Prevalence

Skin ageing that is of sufficient concern for people to seek treatment is increasing annually. According to the American Society of Plastics Surgeons, about 16 million people underwent minimally invasive cosmetic procedures in the US in 2019, an increase of 2% from 2018, and an exponential increase of 3181% since 1992 (ASPS 2019). This increased demand for treatment to address skin ageing is reflected in society's emphasis on youth and beauty.

Psychosocial implications

Advancements in medical science and improvement in socioeconomic status have resulted in an increase in life expectancy. This means that individuals are now exposed to environmental factors over a longer time, allowing cumulative damage to occur. Some consider the visible changes of skin ageing as cosmetically unappealing, leading to increased demand for topical treatments and procedures that have rejuvenating effects on the skin. Furthermore, there are psychological implications associated with skin ageing due to societal emphasis on a youthful appearance. Increasing numbers of individuals are becoming concerned about skin ageing, and in some cases, this can lower one's self‐esteem and confidence, leading to issues with interpersonal relations (Gupta 1996).

Causes and risk factors 

There are multiple factors leading to skin ageing (Farage 2008; Dupont 2013). The prevalence of skin ageing is dependent on intrinsic factors, such as increased age, gender, amount and type of skin pigmentation, as well as extrinsic factors such as smoking status and exposure to UV radiation (Tsukahara 2004; Oldenburg 2013). In general, the less pigmented the skin, the greater the risk for skin ageing and other sun‐induced conditions including skin cancer (Richmond‐Sinclair 2010). Skin ageing is observed more often in individuals with a lower amount of pigmentation (Table 1; Dobos 2015). Unlike intrinsic ageing, extrinsic ageing may be ameliorated by avoidance of modifiable factors. Excessive exposure to UV radiation is the most significant factor, which leads to sunburn and suppression of cellular immunity in the short‐term, and skin ageing and skin cancer in the long‐term (Dupont 2013; Marmon 2014). Smoking status is linked with facial wrinkling in both genders (Chung 2001; Manríquez 2014). Cigarette smoking is postulated to decrease capillary and arteriolar blood flow in the skin, damaging connective tissue components that are important to maintain skin elasticity (Grady 1992; Oldenburg 2013). In postmenopausal women, oestrogen deficiency is an important contributory factor for wrinkles (Thornton 2013), while in men, skin ageing is associated with outdoor occupations and outdoor activities due to prolonged and repeated UV radiation.

Clinical manifestations

Intrinsic and extrinsic skin ageing are associated with different characteristic clinical features. The overall appearance is related to the relative contribution of environmental factors imposed on the natural changes related to intrinsic ageing (Benedetto 1998). Clinical features of intrinsically aged skin include smooth texture, skin atrophy, loss of elasticity and fine wrinkles (Gilchrest 1996). Clinical features of extrinsically aged skin include rough texture, loss of elasticity, telangiectasia, elastosis, irregular pigmentation and coarse wrinkles (Yaar 2002). Facial areas most susceptible to skin ageing include the eyelids, forehead, corner of the mouth, cheek, glabella and the nasolabial groove (Nouveau‐Richard 2005). The rate of UV radiation‐induced skin ageing depends on the balance between the frequency, intensity and duration of exposure and the natural protection by skin pigmentation (Kammeyer 2015).

Pathophysiology

At the cellular level, skin ageing from sun damage results in irregular thickening of the stratum corneum, epidermal thinning, collapsed fibroblasts, reduced basal cell division and reduced levels of glycosaminoglycans (GAGs), resulting in decreased moisture retention in the epidermis and dermis, reduced and fragmented collagen and elastin resulting in skin fragility, loss of elasticity, and lines and creases in the skin (Thibault 1998; Katz 2015). Microscopic changes include atypical epidermal cells, skin thinning and atrophy, elastosis, increased melanogenesis, excessive deposition of GAGs and decreased collagen. At the molecular level, regardless of whether the cause is extrinsic or intrinsic, skin ageing involves DNA damage, decrease in antioxidant levels, and an increase in matrix metalloproteinases (MMPs), which degrade collagen and elastin in the dermis (Gonzaga 2009; Kammeyer 2015; Lephart 2016).

Classification system 

There are several scales to describe skin ageing caused by photodamage. The main classification systems include:

1. Glogau Classification of Photoaging (Glogau 1996); and

2. Rubin's System (Rubin 1995).

The Glogau Classification of Photoaging is a validated descriptive scale, which evaluates the severity of wrinkles from a scale of I to IV in relation to age, as well as the presence of keratosis, which can develop into actinic keratosis or precursors to cancerous skin lesions (Table 2). Rubin's system classifies ageing signs according to three levels (Table 3). According to this classification, changes in pigment are related to damage caused by the sun. This includes freckles in younger people and senile lentinges in older people. Also, it recognises that the skin changes in texture with age. Here, texture is defined via descriptive terms such as dull, leathery and rough. Unlike the Glogau system, age is not a consideration for the Rubin's system.

