss may be improved with supplementation, but has not shown efficacy in hair loss overall.^78,79

In the case of AOs, supplements have not shown benefit and in some cases have shown harm. AO supplements were the subject of much research, given promising observational human studies of dietary intake as well as laboratory and animal studies. Unfortunately, multiple trials of high-dose (as opposed to dietary dose) vitamins C and E, beta-carotene, and selenium, indicated that they were not effective in non-melanoma skin cancer (NMSC) prevention.²⁷ In fact, some may even become pro-oxidant at high doses, as in a study of women exhibiting higher rates of skin cancer after use of a supplement containing vitamins C and E, beta-carotene, selenium, and zinc (with median follow-up of 7.5 years).⁸⁰ This emphasizes the point that nutrients must be at the right dose in order to provide benefits. In the case of AOs, the ideal dose appears to be physiologic doses, such as that supplied via whole foods.

This issue of short-term tolerability not necessarily equaling long-term safety is an important point to remember as researchers continue to study promising supplements. Nicotinamide has shown benefit in a sharply defined population, with a 23% reduction in new NMSC in those at high risk, and has been well-tolerated over a 1-year period.⁸¹ The herb Polypodium leucotomos has demonstrated photoprotective abilities in short-term studies, but also lacks long-term data.^82,83

In the case of other supplements, evidence is simply lacking. One review summarized published trials of collagen supplementation used for skin conditions ranging from aging skin, to wound healing, to cellulite.⁸⁴ In total, the authors found only 11 studies, some funded by the manufacturer and some lacking placebo, utilizing at least three different types of collagen at widely differing doses and duration.

Conclusion

A number of research studies have documented the link between diet and skin aging. These results may be used to develop dietary recommendations that combat the forces of oxidation, inflammation, and glycation. For those wishing to promote healthy skin aging, a diet that incorporates these strategies is recommended, with a focus on foods that are naturally rich in antioxidants, are anti-inflammatory, limit hyperglycemia, and inhibit glycation. When counseling patients, it is important to emphasize that a number of eating patterns focusing on these underlying principles (Table 1) may achieve this goal. Table 2 provides more details on dietary strategies that combat these aging processes.

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Related: Skin and Diet: An Update on the Role of Dietary Change as a Treatment Strategy for Skin Disease

¹McGovern Medical School at The University of Texas Health Sciences Center at Houston, Houston, TX, USA
²Rice University, Houston, TX, USA

Conflict of interest:
Rajani Katta: advisory board member for Vichy Laboratories and author of a book for the general public on diet and dermatology. Sophia Huang has no conflicts to declare.

Abstract
Dermatology supplements, often marketed as “skin, hair, and nail” supplements, are becoming increasingly popular. However, many consumers lack an understanding of the science of dietary supplements or the specifics of the supplement industry. While certain supplements at the right dose in the right population may prove beneficial, the evidence is sparse for many supplements. In addition, the use of some supplements has resulted in serious adverse effects. From a regulatory standpoint, the US FDA recognizes dietary supplements as foods. This distinction has multiple ramifications, including the fact that manufacturers do not need to prove efficacy, safety, or quality prior to sale. Therefore, physicians and consumers must evaluate each supplement ingredient and formulation individually. This article outlines an evidence-based approach to assess dermatology supplements. As a starting point, all supplements should be evaluated for PPIES: purity, potency, interactions, efficacy, and safety.

Key Words:
beauty supplements, evidence-based approach, hair, interactions, nails, potency, purity, skin, supplement safety

Background

While consumers used to seek out “hope in a jar”, many now turn to “hope in a capsule”, as global consumer interest in dietary supplements continues to rise. According to a 2017 Council for Responsible Nutrition Survey, 76% of adults in the United States take dietary supplements.¹ Among dietary supplements, the category of “beauty” supplements in particular has experienced a surge in popularity. On social media and in retail stores, these are marketed using a large variety of descriptive terms, such as “age defying”, “for thinning hair”, “for skin, hair, and nails”, and others.

Beauty supplements are big business. While some of this growth is due to increasing consumer interest, another major contributing factor is the lack of oversight and regulation. Without any need to demonstrate safety or efficacy prior to sales, manufacturers continue to enter the market. According to a report by Goldstein Research, in 2016 the global beauty supplement market was valued at about $3.5 billion, and by the end of 2024 this market is estimated to reach $6.8 billion.²

Although extremely popular, many consumers do not understand the science of dietary supplements or the specifics of the supplement industry. Certain supplements at the right dose in the right population may indeed be potentially beneficial. One example is encouraging research on the use of nicotinamide in the prevention of non-melanoma skin cancer (NMSC) in high-risk patients.³ However, the evidence is sparse for most supplements. In fact, while evidence of harm from dietary supplements is extensive and well-documented, evidence of benefit is much more limited. It is therefore extremely important to examine the use of supplements with an evidence-based approach.

The evidence-based evaluation of skin, hair, and nail supplements presents a number of challenges. The sheer number of available supplements is a major concern. It is extremely challenging for physicians, let alone consumers, to have extensive knowledge of available supplement ingredients, not to mention the safety, efficacy, and potential interactions of each. According to an analysis in 2010 by Consumer Reports, the independent organization Natural Medicines Comprehensive Database listed over 54,000 supplements.⁴ Of these, 12% were associated with safety or quality concerns.

Even more concerning is that many supplements simply lack information on safety and effectiveness. In the same analysis, about two-thirds of the listed substances lacked any information on safety and efficacy as supported by scientific evidence.⁴ This underscores the challenges facing physicians when advising patients, especially as they seek definitive recommendations on whether certain supplements are safe and effective for their skin concerns. Physicians must emphasize that our answers are only as good as the evidence that is available. Given the limited research on many supplements, recommendations must often be limited as well.

In this article, we review an evidence-based approach to the evaluation of dermatology supplements. It is important to evaluate each supplement from the standpoint of PPIES: purity, potency, interactions, efficacy, and safety (Table 1). It is also important, when recommending supplementation, to suggest specific brands, as a large variation in quality has been demonstrated. Finally, consumers must be cautioned that supplements have to be used carefully and only when recommended, due to the potential for side effects and drug interactions.

PPIES – Purity, Potency, Interactions, Efficacy, and Safety

Table 1: PPIES: An approach to supplements.

Definition

The category of dietary supplements is extremely large. From a regulatory standpoint, the FDA recognizes dietary supplements as foods.⁵ From a practical standpoint, this category includes such varied substances as vitamins, minerals, and herbs. It also includes plant or food extracts, such as beta-carotene supplements or fish oil capsules. It also includes live microorganisms, as in probiotics. It may include hormones, such as melatonin. It may include protein powders, enzymes, or glandular extracts. It also includes combinations of all of the above.

