Investigating the challenges of ageing skin

The subcutaneous tissues, particularly fat, both atrophies as well as migrates as a result of gravity. Blood vessels will become abnormally large or sclerosant, the skin as a result can show atrophy, solar and semile purpura. In addition, subcutis ageing (Fig. 2) involves collagen, elastin degeneration and muscle atrophy. Skin ageing may be both intrinsic as well as extrinsic. Accelerated intrinsic skin ageing may be the result usually of a genetic or underlying disease. Examples of this accelerated intrinsic ageing would be diabetes mellitus, progeria, and xeroderma pigmentosa. Accelerated extrinsic ageing is considered to be a result of external or environmental factors causing an acceleration of the ageing process. The main causes of extrinsic ageing are lifestyle factors such as smoking, sunlight, sun bed use, extreme diets, rapid weight changes as well as the effects of some medications. The signs of intrinsic skin ageing include poor skin texture, larger sebaceous pores and seborrhoeic keratoses (Fig. 2). There is loss of subcutaneous volume i.e. fat, muscle, connective tissue, subcutaneous fat migration leading to skin laxity and sagging, weakening of the periocular muscles and fat loss of periorbital support. Fat and ligament laxity leads to upper eyelid and brow ptosis plus infraorbital fat pads. Loss of substance from the lip leads to lip atrophy and perioral wrinkles. All of these can be seen in Figure 2. Mild sun induced skin ageing may show slightly pigmented lesions e.g. solar lentigo with relatively few fine rhytides. Signs of severe ageing from sunlight or sun beds are: an unevenness of pigmentation with dyspigmentation e.g. lentigo, hypopigmentation, pigmentation from underlying oestrogen induced pigmentation (melasma) from contraceptive hormones or pregnancy plus UVA exposure. Signs of more severe photoageing including deep and superficial rhytides, facial sagging, loss of facial volume, pre-skin cancers e.g. atypical lentigo, pigmented naevi, solar keratoses (Fig. 3). A variety of skin cancers including basal cell cancer, squamous cell cancer and melanoma may also occur.
Skin rejuvenation
What are realistic expectations for treatment of ageing skin?
There are numerous approaches to treatment of ageing skin (see Table 1). Over the last decade dermatologists have developed many new, nonsurgical, noninvasive treatments including lasers, intense pulsed lights, radiofrequency, injectables such as botulinum toxins and volume replacing fillers. All can be highly effective with appropriately trained specialists for skin rejuvenation and repair of ageing skin.
Role of topicals
A variety of non-prescription and prescription topical products have been shown to effectively repair some of the damage in ageing skin. Efficacy claims may come under regulatory scrutiny if they actually change skin structure and function. Cosmetic or ‘cosmeceutical’ products have to be restrained in their claims to avoid medicines regulations. Prescription anti-ageing retinoid cream and gel studies have well proven efficiency over 12 to 16 weeks and have undergone rigorous efficacy testing.
Role of sun protection
 It has been proven that daily photoprotection with UVB and UVA absorbing and reflecting sunscreens are able to reduce the impact of photodamage on the skin, reducing both ageing as well as skin carcinogenesis.
Photoprotection to reduce photoageing
Photoprotection does much more than only prevent sunburn. Effective photoprotection can reduce most if not all signs of mild and severe photoageing. Photoprotection may be divided as follows:
•  Ultraviolet absorbing sunscreens that are effective between the wavelengths of 290 nanometers to 400 nanometers. Many of the available ultraviolet absorbing sunscreens are highly efficient throughout UVB but variably efficient as UVA absorbers. Some of them, e.g. stabilised forms of avobenzone and various triazines are highly effective through most of the UVA spectrum, although they usually have a reduced absorption above 360 nm.
