Effects of smoking and nicotine
Cigarette smoking is strongly associated with elastosis in both sexes,  and telangiectasia (red spots on skin) in men . Smoking causes skin damage primarily by decreasing capillary blood flow to the skin, which, in turn, creates oxygen and nutrient deprivation in cutaneous tissues. It has been shown that those who smoke have fewer collagen and elastin fibres in the dermis, which causes skin to become slack, hardened and less elastic. Smoke causes damage to collagen and elastin in lung tissue and may do so in skin as well . In addition, constriction of the vasculature by nicotine  may contribute to wrinkling  (Fig. 1).
Smoking increases keratinocyte dysplasia and skin roughness . A clear dose–response relationship between wrinkling and smoking has been identified , with smoking being a greater contributor to facial wrinkling than even sun exposure . Smoking was demonstrated to be an independent risk factor for premature wrinkling even when age, sun exposure and pigmentation were controlled . In addition, although hormone-replacement therapy was demonstrated to reverse wrinkling, the skin of long-time smokers did not respond . The relative risk for moderate-to-severe wrinkling for current smokers compared to that of life-long non-smokers was 2.57 with a CI of 1.83–3.06 and a P < 0.0005 . Wrinkle scores were three times greater in smokers than in non-smokers, with a significant increase in the risk of wrinkles after 10 pack-years . Pack-years are calculated by multiplying the number of packs of cigarettes smoked per day by the number of years the person has smoked . For example, 10 pack-years would define both as smoking one pack a day for 10 years, or two packs a day for 5 years . Smoking also increases free radical formation and is an important risk factor in cutaneous squamous cell carcinoma .
Exposure to UV light (photoageing)
Intrinsic changes occur in all skin as people age, including decreased turnover, chemical clearance, thickness and cellularity, thermoregulation, mechanical protection, immune responsiveness, sensory perception, sweat and sebum production and vascular reactivity [21, 49]. These changes represent a generalized atrophy with few structural alterations up to the age of 50, followed by slow deterioration . In contrast, solar exposure to UV light initiates a flurry of molecular and cellular responses that end with a rapid dynamic disorder .
The effects of sunlight on the skin are profound, and are estimated to account for up to 90% of visible skin ageing [21, 22], particularly in those without the natural protection associated with higher levels of melanocytes in the skin . Sunlight is composed of three different types of radiation: UVC, UVB and UVA. UVC (100–290 nm) is largely blocked by the ozone layer and has little impact on skin . UVB (290–320 nm) penetrates only into the epidermis and is responsible for the erythema associated with a sunburn . UVA requires 1000-fold higher levels of radiation to cause sunburn, so it was long considered irrelevant to skin damage. It is now known that because it penetrates into the dermis, UVA may be responsible for most of the chronic skin damage associated with photoageing .
Sunlight damages skin across a spectrum of physiological processes. UV radiation in the dermis causes a molecular chain reaction which ultimately results in the upregulation, in both dermis and epidermis, of matrix metalloproteinases which stimulate the production of collagenase, gelatinase and stromelysin-1 in both fibroblasts and keratinocytes. The result is a deterioration of both collagen and elastin, as well as other components of the dermal extracellular matrix. Repeated exposure to solar radiation yields repeated, and increasingly faulty, attempts to repair the dermal matrix, with a cumulative effect on the structure and organization of its collagenous foundation. Invisible flaws in the repaired dermal matrix, with repeated cycles of exposure, eventually become visible to the naked eye in the form of sagging skin and wrinkles .
Ultra violet radiation also initiates damage to the genetic material. UVB primarily acts to create pyrimidine dimers that eventually result in mutation through errors in DNA replication; UVA radiation primarily initiates genetic damage through the creation of reactive oxygen species or free radicals . Free radicals can also wreak havoc on numerous cellular processes, e.g. facilitating the upregulation of matrix metalloproteinases (discussed above) .
In addition, UV radiation acts indirectly to damage skin by interfering with enzymes critical to the DNA repair process, and by interference with components of the immune system (specifically T cells and Langerhans cells) that act to eradicate carcinogenic cells . It has recently been shown that UV radiation may also act to prevent apoptosis in sun-exposed cells, thereby potentially promoting tumour development .
In this respect, UV radiation is a complete carcinogen, as it both initiates cancer through DNA mutation and promotes cancer growth through the inflammatory processes inherent in cumulative UV exposure (Fig. 2) [21, 53].
Photoageing is the superposition of this solar damage on the normal ageing process, defined specifically by damage produced in tissue by single or repeated exposure to UV light, believed to account for the vast majority of not only aesthetic effects of skin ageing, but also clinical problems as well [21, 49]. Modern Western culture has promoted tanned skin as healthy, resulting in steadily increasing rates of skin cancer and prematurely aged skin [21, 41]. Virtually all Caucasian Western individuals with normal recreational practices have subclinical signs of skin damage by the time they are 15 years old , whereas skin changes start to become discernible in unexposed skin in the early 30s [2, 21].