Many different formulations and delivery vehicles may be utilized. These include tablets, capsules, liquids, powders, softgels, timed-release tablets, chewables, gummies, and others.

Regulation of Manufacturing and Marketing

Despite their remarkable popularity, there is a notable lack of oversight and scientific rigor in the manufacturing and marketing of supplements. Much of that is due to the regulatory framework around dietary supplements.

There is a stark difference in the laws governing pharmaceutical medications versus those governing supplements. In the case of pharmaceuticals, manufacturers must provide evidence of both safety and efficacy to the FDA before approval for sale. In the case of supplements, it is almost the polar opposite.

In 1994, the Dietary Supplement Health and Education Act (DSHEA) was passed.⁶ The DSHEA legally recognized dietary supplements as foods, as opposed to drugs. This distinction has multiple ramifications. To begin with, supplement manufacturers do not need to confirm safety, efficacy, or quality before selling to the public. Supplements which include a combination of multiple ingredients do not need to demonstrate a lack of interactions between ingredients.

While manufacturers are expected to utilize current good manufacturing practices, no confirmatory pre-market testing is required. In fact, the FDA is only able to inspect a small fraction of manufacturing facilities, and reports reveal frequent noncompliance. As information received under the Freedom of Information Act revealed, the FDA inspected only 583 dietary supplement manufacturing facilities in 2016, with 61.5% of inspected facilities in the US receiving citations of noncompliance.⁷ Consumer Lab, an independent testing organization, has reported multiple quality issues with supplements. Their results indicate that overall about 1 in 5 supplements are considered poor quality, with herbal products even higher at 39%. Documented issues range from poor quality ingredients to little or no ingredient, to inadequate disintegration of pills.⁸

Evaluating Individual Supplements

The evaluation of a specific supplement requires several distinct considerations. The first relates to the primary active ingredient, such as vitamin D. It is also important to consider the particular supplement formulation, which encompasses the delivery vehicle (e.g., capsule, tablet, gummy), inactive ingredients, and any other active ingredients (e.g., multivitamin, combination supplement). Finally, the specific brand must be evaluated.

With every supplement, we recommend the PPIES approach. It is important to evaluate each specific supplement for its purity, potency, interactions, efficacy, and safety.

Purity is a major concern, as multiple reports have described contamination with microbes or heavy metals, as well as adulteration with prescription medications.^9-11 In terms of potency, concerns include variability of doses from bottle to bottle, as well as doses that are either much higher or lower than stated on the label.¹² Another concern is determining a safe and effective dose. In terms of interactions, many supplements have the potential to interact with foods, drugs, or other supplements, and such information is not required on the label.¹³ Issues of efficacy are very complex. Manufacturers do not need to prove efficacy, and therefore research studies evaluating supplements are limited. When present, some define efficacy for only a narrow indication in a narrow population,¹⁴ while others have methodological limitations.¹⁵ Finally, safety is a major concern. Consumers often mistakenly assume that “natural” supplements are entirely safe, despite evidence of harm from such natural substances as vitamin A, iron, beta-carotene, vitamin B6, and many others.^16-18

Table 2 provides a brief summary of these important issues that patients must take into account when considering supplement use.

Advice to Patients

Table 2: Summary of key points for patients to consider.

Purity

Purity of supplements is an important consideration, as reported issues have ranged from microbial contamination to adulteration.

Contamination with both microbes and heavy metals is a concern. Bacterial contamination has been demonstrated in both liquid¹⁹ and herbal supplements⁹. Bacterial contamination has also been described in “whole foods” or “greens” powders and pills, such as those made from wheat grass or leafy vegetables,²⁰ while contamination with pathogenic fungi was documented in children’s probiotics.²¹

In terms of heavy metals, one-fifth of Ayurvedic medicines purchased via the internet (both US-manufactured and Indian-manufactured) contained detectable lead, mercury, or arsenic.¹⁰

Adulteration with other ingredients is a concern as well. Over the span of 9 years, the FDA identified 776 adulterated supplements. Most were in the categories of weight loss, sexual enhancement, and muscle building, and the most common adulterants included sildenafil, sibutramine, and synthetic steroids.¹¹

Potency

In terms of potency, two main issues exist. The first is ensuring that the supplement contains the dose specified on the label, and that doses are consistent in all packages. The second concern is determining the correct dose, in terms of efficacy and safety, for a particular medical indication.

Ensuring accuracy and consistency of dosing is a major consideration, as many reports have documented serious errors. In one case, a patient consumed more than 1,000 times the labeled dose of vitamin D, due to serious manufacturing and labeling errors in a US-manufactured supplement.²² In a case series, a multivitamin contained as much as 200 times the intended dose of selenium, leading to an FDA warning describing patients with “significant hair loss, muscle cramps, diarrhea, joint pain, and fatigue.”¹² In another study, 71% of melatonin supplement bottles misreported the actual amount. Some contained over four times the amount of melatonin represented on the label.²³

Another issue is that of the correct dose for the patient. With micronutrient supplementation, more is not necessarily better. Rather, the “right” dose is better. It is well known that many micronutrients must be maintained within a defined therapeutic window. Iron supplements, for example, can lead to iron overload even at low doses, if taken for a long period of time.¹⁶ Even the dosing of “natural” antioxidants (AOs) can be a concern, as in male smokers who exhibited higher rates of lung cancer after beta-carotene supplementation.¹⁷

The research regarding AOs is particularly instructive on the difficulties inherent in supplement research. This research initially appeared very promising, as multiple animal and laboratory studies found that AO supplements reduced carcinogenesis. In human studies, populations with a higher intake of AO-rich fruits and vegetables demonstrated lower rates of certain cancers.²⁴

However, human studies of high dose AO supplements (as opposed to dietary intake of AOs) have shown that these do not help and in fact may even promote carcinogenesis in some cases.²⁵ One possible explanation is centered on “the Goldilocks principle”. In other words, AO intake should be maintained within an ideal range, not too low but also not too high. This is due to the fact that the process of oxidation and anti-oxidation is a finely balanced process, and at high doses some AOs may exhibit pro-oxidant effects.²⁵

Physicians, therefore, should advocate an individualized approach to keep levels within an optimal range. This approach includes a consideration of dietary sources and may include laboratory testing. For many nutrients, baseline status is an important consideration, and evaluation may be recommended prior to supplementation. For example, vitamin D supplementation in patients with AD and low serum vitamin D levels may be helpful, but has not consistently shown efficacy in those with baseline normal levels.²⁶ It has also been noted that patients consuming adequate dietary selenium may easily exceed the recommended upper limits of intake if also supplementing with selenium.¹² This is of concern as selenium is a frequent component of “hair loss supplements”.²⁷

Interactions

It is well documented that supplements may interact with medications, foods, and other supplements. As described in one review of herb-drug interactions, concurrent use may “mimic, magnify, or oppose the effect of drugs.”¹³ Therefore, all patients considering supplements require a thorough medication review, including all prescription and over-the-counter medications as well as all supplements.

