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

¹The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
²Georgetown University School of Medicine, Washington, DC, USA

Conflict of interest:
AJF is a consultant for Aclaris Therapeutics. ECM has no conflicts to declare for this work.

Abstract:
HP40 (Eskata™) is a stabilized, topical solution of 40% hydrogen peroxide (H₂O₂) packaged in an applicator pen that is US FDA-approved to treat seborrheic keratoses (SKs). By harnessing the oxidative capabilities of H₂O₂ , 1-2 treatments with HP40 produced a higher rate of clearance of four SKs per patient compared to vehicle in two phase 3 trials. The clearance rate was higher for the face than the trunk and extremities. Similarly, the risks of pigmentary changes and scarring from HP40 were lower for the face than other locations. Further, based on an ex vivo study, HP40 may be less cytotoxic to melanocytes than cryotherapy, but clinical trials comparing these therapies are needed. Limitations of HP40 are its low efficacy and requirement of multiple treatments, which can result in elevated costs. The application can also be time-consuming, though extenders or even staff members can apply it. Therefore, HP40 may be better reserved for the treatment of facial SKs.

Key Words:
efficacy, Eskata, hydrogen peroxide, safety, seborrheic keratoses, topical therapy

Introduction

Seborrheic keratoses (SKs) are benign epithelial tumors estimated to affect more than 83 million Americans.¹ Existing as at least nine variants, SKs present as round to oval macules or papules with variable surface textures that appear “stuck on” and can occur anywhere on the body, except the palms and soles.^2-4 The incidence and frequency of SKs per person increase with age.⁴ In one study of Korean males, the authors found that 79% of patients had SKs at age 40 (with 5.5 SKs per patient) compared to 94% of patients at age 50 (with 9.9 SKs per patient).⁵

In addition to increasing age, potential risk factors for SKs include ultraviolet light, as they occur with a higher prevalence on sun-exposed skin,^5,6 friction given they commonly occur in intertriginous areas,⁷ and genetic predisposition.^7,8 However, the true etiologic risk factors and pathogenesis of SKs are not fully known. Inhibition of apoptosis may occur in SKs, contributing to their formation.⁴Additionally, mutations in the fibroblast growth factor receptor⁸ and oncogenic phosphoinositide 3-kinase pathway⁹ may impact their development; however, these changes are not present in all SKs so additional genes are likely involved.⁸

While SKs do not require treatment, patients often request removal to relieve symptoms of irritated SKs or for cosmetic reasons.¹⁰ The most common treatment is cryotherapy with liquid nitrogen; surgical therapies are also used including electrodessication, curettage, shave excision, or laser therapy.^7,11

Among other side effects, these invasive methods can cause pain, bleeding, pigmentary changes, and scarring.^7,12-15 The risk of pigmentary changes is especially high in patients with skin of color.⁷ These side effects motivated the pursuit for efficacious topical therapies that minimize long-term adverse effects. Existing keratolytics (ammonium lactate, imiquimod, and tazarotene) and vitamin D analogs were examined to treat SKs, but these agents demonstrated limited efficacy in small clinical trials.^16-19

The first topical therapy to be US FDA-approved for the treatment of raised SKs is HP40 (Eskata™), a stabilized topical solution of 40% hydrogen peroxide (H₂O₂).²⁰ This therapy was approved in December 2017 based on the results of two phase 3 trials.²⁰ An earlier phase 2 dose-ranging trial additionally confirmed that HP40 was more efficacious than 32% H₂O₂ while still having a satisfactory side effect profile.^21, In this review, we will discuss the evidence for and limitations of HP40 based on these clinical trials as well as an ex vivo model of Fitzpatrick Skin Type (FST) V skin that examined HP40’s cytotoxicity.^20,22,23

Application and Mechanism

HP40 is applied by a healthcare professional with a single use pen that includes 0.7 mL of 40% H₂O₂ and can treat about seven SKs.²⁴ According to the manufacturer’s instructions, the tip of the pen is pressed to an SK and the solution is applied in a circular motion for about 20 seconds. This process is repeated up to three additional times per SK with 1 minute between each application. After 3 weeks, the SK can be re-treated if satisfactory clearance was not achieved.

