SKIN AGING: PATHOGENESIS, PREVENTION AND TREATMENT

: Skin aging is a consequence of genetically programmed processes of intrinsic aging and extrinsic aging caused by ultraviolet light and other environmental insults. There are many different approaches to reduce or postpone the untoward effects of intrinsic programmed aging and extrinsic environmental injury. The prevention of extrinsic aging utilizes various methods of photoprotection and antioxidants. Treatments of aged skin are not limited to a single procedure but may consist of a combination of many adjuvant treatments each of which offers different degrees of effectiveness, risk, duration and cost. It is important to have an understanding of the likely benefits and limitations of available treatments. Scientific evaluation and education about the modalities available for treatment of aged skin can help to achieve these goals


INTRODUCTION
The aging process begins at birth and cutaneous manifestations of aging generally begin to be visible in the second decade of life (Oikarinen, 1994).Aging is gradual, but persistent and irreversible and occurs at different rates in individuals.Cutaneous changes associated with aging include decrease of skin elasticity, sagging secondary to gravity, and fat atrophy which result in facial wrinkles and jowls.
The aging process of the skin can be divided into chronological or intrinsic aging and extrinsic aging.Intrinsically aged skin is generally smooth, pale, more evenly pigmented, and finely wrinkled (Chung, 2003).The histologic findings of intrinsic aging include a decrease in the extracellular matrix characterized by reduced elastin and elastic fiber disintegration.In contrast, photoaged skin is sallow, coarsely wrinkled, and associated with irregular pigmentation and telangiectasias (Chung, 2003).Dermatoheliosis is the term used to describe these photoaging-associated clinical changes.Histologically, photoaged skin has an atrophic epidermis, thinned spinous layer, loss of rete ridges, and decreased numbers of Langerhans' cells.There is condensed collagen beneath the basement-membrane zone, basophilic degeneration of deeper dermal collagen, and telangiectasia in the upper dermis.Collagen deficiency in chronically photodamaged skin may result from increased, repetitive degradation of collagen by ultraviolet (UV)-induced matrix metalloproteinases (Chung et al., 2001).
Chronic sun exposure is widely accepted as the principal environmental cause of extrinsic skin aging.Ultraviolet B (UVB) radiation is mainly responsible for sunburn, suntanning, and photocarcinogenesis following sun exposure (Afaq et al., 2005).Ultraviolet A (UVA) is suspected of playing a proportionately larger role in photoaging because of its greater abundance in the sunlight reaching the earth's surface, greater year-round and day-long exposure, and greater depth of penetration into the dermis compared with UVB (Lavker et al., 1995).
Photoaging depends primarily on the degree of sun exposure and skin pigment.Individuals who have outdoor lifestyles, live in sunny climates, and are lightly pigmented will experience the greatest degree of photoaging (Fisher et al., 2002).
Synergistic with sun exposure, cigarette smoking may further contribute to extrinsic aging, particularly in women, with a direct correlation between the number of pack-years smoked and the severity of wrinkling and grayish discoloration (Smith and Fenske, 1996).
Premature aging of the skin is observed in several hereditary disorders and has been associated with mutations of genes that code for proteins involved in repair of DNA damage (Pesce and Rothe, 1996).For example, patients with Cockayne syndrome and Werner syndrome display mutations in DNA helicases.This suggests that decreased DNA repair capacity is associated with accelerated aging and that cellular injury, particularly cumulative DNA damage, plays a major role in the aging process (Furuichi, 2001).Modern society's increasing emphasis on a youthful image and physical beauty has resulted in soaring demand for and resultant development of a wide range of skin care products and procedural interventions for use by the aging population.Available products to prevent aging include sunscreens and antioxidants.The most commonly utilized interventions to "treat' aged skin include topical pharmaceuticals and a wide range of surgical procedures.