Medical terms are defined in the glossary table (Table 4).

Topical retinoids

Topical retinoids are natural derivatives of vitamin A. First‐generation retinoids include topical tretinoin and isotretinoin, while tazarotene and adapalene are in the third generation of topical retinoids. Retinoid‐containing derivatives are established treatments based on clinical trials, demonstrating efficacy in improving skin changes associated with photodamage (Kang 2001; Babcock 2015).

Regimen: topical retinoids are applied via a thin layer once daily to clean, dry skin. It is applied to skin away from eyes, mouth, nasal creases and mucous membranes.

Adverse effects: common adverse effects include erythema, scaling, dryness, burning, stinging and irritation. Irritation to the skin is exacerbated by sun exposure. Therefore, it should be applied once daily at bedtime. To assess irritation, a test dose may be applied and washed off one hour later. To minimise irritation, topical retinoids should be started at a low concentration, and titrated upward as needed (Yoham 2020).

Interactions: interactions from topical retinoid application include increased photosensitivity, and sunscreen application is needed. Due to the known teratogenic effects of oral vitamin A products, topical retinoids are listed as pregnancy Category C drugs.

5‐Fluorouracil

The antimetabolite 5‐FU is formulated as a solution and cream. Topical 5% 5‐FU, which is approved for use in superficial basal cell carcinoma and actinic keratosis, has been suggested for use in reversing skin ageing (Korgavkar 2017). Multiple studies have reported improvement in skin texture and wrinkling with systemic 5‐FU use (Guimarães 2014). Similarly, there is accumulating evidence that topical 5‐FU can lead to improvement in photodamaged skin (Sachs 2009).

Regimen: topical 5‐FU creams are applied once daily to clean, dry skin, using enough to cover the entire area with a thin film. Skin near the eyes, nostrils or mouth should be avoided. A standard course is up to four weeks as tolerated and used in clinical studies (Korgavkar 2017). It has minimal systemic adverse effects due to limited skin absorption.

Adverse effects: common adverse effects arising from topical application include skin irritation, pain, pruritus, erythema and eczematous skin reactions (Prince 2018). Similar to retinoids, people using topical 5‐FU are advised to avoid prolonged exposure to sunlight or other forms of UV radiation during treatment due to increased photosensitivity.

Interactions: contraindications to treatment with 5‐FU include people with a documented deficiency of dihydropyrimidine dehydrogenase, an enzyme which degrades over 80% of 5‐FU into biologically inactive metabolites, which can otherwise lead to life‐threatening toxicity if these metabolites accumulate. It is also contraindicated in women who are or may become pregnant.

Imiquimod

Imiquimod is a synthetic compound that works as a topical immune‐response modifier, and is approved for use in several dermatological conditions, such as actinic keratoses, superficial basal cell carcinoma and genital warts. The use of imiquimod cream for ageing skin is described in the literature, which documents clinical and histological improvement in aged skin (Kligman 2006; Metcalf 2007). However, the exact mechanism of action remains unclear, and there is limited evidence for the efficacy and safety of topical imiquimod for skin ageing (Smith 2007).

Regimen: imiquimod is applied to clean, dry skin via a thin film, covering a 1‐cm margin around affected skin. It is prescribed as a daily application for three months, unless rest periods are necessary due to intolerability to adverse effects. Based on existing studies, histological effects are more pronounced with sustained use, with a noticeable dermal effect after three months of use. Shorter use of imiquimod limits the effects within the epidermis (Metcalf 2007).

Adverse effects: common adverse effects include severe erythema, scabbing and skin ulceration, with clinicians strongly advised to prescribe strategies including a pause in treatment, use of emollients and, in some instances, topical steroids. It has been reported that topical imiquimod application can result in pemphigus‐like lesions both at and distant from the application site, which resolved after treatment cessation (Bauza 2009).

Interactions: there are no known interactions of topical imiquimod with other drugs so far. 

Skin‐resurfacing techniques

Current skin‐resurfacing techniques are chemical peeling, classic dermabrasion, microdermabrasion (MDA), ablative and non‐ablative lasers, and photodynamic therapy (PDT) (Clark 2008).

Photodynamic therapy 

PDT is the use of a light source in combination with a photosensitising agent to induce tissue damage via the generation of singlet oxygen, and studies have suggested this is effective in treating the visible signs of skin ageing (Friedmann 2016; Sanclemente 2018). Photosensitising agents include aminolevulinic acid (ALA) and methyl aminolevulinate, the methylated derivative of ALA.