The mechanism by which HP40 destroys keratinocytes is not fully elucidated, but is thought to involve H₂O₂‘s oxidizing power²¹ as both a direct oxidant and indirect oxidant through the formation of hydroxyl radicals.²⁵ When this oxidative stress overwhelms the antioxidant properties of the skin, H₂O₂ can lead to cellular destruction by damaging proteins, lipids, and nucleic acids.²⁵ Applied at a supra-physiologic concentration, a portion of the HP40 dose likely diffuses through the stratum corneum (SC) and into the epidermis.^20,21 Free radicals generated by H₂O₂ can then induce apoptosis or necrosis of seborrheic keratinocytes among other cell types (Figure 1). Given this mechanism, HP40 should not be applied to open or infected SKs; without an intact SC to act as a barrier, high concentration H₂O₂ can cause rapid death of adjacent cells (Figure 1).²⁶ Additionally, HP40 should not be applied within the orbital rim where contact with H₂O₂ can cause corneal injury.²⁴

Efficacy of HP40

In two phase 3 trials with a total of 937 patients, four raised SKs per patient were treated with either HP40 or vehicle using the previously described method (Application and Mechanism).²⁰ Three weeks later, residual SKs were re-treated. Pedunculated SKs or SKs in intertriginous areas, hair-bearing areas, or within 5 mm of the orbital rim were excluded. The therapeutic efficacy was assessed with a 4-point scale, Physician’s Lesion Assessment (PLA), developed by the manufacturer where 0 is clear, 1 is nearly clear, 2 is a thin SK with a depth of 1 mm or less, and 3 is a thick SK with a depth greater than 1 mm. The primary endpoint was complete clearance (0 on PLA) of all four SKs.²⁰

The treatment and control groups had similar demographic characteristics, with an average age of 68.7 years, and the completion rate was nearly 100% for each trial (99%, 98% per trial). At the end of the study (day 106), HP40 resulted in a significantly higher rate of complete clearance of all four SKs than vehicle; however, the rate of clearance of all four SKs with HP40 was low overall (4%, 8% per study for HP40 versus 0% for both studies for vehicle). Post hoc, the authors also calculated the mean per-patient percentage of clear/nearly clear SKs, which was higher for HP40 than vehicle (47%, 54% versus 10%, 5%, respectively).²⁰

To examine the efficacy of HP40 by location, the percentage of clear/nearly clear SKs at day 106 for each anatomic site was calculated in another study.²² A total of 1,868 SKs were treated in the HP40 group and 1,880 SKs were treated in the vehicle group; 59% of SKs were on the trunk, 30% on the face, and 11% on the extremities. The highest rate of clearance/near-clearance with HP40 treatment was observed for the face (65%), followed by the trunk (46%), and then the extremities (38%). The authors theorized that these efficacy differences may be due to variations in skin topography, such as varying water or lipid content or SC thickness. For instance, the thin SC of the face may allow enhanced penetration of HP40 compared to other anatomical sites. Another explanation proposed by the authors was that the high exposure of the face to ultraviolet radiation may impair its ability to respond to H₂O₂-induced oxidative stress.²²

Adverse Effects of HP40

In the phase 3 trials, 21% of the HP40 group and 19% of the vehicle group reported adverse effects; most were mild to moderate and all were limited to local skin reactions.²⁰ Three events related to HP40 were considered severe: application site pain, a burn from treatment, and a burning sensation. Ten minutes after HP40 application, erythema was observed in 91% of SKs and edema in 75% of SKs. By day 106, the percentage of HP40-treated SKs with erythema decreased to 10.1% and no SKs exhibited edema. Other symptoms at day 106 included scaling (8.0%), hyperpigmentation (7.8%), crusting (5.4%), hypopigmentation (3.0%), scarring (<1%), and erosion (<1%).²⁰ Examining skin reactions by anatomic location, Smith et al. found that SKs on the face showed the lowest rates of hyperpigmentation (2.3% versus 10.8% trunk, 6.9% extremities), hypopigmentation (1.9% versus 3.5% trunk, 3% extremities), and scarring (0% versus 0.6% trunk, 1% extremities).²²

