Vitamin A

Retinol is one of the most abundant forms of vitamin A in animals. It is the precursor to other forms of vitamin A therefore, it can convert into active forms, such as retinoic acid and retinaldehyde or inactive forms, such as retinyl esters.^[1] 

Retinol is unstable due to its pure alcohol form. Therefore, it is converted into retinyl ester via esterification of a fatty acyl group to the hydroxyl terminus of retinol. This allows the unstable retinol to be stored in tissues as retinyl esters. The most abundant forms of retinyl esters in the body are palmitic acid, oleic acid, stearic acid, and linoleic acid.^[2] 

The active forms of vitamin A are retinoic acid and retinaldehyde while the inactive forms are retinol and retinyl esters.

Animal foods supply vitamin A in the form of these biologically inactive retinyl esters while plant foods supply provitamin A carotenoids such as beta-carotene, alpha-carotene, gamma-carotene and cryptoxanthin.^[3] 

Retinyl esters are not biologically active and serve the sole purpose of storing retinol in tissue.^[2] They are stored in the liver, in specialized cells known as hepatic stellate cells, which account for less than 10% of total liver cells.

A carboxylic acid ester of retinol known as all-trans retinoic acid (ATRA), also known by names such as Tretinoin, is the most commonly used supplemental and hormonally active form of vitamin A. It is a medication often used to treat acne and acute promyelocytic leukemia

In culture, ATRA has been noted to increase the synthesis (anabolism) of collagen.^[4]

In regards to the breakdown (catabolism) of collagen, ATRA has been noted to inhibit enzymes responsible for collagen degradation collagenase (EC₅₀ of 0.25-1µM) and gelatinase (EC₅₀ of 3-6µM)^[5][6] which seems to be via reducing the overall amount of enzyme present.^[6] The increase in breakdown from corticosteroids^[7][8] and UV radiation are both reduced in the presence of ATRA.

Incubation of the medium with ATRA appears to produce an intermediate which inhibits collagenase despite retinoic acid not having direct inhibitory actions itself,^[5] which may be due to production of tissue inhibitor of metalloproteinases (TIMP) mRNA seen with ATRA.^[9]

Glycosaminoglycan expression has been noted to be increased with 0.4% ATRA application.^[10]

At the molecular level in human skin, ATRA appears to have dual actions in both increasing the rate of collagen synthesis and suppressing the degradation thereof

Photoaging is a term used to refer to the aging of skin which is accelerated under exposure to the sun, resulting in a wrinkling phenotype^[11] whereas aging of the skin not related to UV exposure (chronological or 'natural' aging) is characterized by an appearance of finer wrinkles but is thinner and laxer.^[12] The former's wrinkling phenotype is known to be associated with less collagen synthesis^[13] due to a blocking of TGF-β/Smad signalling suppressing procollagen I synthesis.^[14]

Application of 0.4% ATRA lotion can increase expression of procollagen I when applied thrice weekly over 24 weeks^[10] and 0.1% over 10-12 months (reaching a 119% increase in immunostaining of fibroblasts, 80% in papillary dermis)^[13] while in studies that take skin biopsies it is noted that topical application of ATRA (0.1%) can increase the thickness of skin from the forearm by 273% relative to an 18% increase in placebo;^[15] improvements in thickness have been noted on the face as well although to a smaller magnitude (28-30%).^[16]

In photoaged skin, topical application of ATRA appears to be able to increase procollagen I expression and subsequently the thickness of the skin secondary to reducing the suppressive effects of sun exposure on collagen synthesis

Application of an 0.4% ATRA lotion thrice weekly for 24 weeks in elderly subjects has been noted to significantly improve the visual appearance of wrinkling relative to placebo lotion within four weeks^[10] which is also seen with nightly application of an 0.1% ATRA cream over 16 weeks^[15] and 48 weeks.^[16]

Topical application of an ATRA cream has been noted in some studies (not measuring this as an end point) to reduce dark spots or sunspots associated with aging^[15] and studies that directly investigate this note that 0.1% ATRA over 40 weeks can improve visual scores in 90% of patients and reduce skin pigmentation.^[17]

Usage of 0.4% ATRA thrice weekly for 24 weeks in elderly subjects has been noted to be associated with frequent but mild side-effects related to erythema, peeling, dryness, and burning/stinging^[10] which has been noted in other studies using nightly applications of lower concentrations of ATRA; the frequency of side-effects, rather than intensity, seems to be reduced with lower concentrations.^[18][15]

One study comparing 0.1% ATRA against 0.025% ATRA noted that both creams exerted similar degrees of improvement on signs of photoaging although the lower concentration was associated with less mild side-effects^[16] while elsewhere 0.05% was effective in improving photoaging signs and whlie 0.01% had less symptoms it was also less effective.^[18]

Any cream or lotion containing 0.1% ATRA or greater can cause mild side-effects related to dryness, peeling, redness, and warmth while a lower concentration of 0.025-0.05% appears to have less chance of these side-effects while being just as effective on reducing signs of photoaging