Photodamage to the skin is due to extrinsic, ultraviolet radiation (UVR). There are currently two theories about aging: the first maintains that aging is genetically pre-determined,1 while the second suggests that aging is
related to the cumulative effects of environmental damage.2,3 Our perception of a person’s age and beauty mainly depends on the appearance of his or her skin.

Photoaging—Clinical and Histological Features

The clinical features that are associated with photodamage include dyspigmentation, laxity, yellow hue, wrinkling, vascular ectasia, thickened skin, and malignancies. In contrast, intrinsically aged skin shows signs of laxity, skin sagging, and wrinkles, but lacks evidence of UV damage. Histologically, photodamaged skin has undergone changes termed ‘heliodermatitis.’4 These changes include increased fibroblasts, flattened dermo-epidermal junction, atrophy, inflammatory infiltration, disorganized collagen fibers, and accumulation of amorphous elastincontaining material.2,5,6 Glogau classified photoaging into four types (see Table 1). Type I patients
with early photoaging are in their 20s to 30s and experience mild pigmentary changes, but no rhytides. Type II patients have moderate photoaging and are in their 30s to 40s, and have dynamic wrinkling and
dyspigmentation. Type III patients have advanced photoaging and are typically in their 50s. They have wrinkles at rest, dyschromias, vascular ectasias, and visible keratoses. Type IV patients have severe photoaging.
Generally, they are in their 60s to 70s, but may be younger. They have wrinkles covering the majority of the face, thickened coarse skin, a yellow-gray skin color, and a history of cutaneous malignancies.
Photodamage—Biology
There is evidence that reactive oxygen species (ROS) formation in response to UVR leads to photodamaged skin. Levels of antioxidants and enzymatic protection decline with age.7 Both UVA and UVB cause photodamage. UVB induces DNA mutations with subsequent carcinogenesis. UVA is believed to induce ROS, mitochondrial DNA damage, and carcinogenesis, and contributes to the aging process.8,9 The other biological effects of photodamage include dyschromias, such as lentigines and guttate hypomelanosis.2 Sunburn as a result of UV exposure is thought to be induced by nuclear factor-kappa B (NF-κB) pathways. UVR induces angiogenesis by increasing vascular endothelial growth factor (VEGF) production. An extremely important biological effect of UVR is immunosuppression—both local and systemic. After UVR exposure, Langerhan cells are depleted from the epidermis,10 which prevents the immune system from fighting photodamage.

Intrinsic Protection Against Photodamage
There are various responses and mechanisms utilized by the skin to counteract or reduce photodamage. Melanin production and distribution provide a protective mechanism against photodamage, as is evidenced by
a comparison of black and white skin, which have different levels of response to UVR exposure. UVR exposure induces protein (p)-53, which participates in the repair process, halting the cell cycle in the G1 phase
for DNA repair.11 There are conflicting reports regarding the role of tissue inhibitors of metalloproteinases (TIMP) after UV exposure. Human skin possesses antioxidants such as vitamin E, co-enzyme Q10 (CoQ10),
ascorbate, carotinoids, and enzymatic antioxidants such as superoxide dismutase, catalase, and glutathione peroxide. These antioxidants are  depleted as a result of excessive UVR exposure.12

Treatment Options for Photodamage
The treatment options for photodamaged skin can be categorized into a disease-prevention-based paradigm (see Table 2).13 Primary prevention refers to the reduction of risk factors before a disease has occurred.
Secondary prevention includes early detection, prevention, postponement, and attenuation of a clinical condition. Tertiary prevention is the treatment of an existing disease.