Sun Protection
In the absence of adequate protection from the sun, other treatments will be less effective and may even be detrimental.Good protection strategies include wearing broad-brimmed hats, protective clothing, and sun avoidance, particularly during midday hours.In addition, tanning must be discouraged (Stern, 2004).One of the main pharmaceutical approaches to prevention of photoaging is sunscreen.In a randomized trial in humans, the use of a sunscreen with a sun protection factor (SPF) of 29 for two years stabilized histologic changes in the skin, as compared to the placebo group where photoaging-associated changes increased (Boyd et al., 1995).Furthermore, in large multicenter studies investigating topical tretinoin as a treatment for photoaging, patients in the control groups who used only daily sunscreen and moisturizer for 6 months were found to have statistically significant improvement in fine wrinkling, roughness, dyspigmentation, and overall appearance as compared with their own baseline status (Gilchrest, 1996).Avoidance of sun exposure and use of sunscreen also leads to regression of skin pre-cancers, actinic keratoses (Thompson et al., 1993), which indicates the skin has an intrinsic repair capacity.These studies underscore the importance and mandate the inclusion of photoprotection in any treatment regimen.

Antioxidants
Antioxidants are another pharmaceutical approach to prevention and also treatment or reversal of skin photoaging.They neutralize reactive oxygen species generated by ultraviolet (UV) light exposure (Kullavanijaya and Lim, 2005).Substances marketed as antioxidants include vitamins C and E, coenzyme Q10, idebenone, ferulic acid, and cytokinins.Objective evidence to support the role of these substances is available but limited.Fitzpatrick and Rostan (Fitzpatrick and Rostan, 2002) documented statistically significant increased skin hydration, increased collagen production and wrinkle reduction in 4 of 10 subjects who applied 10% vitamin C for 12 weeks.Average improvement on the treatment side was 25% compared to 7.7% on the control side.Biopsies showed increased Grenz zone collagen, and increased type I collagen mRNA.
Topical vitamin E provides photoprotection by both antioxidant and UV absorptive properties (Krol et al., 2000).
Coenzyme Q10 (CoQ10) occurs naturally in human cells and is believed to prevent oxidative stress-induced apoptosis by inhibiting lipid peroxidation in plasma membranes (Baumann, 2004).CoQ10 levels decrease naturally with age as well as with stress and illness.
Idebenone, an analog of CoQ10, and ferulic acid, a plant extract, are recently available antioxidant ingredients in topical formulations.
Cytokinins are plant-growth substances that promote cell division and play a role in cell differentiation (Barciszewski et al., 1999).Most commonly cytokinins are N6-substituted adenine derivatives.Kinetin (N6-furfuryladenine), a cytokinin which is naturally occurring in DNA and cell extracts, retards senescence of plants (Van Staden et al., 1988) and delays age-related changes in human skin fibroblasts in culture (Rattan and Clark, 1994).Studies of the molecular pathways through which kinetin brings about its biological effects have shown that kinetin prevents oxidative damage to DNA (Olsen A et al., 1999) and glycoxidationmediated damage to proteins (Verbeke P et al., 2000).In a 52-week study in 96 subjects with photodamaged facial skin, twice daily application of kinetin improved skin roughness (63%), mottled hyperpigmentation (32%) and fine wrinkles (17%) (McCullough, 1999).Treatments also improved skin-barrier function as measured by a decrease in transepidermal water loss.Extended treatment with kinetin was well tolerated and did not cause clinical signs or subjective symptoms of irritation (McCullough and Weinstein, 2002).
Recent studies have demonstrated that trans-zeatin (6-[4-hydroxy-3-methyl-but-2-enylamino]adenine, a cytokinin isolated from plants (Letham, 1963) and present in the tRNA of a wide variety of organisms (Mok and Mok, 1994) also has gerontomodulatory, youth preserving and anti-aging effects on human fibroblasts undergoing aging in culture (Rattan, 2005).Zeatin and other cytokinins or their derivatives may provide useful compounds with applications in aging prevention, intervention and therapy for the future.

TREATMENT OF SKIN AGING
As noted above, a wide range of treatments are available for aged skin including topical pharmaceuticals, microdermabrasion, chemical peels, botulinum toxin (BTX), soft tissue fillers, dermabrasion, ablative resurfacing, non-ablative light-based rejuvenation, radiofrequency, fractional photothermolysis and traditional cosmetic surgery (Table 1).

Topical Interventions
Topical pharmaceuticals available for treatment of photoaged skin include antioxidants (see above), retinoids and alpha-and beta-hydroxy acids.Of these approaches, only topical retinoids, particularly tretinoin (all-trans retinoic acid), have a welldocumented ability to repair photoaged skin at the clinical, histological and molecular level.

