Retinoids

Retinoids act on both the epidermis and the dermis6. Tretinoin (all-trans-retinoic acid) is the most investigated retinoid in the treatment of skin ageing. The US Food and Drug Administration (FDA) has approved the use of 0.05% and 0.02% tretinoin emollient creams141. It directly activates RARs, indirectly activates RXRs, and has been found to help combat both intrinsic142 and extrinsic skin ageing. Studies suggest that local treatment should be carried for more than 6 months for an appreciable dermal level improvement143, 144. A randomised, double-blind controlled trial compared tri-retinol 1.1% gradual release cream and tretinoin 0.025% cream in females with mild-to-moderate photodamaged facial skin145. After 12 weeks of treatment, both products showed significant improvements in skin tone, firmness, roughness, pigmentation and fine and course wrinkles, with no significant difference between the two products145.

Isotretinoin (13-cis retinoic acid) is another retinoid studied for anti-ageing treatments, and studies have found a clinical improvement in photoaged wrinkles and pigmentation146–149. A multicentre, randomised, double-blind trial in 346 patients with photoaged skin showed a significant improvement in fine wrinkles and less side-effects with the use of 0.05% isotretinoin in combination with sunscreens when compared with the vehicle-treated group150.

Retinol derivatives and combinations

All-trans-retinol is another first generation retinoid. It is an endogenous retinoid and a precursor of retinal and retinoic acid6. Although retinol reduces wrinkles by inhibition of MMP, collagenase and gelatinase expression, while also inducing collagen synthesis, it is still 20-times less effective than tretinoin37, 151. As retinol is extremely unstable on exposure to sun and light, the vehicle used is crucial for optimal efficacy6. Retinol derivatives have been developed to improve the chemical stability of retinol. One such derivative is N-formyl aspartame, which was found to suppress collagenase expression as effectively as retinol152. Retinol combinations are also gaining popularity. A retinol (0.3%) and hydroquinone (HQ) (4%) combination has shown to diminish the signs of photoageing more effectively than 0.05% tretinoin cream after 16 weeks of treatment153. Daily application of retinol/dimethylenolamine (DMEA) in post-menopausal women showed significant improvements in the appearance of photoaged skin154. Retinyl retinoate is a new hybrid formed by the condensation of retinol and retinoic acid. It has excellent stability, causes less skin irritation, and reduces skin wrinkles155. A double-blind, randomised controlled trial showed that the use of 0.06% retinyl retinoate cream for 3 months improved wrinkles when compared with 0.075% retinol cream156. Larger clinical trials are needed to confirm its efficacy.

Tazarotene is a third-generation retinoid, which selectively binds to RAR-β and RAR-γ. Like tretinoin, the use of 0.1% tazarotene cream is approved by the FDA for the treatment of photodamaged skin141. In a 24-week, multicentre double-blind, randomised vehicle-controlled study in 562 patients, when compared with the vehicle group, the application of 0.1% tazarotene cream showed significant improvement in photodamaged skin157. In addition, after 52 weeks the patients showed additional clinical improvement indicating that the treatment had not plateaued157. A high dose of tazarotene produces faster improvements in wrinkling and pigmentation when compared with 0.05% tretinoin158.

Skin irritation is a clinical problem with most retinoids6. This led to the development of less irritating retinoids such as adapalene, retinol, retinaldehyde and novel receptor-specific retinoids like seletinoid G6. Adapalene is a third-generation synthetic retinoid selective for RAR β/γ. It has anti-inflammatory properties and targets abnormal desquamation of the skin159. As it is selective for its receptor, it causes less skin irritation. Actinic keratoses and lentigines were reduced with 0.1% gel of adapalene when applied once daily for 4 weeks, followed by twice daily for 9 months160. In a 6-month open-label study, 0.3% gel of adapalene showed significant clinical improvements in wrinkles, skin hydration and tone161.

A small study of 23 subjects showed that unlike tretinoin, the topical application of seletinoid G caused no skin irritation162. Furthermore, it increased the expression of ECM proteins and decreased the production of MMP-1162. Large-scale clinical trials are still needed to show the efficacy of adapalene and seletinoid G for photoageing.

Hormones

Studies have shown that post-menopausal women taking hormone replacement therapy (HRT) have an increase in skin elasticity and a decrease in existing wrinkles163–165. Oestrogens modulate epidermal keratinocytes, dermal fibroblasts and melanocytes. HRT seems to be more effective in photodamaged skin than sun protected skin163, 164. The use of HRT for 5 years after menopause may result in less wrinkling when compared with the non-treated group165. In contrast, other investigators observed no improvements in skin elasticity in the HRT-treated groups166, 167. The reason for this could be because the women in the study were amenorrhoeic for 6 months to 2 years.

HRT not only improves the existence of wrinkles, but prevents the development of new wrinkles168. The dosage of the oestrogen seems to have an efficacy in wrinkle reduction, but HRT did not have any effect after 48 weeks of treatment with low-dose oestrogen169.

Other than systemic use, the topical application of oestrogen has also been investigated. In a 2-week clinical trial in 70 volunteers (post-menopausal women and aged-matched men), the application of topical oestradiol (0.1%, 1% or 2.5%) only had an effect on sun-protected skin and not photodamaged skin170. In sun-protected skin, an increased production of procollagen I and III messenger RNA and collagen I protein levels was observed, while no significant production was observed in photodamaged forearm or face skin in both women and men170. This study also showed that the application of 0.01%, which was the lowest concentration used in this trial, did not have an effect in both groups. However, 2 weeks could be too short for topical oestradiol to have any effect on photodamaged skin. Other studies showed that after 6 months of topical 0.01% oestradiol and 0.3% oestriol, facial skin improved in thickness and collagen content, improved skin moisture and lowered pore sizes and wrinkle depth in both peri- and post-menopausal women171, 172.

Oestrogen receptor β (ER-β) could be a new therapeutic target for the prevention and reversal of wrinkles in photoaged skin as it inhibits MMPs and COX-2 in activated skin cells173. This is supported by the fact that oestradiol itself did not have a significant impact on collagen production in photodamaged cells173. Genistein aglycone is also an ER-β selective ligand, and after 12 weeks of subcutaneous injection into ovariectomised rats, it increased collagen thickness and the skin strength. Its efficacy was comparable to the oestrogen-treated group174.

Progesterone cream (2%) used for at least 4 months increases skin elasticity and firmness in both peri- and post-menopausal women175. Unfortunately, studies on the effect of progesterone against skin ageing are limited.

Anti-inflammatory agents

Celecoxib is a selective COX-2 inhibitor and its topical application on mice has shown to reduce inflammation caused by UV radiation, suggesting that it may help against photoageing176. On the contrary, another study indicates that only NS-398 (selective COX-2 inhibitor) inhibits skin ageing, while celecoxib and aspirin (non-selective COX-2 inhibitor) accelerate it177.