While the risks of pigmentary changes and scarring at day 106 were low, especially for facial SKs, 98.8% of the study sample were FST I-IV, with only 7.3% having FST IV, so the effects on patients with FST IV or higher could not be adequately assessed.²⁰ A study by Kao et al. used an ex vivo model of human FST V skin to explore the toxicity of HP40 (1 and 2 μL) compared to cryotherapy (5- and 10-second cycles).²³ A colorimetric MTT assay was used to measure overall cytotoxicity and S100 stained-melanocytes were quantified to assess melanocyte toxicity. The authors found that HP40 was less cytotoxic overall and to melanocytes compared with cryotherapy, meaning that HP40 may cause less pigmentary changes in patients with dark skin.²³ However, clinical trials comparing the adverse effects of HP40 and cryotherapy are needed before conclusions can be drawn. Given hyperpigmentation was seen in 8% of HP40-treated SKs²⁰ and patients with darker skin are more prone to pigmentary changes,⁷ HP40 should be used cautiously in FST IV-VI patients until further research is done.

Limitations and Future Directions

HP40 was found to be superior to vehicle for the treatment of raised SKs, but its efficacy is limited overall, producing complete clearance of all four SKs in only 4% and 8% of patients per study.²⁰ As Bauman et al. discussed, patient satisfaction was not evaluated in the trials, and considering patients determine therapeutic success based on their appearances in the mirror rather than on physician-completed scales, superior results may have been observed with self-assessments.²⁰ Regardless, patients still often require repeat treatments to produce adequate SK clearance (97% of the trial participants required second treatments), which can be cost prohibitive and time intensive for patients.²⁰ HP40 is not covered by insurance and costs about $131 (US dollars) per treatment (as reported by The Medical Letter on Drugs and Therapeutics²⁴).

HP40 is also time consuming to apply for the dermatology clinic. In the clinical trials, treatment of four SKs took about 5 minutes and 20 seconds,²⁰ and this time would be almost doubled for the average of seven SKs that can be treated with each HP40 pen.²⁴ With four 20-second treatment cycles recommended per SK, this therapy is more time intensive than cryotherapy, which requires only 5 to 10 seconds of freezing for thin lesions.¹² Thicker SKs may require an additional freeze-thaw cycle with cryotherapy,¹² but this is still a shorter process than HP40 application. However, trained non-physician staff can also administer HP40, so practices can develop protocols to maximize application efficiency.

Patient Selection

When choosing a strategy for SK removal, it is important to consider the SK’s location as well as the patient’s skin type and treatment expectations. Based on the finding that HP40 is most efficacious for SKs on the face compared to the trunk and extremities, HP40 may be a good therapy to discuss with patients seeking treatment for SKs in cosmetically-sensitive areas like the face. While additional clinical studies are needed to explore this assertion, HP40 may destroy fewer melanocytes than cryotherapy, meaning that HP40 may be a potentially beneficial therapy for patients with dark skin who are susceptible to pigmentary changes with cryotherapy.⁷ On the contrary, because of the high cost of HP40 and need for repeat treatments, it is likely less useful for symptomatic SKs in non-cosmetically sensitive locations where patients desire rapid relief without as much concern about the cosmetic outcomes.