In a literature review of documented interactions between medications and herbs/dietary supplements, the authors identified a total of over 1,400 unique pairs of interactions involving over 200 herbs and supplements. The greatest number of documented interactions involved magnesium, calcium, iron, St. John’s wort, and Ginkgo biloba.²⁸ Particular caution must be exercised in patients on medications that impact bleeding time or in those who have a history of cardiac conduction issues. For example, saw palmetto, found in some hair loss supplements, has been reported to increase bleeding time.²⁹ In one study evaluating supplement use among older adults, it was found that many patients are at risk for such interactions: 63% of subjects used dietary supplements, and approximately 15% were considered at risk for a potentially major drug-drug interaction between prescription medications, over-the-counter medications, and supplements.³⁰ Examples included increased risk of bleeding with warfarin and omega-3 fish oils or garlic.

Another potential interaction is with lab testing. Biotin has been found to interfere with a number of lab tests, including troponin (used in the diagnosis of myocardial infarction) and tests for thyroid function.³¹

Efficacy

Efficacy can be extremely challenging to determine when it comes to dietary supplements. It is important to emphasize to patients that our recommendations are only as strong as the evidence available. In the case of supplements, some have little to no published scientific research. While others have been the subject of scientific research, many of these studies have important limitations, ranging from poor methodology to a lack of generalizability.

To begin with, supplements that have worked in animal or laboratory studies may not work in human populations, as in the case of multiple randomized placebo controlled trials of high-dose AOs showing no efficacy in the prevention of NMSC.²⁵

Even when human studies are available, there are multiple considerations. For all research studies, it is critical to consider the source and quality of the evidence. For some supplements, human research studies have been conducted, but run the risk of bias, as in collagen supplement studies that have no placebo¹⁵ or that are sponsored by the manufacturer.³² Even publication in a peer-reviewed medical journal does not equate to high quality evidence. For example, one supplement containing “green coffee bean extract” became very popular for weight loss, with results from a “randomized, double blind, placebo controlled study” published in a peer-reviewed journal.³³ However, later investigations highlighted major concerns: the study included only 16 subjects, and all data was collected in India and then sent to a US researcher paid by the manufacturer to write the article.³⁴ Two years later, the article was retracted as “the sponsors of the study cannot assure the validity of the data.”³⁵

In the case of supplements such as biotin, efficacy has only been shown in research performed for a narrow indication (brittle nails)¹⁴ or in a narrow population (those with hair loss and inherited or acquired biotin deficiencies).³⁶ Unfortunately, success in limited areas is often mistakenly assumed to indicate efficacy in other situations. Despite a lack of evidence for other indications, many “beauty” supplements contain biotin and advertise its use for “skin, hair, and nails”.

In a related issue, manufacturers often rely on “deficiency-state” outcomes to support supplementation in normal populations, without evidence. For example, hair loss supplements often contain ingredients such as vitamin A. While those deficient in vitamin A may experience hair loss, there is no evidence that it is useful in individuals with normal levels. In fact, high levels of vitamin A can actually trigger hair loss.²⁷

Finally, little research has compared the efficacy of supplementation to dietary change. While it may be tempting to reach for a capsule, beneficial dietary changes typically have many benefits beyond a single micronutrient. Research to date has simply not demonstrated that, outside of deficiency states, supplements are consistently better than dietary change.

Safety

Since warning labels are not legally required on most supplements, the consumer must beware. Even when of high-quality and delivered in appropriate doses, many “natural” supplements have well-known and documented side effects, ranging from allergic reactions to gastrointestinal upset to sedation and more.

While some research studies have evaluated short-term safety, many lack information on long-term safety. This is a concern, as even supplements exhibiting few side effects in short-term studies can result in long-term damage. One of the best examples is that of beta-carotene supplements. Although these were tolerated well in the short-term, male smokers who took these supplements for a median interval of 6.1 years had an increased risk of lung cancer.³⁷ In another example, the long-term use of high-dose vitamin B6 and B12 supplements, at doses commonly used in individual supplements, was associated with an increased lung cancer risk in men,¹⁸ with smokers who took high-dose B6 supplements over 10 years demonstrating a three-fold increased risk.

It is also important to consider the patient population. Little research has been done to ensure safety in pregnant or breastfeeding women. One well-known example is the risk of birth defects following ingestion of high-dose vitamin A. Similar concerns would arise in children, the elderly, and those with impaired liver or renal function.

Another major concern is the proliferation of multi-ingredient supplements. If considering such a supplement, it is important to ask what studies have been done to ensure that these ingredients may be safely combined.

Resources

In terms of purity and potency, the use of third-party independent investigative laboratories provide the most straightforward evidence. If these seals are found on the bottle, then an independent laboratory has affirmed the accuracy of the label. The supplement contains the ingredients specified, at the doses listed. Such seals also affirm that the product is not contaminated with microbes or heavy metals.

Independent labs providing these verifications include Consumer Lab, US Pharmacopeia, NSF International (National Sanitation Foundation), and UL (Underwriters Laboratories).⁵³

Unfortunately, when evaluating interactions, efficacy, and safety, there is no such “seal of approval”. Every supplement must be approached on an individual basis. Considerations include the active ingredient, the formulation, all inactive ingredients, and the specific brand. It is also important to consider the dose, the patient population for whom it is under consideration, and the medical indication.

For more information on interactions, one subscription service that provides a large, searchable database is the Natural Medicines Comprehensive Database (www.NaturalDatabase.com).⁵⁴ The subscription service ConsumerLab.com is another useful resource. This website publishes comparisons of different brands, with information on purity, potency, and cost. The service also provides reviews of the scientific research behind specific supplements.

Conclusion

Despite the increasing popularity of skin, hair, and nail supplements, many consumers are unaware of the potential concerns associated with their use. As manufacturers do not need to provide any evidence of safety, efficacy, or even quality prior to sale, it is imperative that consumers approach all supplements with caution. An evidence-based approach to the use of an individual supplement should include research on PPIES: purity, potency, interactions, efficacy, and safety.

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CONFLICTS of INTEREST:
Rajani Katta reports no relevant conflicts of interest. Mary Jo Kramer reports no relevant conflicts of interest.