Photoprotection
Sun protection is both a primary and a secondary preventive measure  against photodamage. Sun protection can be achieved by the use of protective clothing, hats, sunglasses, etc. Photoprotective clothing is measured by its ultraviolet protection factor (UPF) value. For example, a clothing item with UPF 40–50 protects by transmitting only 2.6% of effective UVR.14 Sunscreens are designed to protect against UVB 290–320nm, UVA 320–400nm, UVC <290nm. The deeper penetrating UVA rays are mostly responsible for photoaging, while UVB rays are more responsible for photocarcinogenesis. In studies, sunscreens with both UVA and UVB protection have provided better protection than sunscreens with only UVB filters.
Sunscreens have different formulations worldwide (see Table 3). The ideal agent should be cosmetically pleasant, non-toxic and non-allergenic, effective against both UVA and UVB, photostable, and water-resistant.
Sunscreens have traditionally been divided into chemical or organic sunscreens that absorb UVR and convert it to heat, thus preventing UV interaction with skin. Sunblocks or inorganic agents have particles that reflect photons away from skin. UVB-absorbing sunscreens include p-aminobenzoic acid and its esters (padimate A and O), the cinamates, and salicylates. UVA sunblocks contain titanium dioxide and zinc oxide, and UVA-absorbing sunscreens include avobenzone (Parsol® 1789). Titanium dioxide provides excellent UVA II protection, but is less effective for UVA I. Parsol 1789 and zinc oxide have good UVA I protection, but lack UVA II protection.15 There are newer products on the market such as Mexoryl® and Helioplex™. Mexoryl has been shown to decrease DNA damage and instability in the melanocyte layer by reducing the formation of free radicals. It has also been shown to reduce the p53 mutations caused by UVA radiation.16 The new chemicals being developed provide efficient UVA coverage and better photostability.
Retinoids
Albert Kligman first reported the beneficial effects of tretinoin on photoaged skin of middle-aged women undergoing treatment for acne.17,18 Statistically significant improvement was noted in their appearance, surface roughness, fine and coarse wrinkling, mottled pigmentation, and sallowness in a clinical trial.19 Epidermal acanthosis and hypergranulosis regressed within the first 12 months of therapy.
Improvement of wrinkling corresponded to increased papillary dermis collagen deposition.21 Tretinoin treatment also appears to reverse histological changes of aging both in vivo and in vitro.

Tazarotene has also been shown to reduce roughness, wrinkling, mottled pigmentation, and pore size. There is convincing evidence that topical tretinoin repairs mild to moderate photodamage.
Antioxidants
Many studies have established a link between the application of topical antioxidants and the treatment of photoaging. These studies are small and most of the changes are considered to be associated with use of the antioxidant, and may not be statistically significant (p<o.05). Topical vitamin C has been shown to reduce erythema and sunburn cell formation. Vitamin C upregulates collagen and TIMP synthesis in human skin.22 CoQ10 is part of the mitochondrial electron transport chain. Topically applied, it has been shown to reduce wrinkles23 and is a potent antioxidant.
Oral soy isoflavinoids enhance the endogenous anitoxidant enzymes. Genistein and N-acetyl cysteines reduce collagenase upregulation after UV exposure. Gluconolactone has antioxidant properties and alphahydroxy
acids (AHA)-like effects. When taken orally, green tea propophenols inhibit metalloproteinase expression after UV exposure.
N-furfuryladenine is a synthetic plant growth hormone with antioxidant properties.24 The list grows daily and has led to a booming cosmetic industry known as ‘cosmeceuticals.’
Growth Factors and Cytokines
A fructose-rich polysaccharide, ‘FROP3,’ increased glycosaminoglycan  synthesis by fibroblasts.25 In a pilot study, a cream containing FROP3 showed a 10–15-year decrease in apparent age after four weeks of use.

Chemical Peels

Chemical peels with AHAs, salicylic acids, trichloracetic acid, and phenol are used to treat photodamage and mottled pigmentation. The peels are classified as superficial, medium, or deep correlating to the depth of
injury induced.27 Glycolic acid is an AHA that reduces fine wrinkling.  It has also been shown to thin the epidermis and induces dermal collagen synthesis.

Cutaneous Resurfacing Techniques
Microdermabrasion
This process exfoliates and ablates the superficial dermis. Microdermabrasion activates a closed, dermal wound-healing process and increases cytokines, matrix metalloproteinases (MMPs), and type I procollagen messenger (m)-RNA production.29 Significant increases in papillary dermal thickness and improved elastin organization have been observed.