•  Reflecting sunscreens that comprise mainly either zinc or titanium dioxide can be effective throughout UVB and partly UVA. The size of the particles of zinc oxide and titanium dioxide will have a big impact on their cosmetic and safety acceptability. In general, particle sizes of less than 13 nanometers are thought to be capable of penetrating the whole of the stratum corneum and therefore have possible risk of percutaneous absorption. Twenty-five nanometer particles of zinc oxide only penetrate into the top three to five stratum corneum layers and may be a good compromise particle size for zinc oxide. Particles of zinc oxide of 35 nanometers and larger will show an unacceptable visible whiteness on phototypes four and five, but not on the lighter skin phototypes and while particle size 10 nanometers is not visible on any phototype it has the risk of percutaneous penetration. Titanium dioxide on the other hand needs to be less than 200 nanometers for transparency and avoidance of whitening. There is a recent development of ‘aggregates’ of nanopaticle Ti02 and it is hoped this will this give better cosmetic acceptability and protection. The concept of combining ultraviolet absorbers with ultraviolet reflectors as a combination approach to sun protection is a logical one. There are specific EU and US regulations on this subject. Zinc oxide is still not accepted as a sunscreen active in the EU although you can formulate with it and not include it in sunscreen claims.
Sun protective clothing including hats
 These are tightly woven textiles that have been rigorously tested for their sun protection. They have the great advantages of staying effective all day when worn; examples include: Sun Precautions Clothing USA and Coolibar Australia. Hats with broad brims, manufactured with protective textiles are essential as a programme of photoprotection.
How much sunscreen should we apply?
 It has been estimated that most people will apply 25% or 50% of the optimum 2 mg/cm2 amount of sunscreen application. For example it has been shown that SPF numbers fall significantly when the density of sunscreen drops below the optimum sunscreen skin application. This is a potential argument in favour of better education and higher SPFs when exposed to sunny climates with high intensity ultraviolet. Conversely higher SPFs lull some into a false sense of security where they do not reapply when needed and as a result photodamage their skin.
What is the optimum SPF level for adequate protection?
If the sunscreen is applied at 2 mg/cm2 then SPF 15 will absorb 93.3% of the UVB absorption, SPF 30 will absorb 96.7% and an SPF 50 98% (Sayre R). In other words the most important aspect of sunscreen protection is obtained by applying adequate quantities, not particularly by using higher and higher SPF values. Indeed higher SPF values have been suggested to lull the consumer into a false sense of security. See the discussion above. Another suggestion is to apply a second layer of sunscreen to try to achieve the optimum thickness. The answer ideally is to educate the public – e.g. 1 teaspoon of sunscreen for the average size adult face and neck to apply the optimum amount – and reapply regularly, particularly after swimming, exercising, sweating and towelling the skin.
How damaging is UVA exposure for your skin and why do we need to use ‘broad-spectrum’ sunscreens daily year round?
There has been growing scientific evidence of the risks of UVA exposure to the skin, causing photoageing and increased skin carcinogenesis. In previous decades, unexpected UVA exposure resulted from the use of sunscreens with a high SPF in relation to poor UVA protection. Today hazardous UVA exposure occurs from modern sun beds which emit very large amounts of UVA. These should be banned or severely restricted as a public health risk factor. Evidence that the amount of ultraviolet A experienced during a normal day’s activity is damaging came from past research. In the 1990s I did collaborative research with Unilever scientists, Dr David Meyers and Dr Ian Scott. We radiated previously nonsun exposed skin of human volunteers with various wave lengths of ultraviolet twice weekly for 12 weeks. We carefully chose UVA exposures that a person would likely be exposed to after 30 minutes exposure in a normal day’s activity in spring or autumn in the UK – either outdoors and though car windows for example. We showed that there was injury to the elastin and collagen component of the skin. There was increased vascularity in the radiated skin and in addition, there was persistence of pigmentation. These events occurred after just six weeks of twice weekly exposure (i.e.) 12 exposures to the small amounts of UVA (Fig. 4). Other groups have confirmed these findings. Other research by Bisset et al showed that it was possible to produce skin sagging in the hairless mouse with UVA radiation. It was possible to protect against this sagging with 4% avobenzone sunscreen. It is for these and other reasons, that my day protection creams have all been fully tested for human in vivo SPF and in vitro UVA tests to prove ‘broad-spectrum’ protection. Other research that we and others have performed have shown that this type of day protection can be shown clearly to reverse pigmentation and other markers of photodamage (Fig. 5). Solar keratoses (Fig. 6) are felt by dermatologists to be precursors for squamous cell cancer and a sign of precancerous epidermal photodamage from repetitive sunlight exposure. Australian studies showed that daily use of a SPF 15 sunscreen during an Australian summer is capable of reducing solar keratoses frequency in protected patients.