ABSTRACT:
An increasing body of research indicates that dietary change may serve as a component of therapy for certain skin conditions. This includes conditions such as acne, atopic dermatitis, aging skin, psoriasis, and rosacea. Certain nutrients, foods, or dietary patterns may act as disease “triggers”, while others may prove beneficial. Avoidance or elimination diets may be helpful in some conditions, although testing may be recommended first. In terms of beneficial effects, an eating pattern that emphasizes the consumption of whole foods over highly processed foods may help in the treatment of certain skin conditions, and will certainly help in the prevention of associated co-morbidities.

KEY WORDS:
diet, elimination diet, skin, whole foods

TABLE OF CONTENT:

1. Introduction
2. Diet and Acne
3. Diet and Aging Skin
4. Diet and Atopic Dermatitis
5. Diet and Psoriasis
6. Diet and Rosacea
7. Conclusion

Introduction

Dietary change has long been considered an important treatment strategy for certain skin conditions. For example, dermatologists have long discussed the role of dietary triggers in rosacea and insulin resistance in acanthosis nigricans. As an increasing body of research has demonstrated, dietary change may play a role in treatment strategies for other skin diseases as well.

In this review, we focus on five major skin conditions for which dietary change may be advised as one component of treatment. As a quick Internet search will reveal, there is much misinformation on the link between skin and diet. Some recommendations are ineffective, while others are potentially harmful, such as untested dietary supplements or severely restrictive elimination diets. It is critical, therefore, that physicians be well-informed in this area in order to provide evidence-based recommendations.

In this article, we review information on specific nutrients, foods, or dietary patterns that may act as disease “triggers”, as well as those that may prove beneficial in therapy. This review provides a synopsis, highlighting promising research findings.

Diet and Acne

Triggers

The strongest evidence to date on dietary triggers for acne is for high-glycemic-load diets. In a randomized controlled trial (RCT), acne patients demonstrated significant improvement after 12 weeks of a low-glycemic-load diet.¹ Later studies documented that this dietary pattern resulted in lower androgen bioavailability and altered skin sebum production.^2,3 In another RCT, a 10-week low-glycemic-load diet improved acne, and histopathological exam revealed decreased skin inflammation and reduced sebaceous gland size.⁴

Some studies have demonstrated an epidemiologically weak association between acne and dairy consumption, possibly more so with skim milk.^5,7 While further research is needed, it may play a role in some patients, as in a report of five teenagers who developed treatment-resistant acne after starting whey protein supplements.⁸

Beneficial Measures

Studies in humans are limited and, therefore, despite promising in vitro, animal, or anecdotal reports, recommendations for foods or supplements containing probiotics, omega-3 fatty acids, zinc, antioxidants, fiber, and vitamin A cannot be made with certainty at this time.⁹ Omega-3 fatty acids warrant further study; in one 10-week RCT, omega-3 fatty acid supplements and gammalinolenic acid supplements both resulted in clinical and histopathological improvement in acne lesions.¹⁰ Probiotics warrant further study as well; in one RT, minocycline with probiotic supplementation resulted in a lower total lesion count as compared to antibiotics alone.¹¹

Zinc bears special mention, as it has been studied in several RCTs. While some trials have not been successful, others have demonstrated efficacy in acne treatment.^12,13 Further research is warranted, as published trials have utilized multiple dosages and forms of zinc, including zinc gluconate, zinc sulphate, and methionine-bound zinc, among others. Some formulations have better absorption and result in less gastrointestinal side effects. Other factors that impact zinc absorption include age and meal components.¹⁴ In addition, some successful trials have utilized zinc in combination with other components, such as antioxidants and lactoferrin.^15,16 Future research must account for these multiple factors.

Diet and Aging Skin

Triggers

For patients who present for cosmetic treatment of aging skin, lifestyle factors that impact this process are an important aspect of treatment. While smoking and sun protection are commonly reviewed, dietary factors should be as well.

While it has long been recognized that diabetics experience poor wound healing, there is now a greater recognition that these effects on collagen can promote skin wrinkling. Higher levels of blood sugar can result in the production of advanced glycation end products (known as AGEs) via glycation and cross-linking of collagen fibers, which ultimately results in a loss of elasticity.¹⁷ Consumption of pre-formed AGEs, created during certain cooking processes such as deep-frying, can also be detrimental.¹⁸

Even in non-diabetics, effects on collagen may be seen. Even after accounting for degree of sun damage and smoking, as study subjects’ blood glucose level increased, their perceived age increased.¹⁹

Beneficial Measures

Many laboratory and animal studies have found that multiple different antioxidants (AOs), found in foods ranging from various fruits and vegetables to tea leaves and seeds, act to limit the damaging cutaneous effects of ultraviolet (UV) radiation.²⁰ Experimental human studies of a few AOs have noted the same, as in one study in which subjects consuming tomato paste daily for 12 weeks experienced less UV-induced erythema, as well as lower levels of UV-induced matrix metalloproteinase.²¹ It is important to note that research indicates AOs consumed via dietary sources appear to function in a different fashion than those found in isolated supplements.²²

Other human studies suggest that a diet high in phytonutrients can limit photodamage. One study reported higher intake of vegetables, legumes, and olive oil appeared to protect against actinic damage.²³ In another study of over 4000 women, patients’ skin was analyzed for features of skin aging. After controlling for other factors, a diet reported as high in potassium and vitamins A and C correlated to fewer wrinkles.²⁴

Diet and Atopic Dermatitis

Triggers

Food allergies are highly correlated with atopic dermatitis (AD). In some cases, they are causative.²⁵ Foods may trigger an AD flare via three main mechanisms.²⁶

Immunoglobulin E (IgE)-mediated allergy, also known as Type 1 or immediate-type hypersensitivity, may trigger a flare within minutes to hours.²⁷ The six common trigger foods are milk, eggs, wheat, soy, seafood, and nuts. Testing with skin prick test or blood test may screen for this allergy, but due to a high rate of false positive results, confirmation requires double-blind, placebo-controlled food challenge (DBPCFC).

Late eczematous reactions, due to the same trigger foods, may cause an AD flare up to 48 hours later.²⁸ As the immunological mechanism is unknown, testing requires DBPCFC.

Systemic contact dermatitis, screened for by patch testing, is a T-cell mediated reaction. In balsam of Peru allergy, some persons allergic to fragrance additives may experience a cutaneous flare following ingestion of certain foods, including tomatoes, citrus, and cinnamon.²⁹

An expert panel, representing 34 agencies and groups, published guidelines on food allergy, and concluded that elimination diets are not recommended in unselected AD patients.³⁰ In other words, dietary changes should be guided by results of testing. If suspected by history, though, a single food elimination diet for 6 weeks may be attempted in adults.