In terms of pregnancy and lactation risk, topical H₂O₂ is not systemically absorbed. Therefore, application of HP40 during pregnancy or while lactating should not result in exposure of the fetus or breastfeeding infant.²⁴

Conclusion

Given our current options for the treatment of SKs include only more invasive, non-topical therapies, HP40 fills a void in our therapeutic repertoire as the first FDA-approved topical therapy for SKs. However, this therapy has limited efficacy with 1-2 treatments, producing only about 50% clearance per patient.²⁰ Further, HP40 is expensive and can be time-intensive to apply. Nevertheless, considering HP40 produces higher clearance of SKs on the face than other anatomic locations²² and that it may be less cytotoxic to melanocytes than cryotherapy,²³ HP40 may be useful for the treatment of facial SKs. Given 92% of the phase 3 trial participants were FST I-III, further research is needed to explore the risk of pigmentary changes with HP40 in patients of FST IV or higher.

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Conflict of interest:
Dr. Emer has been a consultant for Regen Lab and Eclipse.

Abstract
Platelet-rich plasma (PRP) is an autologous serum containing high concentrations of platelets and growth factors. PRP continues to evolve as an important treatment modality with many applications in dermatology, particularly in the areas of hair restoration, skin rejuvenation, acne scars, dermal augmentation, and striae distensae. Furthermore, combining PRP with laser therapies, microneedling, dermal fillers, and autologous fat grafting produces synergistic effects, leading to improved aesthetic results. Future studies should standardize PRP treatment protocols for specific indications. PRP holds considerable promise in dermatology with therapeutic applications continuing to expand.

Key Words:
acne scars, aesthetic, androgenic alopecia, autologous fat grafting, cosmetic, dermal fillers, dermatology, facial rejuvenation, fractional laser resurfacing, hair restoration, microneedling, platelet rich plasma, PRP, rhytids

Introduction

Platelet-rich plasma (PRP) is an ever-expanding treatment modality that continues to demonstrate considerable promise in the field of dermatology. PRP has long been used in the medical fields of cardiac surgery, oral surgery, orthopedics, and facial plastic surgery, and it continues to develop as a versatile therapy in dermatology. PRP is an autologous serum containing high concentrations of platelets and growth factors.¹ Alpha granules within the platelets are responsible for promoting stem cell regeneration and soft tissue remodeling.² Many fundamental growth factors are contained within the PRP alpha granules, such as platelet-derived growth factors (aa, bb, ab), vascular endothelial growth factor, epithelial growth factor, transforming growth factor beta, and insulin-like growth factor.³ Mitogenesis and differentiation of monocytes, fibroblasts, stem cells, keratinocytes, and endothelial cells occur as a result of PRP alpha granule growth factors.² These growth factors are also known to induce cell proliferation, angiogenesis, and chemotaxis, as well as contain serotonin, dopamine, histamine, adenosine, and calcium, which increase membrane permeability.^2-4

The use of PRP results in improved cosmetic dermatologic outcomes through angiogenesis, neocollagenesis, and adipogenesis.² Applications for hair restoration and skin rejuvenation remain the most highly-supported indications for PRP in aesthetic dermatology (Table 1). Moreover, the use of PRP when combined with other treatment modalities, such dermal fillers, lasers, and other devices demonstrates significant improvements in skin appearance, texture, and tone. There is also emerging potential for the use of PRP with augmented fat injections to enhance fat survival (Figure 1). Although few clinical trials have been performed on the numerous above-mentioned therapeutic options, physicians note enhanced results with treatments combined with PRP versus solo treatment. PRP shows promising uses in the field of dermatology, and more studies are needed to test its validity alone or in combinations for enhancing outcomes.