Topical retinoids
A large number of controlled clinical trials have been published demonstrating that the topical application of 0.025% to 0.1% tretinoin (Retin-A ® , Renova ® (OrthoNeutrogena, Skillman, NJ, USA); Avita ® (Mylan Laboratories, Inc., Canonsburg, PA, USA)) improves the appearance of photoaged skin by significantly reducing fine wrinkling, skin roughness, and mild to moderate hyperpigmentation (Kang and Voorhees, 1998).The histologic changes correlating to these clinical improvements include epidermal thickening, increased granular layer thickness, stratum corneum compaction, and decreased melanin content (Gilchrest, 1999).At the molecular level, topical tretinoin has been shown to induce type I and type III procollagen gene expression in photoaged human skin.Because procollagen is the precursor to collagen, it is likely that increased production of procollagen results in increased deposition of collagen (Griffiths et al., 1993).
In addition to tretinoin, another topical retinoid, tazarotene (Tazorac ® )(Allergan, Inc., Irvine, CA, USA), has been approved by the Food & Drug Administration (FDA) for the improvement of fine wrinkles and irregular pigmentation associated with photoaging.In a multicenter, randomized trial evaluating the efficacy of 0.1% tazarotene cream for photodamage, clinically and statistically significant improvements were noted in a variety of skin characteristics (ie, fine wrinkling, mottled hyperpigmentation, lentigines, elastosis, pore size, irregular depigmentation, tactile roughness, and coarse wrinkling) (Phillips et al., 2002).

Alpha-and beta-hydroxy acids
Alpha-hydroxy acids (AHAs) and beta-hydroxy acids (BHAs) are naturally found in foods, including dairy products (lactic acid), fruit (citric acid), and sugar cane (glycolic acid).Hydroxy acids in low concentrations (typically 4 to 12 percent) are components of nonprescription creams and lotions that are promoted as ameliorating the signs of aging.In higher concentrations, these preparations are used as "peels." The topical treatment of photodamaged skin with AHAs results in subtle clinical improvements in wrinkling, roughness, and dyspigmentation within months of daily application (Stiller et al., 1996).Histological improvement has been reported after 6 months of daily applications of products containing 25% glycolic, lactic, or citric acid (Ditre et al., 1996).Bernstein et al. (2001) demonstrated that epidermal and dermal hyaluronic acid and collagen gene expression were increased in skin treated with 20% glycolic acid (twice daily for 3 months) as compared to vehicle-treated controls.

Surgical Interventions
An array of surgical approaches are available for treatment of photoaging.

Microdermabrasion
Microdermabrasion is used to treat individuals with early photodamage and other skin imperfections.The procedure involves using tiny particles of either aluminum oxide, sodium chloride, or sodium bicarbonate crystals directed at the skin through a vacuum tube causing mechanical removal of the superficial epidermis and stimulation of new cell growth.Studies demonstrate small but quantifiable improvements post-microdermabrasion.Shim et al. (2001) evaluated clinical and histopathologic effects of microdermabrasion.In 14 subjects with photoaging, acne, and acne scarring who underwent 6-7 treatments over 12-14 weeks, there was significant decrease in roughness, mottled pigmentation, and enhancement of overall skin appearance but only minimal improvement in rhytides as judged by patient assessment.Microdermabrasion can also be used as an adjuvant therapy to facilitate the efficacy of other rejuvenation procedures including photodynamic therapy (Sadick and Finn, 2005).