Beneficial Measures

Synbiotics, which are probiotics in combination with prebiotics, have shown promise in the treatment of AD. Probiotics are live bacteria, similar to those found naturally in the human body, and which may be beneficial to health. They may be found in supplements or in certain foods containing live, active cultures.³¹ Prebiotics, such as certain plant fiber, are defined as nondigestible carbohydrates that stimulate the growth of probiotic bacteria in the intestine.³² A meta-analysis of synbiotics in AD treatment found the most promise with a combination of different strains of bacteria and when used for at least 8 weeks in adults and children over the age of 1 year.³³ However, the optimal dose, bacterial strains, and treatment duration remains unclear.

Vitamin D has not been shown to be helpful in most AD patients, but further research is recommended for certain groups, specifically those with very low levels of vitamin D, those with food allergies, and those with frequent bacterial skin infections.^34,35 Studies of evening primrose oil and borage seed oil have been disappointing, while studies of Chinese herbal medicine have either not shown efficacy, or have been of low quality.^36,37 Limited research is available for fish oil supplements.³⁸

Diet and Psoriasis

The importance of diet should be emphasized to all psoriasis patients, primarily due to the higher risk of comorbid conditions, including diabetes, hypertension, and cardiovascular disease, that may be prevented or ameliorated by dietary approaches.³⁹ In addition, dietary change leading to weight loss has resulted in better treatment efficacy, as well as improved psoriasis area and severity index (PASI) scores in some patients.

Triggers

It is well recognized that smoking and increased alcohol intake are associated with psoriasis, and all psoriatic patients should be advised of their potential role.^40,41

Dietary factors may also play a role. Gluten-containing foods may act as a trigger in some patients, and testing for celiac antibodies is warranted in those who report gastrointestinal symptoms. While estimates vary, one large study found a 2.2 fold higher risk of celiac disease as compared to matched controls, while a meta-analysis found a 2.4 fold higher risk of certain celiac antibodies.^42,43 In such patients, a gluten-free diet may result in psoriasis improvement, as demonstrated in small trials and case reports, although further studies are required to confirm.^43,44

Beneficial Measures

In a systematic literature review, increased severity of psoriasis appeared to correlate with a higher body mass index (BMI), although the authors noted the difficulty in determination of temporality due to study designs.⁴⁵ It is believed that obesity likely predisposes to psoriasis, and vice versa.⁴⁶ While the reasons for this are multifactorial, it has been shown that weight loss can improve response to systemic psoriasis therapies and improve disease severity.

An excellent review article summarizes the effects of weight loss interventions in psoriasis.⁴⁷ In a meta-analysis of five RCTs of lifestyle intervention via diet or exercise in overweight or obese psoriasis patients, a greater reduction in PASI score was seen in weight loss intervention groups.⁴⁸ In a limited number of case reports and retrospective studies, some obese patients have experienced significant improvements in psoriasis following gastric bypass surgery.⁴⁹

Weight loss has also improved response to systemic therapy, as in one RT trial of patients on cyclosporine.⁵⁰ In examining factors associated with response to biologic therapy, one analysis found that BMI had the strongest effect across studies, although several studies found no association.^47,51

While specific dietary recommendations are not clear, one observational study found an inverse association between PASI score and degree of adherence to the Mediterranean diet.⁵²

In terms of nutritional supplements, Millsop et al. summarized multiple studies and found that further investigation was needed, with fish oil showing the most promise and oral vitamin D demonstrating some promise in open label studies. There was limited evidence for benefit of vitamin B12 and selenium
supplementation.⁵³

Diet and Rosacea

Triggers

Although dermatologists frequently counsel rosacea patients on avoidance of dietary triggers, there is a lack of research in this area. In one survey of patients by the National Rosacea Society, 78% had altered their diet, and 95% of this group reported subsequent reduction in flares.⁵⁴

In this group, 75% were affected by spices and 54% by hot sauce. Other trigger foods included tomatoes (30%), chocolate (23%), and citrus (22%). Alcohol was another frequent trigger, including wine (52%) and hard liquor (42%), as well as hot beverages such as coffee (33%) and tea (30%).

While the underlying pathophysiologic mechanism of these reported triggers is unknown, transient receptor potential (TRP) channels may play a role. These are expressed throughout the body, including on neuronal tissues, and may be activated by cold or hot temperatures, as well as certain foods.⁵⁵ Specific dietary activators include capsaicin and cinnamaldehyde, which act on certain of these channels to stimulate an increase in skin blood flow via neurogenic vasodilatation.⁵⁵ Capsaicin is found in some spices, while cinnamaldehyde is found in cinnamon, tomatoes, citrus, and chocolate.⁵⁶

Beneficial Measures

Research indicates the possible role of a gut-skin connection in rosacea. In a population-based cohort study of close to 50,000 patients with rosacea, the prevalence of celiac disease, Crohn’s disease, ulcerative colitis, Helicobacter pylori infection, small intestinal bacterial overgrowth (SIBO), and irritable bowel syndrome were all higher among patients with rosacea as compared with control subjects.⁵⁷

Although research is ongoing, the pathogenic link remains unknown. One intriguing study found that patients with rosacea were 13 times more likely to have SIBO, with a suspected role for increasing circulating cytokines.⁵⁸ Treatment of SIBO with antibiotics in 40 patients led to remission of rosacea in all cases, which persisted in the majority at 3-year follow-up.

In one case report, a reduction of gut transit time via a high-fiber intervention resulted in improvement of rosacea.⁵⁸ As SIBO has been linked to decreased gut motility, further research on such intervention is warranted.

Conclusion

This article is intended as a general overview. There are several other conditions (not touched upon here) for which dietary intervention may be considered. For example, emerging research indicates that patients with hidradenitis suppurativa have a higher risk of adverse cardiovascular events, which may necessitate dietary change.⁶⁰ In the arena of prevention, research continues into the role of diet and supplement use in skin cancer prevention. As research continues, dietary interventions may play a role in other dermatologic diseases as well.

The five conditions reviewed here are very disparate, and yet patients with each often seek dietary advice. In discussing the link between skin and diet, it is important to recognize and convey the limitations of nutritional research. Specifically, such research may not lead to definitive answers applicable to every patient, but rather general recommendations.

This is in part due to the notable variability of individual responses to different foods and nutrients, as in marked differences in blood glucose responses to the same quantity of carbohydrates.⁶¹ Confounding factors present a notable research challenge, as does the fact that many health effects may take months to years to manifest, which makes valid controlled dietary trials extremely challenging. Despite these challenges, nutritional research can indicate directions for further study, or add to an increasing body of evidence to support specific recommendations.

Based on research findings to date, certain dietary recommendations are suitable for patients with multiple different types of skin disease.