Other anti-ageing active topical ingredients
The use of antioxidants in many skin preparations is based on the free radical theory of skin damage that accumulation of endogenous oxygen radicals causes skin ageing. The overproduction of reactive oxygen species is also related to inflammation from, for example, acne inflammation leading to dermal collagen elastin damage, with scarring, skin wrinkling and sagging evident many years after the acne has cleared. It is known that ultraviolet induced sunburn is able to be partially reduced by antioxidants such as oral lycopene. It remains to be proven if antioxidants can protect or reverse skin damage and ageing caused by repetitive sunlight exposure. There are now many botanical and synthetic antioxidants that are utilised in skin care products, e.g. acai, blueberry, green tea, pomegranate, raspberry are some botanical extracts. Coenzyme Q-10, ferrulic acid, genisten, idebenone, kojicacid, resveratrol, soy isoflavones, sodismutase, vitamins A, C and E are some synthetic antioxidants. Oral antioxidants may be found in blue, green, red, orange, purple, yellow, drinks, fruits and vegetables. Examples of these which likely do have antioxidant activity include blueberries (anthocyanins), tomatoes, red and yellow peppers (lycopene), red grapes (resveratrol), pomegranate extracts (ellagitannins), and green tea (polyphenols). Not all studies have shown antioxidants to protect against skin carcinogenesis. An oral beta carotene study that the author was an investigator for in the 1980s (funded by the National Cancer Institute in the US) studied the effects of daily beta carotene capsules of an amount that produces measurable levels of serum betacarotene. Over a thousand volunteers at several centres in the US all had at least one prior non-melanoma skin cancer. At the end of the eight-year study there was no significant protection from the beta carotene measured by incidence of new skin cancers compared to the placebo group, i.e. both groups developed similar incidence of skin cancers. One criticism of this study is that antioxidants may be effective protectors against skin cancers only if they are available to the skin cells at the time of the injury. In our National Cancer Institute study, UV damage had already been done as the subjects had already developed at least one prior skin cancer. Disappointedly, other studies including bowel polyp and colon cancer studies also have failed to show any protective benefit with beta carotene. Conversely, lycopene has been shown to reduce sunburn erythema and the incidence of sunburn cells, however, whether this will translate into protection again skin cancer and skin ageing has not been studied.
Can calorie and glycaemic damage restriction prolong life?
This question leads to a discussion of glycation cell damage also known as advance glycation end products or AGEs. Sugars damage functional proteins in the heart, blood vessels, skin and other organs by binding to the cellular nucleic acids that decrease cell transcription, cell division and mitochondrial function. Increased glycation end products are found in diabetes mellitus which is considered to be an example of accelerated ageing. It is now possible to measure glycation end products in the skin and further research is needed to see any link between reduced skin ageing and or reduction of glycation end products. The question of whether you can prolong life with calorie restriction was studied at length by the late Professor Roy Walford at UCLA in the 1980s. He examined the affects of calorie deprivation and found that there was increased longevity in rodent models and that this was proposed to be linked to a reduction of glycaemic cell damage. A more recent study in 2012 in fooddeprived primates however failed to show increased longevity. There are some available antiglycation agents that can reduce glycation end products. These include the antioxidants vitamin C, vitamin E, green tea extracts, and blueberry extract. Aminoguanidine and carnosine are two other antiglycation agents. Some of these have been active in a test utilising the mouse tendon snap test and also skin sagging assays in mice. The question of their efficacy for human skin is proposed but needs to be further researched.
Other theories of ageing
These include mutation and gene regulation theory of ageing. This theory suggests an accumulation of genetic mutations in the cells that eventually will cause impaired cell function and ageing. There are changes in gene expression and also abnormal gene coding sequences can lead to senescence.