Harvesting Platelet-Rich Plasma

There are many commercially available PRP systems and kits, and protocols vary according to brand name and treatment indication (Table 2). Traditionally accepted preparations involve initial venipuncture to obtain 10 to 22 mL of whole blood, which is combined with an anticoagulant agent. Centrifugation then separates the whole blood sample into three layers: red blood cells (RBCs), platelet-poor plasma (PPP), and the of-interest PRP layer. Subsequent centrifugations isolate and harvest the PRP layer, while discarding the RBCs and PPP. The now concentrated PRP pellet may be treated with calcium chloride or thrombin to activate the platelets (many harvesting systems do not require activation), releasing alpha granules and growth factors. For the most common dermatological uses, activation is not required, as a more viscous substance (once activated) is better suited for wound healing, post-surgical healing, and orthopedic uses. Activation of growth factors occurs within 10 minutes, with nearly 100% activation occurring within 1 hour.⁵ Some cosmeceutical brands have started to create “customized” skin care products that allow patients’ PRP to be added to a base formulation to complete a bespoke growth factor anti-aging skin care product. However, it is not yet known for how long the activated growth factors remain viable. It is thought that changes in pH and temperature may affect the viability of PRP within a few hours after collection. Current US Food and Drug Administration (FDA) guidelines also indicate that platelets should not be used beyond 5 days after collection, due to bacterial contamination during venipuncture. Nevertheless, patient demand for such autologous customized skin care products remains high.

Commercially Available PRP Harvesting Systems

Eclipse PRP® (Eclipse)

Magellan® (Isto Biologics)

PurePRP® (EmCyte)

RegenKit® (Regen Lab)

Selphyl® PRFM (UBS Aesthetics)

Table 2: Commercially available platelet-rich plasma harvesting systems commonly used in dermatology.

Platelet-Rich Plasma Subtype Families

Platelet concentrations vary per harvest protocol; a platelet count of 1 million/mL is widely accepted as the necessary PRP platelet concentration for therapeutic efficacy.⁶ Moreover, PRP contains plasma at concentrations 2 to 8 times greater than unaltered whole blood.² PRP preparations have been classified into four subtypes: pure platelet-rich plasma (P-PRP), leukocyte platelet-rich plasma (L-PRP), pure platelet-rich fibrin matrix (P-PRFM), and Leukocyte and platelet-rich fibrin matrix (L-PRFM). Aesthetic dermatology indications predominantly use the pure PRP preparation with minimal leukocyte collection.³ The P-PRFM preparation has a lower platelet concentration and includes fibrin. The fibrin matrix created in P-PRFM binds and traps growth factors, releasing them more slowly over several days. This preparation may be used for fat grafting procedures, as it allows for sustained, prolonged release of growth factors within the grafted tissues.⁷

Hair Restoration

PRP has demonstrated significant improvements in hair growth when treating androgenic alopecia (AGA) (Figure 2). PRP growth factors promote hair regrowth by stimulating stem cell differentiation of hair follicles, inducing and prolonging the proliferative anagen phase of hair follicles, as well as activating anti-apoptotic pathways and promoting angiogenesis to increase perifollicular vascularization and the survival of dermal papilla fibroblasts.^2,8-10

A wide array of studies indicates that PRP is a promising treatment for thinning hair.² Both male and female pattern hair loss, as well as alopecia areata, can be improved with PRP. Injections of PRP may be combined with progesterone, dalteparin microparticles, or CD34+ cells. PRP administered with progesterone naturally inhibits 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT). DHT damages hair follicles and is culpable in genetic hair loss. Progesterone inhibits 5-alpha reductase and thus DHT, which allows hair growth to recover. PRP with dalteparin induced significant increases in hair diameter and proliferation of collagen fibers and fibroblasts, along with thickened epithelium and hair follicles due to increased angiogenesis.¹¹ Using CD34+ cells with PRP showed significant improvement in hair thickness and overall presentation.¹²