1. The results of research support the promotion of eating patterns over specific foods or nutrients.
2. An eating pattern that emphasizes the consumption of whole foods over highly processed foods may help in the treatment of certain skin diseases. It will certainly help in the prevention of associated comorbidities.
3. Multiple eating plans emphasize whole foods as a foundational approach, and may be recommended to patients with skin disease. Such eating plans, rich in dietary antioxidants, fiber, and other phytonutrients, have demonstrated multiple overall health benefits. These may be either cuisine-based, such as the Mediterranean diet, or guideline-based, such as the DASH diet. These particular plans have been shown to reduce the risks of cardiovascular disease and hypertension, respectively.^62,63
4. An increased intake of fiber is seen as one key benefit of these whole foods diets. Some plant-derived fiber serves as a prebiotic, which may promote a healthy gut microbiome. Given an increasing body of research demonstrating a gut-skin connection, this may benefit certain inflammatory skin diseases.
5. For some skin diseases, specific dietary “triggers” should be reviewed. Some patients may choose a trial of an elimination diet, such as avoidance of high-glycemic-load foods in acne or vasodilating foods in rosacea. For other conditions, medical testing may be recommended prior to dietary change, as in testing for celiac disease in psoriasis.
6. Dietary supplements, used in the absence of a documented nutrient deficiency, have been demonstrated as beneficial in only a few very specific instances. Despite the marketing of many over-the-counter supplements for the treatment of skin disease, the vast majority of these are not supported by evidence.
7. Referral to integrative physicians, dieticians, or nutritionists may be recommended to help implement and tailor dietary approaches according to food allergies, personal or cultural preferences, and other medical conditions.

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Department of Dermatology, Baylor College of Medicine, Houston, TX, USA

Conflict of interest:
None Reported.

ABSTRACT
First described in the context of diabetes, advanced glycation end products (AGEs) are formed through a type of non-enzymatic reaction called glycation. Increased accumulation of AGEs in human tissue has now been associated with end stage renal disease, chronic obstructive pulmonary disease, and, recently, skin aging. Characteristic findings of aging skin, including decreased resistance to mechanical stress, impaired wound healing, and distorted dermal vasculature, can be in part attributable to glycation. Multiple factors mediate cutaneous senescence, and these factors are generally characterized as endogenous (e.g., telomere shortening) or exogenous (e.g., ultraviolet radiation exposure). Interestingly, AGEs exert their pathophysiological effects from both endogenous and exogenous routes. The former entails the consumption of sugar in the diet, which then covalently binds an electron from a donor molecule to form an AGE. The latter process mostly refers to the formation of AGEs through cooking. Recent studies have revealed that certain methods of food preparation (i.e., grilling, frying, and roasting) produce much higher levels of AGEs than water-based cooking methods such as boiling and steaming. Moreover, several dietary compounds have emerged as promising candidates for the inhibition of glycation-mediated aging. In this review, we summarize the evidence supporting the critical role of glycation in skin aging and highlight preliminary studies on dietary strategies that may be able to combat this process.

Key Words:
AGEs, advanced glycation end products, collagen, dietary sucrose, fibroblasts, nutrition, skin aging

Background: Glycation and Aging Skin

Societal obsession with the process of aging dates back to ancient history, and myths related to the conservation of youth—ranging from a bathing fountain that confers eternal youth to a philosopher’s stone that could be used to create an elixir of life—populate both past and contemporary folklore. However, it is only within recent years that aging has been investigated from an empirical approach, as it continues to garner increasing attention from the scientific community. While several hypotheses have been proposed to explain the pathophysiology responsible for senescence, no single theory accounts for the diverse phenomena observed. Rather, aging appears to be a multifactorial process that results from a complex interplay of several factors and mechanisms.

Nevertheless, stratification of factors and mechanisms contributing to senescence is critical for the development of initial strategies in combating the aging process. The skin is an excellent paradigm for studying aging, in large part due to its easy accessibility. Moreover, in addition to its vulnerability to internal aging processes because of its diverse role in cellular processes, such as metabolism and immunity, the skin is subject to a variety of external stressors as the chief barrier between the body and the environment.

Aging factors can generally be classified as exogenous or endogenous. As ultraviolet (UV) radiation exposure is so strongly associated with a host of age-related skin diseases, endogenous and exogenous factors can theoretically be studied somewhat independently in the skin by differentiating between UVprotected and UV-exposed sites.¹ Endogenously aged skin displays characteristic morphological features with resultant alterations in functionality. These include epidermal, dermal, and extracellular matrix atrophy leading to increased fragility, diminished collagen and elastin resulting in fine wrinkle formation, and marked vascular changes disrupting thermoregulation and nutrient supply. Endogenously aged skin also displays decreased mitotic activity, resulting in delayed wound healing, as well as decreased glandular function, resulting in disturbed re-epithelialization of
deep cutaneous wounds. Also seen is a reduction of melanocytes and Langerhans cells manifesting as hair graying and higher rates of infection, respectively.^2-10 Exogenously aged skin, in which environmental factors such as UV radiation act in concert with endogenous processes, shares many of the characteristics of endogenously aged skin. In addition, exogenously aged skin displays a thickened epidermis and aggregation of abnormal elastic fibers in the dermis (i.e., solar elastosis).¹

Among the many mechanisms thought to underlie aging, glycation has emerged in recent years as one of the most widely studied processes. Testament to the rapidly growing attention from the scientific community, a cursory literature search will yield thousands of articles related to glycation, the majority of them published in the last decade. Glycation refers to the nonenzymatic process of proteins, lipids, or nucleic acids covalently bonding to sugar molecules, usually glucose or fructose. The lack of enzyme mediation is the key differentiator between glycation and glycosylation. Glycosylation occurs at defined sites on the target molecule and is usually critical to the target molecule’s function. In contrast, glycation appears to occur at random molecular sites and generally results in the inhibition of the target molecule’s ability to function.The products of glycation are called advanced glycation end products (AGEs).

Increased accumulation of AGEs was first directly correlated to the development of diabetic complications. Since then, AGEs have been implicated in a host of other pathologies, including atherosclerosis, end stage renal disease, and chronic obstructive pulmonary disease.¹¹ (It should be noted that AGE levels have been shown to vary by race and gender, and until larger studies are done to create ethnic- and gender-specific reference values, increased accumulation of AGEs should be defined as levels that are elevated for all demographic groups.¹²) Not coincidentally, many of the pathologies associated with AGEs, including diabetic sequelae, are closely related to senescence.

This extends to aging skin, as methods of AGE detection, such as immunostaining, have demonstrated the prevalence of glycation in aged skin. Glycation results in characteristic structural, morphological, and functional changes in the skin, a process colloquially known as “sugar sag.” With glucose and fructose playing such a prominent role in the mechanism, it is not surprising that diet plays a critical role in glycation and thus aging skin.