Chemical peels
Chemical peels have a long history of safety and efficacy and are relatively easy to perform.Chemical peels are classified as superficial, medium-depth, and deep.Superficial peels cause epidermal injury and occasionally extend into the papillary dermis; medium-depth peels injure through the papillary dermis to the upper reticular dermis; and deep peels injure to the mid reticular dermis.Degree of clinical improvement, length of recovery period, and risk of complications are all proportionate to the depth of tissue injury.Superficial chemical peels, often referred to as "lunch time" peels, are used in the management of mild photoaging.Superficial peeling agents include salicylic acid, glycolic acid, low-dose trichloroacetic acid (10-20% TCA), and Jessner's solution (resorcinol, salicylic acid, lactic acid, and ethanol).In a double-blind, vehiclecontrolled study with 41 subjects, either glycolic acid (50%) or vehicle was applied topically for 5 minutes to one side of the face, forearms, and hands, once weekly for four weeks (Newman N et al., 1996).There was a statistically significant decrease in rough texture, fine wrinkling, number of solar keratoses, and slight lightening of solar lentigines on areas treated with glycolic acid.This corresponded histologically to thinning of the stratum corneum, granular layer enhancement, and epidermal thickening.Some specimens showed increased collagen thickness in the dermis (Newman J et al., 1996).Superficial peeling agents require multiple procedures to obtain results.All of them share the advantages of only mild stinging and burning during application as well as minimal time needed for recovery.However, noted improvements are usually subtle because there is little to no effect on the dermis.Thus, the results of repetitive superficial chemical peels never approach the effect obtained with a single medium-depth or deep peel.
Most medium-depth chemical peels are performed utilizing 35% TCA in combination with either 70% glycolic acid or Jessner's solution (Tse et al., 1996).These latter agents both weaken the epidermal barrier and allow deeper, more uniform, and controlled penetration of the 35% TCA.Medium depth chemical peels can be repeated at 6 months intervals (Monheit, 2001) but frequently one procedure achieves the desired effect.Potential complications include skin discoloration or scarring.
Deep peeling can be achieved with TCA in concentrations above 50% (Matarasso and Glogau, 1991) or a phenol-containing preparation, such as the Baker-Gordon phenol formula (3 mL Phenol, USP, 88%, 2 mL tap or distilled water, 8 drops septisol liquid soap, 3 drops croton oil).The use of phenol results in new collagen formation, leading to wrinkle reduction, but its cardio-toxic profile also increases the procedure's associated risks.Patients with liver and renal impairment can quickly accumulate toxic levels and develop cardiac arrhythmias.Therefore, careful monitoring is required throughout the procedure.Other disadvantages of this procedure include having a longer recovery period and greater risk of adverse effects, mainly permanent hypopigmentation and scarring.

Botulinum toxin
Different strains of the bacterium Clostridium botulinum produce distinct types of botulinum toxins (A,B,C1,D,E,F,and G), all of which block the release of acetylcholine and relax muscles.In 1992, Drs.Jean and J. Alastair Carruthers noted smoothing of the glabellar brow furrow in a patient who had been treated with botulinum toxin injection for blepharospasm (Carruthers and Carruthers, 1992).
Open-label studies and two double-blind, placebo-controlled studies documented the safety and efficacy of botulinum toxin injections (Keen et al., 1994;Lowe et al., 1996) for cosmetic purposes, and in 2002 the FDA granted approval of Botox ® Cosmetic (botulinum toxin type A, Allergan, Inc., Irvine, CA, USA) for "temporary improvement in the appearance of moderate to severe glabellar lines in adult patients 65 or younger".One large randomized, multicenter, doubleblind, placebo-controlled trial of 264 patients found at least moderate improvement in 50 to 75 percent of patients treated for glabellar lines (Carruthers et al., 2002).Improvement was rapid (nearly peak effect by day 7 with a small degree of continued enhancement up to one month post-injection) and effects lasted 3-4 months.Botox ® Cosmetic is the most studied brand of botulinum toxins, although other forms are commercially available.Ipsen Ltd (UK) markets BTX-A in Europe under the brand name Dysport ® and Solstice Neuroscience, Inc.
(San Diego, CA, USA) produces MYOBLOC ® , a formulation of botulinum toxin type B.
The most common use is treatment of dynamic expression lines of the upper third of the face (glabellar brow furrow, horizontal forehead frown lines and periocular "crow's feet" rhytides); however, in recent years, BTX has been increasingly used in the mid and lower face and neck for "bunny lines" (downward radiating lines on the sides of nose), perioral rhytides, dimpled chin, and platysmal bands (Matarasso et al., 1999;Semchyshyn and Sengelmann, 2003).Consensus treatment guidelines were developed in 2004 (Carruthers et al., 2004).BTX can be used alone or in combination with other cosmetic procedures such as soft tissue augmentation and laser resurfacing, to enhance and prolong effects (Patel et al., 2004;West and Alster, 1999).BTX injections are minimally invasive, well tolerated, and do not require a lengthy recovery period.
Side effects are uncommon and generally mild but can include bruising, eyelid & brow ptosis, and headaches (Klein, 2004).Peripheral motor neuron disease is a relative contraindication to treatment because this condition can be potentiated by the toxin.