Lasers, Light Sources, and Radiofrequency Devices
Ablative Laser Systems
These systems include CO2 lasers and erbium-yttrium aluminium garnet (Er:YAG) lasers. The CO2 laser was once the gold standard in facial resurfacing, and can produce dramatic improvements in skin tone, wrinkle severity, and atrophic scar depth.31–34 The Er:YAG was developed to reduce the morbidity associated with CO2 and has demonstrated comparable results. The biochemical changes seen with ablative resurfacing include increased interleukin (IL)-1β, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, type I and III procollagens, and MMPs.
Non-ablative Laser Systems
Treatment of photodamaged skin with non-ablative lasers has become increasingly popular and effective. These devices induce target-specific rejuvenation and non-ablative skin remodeling. The targets are three-fold:
reduction in vascular anomalies, pigment anomalies, and static fine wrinkles.36–38 Various lasers systems have been used for this purpose and will be briefly discussed. Hemoglobin is the primary target, and melanin or
pigment the secondary target, of 532nm lasers. The main benefit is for facial telengiectasis, but it is also good for lentigines and tattoos.
Flashlamp pulse dye (FPD) lasers are the gold standard for vascular lesions, and operate at 585nm/595nm. Success with dermal remodeling has recently been reported.40 The current trend is to use the longer wavelength of 595nm for less severe vascular bruising. Cooling is accomplished by a dynamic cooling device, e.g. the Candela V Beam™, the Cynosure V Star, or the NLite laser.40–43 Quality-switched (QS) lasers deliver an ultra-short pulse duration, which is critical for target disruption. Primary wavelengths used are 532, 694, 755, and 1064nm. The first three treat vascular and pigmented lesions, and the fourth treats dermal pigments such as tattoos and melanin. The QS 1064 has shown efficacy in dermal collagen deposition and remodeling.44,45 Long-pulsed (LP) near-infrared lasers include the LP 755, 800, and 1064nm models. They target hemoglobin and melanin. If cooling is inadequate, it can lead to full-thickness scar formation.46 LP mid-infrared lasers do not cause melanin or hemoglobin absorption; instead, they target water. New collagen synthesis without epidermal damage has been reported.47–49 The devices include Cool Touch® 1320nm neodymium-doped (Nd):YAG, Candela Smoothbeam 1450nm Diod laser, and Aramis 1540nm Er:Glass laser.

Broadband Light Sources
Broadband light sources are versatile and have proved to be effective clinically and histologically,49–52 and the intense pulsed light (IPL) version is the most studied.53–55 These devices emit light of 515–1200nm that can
be manipulated with various filters. Photothermolysis is obtained via absorption by deoxyhemoglobin, the chromophore at 600–750nm. IPL systems can achieve photorejuvenation by improving mottled pigmentation, telengiectasis, and skin texture. The data also support long-lasting effects of up to five years.56 It is anticipated that after three to five treatments improvement in pigment, vasculature, pore size, and fine wrinkles will occur. Examples include Lumenis Quantum, DDD  Ellipse, Palomar Medilux™, and Starlux®. Fractional Photothermolysis A hybrid novel technology combining ablative and non-ablative resurfacing is fractional photothermolysis. The technique has been validated by many studies and supporting results.57 A mid-infrared laser at 1550nm is used with vertical microthermal columns of 100–160μm width, which can be adjusted for 300–700μm penetration.58 The pixilated laser leaves 70% of the treated area undamaged and promotes rapid healing. There is a reported patient-to-patient consistency in collagen remodeling and epidermal regeneration. Examples include the Reliant Fraxel® Laser, Palomar’s Star Lux, and Cynosure’s Affirm.
Radiofrequency and Infrared Heating
The first non-surgical treatment to address the soft-tissue redundancy has been radiofrequency (RF) with Unipolar RF (ThermaCool TC, Thermage, Inc., Hayward, California).59–62 RF does not target a specific  hromophore; instead, it produces controlled volumetric heating of the deep dermis with subsequent collagen degeneration and tissue shrinkage. Unipolar RF carries a risk of subcutaneous atrophy. More recently, bipolar radiofrequency has been used. Syneron’s Aurora is a widely used bipolar device.

Photomodulation
Photomodulation utilizes non-thermal neo-collagen synthesis. Most widely used are light-emitting diodes (LEDs) such as Gentlewaves® 590nm LED (LightBioScience LLC, Virginia). LED treatments are administered
immediately after fraxel or photorejuvenation treatment.