Regimen: PDT is used as an off‐label indication for skin ageing, and therefore, the regimen for the use in skin ageing has not been established. Multiple treatments spaced at least one month apart are typically needed to establish visible clinical effects.

Adverse effects: adverse effects are mainly local, and include erythema, swelling, pain, pruritis, contact dermatitis and pigment changes.

Interactions: people with photosensitising dermatoses, such as porphyria and systemic lupus erythematous, are advised to avoid using PDT. As the photosensitising agents are under pregnancy Category C, PDT is contraindicated in pregnant women.

Topical retinoids

Topical retinoids improve features of skin ageing via several mechanisms. Studies have shown that many of their tissue effects are mediated by their interaction with specific cellular and nuclear receptors of the nuclear retinoic acid receptor family, which activate transcription of target genes. At an epidermal level, retinoids influence keratin synthesis and sebaceous secretion and decrease epidermal melanin content, which is increased in photodamaged skin causing dyspigmentation. At a dermal level, they modulate the composition of the extracellular matrix through regulation of fibroblastic proliferation and collagen metabolism. Retinoids also stimulate production of collagen I and VII (anchoring fibrils) and production and arrangement of elastic fibres, restoring the fibrillin‐rich microfibrillar network in the papillary dermis. This is likely to be due to induced elastin gene expression and elastin fibre formation via increased messenger ribonucleic acid (mRNA) and protein levels of tropoelastin and fibrillin‐1. The beneficial effects of retinoids in photodamage are also mediated by inhibition of MMP expression, responsible for collagen degradation, facilitating the formation of new collagen in the dermis (Griffiths 1993; Griffiths 1994; Lowe 1994; Griffiths 1995; Maddin 2000; Sorg 2005; Yaar 2007).

5‐Fluorouracil

5‐FU causes injury to the epidermis, which promotes wound healing and remodeling of the deeper layers of the skin. It follows a wound healing pattern similar to laser treatment of photoaging, and results in an increase in levels of procollagen Type I and III, resulting in improved appearance (Sachs 2009).

Imiquimod

Imiquimod acts as an immune response modifier and has potent antiviral and antitumour activity. It is licensed to treat genital warts, actinic keratosis and superficial basal cell carcinoma. It works by binding to toll‐like receptor 7 on the surface of dendritic cells, macrophages and monocytes, thereby inducing the synthesis and release of proinflammatory agents which enhance acquired immunity via a type 1 helper T‐cell immune response (Bilu 2003). Topical imiquimod appears to induce reparative changes to the epidermis and the dermal collagen in chronically sun‐damaged skin. This includes a significant increase in papillary dermal fibroplasia and reduction in solar elastosis together with improvement in epidermal thickness and melanisation, thereby leading to a reduction in skin ageing (Metcalf 2007).

Skin‐resurfacing techniques

Chemical peels work by inducing damage and inflammation of the outer skin layers via controlled chemical ablation. This stimulates epidermal regeneration and postinflammatory collagen synthesis with remodelling of collagen and elastic fibres and deposition of GAGs in the dermis, and the regeneration of new keratinocytes (Piacquadio 1996; Clark 2008). Overall, this results in the rejuvenation of the epidermis and concomitant rise in dermal volume.

Dermabrasion physically removes the skin layer by layer until the desired effect is obtained. By completely removing the epidermis and penetrating into the dermis, there is controlled damage of the skin surface, and this process remodels the skin's structural proteins into a more organised manner during the healing process, which may results in clinically significant improvements in skin structure and appearance (Smith 2014).

MDA exfoliates the skin by removing the most superficial skin layer. It decreases skin sebum, increases epidermal concentration of ceramide, decreases epidermal water loss and enhances skin texture (Smith 2014). MDA also affects deeper layers of the epidermis and dermis, by causing a rearrangement of melanosomes in the basal layer of the epidermis, flattening of rete ridges and increased collagen deposition at the dermal–epidermal junction, and vascular ectasia in the reticular dermis (Tan 2001).

Both ablative and non‐ablative lasers, as well as radiofrequency techniques, coagulate proteins such as collagen within the dermis, stimulating the wound healing process. Fractionated lasers heat deep dermis columns to stimulate the same process. As a result, collagen synthesis occurs on the substrate of the skin and extracellular matrix (Heidari Beigvand 2020).

PDT, in combination with a topical photosensitiser, produces cytotoxic oxygen species, which leads to the elimination of damaged collagen. There is also an upregulation of factors that increases the synthesis of Type I/III procollagen, and downregulate MMPs, thus resulting in sustained collagen synthesis (Park 2010).