Perhaps more surprising, studies have shown that consumption of AGEs is not only tied to the sugar content of food, but is also affected by the method of cooking. Furthermore, as the
connection between diet and aging is more clearly characterized, a host of dietary compounds have surfaced as potential therapeutic candidates in the inhibition of AGE-mediated changes. In this review, we explore glycation as it pertains to skin aging and highlight evidence that demonstrates the quintessential role of diet in modifying the degree to which AGE-related processes are able to alter the largest organ of the human body.

Biochemical Processes in AGE Formation

First described over a century ago, glycation entails a series of simple and complex non-enzymatic reactions. In the key step, known as the Maillard reaction, electrophilic carbonyl groups of the sugar molecule react with free amino groups of proteins, lipids, or nucleic acids, leading to the formation of a Schiff base. This non-stable Schiff base contains a carbon-nitrogen double bond, with the nitrogen atom connected to an aryl or alkyl group. The Schiff base rapidly undergoes re-arrangement to form a more stable ketoamine, termed the Amadori product. At this juncture, the Amadori product can: (1) undergo the reverse reaction; (2) react irreversibly with lysine or arginine functional groups to produce stable AGEs in the form of protein adducts or protein cross-links; or (3) undergo further breakdown reactions, such as oxidation, dehydration, and polymerization, to give rise to numerous other AGEs.¹³ AGE formation is accelerated by an increased rate of protein turnover, hyperglycemia, temperatures above 120° C (248° F), and the presence of oxygen, reactive oxygen species, or active transition metals.¹⁴

AGEs comprise a highly heterogenous group of molecules. The first, and perhaps most well-known, physiological AGE to be described was glycated hemoglobin (hemoglobin A1C), now widely used to measure glycemic control in diabetes. However, the most prevalent AGE in the human body, including the skin, is carboxymethyl-lysine (CML), which is formed by oxidative degeneration of Amadori products or by direct addition of glyoxal to lysine. In the skin, CML is found in the normal epidermis, aged and diabetic dermis, and photoaging-actinic elastosis.^15-17 Other AGEs detected in skin include pentosidine, glyoxal, methylglyoxal, glucosepane, fructoselysine, carboxyethyl-lysine, glyoxal-lysine dimer, and methylglyoxal-lysine dimer.¹⁸

AGEs and the Skin

AGEs accumulate in various tissues as a function, as well as
a marker, of chronological age.¹⁹ Proteins with slow turnover rates, such as collagen, are especially susceptible to modification by glycation. Collagen in the skin, in fact, has a half-life of approximately 15 years and thus can undergo up to a 50% increase in glycation over an individual’s lifetime.²⁰

Collagen is critical not only to the mechanical framework of the skin but also to several cellular processes, and is impaired by glycation in multiple ways. First, intermolecular cross-linking modifies collagen’s biomechanical properties, resulting in increased stiffness and vulnerability to mechanical stimuli.²¹ Second, the formation of AGEs on collagen side chains alters the protein’s charge and interferes with its active sites, thereby distorting the protein’s ability to interact properly with surrounding cells and matrix proteins.²² Third, the ability to convert L-arginine to nitric oxide, a critical cofactor in the crosslinking of collagen fibers, is impaired.²³ Finally, glycated collagen is highly resistant to degradation by matrix metalloproteinases (MMPs). This further retards the process of collagen turnover and replacement with functional proteins.²⁴

Other cutaneous extracellular matrix proteins are functionally affected by glycation, including elastin and fibronectin. This further compounds dermal dysfunction,^18,25 as glycation crosslinked collagen, elastin, and fibronectin cannot be repaired like their normal counterparts.

Interestingly, CML-modified elastin is mostly found in sites of solar elastosis and is nearly absent in sun-protected skin. This suggests that UV-radiation can mediate AGE formation in some capacity or, at the least, render cells more sensitive to external stimuli.²⁶ It is hypothesized that UV-radiation accomplishes this through the formation of superoxide anion radicals, hydrogen peroxide, and hydroxyl radicals. This induces oxidative stress and accelerates the production of AGEs.²⁷ AGEs themselves are very reactive molecules and can act as electron donors in the formation of free radicals. Occurring in conjunction with the decline of the enzymatic system that eliminates free radicals during the aging process, these properties lead to a “vicious cycle” of AGE formation in the setting of UV exposure.

Formed both intracellularly and extracellularly, AGEs can also have an effect on intracellular molecular function. In the skin, the intermediate filaments of fibroblasts (vimentin) and keratinocytes (cytokeratin 10) have been shown to be susceptible to glycation modification.²⁸ Analogous to the diverse role of collagen in the skin, intermediate filaments are essential to both the maintenance of cytoskeletal stability and the coordination of numerous cellular functions. Fibroblasts with glycated vimentin demonstrate a reduced contractile capacity, and these modified fibroblasts are found to accumulate in skin biopsies of aged donors.²⁸

In fact, general cellular function may be compromised in the presence of high concentrations of AGEs. In vitro, human dermal fibroblasts display higher rates of premature senescence and apoptosis, which likely explains the decreased collagen and extracellular matrix protein synthesis observed in both cell culture and aged skin biopsies.^29,30 Similarly, keratinocytes exposed to AGEs express increased levels of pro-inflammatory mediators, suffer from decreased mobility, and also undergo premature senescence in the presence of AGEs.³¹

In addition to intermediate filaments, proteasomal machinery and DNA can undergo glycation. Proteasomal machinery, which functions to remove altered intracellular proteins, decline
functionally in vitro when treated with glyoxal.³² Similar in vitro findings were observed when human epidermal keratinocytes and fibroblasts were treated with glyoxal, leading to accumulation of CML in histones, cleavage of DNA, and, ultimately, arrest of cellular growth.³³

Beyond the modification of host molecular physicochemistry, AGEs also exert detrimental effects through the binding to specialized cellular surface receptors, called the Receptor for
AGEs (RAGE). RAGE is a multiligand protein that, when activated, can trigger several cellular signaling pathways, including the mitogen-activated protein kinases (MAPKs), extracellular signalregulated kinases (ERK), phosphatidyl-inositol-3-kinase (PI3K), and nuclear factor kappa-beta (NFκ-β) pathways.³⁴ These pathways are known to mediate various pathogenic mechanisms through the alteration of cell cycle regulators, gene expression, inflammation, and extracellular protein synthesis.³⁴ Not surprisingly, RAGE is found to be highly expressed in the skin and is present at even higher levels in both UV-exposed anatomical sites and aged skin.³⁵

Combating AGE with Diet

Nearly 70 years ago, Urbach and Lentz reported that the level of sugar both in the blood and in the skin is decreased with a diet low in sugar.³⁶ Although its significance was not appreciated at the time, this finding demonstrated a quintessential connection between diet and skin health. We now understand that food is a source of both monosaccharides that, in high amounts, catalyze the production of AGEs in the body, and preformed AGEs.³⁷