Soft tissue fillers
Soft tissue fillers (Table 2) are used to smooth and correct wrinkles, non-dynamic furrows, and hollows in the face.Other indications include lip augmentation and replacement of lost subcutaneous fat.Products have previously been categorized as either temporary or permanent (Werschler and Weinkle, 2005).Recently the number of available products has increased greatly and "semi-permanent" fillers have emerged that provide augmentation on the face for 2-5 years (Stegman et al., 1988).

Temporary Products
The below described products last 3-6 months and as such, require frequent re-administration to maintain desired results.While the transient nature of these products can be frustrating to patients, there is the advantage that any adverse effects are also generally temporary.
Bovine collagen products were the first FDA approved fillers and achieve correction for approximately 3 months (Stegman et al., 1988).There are three available forms (Zyderm I ® , Zyderm II®and Zyplast ® , Inamed, Santa Barbara, CA, USA) all of which are derived from the skin of an American cattle herd that is carefully monitored to prevent contamination with prion-mediated disease.Prior to initiating therapy, double skin testing is required to evaluate potential for an allergic response to the products.Localized hypersensitivity has been found in approximately 3% of patients and indicates a pre-existing allergy to bovine collagen (Stegman et al., 1988).The issue of whether injection of collagen is associated with an increased risk of developing connective tissue disease is controversial (Drake et al., 1996).
In the last few years, human-derived collagen fillers (Cosmoderm I ® , Cosmoderm II ® , Cosmoplast ® , Inamed, Santa Barbara, CA, USA; Isologen ® , Houston, TX, USA; Dermalogen ® Collagenesis, Beverly, MA, USA; Cymetra ® LifeCell, Branchburg, NJ, USA) have become available in order to address the issue of hypersensitivity associated with bovine collagen.Skin testing is not required prior to use of these products.
More recently hyaluronic acid (HA) derived fillers have gained favor.HA is a ubiquitous natural polysaccharide produced by many cell types which resides in the ground substance, functioning as a space-filling, stabilizing molecule.HA is reduced in aged skin (Piacquadio et al., 1997).HA's enormous ability to bond water, assists in hydration and provides skin turgor and unlike collagen, it is identical across all species, which minimizes the risk of foreign body reactions (Duranti et al., 1998).Products from non-animal (Restylane ® , Q-Med, Uppsala, Sweden; Captique ® , Genzyme, UK; Juvéderm ® , Inamed, Santa Barbara, CA, USA) and animal derived sources (Hylaform®, Genzyme, UK) are available.HA fillers are well tolerated but have been associated with self-limited mild-moderate swelling, erythema, and tenderness at the implant site, with an average duration of 2 weeks (Duranti et al., 1998).Acne has also been noted.Sensitivity is uncommon but can occur.In 709 patients who were treated with either Hylaform ® or Restylane ® , 3 patients (0.42%) developed delayed skin reactions (Lowe et al., 2001).
A study conducted in 177 patients who received Hylaform ® injections found that a two-thirds level of initial correction was maintained by 78% of patients at 3 months, 44% of patients at 6 months, and 8% of patients at 12 months (Duranti et al., 1998).
Preserved particulate fascia lata from cadavers (Fascian ™ , Fascia Biosystems, Beverly Hills, CA, USA), was introduced in 1999 for use as a soft tissue filler (Schecter and Sadick, 2005).By inducing the production of endogenous collagen, preserved fascia grafts have the potential to produce longer-lasting tissue augmentation (Burres, 1999).Burres followed 81 subjects after implantation of fascia grafts (mostly lip augmentation) and observed effects for at least 3-4 months in all patients.No extrusion, allergic reactions, or infection was observed (Burres, 1999).
Autologous fat transplantation is advantageous because it has no risk of immunologic reaction.Disadvantages include the necessity for two procedures (harvesting and insertion of the fat) and the inability to predict the percentage of graft survival (Ersek, 1991).Potential donor areas with easy access, limited postoperative morbidity, and relative insensitivity to dietary fluctuation include the abdomen, medial knee, and upper outer buttock areas (Drake et al., 1996).Areas of aging skin amenable to autologous fat transfer include the dorsal hands, depressed temples, hollow cheeks, deep nasolabial grooves, and defects caused by lipodystrophy (Drake et al., 1996).