Telomere length and senescence
More recently the concept of reducing the length of the protective telomere caps on chromasones has been raised as a key factor in ageing. The telomere theory of ageing proposes that telomeres which are protective caps that exist on the end of chromosomes shorten with age. It is thought that cells have a limited number of cell divisions due to telomere shortening. Partial telomere reduction may lead to senescence via apoptosis (cell death). Agents that have been proposed to stabilise telomeres may prove useful in reducing ageing, but many further studies are needed in this interesting area. Agents that may protect telomere length include astralagus plant extracts and a nutritional supplement ‘T-A65’ from T.A. Sciences in Nevada, US. One problem at present is the absence of an assay to measure telomere in skin samples to correlate telomere length with skin age. Longititudinal studies are needed before we know the relevance of telomere protection or maintenance and their relevance for our skin’s age.
Sirtuins and skin ageing
Sirtuins are named from the gene Sir2, which was shown to regulate cell senescence in yeast cells. It is thought that sirtuins stabilise histones which are proteins that protect cellular DNA and thereby reduce interference with gene transcription and senescence. An example of a product that can stabilise and assist sirtuins is resveratrol. Scientific proof is needed to evaluate whether this agent or other agents that stimulate sirtuin activity have anti-ageing benefits.
Other agents known to be active against skin ageing
Some topical retinoids are highly effective against skin ageing. The pivotal work of the late Professor Albert Kligman (the leader in skin ageing research over the last three decades) in Philadelphia in the 1980s convincingly showed that tretinoin and related retinoids were effective against photodamaged skin in mice and men. He showed that there was a normalisation of the aberrant epidermal differentiation present in photodamaged skin together with increased dermal elastin and collagen following treatment with effective concentrations of tretinoin. Subsequently, many groups including my own research team in California performed extensive work on topical retinoids and their ability to inhibit or reduce changes of skin ageing. We explored other questions regarding whether they were able to inhibit UV induced skin carcinogenesis. Several retinoids have been shown to be capable of reducing chemical, tumour initiation promotion studies of skin cancer where they were effective inhibitors of animal skin tumour promotion. There were variable results on their ability to influence ultraviolet induced skin cancer at least in the mouse model experiments. The proposed ranking of retinoid potency depends not only on the individual characteristics of the retinoid molecule but also on the ability of the different retinoids to penetrate into the skin and also their stability. In a variety of studies it was found that tazarotenic acid was more potent than tretinoin, which was more potent than isotretinoin, which was more potent than retinol, which was more potent than retinaldehyde. Retinoid potency can be changed by selection of the vehicle delivery system. My research group showed in the 1990s that tazarotene 0.05% and 0.1% creams showed significant improvements in large numbers of subjects with improvement in fine wrinkling and also interestingly reduction in sebaceous pore size. The changes with tazarotene were consistently greater than that seen with a tretinoin emollient cream. Tretinoin cream can be obtained by prescription and is extremely useful as an adjunctive treatment against some of the changes of photodamage including fine wrinkling and lentigo lesions. My own preference is to use the lowest concentration and application frequency possible to obtain improvement and to minimise skin irritancy from the retinoid. There are patients where retinoids are not appropriate and they include patients with sensitive skin, a history of eczema, any history of skin sensitivity to creams. Where they are most useful are in areas where there is significant photodamage, where there is not sensitive skin and where the patients can be educated to use the small amounts of the topical retinoid with appropriate frequency. Tretinoin cream is prescribed to be applied nightly, two to three times a week. UVB and UVA absorbing cream should be applied daily and the nights that they do not apply the retinoid they apply an emollient moisturising night cream to reduce the erythema and irritancy thresholds of the topical retinoid. It is important to note from most topical retinoid studies that to reach a steady state of improvement will usually take 12 weeks and continued improvement is seen over a 24-week period.
 Dyspigmentation is both disfiguring and ageing for the skin
Irregular pigmentation on the face, hands and upper chest can be particularly ageing and disfiguring for many of the sun exposed population. This tends to be more frequent in skin of colour e.g. olive, Asian and darker skin phototypes. Examples of dyspigmentation include solar lentigo, melasma or medication induced pigmentation. It is usually photoactivation by UVA wave lengths of melanocytes. Photoactivation of medications or hormones can lead to pigmentation; examples include oestrogens in the oral contraceptive pills or pregnancy. Antibiotics including minocycline and cardiotherapeutic drugs such as Amiodarone can lead to UVA/medication induced pigmentation.