Preformed AGEs are absorbed by the gut with approximately 30% efficiency. They can then enter the circulation, where they may induce protein cross-linking, inflammation, and intracellular oxidative stress. The end result is the amplification of a similar “vicious cycle,” which may be as detrimental as the consumption of excess dietary sugar ³⁸ Interestingly, preformed AGEs largely result from exogenous synthesis mediated by the food cooking process. Grilling, frying, deep fat frying, and roasting methods are all known to produce higher levels of AGEs in food. In contrast, methods of preparation that are water-based, such as boiling and steaming, produce a logarithmically lower amount of AGEs.³⁹

A diet low in AGEs correlated with a reduction in inflammatory biomarkers (i.e., tumor necrosis factor-alpha, interleukin-6, and C-reactive protein) in diabetic human patients, as well as an improvement in wound healing and other diabetes-associated sequelae in mice.^40,41 Other authors have cited the relatively youthful appearance that is often associated with the elderly Asian population as evidence of the long-term impact of employing water-based cooking practices, which are characteristic of Asian cooking.³⁷

Tight glycemic control over a 4-month period can result in a reduction of glycated collagen formation by 25%.^37,38 Consumption of a low-sugar diet prepared through waterbased cooking methods would limit both the consumption of preformed exogenous AGES and endogenous production through physiological glycation. Avoiding foods that result in higher levels of AGEs, such as donuts, barbecued meats, and dark-colored soft drinks, can be an effective strategy for slowing “sugar sag.”³⁹

A diet low in AGEs correlated with a reduction in inflammatory biomarkers (i.e., tumor necrosis factor-alpha, interleukin-6, and C-reactive protein) in diabetic human patients, as well as an improvement in wound healing and other diabetes-associated sequelae in mice.^40,41 Other authors have cited the relatively youthful appearance that is often associated with the elderly Asian population as evidence of the long-term impact of employing water-based cooking practices, which are characteristic of Asian cooking.³⁷

Tight glycemic control over a 4-month period can result in a reduction of glycated collagen formation by 25%.^37,38 Consumption of a low-sugar diet prepared through waterbased cooking methods would limit both the consumption of preformed exogenous AGES and endogenous production through physiological glycation. Avoiding foods that result in higher levels of AGEs, such as donuts, barbecued meats, and dark-colored soft drinks, can be an effective strategy for slowing “sugar sag.”³⁹

Of interest, several culinary herbs and spices are believed to be capable of inhibiting the endogenous production of AGEs (specifically fructose-induced glycation). These include
cinnamon, cloves, oregano, and allspice.⁴² Other dietary compounds that have been linked to inhibition of AGE formation based on in vitro data and preliminary animal models include ginger, garlic, α-lipoic acid, carnitine, taurine, carnosine, flavonoids (e.g., green tea catechins), benfotiamine, α-tocopherol,niacinamide, pyridoxal, sodium selenite, selenium yeast, riboflavin, zinc, and manganese.^42-44 The cosmeceutical industry has taken notice of this data, and several have recently released topical products containing carnosine and α-lipoic acid, with claims related to anti-AGE formation.³⁸ However, data is lacking as to whether topical administration of these compounds is as effective as dietary delivery in slowing the aging process.

Since glycation is accelerated in the presence of reactive oxygen species, antioxidants should theoretically be effective in limiting the production of new AGEs. They may also impact AGE-induced tissue damage. One intriguing study looked at the effects of the antioxidant resveratrol. Popularly known for its abundance in red wine, resveratrol is a natural phenol produced by several plants in response to injury and is found in the skin of grapes, blueberries, raspberries, and mulberries. In one study, resveratrol inhibited AGE-induced proliferation and collagen synthesis activity in vascular smooth muscle cells belonging to strokeprone rats.⁴⁵ Another study found that it decreased the frequency of DNA breaks in methylglyoxal treated mouse oocytes. Although resveratrol does not appear to reverse the glycation process itself, these studies suggest that it can reduce AGE-induced tissue damage.⁴⁶ While these findings are promising, to our knowledge these laboratory results have not yet been demonstrated in human studies.

In one of the few human studies successfully conducted on antiAGE therapeutics, L-carnitine supplementation for 6 months in hemodialysis patients significantly decreased levels of AGEs in the skin.⁴⁷ L-carnitine, which is naturally abundant in meat, poultry, fish, and dairy products, is an antioxidant. Furthermore, it may function synergistically to neutralize oxidative stress when given with α-lipoic acid.⁴⁸

It warrants mentioning that dietary caloric restriction, the most effective strategy for slowing the general aging process known to date, may function to some degree by preventing accumulation of AGEs in the human body. Caloric restriction is capable of decreasing the levels of AGEs detected in rat and mice skin collagen and has resulted in an increased lifespan in mice models.^49,50

Conclusion: Obstacles and Future Directions

There is clearly an abundance of in vitro data and a handful of in vivo animal findings that support various options for dietary therapy directed against “sugar sag.” However, studies in humans are limited by logistical, ethical, and inherent study design issues. In a stimulating commentary as part of a review article on controversies in aging and nutrition, Draelos writes about the frustrating obstacles that she encountered when she attempted to study the impact of vitamin C supplementation on skin health.³⁸ Examples of problems she faced included: identifying a facility that offered affordable measurements of vitamin C levels not only in the serum but also in the skin; designing an ethical study that would include a control arm requiring subjects to adhere to a diet poor in vitamin C without any supplementation; and ensuring participant compliance to the diet and supplementation protocol while also minimizing confounding factors.Most of these challenges also exist in the human studies needed to identify and/or to verify evidence-based dietary strategies in combating glycation-mediated skin aging.

Nevertheless, the role of diet in skin aging is undeniable. As our understanding of how accumulation of AGEs affects a rapidly growing number of pathologies, it is inevitable that our research methods will evolve to better address the challenges that currently seem so discouraging. For instance, a research group reported in early 2014 that they were able to successfully create a model of reconstructed skin modified by glycated collagen to identify biological modifications of both epidermal and dermal markers.⁵¹ Perhaps the creation of an in vitro model that comprehensively and accurately represents aged human skin will serve as the next stepping stone in translating therapeutic findings from bench to bedside.

In the meantime, awareness of the critical impact of AGEformation in both diabetics and non-diabetics must be extended to all patients, regardless of their current health status. That task begins with clinicians. Dietary counseling should be incorporated into our regular interactions with patients, alongside essential discussions about UV-protection and avoidance of tobacco. After all, these are the three most important known exogenous aging factors. Their common grouping is reflective of their interconnected nature and their action in concert to disturb homeostasis.

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