It is important for dermatologists to recognize patients at an increased risk of skin aging early enough to initiate countermeasures. “Wrinkle-prone” skin types can be identified easily through use of the Baumann Skin Type Indicator Questionnaire.1 The wrinkle-prone Baumann skin type is associated with age or with lifestyle factors that increase the risk for promoting skin aging.2 Prevention and treatment of numerous signs of cutaneous aging can be achieved through consistent daily use of oral and topical products suited to the identified specifically wrinkle-prone Baumann skin type.
Because patient compliance is well known to be challenging, patient education is a key element of achieving positive outcomes with treatment regimens.3 This month, the column discusses the causes of aging with a focus on the cells involved in the process and ways to prevent and treat two major causes of skin aging – damage to DNA and mitochondrial DNA. Next month will discuss other causes, as well as oral and topical treatments for skin aging. The goal is to help clarify the science and marketing claims of skin care technologies targeted at treating skin aging.
The numerous causes of skin aging can be divided into two broad categories: intrinsic and extrinsic. Intrinsic aging results from cellular processes that occur over time and is influenced by genetics. Such aging is characterized by decreased function of keratinocytes and fibroblasts, intra- and extracellular accumulation of by-products, reduced function of sirtuins (proteins that regulate cell metabolism and aging), mitochondrial damage, and loss of telomeres.
Extrinsic aging results from environmental exposures that engender cell damage, including UV light, infrared and radiation exposure, air pollution, smoking, tanning beds, alcohol and drug usage, stress, and poor diet. Extrinsic aging occurs as a result of intersecting processes caused by free radicals, DNA damage, glycation, inflammation, and other actions by the immune system. Generally, these factors can be partially mitigated through behavioral change. As much as 80% of facial aging can be ascribed to sun exposure.4 Several mechanisms through which sun exposure promotes aging have been well characterized. DNA damage results when UV light induces covalent bonds between nucleic acid base pairs and forms thymine dimers, which can alter tumor suppressor gene p53 function, thereby increasing the risk of cutaneous cancers and aging.5 UV exposure also yields free radicals that create damaging oxidative stress,6 which can activate the arachidonic acid pathway resulting in inflammation.7 Other skin aging mechanisms are not as well understood.
The cellular role in aging: Keratinocytes and fibroblasts
Keratinocyte cells found in layers that resemble the brick-and-mortar structure of a brick wall compose the epidermis. Each epidermal layer exhibits specific functional roles and characteristics. The top layer of the epidermis, known as the stratum corneum, is notable because it forms the skin barrier. This protective barrier contains cross-linked proteins for strength, antioxidants to protect the cells from free radicals, a bilayer lipid membrane layer to prevent water evaporation from the cells surface, immune cells, antimicrobial peptides, and a natural microbiome. Damage to any layer of the epidermis can unleash a cascade of events that can lead to increased cutaneous aging.
The dermis is composed of fibroblast cells, which synthesize collagen, elastin, hyaluronic acid, heparan sulfate, and other glycosaminoglycans that keep the skin smooth, strong, and healthy. Collagen confers strength, elastin provides elasticity, and the glycosaminoglycans such as hyaluronic acid, heparan sulfate, and dermatan sulfate bind water, impart volume to the skin, and provide support for important cell-to-cell communication.
When keratinocytes and fibroblasts age, they may no longer respond to cellular signals such as growth factors. The primary aim of any antiaging skin care regimen is to protect and rejuvenate these key skin cells.
Cellular damage that contributes to skin aging
The accumulated damage from intrinsic and extrinsic factors yields keratinocytes and fibroblasts that fail to produce important cellular components as well as they did when they were younger. Cellular factors that age cells include nuclear DNA damage, mitochondrial DNA damage, diminished lysosomal function, structural impairment of proteins, and damage to cell membranes. This harm occurs because of the direct effects of UV radiation, pollution, toxins, free radicals (oxidation), glycation, and inflammation.
Preventing and treating DNA damage
DNA damage presents as thymine-thymine dimers, pyrimidine-pyrimidine dimers, impaired telomeres, or other mutations. Broad-spectrum sunscreens and sun avoidance are important steps in preventing DNA damage induced from exposure to UV radiation. Other cosmeceutical agents have been designed to hinder the effects of UV radiation or to foster DNA repair. Besides sunscreen, the key members of the dermatologic armamentarium against DNA damage are various antioxidants. Data have been gathered over the last few decades that support the protective effects of antioxidants such as polypodium leucotomos,ascorbic acid, and green tea. Other antioxidants are associated with less data, but hypothetically should deliver similar benefits.