Treatment of dyspigmentation
This requires a combination approach of protective UVB and UVA protecting day creams and skin lightening creams every night. These may combine prescription products containing up to 5% hydroquinone under dermatologist supervision as well as effective nonprescription products. The author has recently released a skin lightening complex cream, which combines numerous skin lightening active ingredients which do not cause skin irritancy, but results in significant skin lightening activity. Our recent research confirmed reduction of facial pigmentation in a study, where patients were randomised to receive either a skin lightening cream programme or a series of intense pulsed light treatments (Fig. 7). Other clinic treatments for reducing pigment include intense pulsed lights, pigment specific lasers such as the ruby and alexandrite lasers, nonspecific but effective skin lightening lasers such as the Fraxel 1927 nm laser and dermabrasion followed by infusion of skin lightening solutions through a mildly compromised skin barrier. It is this author’s experience that many women protect their faces daily but completely forget to protect their neck, décolletage and dorsal hands. The neck and décolletage is easily photo damaged and is an important area for appropriate protective and repair product.
What can be done about superficial and deeper rhytides?
The advent of botulinum toxins and dermal filler to reduce skin surface lines particularly in the forehead and the periorbital and perioral areas led to a dramatic increase in the concept of cosmetic or aesthetic dermatology. It also led to many poorly trained, inexperienced practitioners embarking upon this area of treatment. The UK is less regulated compared to the more rigid regulation in other countries such as, France, Germany, Spain, etc. This whole area of clinical aesthetic treatments is very much an issue of ‘buyer beware’. Do your homework about the clinicians and clinics before embarking on treatments. Correctly delivered, however, the botulinum toxins often in combination with lasers, pulsed lights and volumising fillers are excellent approaches for nonsurgical facial rejuvenation.
Are there any active skin agents that can mimic Botulinum toxin effect?
This has been an area of active marketing and research in the beauty product industry. Different agents will tighten the skin surface such as marine extracts, certain peptides as well as other skin tightening formulations. Optical blurrers can reduce the appearance of skin surface lines. As seen in Figure 8 some results can be observed within a matter of minutes with some of these products, which suggests that one component of skin tightening is perhaps rapid skin surface tightening. Whether activities of agents such as acetyl hexapeptide truly have a long acting effect against the release of wrinkle inducing neuropeptides this author feels remains to be proven. Having said that, there is no doubt that the appropriate formulation can produce a visible improvement in skin surface lines (Fig. 8).
The importance of patient education
It is possible to improve the appearances of skin ageing including photodamage using a variety of different products and ingredients. It is important that the consumer knows and can identify their type of skin. There are many pitfalls in the use of individually inappropriate products that can cause problems for sensitive skin, acne-prone skin, rosacea-prone skin, etc. It is very important with any education of the consumer public to make certain that important details are remembered. It has been shown that most patients only remember about 10% of the facts given to them by physicians. It is therefore essential to have them look, listen and learn about their skin problem and to educate clearly and repetitively.
Conclusion
There remain challenges and opportunities to improve the ageing skin as I hope this article has emphasised. I would summarise the achievable goals for non-prescription products as wrinkle reduction, reduction of sebaceous pore diameter, skin smoothing, skin textural improvement, facial erythema control and improvement of dyspigmentation. Daily use of effective photoprotective products have been clearly shown to reduce accelerated skin ageing as well as skin cancers and pre-skin cancers. There are goals that I consider unrealistic and include claims for nonprescription products being able to lift faces, lift and enlarge busts, firm and lift buttocks, cure cellulite, and get rid of enlarged veins and telangiectasia. At present the technology is not available in my opinion to achieve these goals. I remain enthusiastic that ongoing collaborative research between dermatologists, dermatologic scientists, skin formulators, cosmetic chemists and marketing specialists will continue to yield benefits for protection, prevention and treatment of ageing skin (Fig. 9).
References
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