While some studies reveal minimal improvement in hair restoration, it is hypothesized that inadequate treatment protocols have been used. Studies using an insufficient number of treatments lacked substantial improvements.² Multiple continued treatments with PRP is necessary for significant aesthetic improvement of increased hair density. It is thought that three injections per year is the minimum frequency in order to observe any clinically beneficial result. In clinical practice, most physicians commence with a series of monthly injections until improvement is seen, then continuing with maintenance therapies every 2 to 3 months indefinitely. More research is needed nevertheless to determine proper frequency, dosing, and maintenance. Furthermore, combining PRP injections with other hair restoration treatments, such as finasteride (male patients), minoxidil, low-level light therapy, and spironolactone (female patients), may enhance the overall efficacy. PRP injections may also improve the outcome of hair transplantation and may soon be part of the pre-treatment and post-treatment maintenance protocols. In clinical practice, the author (JE) has found substantial improvement with the use of ACell® (naturally-occurring urinary bladder matrix epithelial basement membrane; MicroMatrix®) and/or human exosomes (placental mesenchymal stem cell and amniotic fluid derived; Kimera Labs, Inc.) combined with PRP in patients with less than substantial improvement with PRP injections alone. Combined with hair transplantation, injectable regenerative therapies have shown improved outcomes in the author’s experience.

Skin Rejuvenation

Several reports demonstrate improvements in traumatic scars and acne scars with PRP treatment. Increases in collagen density and dermal elastic fibers are notable benefits when using PRP in aesthetic dermatology. When PRP is used in combination with other therapies, such as laser treatments, microneedling, and hyaluronic acid fillers, further improvements in skin appearance are achieved (Figure 3). Autologous fat grafting combined with PRP to enhance long-term fat survival has preliminarily shown positive results. Furthermore, cosmetic improvements in striae distensae have been noted when combining radiofrequency, laser, and ultrasound therapies with PRP.

Acne Scars & Traumatic Scars

Multiple studies indicate significant improvement in appearance of acne scars, as well as traumatic scars, when using PRP^13,14 (Figure 4). Cutaneous injuries may result in scar tissue, presenting aesthetic and functional issues. Optical coherence tomography revealed improved acne scar depth when PRP was used with fractional laser therapy, compared to laser alone.³

A decrease in erythema and edema is observed when treating acne scars with PRP. Improved skin elasticity and increased collagen and fibroblasts are also noted when treating scars.¹⁵

Combination Therapies: Lasers & Microneedling

The use of PRP in conjunction with laser therapies and microneedling is increasingly popular in aesthetic dermatology. Fractional laser resurfacing and microneedling treatments create small holes in the skin, which act to enhance uptake and delivery of PRP.² Combining PRP with laser therapies and microneedling procedures improves wound healing and shortens recovery times, as well as reduces erythema and melanin index of treated areas.^14,16,20 Transepidermal water loss (TEWL) and inflammatory hyperpigmentation are also found to be significantly lower when combining PRP with device treatments. Patients treated with PRP after CO₂ or erbium fractional resurfacing have improved skin elasticity, increased fibroblasts, and notably thicker collagen bundles when compared to laser treated sites without added PRP.²⁰ Furthermore, there is anecdotal evidence of improved healing times with PRP combined with laser therapy, as well as earlier granulation, decreased erythema, and improved outcomes.

Dermal Augmentation

Combining PRP with hyaluronic acid-based fillers has been popular and widespread in cosmetic dermatology for several years. The “Vampire Facelift” was coined after combining PRP and dermal fillers; this technique has become well-known via social media. The numerous growth factors in PRP are thought to rejuvenate the skin, improving texture and smoothness, while also decreasing rhytids.^22,23 Hyaluronic acid fillers or other dermal augmentation agents serve as a scaffold to which PRP can bind and enhance skin rejuvenation, as well as enhance soft tissue augmentation² (Figure 5). Lasting cosmetic improvements are seen when treating nasolabial folds, horizontal neck bands, skin homogeneity and tonicity, and facial rhytids with dermal fillers combined with PRP. Studies have also indicated significant improvements in rhytids and skin tone in the infraorbital region.²⁴