3.2.4.2
Semi-Permanent Products Substances categorized as semi-permanent fillers include poly-L-lactic acid (Sculptra ™ , Dermik, Berwyn, PA, USA) and calcium hydroxylapatite (Radiesse®, Bioform Medical, Franksville, WI, USA).In August 2004, the FDA approved Sculptra ™ for treatment of human immunodeficiency virus (HIV) facial lipoatrophy.It is an immunologically inert polymer derived from lactic acid, which achieves gradual volume enhancement.The precise mechanism is unknown but it may stimulate new collagen production through a normal foreign-body reaction (Werschler and Weinkle, 2005).Its durability is thought to range from 2 to 4 years (Werschler and Weinkle, 2005).
Calcium hydroxylapatite is the principal mineral component of bone.Radiesse ® (formerly known as Radiance ® ) is presently approved in Europe for subdermal augmentation.The product has received FDA approval for vocal cord injection, as a radiographic tissue marker, and for oral maxillofacial defects, but is not presently approved for wider cosmetic applications.Radiesse ® was evaluated in a trial of 64 patients undergoing a total of 101 treatments for cosmetic improvement of a wide variety of facial defects (Sklar and White, 2004).Aesthetic correction was immediate and well-tolerated.The most common complication was palpable, nonvisible nodules reported in 20% of patients who underwent lip augmentation.The longevity of the product is also to be determined.

3.2.4.3
Permanent Products Permanent products do not degrade with time and seemingly have the advantage of long-term correction.Longevity may however be detrimental as long-term complications can occur.Artecoll ® (Europe)/ Artefill ™ (US) (Artes Medical, San Diego, CA, USA) is a solution that contains polymethylmethacrylate (PMMA) microspheres suspended in bovine collagen and lidocaine.Once the collagen is degraded, the remaining inert, non-biodegradable PMMA beads remain intact and provide permanent augmentation.A randomized, controlled, multicenter trial of 251 patients treated with either Artecoll ® or a collagen filler demonstrated significantly greater maintained augmentation with Artecoll ® as compared to collagen at 6 months (Cohen and Holmes, 2004).Twelve month follow-up was obtained for 87% who sustained improvement with Artecoll ® at 1 year (Cohen and Holmes, 2004).
Silicone was used for years as a tissue filler before the FDA prohibited marketing of injectable liquid silicone for cosmetic purposes because of safety issues, including development of potentially severe foreign-body-type silicomas up to 11 years after implantation (Ellenbogen et al., 1975).Monitored clinical trials are permitted.

Ablative Resurfacing Procedures
Ablative resurfacing procedures including dermabrasion, dermasanding and laser skin resurfacing (LSR) injure or remove superficial cutaneous layers resulting in formation of a new epidermis and promoting synthesis of dermal collagen.Dermabrasion uses wire brushes, diamond fraises and serrated wheels attached to a dermabrader to remove the upper layers of the skin while dermasanding uses sand paper.In LSR, collimated light is absorbed by tissue water and converted to heat to precisely remove tissue.Two lasers are commonly utilized: 1) the carbon dioxide CO 2 laser with a wavelength of 10,600 nm; and 2) the erbium:yttrium aluminum garnet (Er:YAG) laser with a wavelength of 2940 nm.Combination devices are also utilized.
The wrinkle reduction and skin tightening potential of ablative procedures is second only to plastic surgery and ablative procedures have an advantage of also improving skin surface texture.Areas most amenable to wrinkle reduction during ablative procedures are perioral and periorbital regions, which are traditionally unresponsive to face-lifting procedures.However, epidermal removal creates an open wound which requires extensive care and puts the patient at risk for the development of infections, dyspigmentation, and scarring.Re-epithelialization occurs over 5-7 days but residual erythema commonly lasts 4 weeks (Gold, 2003) or more.Local anesthesia and sedation, regional nerve blocks, or general anesthesia is generally used secondary to significant intra-operative discomfort.Holmkvist et al. (2000) treated half of the perioral area of 15 patients with a pulsed CO 2 laser and the other half with dermabrasion using a hand engine-drive diamond fraise or a medium-grade drywall sanding screen.Dermabrasion resulted in more bleeding during the immediate post-operative period.Significantly more crusting and initial erythema (up to 1 month post-treatment) was noted on the CO 2 laser-treated side.Both treatment methods resulted in statistically significant improvement in rhytid score.The mean decrease in rhytid score was 1.09 for laser-treated skin and 0.94 for dermabrasion-treated skin but the difference was not statistically significant.Fine wrinkles were more responsive than deep wrinkles with both treatments.