Ultraviolet light induces photochemical changes that can lead to either acute effects (e.g. erythema or sunburn) or chronic effects (e.g. premature skin ageing and neoplasms) [21, 41]. The clinical signs of cutaneous photoageing include changes in visible colour, surface texture [21, 41] including early appearance of dyschromia and lentigines, sallow yellow colour, loss of normal translucency or pink glow, gradual appearance of telangiectasia and purpura [21, 41]. Textural changes include increased roughness, frank keratoses and the development of fine rhytides which progress to deeper folds and creases [21, 41].
Corneocytes in sun-exposed areas become pleomorphic with increasing anomalies: retention of nuclear remnants, loss of lines of overlap and roughening of border edges [2, 54]. Also, UV radiation alters the skin’s immune function systemically [20, 21]. Epidermal thickness increases, then decreases, with an eventual loss of epidermal polarity (orderly maturation) and increased atypia among individual keratinocytes [20, 21].
Ultraviolet band A (UVA) light penetrates more deeply. Although it does not cause pronounced erythema, it may damage dermis more than UVB light, particularly elastic tissue related to skin ageing . Changes in the dermis include the degeneration of collagen and deposition of abnormal elastotic material, seen as wrinkles, furrows and yellowing of skin [20, 21]. With severe photodamage, the dermis becomes a massive quantity of thickened, tangled and degraded elastic fibres. Tightly packed collagen fibrils replace elastic microfilaments, becoming finally an amorphous mass [20, 21]. Damaged dermal tissue provides less support to its vascularization, causing vessels to widen and become visible at the skin surface as telangiectasia . The decrease in perfusion in aged skin is more pronounced in photoaged areas . It has recently been reported that it may be UVA that is responsible for the bulk of epidermal skin damage. UVA excitation of trans-urocanic acid initiates chemical processes that result in photoageing of the skin .
Although the primary effect of photodamage is skin thickening, severe damage results more in dramatic thinning [20, 21]. Sun damage creates a state of chronic inflammation, with ongoing release of proteolytic enzymes by inflammatory cells, disrupting the dermal matrix [20, 21]. Irradiated skin was observed to have a decreased capacity for inflammatory response [21, 43]. UV light also reduced the quantity of epidermal Langerhans cells, while it induced proliferation of suppressor T cells, facilitating tumour induction [21, 43]. Although plasma concentration of retinol increases with age, within the epidermis, vitamin A is destroyed by sun exposure .
With acute sun exposure, genes with reparative, protective or apoptotic functions as well as stress communication genes are rapidly activated [19, 57, 58]. Ageing strikingly increases the expression of related genes when exposed to UV .
Ultraviolet exposure modulates expression of collagen I, III and VI genes; heat shock protein 47 (Hsp47) genes and matrix metalloproteinase 1 (MMP 1), contributing to the general disruption of skin structure. Collagen I is time- and age-dependent, where it is reduced after a single UV exposure in human skin in vivo [21, 22]. Photoageing is associated with increased expression of MMP 1 and MMP 9 [21, 60].
Characteristics of photoageing when compared to intrinsic ageing are in Table I.
Table I. Comparing photoageing to intrinsic ageing
| Metabolic processes||Pronounced increase||Slow down||Soter |
| Clinical appearance||Nodular, leathery, blotchy||Smooth, unblemished||Glogau |
| ||Coarse wrinkles, furrows||Loss of elasticity, fine wrinkles||Glogau  |
| Skin color||Irregular pigmentation||Pigment diminishes to pallor||Rees |
| Skin surface marking||Markedly altered, often effaced||Maintains youthful geometric patterns||Gilchrest |
| Onset||As early as late teens||Typically 50s–60s (women earlier than men)||Kligman |
| Severity||Strongly associated to degree of pigmentation||Only slightly associated to degree of pigmentation||Rees |
| Thickness||Acanthropic in early stages||Thins with ageing||Takema |
|Atrophy in end stages|| ||Lavker |
| Proliferative rate||Higher than normal||Lower than normal||Lavker |
| Keratinocytes||Atopic and polarity loss numerous dyskeratoses||Modest cellular irregularity||Kligman  |
| Dermo–epidermal junction||Extensive reduplication of lamina dense||Modest reduplication of lamina dense||Gilchrest |
| Vitamin A content||Destroyed by sun exposure||Plasma content of retinol increases||Seite |
| Elastin||Marked elastogenesis followed by massive degeneration, dense accumulations on fibres||Elastogenesis followed by elastolysis –‘moth-eaten fibres’||Kligman  |
| Elastin matrix||Massive increase in elastic fibres, replacing the collagenated dermal matrix||Gradual decline in production of dermal matrix, only modest increase in the number and thickness of elastic fibres in the reticular dermis||Hanson  |
| Lysosyme deposition on elastic fibres||Increased||Modest||Gilchrest  |
| Collagen production||Decrease in amounts of mature collagen ||Mature collagen more stable in degradation||Lavker |
| Grenz zone||Prominent||Absent||Lavker |
| Microvasculature||Abnormal deposition of basement membrane-like material||Normal||Gilchrest |
| Microcirculation||Vessels become dilated, deranged||Microvessels decrease, remaining vessels do not change||Gilchrest  |
| Inflammatory response||Pronounced inflammation, perivenular, histocytic-lymphocytic infiltrate||No inflammatory response observed||Gilchrest  |