Polypodium leucotomos (PL), an oral extract derived from ferns, has been demonstrated to display photoprotective effects at an oral dose of 7.5 mg. PL has consistently exhibited antitumor and skin protective effects.8 A 2004 study in humans revealed that two oral doses of PL contributed to a significant reduction in DNA damage after UV exposure,9 and a 2017 study showed that PL protected skin DNA from UVB.10 Although PL has been linked to topical benefits, it is the oral form that is most often used to protect skin.
Ascorbic acid, also known as vitamin C, has been amply demonstrated to confer benefits when given both orally and topically. An acidic environment is necessary for optimal absorption. Topical application of ascorbic acid, along with vitamin E and ferulic acid, has been demonstrated to decrease the formation of thymine dimers.11 Unlike other antioxidants, ascorbic acid also stimulates procollagen genes in fibroblasts to increase collagen synthesis.12
Niacinamide, also known as nicotinamide, is an integral part of the niacin coenzymes nicotinamide adenine dinucleotide (NAD+), nicotinamide adenine dinucleotide phosphate (NADP+), and their reduced forms NADH and NADPH. These contribute to DNA production and repair and are involved in multiple other important enzymatic reactions. Topical niacinamide has been demonstrated to play a role in DNA repair13 by providing cells with the energy that the DNA repair enzymes need to unwind the DNA strand, replace the nucleosides, and rewind the strand. Specifically, niacinamide is known to enhance DNA excision repair and repair of UVB-induced cyclobutane pyrimidine dimers and UVA-induced 8-oxo-7,8-dihydro-2´-deoxyguanosine.14 Niacinamide is used topically because oral forms of niacin have been found to provoke flushing.
EpiGalloCatechin-3-O-Gallate (also known as EGCG), the primary active constituent of green tea, has been demonstrated to induce IL-12 to increase the production of enzymes that repair UV-induced DNA damage.15 The proven photoprotective effects of topical and oral green tea include reducing UV-induced erythema, decreasing sunburn cell formation, and attenuating DNA damage.16
Preventing and treating mitochondrial DNA damage
UV radiation elicits mitochondrial DNA damage known as the “common deletion.”17 Damaged mitochondria produce harmful free radicals known as reactive oxygen species. Mitochondria damage caused by ROS decreases the mitochondria’s ability to generate ATP energy, which is necessary for DNA repair and other cellular processes.
Free radicals and UV radiation damage mitochondria, as does normal cellular metabolism. The range of damage includes mitochondrial DNA impairment, loss of mitochondrial enzymes, and decreased ATP production. This leads to less energy for DNA repair and other reparative processes. While there is no established way to reduce mitochondrial damage once it has occurred, several research initiatives to achieve this end are underway. Currently, protecting the mitochondria from harm with sunscreens and antioxidants is the best option.
Antioxidants are effective in preventing the damaging effects of free radicals on vulnerable mitochondria. As a component of the mitochondrial respiratory chain and an antioxidant itself, coenzyme Q10 is particularly useful in this role. CoQ10 is available in both oral and topical formulations. Oral forms should be taken only in the morning because of a caffeine-like effect. Topical forms of CoQ10 have a dark yellow color that may be unappealing to patients. Polypodium leucotomos has been shown to lower the number of common deletions found in the mitochondria of irradiated keratinocytes and fibroblasts.18 The oral form is recommended. Another potent antioxidant, curcumin, is being studied for mitochondrial protective properties.19 Its strong yellow color and smell render it better suited for oral use although many companies are trying to develop cosmetically elegant topical formulations.
Scavenging free radicals
Ultraviolet light, pollution, and other insults engender free radical formation. Even sunscreen use has been linked to increased production of free radicals. Free radicals, also known as reactive oxygen species, harm cells in many ways including mitochondrial damage, DNA mutations, glycation, lysosomal damage, and oxidation of important lipids and other cellular components such as proteins. Antioxidants present various beneficial effects including scavenging free radicals, decreasing activation of mitogen-activated protein kinases, chelation of copper required by tyrosinase, and suppression of inflammatory factors, such as nuclear factor (NF)-kB.20. Antioxidants are essential in preventing aged skin.
In summary, skin aging has many causes. Although they are not all understood, some of the processes have been elucidated. Next month, this column will focus on the prevention and treatment of inflammation and glycation, as well as reversing the effects of aging on skin cells.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014). She also wrote a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.
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