Non-Ablative Light-Based Rejuvenation
Ablative procedures offer significant rejuvenation; however, they are associated with prolonged healing times, potential complications such as scarring, infection, and pigmentary alteration, and moderate discomfort (Fitzpatrick, 1997).As such, non-ablative light rejuvenation systems were developed and are associated with minimal down time and less patient discomfort.

3.2.6.1
Non-ablative Rejuvenation Lasers Non-ablative laser rejuvenation is designed to confine selectively thermal injury, avoiding epidermal injury while achieving fibroblast activation and synthesis of new collagen and extracellular matrix material (Nelson et al., 2002).The skin surface is not removed or modified which minimizes or eliminates downtime but also eliminates any improvement in surface textural and chromatic irregularities.Wrinkle reduction varies with device and technique, but in general, improvement is significantly less as compared to LSR. Kelly et al. (1999) evaluated periorbital rhytid improvement in 35 adults who were given 3 treatments with the 1320 nm CoolTouch ® Neodymium Yttrium Aluminum Garnet (Nd:YAG) laser used in combination with cryogen spray cooling.Small but statistically significant improvements were noted in the mild, moderate, and severe rhytid groups 12 weeks after the final laser treatment.A final assessment performed 24 weeks after the last treatment showed statistically significant improvement only in the severe rhytid group.The procedure was found to be safe, although four sites (5.6%) developed transient hyperpigmentation and two sites (2.8%) developed barely perceptible pinpoint-pitted scars.Subsequent device improvements minimized the risk of adverse effects.

3.2.6.2
Intense Pulsed Light Intense pulsed light (IPL) is a noncoherent filtered flashlamp that emits broadband light in the 500 to 1200 nm range (Raulin et al., 2003).A multi-center study evaluated IPL for non-ablative rejuvenation of 93 patients with photoaged skin (Sadick et al., 2004).Up to five treatments were performed at 4-week intervals with follow-up visits at 4 and 6 months after the last treatment.Patients received full-face treatments with the Quantum SR/HR (Lumenis Inc., Santa Clara, CA, USA) and results were based on physicians' assessments as well as patient satisfaction.Wrinkling score improved significantly by 1.39 and 1.32 units at 4 and 6 months, respectively, correlating to improvements noted for 82% and 75% of the patients at each of these time points.Significant improvement was also seen using the investigators' assessment of overall improvement in facial appearance, which reflected pigmentary, vascular, and rhytid reduction.The first IPL treatment improved overall appearance in 61% of the study population.Number of patients with improvement were 98% and 90% respectively, four and six months after the last treatment.
The use of short-incubation topical 5-aminolevulinic acid (5-ALA) (Levulan ® Kerastick™, DUSA Pharmaceuticals, Wilmington, MA, USA) enhances the effectiveness of IPL for facial rejuvenation, reducing the number of treatments required and enhancing the clinical effects (Alster et al., 2005).A retrospective review demonstrated that one ALA-IPL treatment was equal in efficacy to 3 IPL treatments alone (Carcamo et al., 2005).A variety of lasers, including blue light (405-420 nm), red light (635 nm), and pulsed dye lasers (585 nm), used with 5-ALA photodynamic therapy, have also shown safety and efficacy in photorejuvenation (Gold and Goldman, 2004).Recently, the application of 5-ALA photodynamic therapy with a combined IPL and radiofrequency device has been reported (Hall et al., 2004).

3.2.6.3
Light-emitting diode photomodulation Light-emitting diode (LED) photomodulation is a process which modifies cell activity using low energy light delivered in a specific pattern without thermal effect (Weiss et al., 2005).Weiss et al. evaluated 90 patients after a series of 8 treatments with 590 nm LED photomodulation delivered over 4 weeks.Ninety percent of subjects demonstrated some improvement in skin texture or reduction of periorbital rhytids, erythema or pigmentation.Histologic analysis of biopsies demonstrated a 28% average increase in collagen density and a 4% average reduction of matrixmetalloproteinase (MMP)-1.No side effects or pain were noted.The GentleWaves LED Photomodulation ® System (Light BioScience, Virginia Beach, VA, USA) received FDA clearance for the treatment of periorbital rhytids in 2005.