Augmented Fat Injections

Combining PRP with autologous fat grafting is thought to bolster survival of the injected fat. Autologous fat injections have gained popularity for facial rejuvenation and dermal augmentation, as the fat grafts are deemed safe and free from potentially transmissible blood-borne pathogens due to the autologous origin of the fat. Pure PRP preparations with a fibrin matrix (P-PRFM) binds and traps growth factors contained within PRP, releasing them more slowly, ensuring prolonged survival of injected fat.⁷ Reports have indicated considerable potential for the use of PRP with augmented fat injections, while some investigations indicate no significant improvement was observed. Patients with HIV-associated facial fat atrophy treated with PRP fat grafting did not experience a significant difference in cosmetic appearance when compared to fat injections alone.¹⁷ However, results from other studies indicate PRP enhances volume retention of injected fat, maintains volume overtime, and reduces revision rates.^7,18,19 In the author’s opinion (JE) there is a substantial improvement in fat viability and retention with the use of PRP in a high enough ratio of PRP to fat; although that “ratio” is not defined based on the current studies in the literature and in practice at least 4-8:1 (fat to PRP) is utilized for a noticeably improved long-term outcome.

Striae Distensae

Continuous stretching of the skin often leads to atrophic dermal scars, known as striae distensae. Reports indicate beneficial cosmetic outcomes when combining intradermal radiofrequency and ultrasound devices with PRP.^21,25 Ultrasound therapies often follow radiofrequency treatments, as ultrasound assists in transepidermal penetration of PRP. Abdominal biopsies posttreatment have indicated increases in collagen density and elastic fibers, and the majority of patients report good or very good improvements in cosmetic appearance of their striae distensae.²¹

Conclusion

PRP continues to evolve as a consequential therapeutic tool in dermatology. Numerous growth factors contained within PRP promote neocollagenesis, angiogenesis, and overall proliferation of stem cells and soft tissue remodeling. PRP is easily harvested from patients’ own whole blood using numerous commercially available systems, making it a safe, in-office procedure. Top evidence-based dermatologic indications for PRP include hair restoration and skin rejuvenation, as well as improvements in acne scars. Moreover, combining PRP with other treatment modalities, such as laser therapies, microneedling, dermal fillers, and autologous fat injections has demonstrated synergistic effects, enhancing overall cosmetic outcomes. The dermatologic community stresses that more studies are needed to further standardize and define PRP protocols beyond anecdotal experience for specific indications.

Acknowledgement

The author gratefully acknowledges the editorial support from Bradford Ferrick in preparing this manuscript.

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Dr. Bryce Cowan says that patients should first consider what changes that they are undergoing, so that they can understand what the surgeon is proposing to address these problems better.

Next, the patient should research the surgeon to ensure that they have the education and experience necessary. Patients should ensure that they have a good relationship and communication with the surgeon as well. Good communication and clarity goes a long way to ensuring a more satisfactory outcome. The patient should feel comfortable with their surgeon.

At the same time, skill and experience is important. The unfortunate reality is that everything will not go exceptionally well all the time. It’s important that surgeons perform when things are smooth, but it’s also important that surgeons are also able to handle the procedure well when things aren’t ideal, and complications occur. There’s a protocol for how to deal with complications and patients and surgeons should discuss these scenarios as well.

Patients should also feel comfortable seeking a second opinion or alternative, and surgeons should not feel offended by this. It’s important for patients to educate themselves more about their concerns as well as possible solutions so patients should feel empowered to learn more. Patients should be wary if a surgeon seems to be wanting to give a hard sell. Cosmetic surgery is patient focused. It’s extremely important that you be educated and comfortable with the procedure. The right time is when you want to go through with it, not when someone else wants you to.

Being cosmetic or elective procedures, these costs are privately paid by the patient. First, there are many factors affecting the cost of the treatment such as the country, state/province, the performing surgeon and their experience or reputation, facility, and of course the type and scope of the procedure or procedures. In general terms, however, Botox and fillers are in the range of hundreds of dollars. These treatments are quite reasonable and are affordable for people even in their 20s and have a wonderful effect on their appearance. At some stage, as the patient ages more and is starting to see other more significant facial changes, they will start requiring multiple syringes of filler for the same effect. As fillers and Botox are temporary, only lasting for 6-9 months, the costs can start to balloon at this point. At this point, a patient may start to consider a more fundamental and lasting correction with cosmetic surgery. This can end up being more cost saving over time as the changes are lasting, and it can address some problems that simply revolumizing with fillers simply cannot change. For younger patients, however, I think Botox and fillers will often serve their maintenance needs better in most cases.