Soft-tissue Augmentation by Fillers
Restoration of facial volume and contour by fillers has become a popular and effective treatment of photoaged skin. Fillers are used to either correct pre-existing defects or augment existing facial structures. There is a plethora of available filling substances and the choice of the filling material depends on many factors.
Autologous fat is one of the oldest fillers and is still widely used. Its advantages include high volume, ease of use, and low cost, and, being autologous, it causes no reactions. Fat is excellent for nasolabial folds, marionette lines, and cheeks. It is transplanted to the face after being harvested from another region of the body, such as the abdomen or thighs.
Bovine collagens have been available for many years, e.g. Zyderm I, Zyderm II, and Zyplast. They have been used for depressed scars, nasolabial folds, and lips. Two of the disadvantages are adverse reactions and a need for skin tests prior to administration.
Synthetic human collagens are available i.e. CosmoDerm I® and CosmoPlast®, and the advantage is avoidance of reactions. All collagens are limited by longevity, and rarely persist six months after injection. They can
be used for many sites, but are most often used for lip augmentations. A new collagen called Evolence™ promises one-year longevity.
Hyaluronic acid (HA) materials are derived from rooster combs or bacterial sources.63 They are less immunogenic than other methods, as HA is identical across species. It is a naturally occurring polysaccharide, and is the most plentiful glycosaminoglycan in the dermis. It is negatively charged, and able to hold large amounts of water. Compared with bovine collagen, no signs of incompatibility are noted in HA products.64 These products last for six to 12 months and undergo isovolumic degradation. There are no skin tests required, and there is no overcorrection with the injections. Many products are available, including Hylaform®, Achyl®, Restylane®, Dermalive®, Perlane®, Hyacell®, Juvederm®, and Viscontour®.
The products are used for various conditions such as facial rhytides and contouring, nasolabial folds, patulous scars, and lip volumization. These products are not suitable for dynamic rhytides, ice-pick scars, striae, or actinically damaged lips. Absolute contraindications include
hypersensitivity, history of anaphylaxis, and implantation for breast, muscle, bone, and tendon augmentation.
Long-lasting filler agents include Sculptra™ (containing poly-L-lactic acid), Radiesse® (calcium hydroxylapatite), and silicon. Sculptra is approved by the US Food and Drug Administration (FDA) for treating HIV-lipoatrophy for high-volume correction of the face, and it is easy to use. Often, several treatment sessions are required to obtain the desired effect. Radiesse is approved by the FDA for facial rhytids in the nasolabial folds. It is similar to HA in many ways, but the injection technique is slightly deeper. Radiesse is not yet recommended for injection into the lips.
Photodynamic Therapy
Actinic keratosis (AK), a pre-malignant condition, is a feature of chronically
photodamaged skin. Topical photodynamic therapy (PDT) with aminolevulonic
acid (ALA) (Levulan Kerastick®, DUSA, Wilmington, Massachusetts) and
methyl-aminolevulonic acid (MAL) (Metvix®, Galderma, Watford, UK) is an
effective treatment option for AK and also offers excellent cosmesis.65
Recent studies show that PDT induces photochemo-rejuvenation of some
manifestations of photoaging. Both ALA and MAL have been used in
conjunction with blue light, IPL, and other laser wavelengths for
treatment of AK. Many of the studies have also shown other benefits of
PDT for photodamaged skin, including improvement in skin texture,
global quality, fine wrinkling, and sallowness.66 In recent studies,
ALA–IPL–PDT has shown superiority over IPL alone in reducing mottled
pigment and fine wrinkles.67 Clinical findings indicate that Levulan with
blue light and Metvix with red light induce a high clearance of AKs, as
well as improved fine wrinkles, texture, and sallowness, whereas IPL–PDT
assists in improving telengiectasis and erythema.68 So far, the mechanism
of action of PDT in photochemo-rejuvenation is largely unknown.

Botulinum Toxin A
In 2002, botulinum toxin A was approved by the FDA for treatment of glabellar lines. The toxin blocks the post-synaptic release of acetylecholine, thereby inhibiting muscle contraction. Botulinum toxin does not directly
reverse photodamage, but delivers a rejuvenated look by relaxing muscles causing dynamic wrinkling of the face. The effect typically lasts for between three and nine months.

Fluorouracil and Imiquimod
Both fluorouracil (5-FU) and imiquimod have been successfully used to treat AK, Bowen’s disease, and superficial basal cell carcinomas. All of these conditions are as result of UV photocarcinogenesis and a part of chronically photodamaged skin. The treatments of AK result in excellent cosmesis and prevention of skin cancers.
Conclusion
Effective treatment of photodamage is complex. Cosmetic treatments often target complaints of discoloration or wrinkling. Medical treatments target carcinogenesis. The number of healthy older patients is increasing
and thus the demand for better, longer-lasting treatments is on the rise. It is an exciting time in the field of treatment of photodamage.

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