Radiofrequency devices
Radiofrequency (RF) is a newer skin rejuvenation method which has generated significant interest over the last 5 years.The first radiofrequency device designed for skin rejuvenation was the monopolar ThermaCool TC™ System (Thermage, Inc., Hayward, CA, USA) which utilizes two electrodes on the skin to produce an electric field (Kelly et al., 1999).Ions and charged molecules within the electric field move and/or rotate and inherent resistance to this movement causes heat.The epidermis is protected by a proprietary tip which utilizes cooling spray.The ThermaCool ™ System received 510K clearance for non-invasive treatment of periorbital wrinkles and rhytids but has also been used for cheek, (Alster and Tanzi, 2003) neck, (Tanzi and Alster, 2003) and brow (Fitzpatrick et al., 2003) lifting.
A multicenter study evaluated 86 subjects up to 6 months after a single treatment to the periorbital area with the ThermaCool TC™ System (Fitzpatrick et al., 2003).Objective photographic analysis showed that 61.5% of eyebrows were lifted by at least 0.5 mm.Three independent reviewers noted improvement of at least 1 Fitzpatrick wrinkle score (a 9-point scale) in 83.2% of subjects and fifty percent of subjects were satisfied or very satisfied with periorbital wrinkle improvement.Three patients had small areas of residual scarring at the 6-month follow-up (Fitzpatrick et al., 2003).Subsequent device and technique improvements have significantly reduced the incidence of scarring.Another study demonstrated that 14/15 patients had facial skin tightening induced by the ThermaCool TC™ System.No scarring was noted in this study (Ruiz-Esparza and Gomez, 2003).
The Aurora™ and the Polaris™ WR (Syneron, Inc., Richmond Hill, Ontario, Canada) combine bipolar RF and IPL (Aurora™) or bipolar RF and a 900 nm diode laser (Polaris™ WR) to tighten collagen fibers and reduce wrinkles and pigmentation.Monopolar and biopolar RF have different mechanisms of action and likely different clinical effects.

Fractional photothermolysis
In 2004, fractional photothermolysis (Fraxel™, Reliant Technologies, Palo Alto, CA, USA) was introduced.This novel 1550 nm laser creates localized microscopic treatment zones (MTZs) of thermal injury in the skin which are surrounded by zones of normal tissue, limiting damage and allowing more rapid recovery (Manstein et al., 2004).MTZs typically have a diameter of 100 m and penetrate 300 m into the skin.In one study, periorbital treatment of 30 subjects using moderate MTZ density (pattern density with spacing of 250 m or more) improved wrinkle score by 18% at 3 months, and histology revealed enhanced undulating rete ridges and increased mucin in the papillary dermis.The procedure was also well tolerated, with minimal erythema and edema.The study concluded that both efficacy and side effects are dependent on the shape and location of individual MTZs and on the pattern in which the MTZs are arranged (Manstein et al., 2004).Rokhsar et al. (2005) evaluated 12 patients who received 4-5 Fraxel™ treatments to rhytids of the face, neck, or chest at 1-4 week intervals.Improvement was seen in texture, dyschromia, and wrinkles, and biopsies demonstrated new collagen formation.Side effects were minimal and were limited to post-treatment erythema lasting a few days, mild edema, and small linear abrasions which healed uneventfully.

Cosmetic surgery
The greatest improvement in wrinkles and skin laxity can be achieved with cosmetic surgery.Natural-looking appearance enhancement is the goal which can be achieved through a variety of procedures including face-lifts, brow lifts and eyelid surgery.Enhanced effect is accompanied by increased risk and prolonged recovery.A more thorough discussion of plastic surgery options is beyond the scope of this manuscript, but it is useful to note that endoscopically-assisted cosmetic surgery reduces invasiveness and minimizes recovery time.

CONCLUSION
An array of topical and procedural treatments are available to benefit the aging face.Perhaps the optimal method lies in a combination of treatments which are complementary and can together achieve an enhanced result.Patients need to be aware that there are no "quick fixes" or "miracle cures" and that use of cosmeceuticals, medications, and certainly performance of any procedure, is associated with some risk.Anyone seeking treatment for the aging face should be informed about their options in order to determine the best approach which will meet their needs and goals.

Table 1 .
Treatments for Skin Aging