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Patient Research: How Would Patients Choose Their Surgeon?

The first groups of patients that cosmetic surgeon Dr. Bryce Cowan advises against surgery is smokers. Smoking elevates the risks of complications as tissue healing is affected, and there are higher rates of infection, and higher rates of tissue death or necrosis can be expected. Given that the patient is already paying significant sums for a cosmetic procedure,they should want to ensure that all goes well, and it’s not ideal to do it when the risks of complications are this high. However, those patients could become great candidates for cosmetic procedure once they’ve stopped smoking for a significant period of time.

Patients need to be able to both understand and accept the risks of surgery. It’s a balance between their motivation and desire to undergo surgery and their willingness to accept the risks involved with that procedure. Surgery does come with risks, and patients need to weight these out against their desires. Finally, patients should truly desire to undergo surgery of their own accord. Sometimes there are external reasons like their job or their loved ones that drive some people to undergo surgery. In many of these cases, we advise that the patient rethink their decisions and motivations.

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The Cost of Treating Aging Face

The ideal candidate depends on the specific treatment, but in general terms, we are looking at a patient who is a healthy, non-smoker, does not have high blood pressure, does not require anti-coagulants, is in their late 40s or early 50s, where the impact of the surgery is highest.

This person would have a clear appreciation and understanding of what they desire from the procedure, and at the time both understands and accepts the risks that come with the surgical procedure.

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Unfit Candidates for Cosmetic Surgery

Plastic surgeon Dr. Bryce Cowan explains that the main advantage is that cosmetic surgery allows for a more profound and long lasting correction that’s not possible with other treatment options. Treatments are rarely one treatment versus another. Cosmetic surgery is often used in conjunction with treatments like Botox and fillers for maximum effectiveness, as corrections are often multi-faceted.

Another very important point is that the appropriate timing for cosmetic surgery can be critical. Some time between the early 40s to the early 50s is when the face begins to change in profound ways. As changes in the positions of the facial structure and the shape consequently changes, it’s at that point that cosmetic surgery can uniquely provide lasting and impressive change. Many cosmetic surgeons say that there is a “sweet spot” in time, between a person’s early 40s to early 50s that cosmetic surgery has the most profound effect.

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Who Would be the Ideal Candidate for Cosmetic Surgery to treat Aging Face

Patients should assess their age, the changes associated with aging that are taking place, and their willingness to undergo the procedure, and the willingness to take on the risks and potential complications associated with the procedures.

Botox and cosmetic fillers have a good safety profile when used by a trained injector. The cost of these treatments are far lower compared to cosmetic surgery. These treatments typically require ongoing maintenance. Soft treatments are often more popular with a younger age group as the facial changes are typically more minor, and for these types of needs, Botox and dermal fillers are invaluable.

With age, these treatments often become insufficient, although they still provide some value in maintenance. A more profound correction is often needed in the older person to maintain the appearance of youth. It’s at this point when structural changes begin to occur that cosmetic should be considered.

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Advantages of Cosmetic Surgery when Treating Aging Face

What cosmetic procedures might be useful for a given patient? The two key principles of aging of the face are volume loss and tissue malposition. There are many elements changing simultaneously, so it’s very rare that there is an effective singular procedure that can act as a fix all solution.

Early on, perhaps in a patient’s late 20s or 30s cosmetic fillers, Botox and other soft procedures can make great improvements, but at a certain stage, when there is significant change in the shape of the face, only a cosmetic surgery can restore the normal position of the facial structural elements like the fat pads and the tissues before adding back the volume with a filler or Botox. It’s the combination of repositioning through cosmetic surgery, and restoring lost volume through fillers or Botox that optimize the final outcome.

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Botox, Injectable Filler, and Cosmetic Surgery to Treat Aging Face