Title: Retinoids and wrinkles

Key words: cosmetics, skin care, tretinoin, epidermis, dermis, collagen, photodamage, sunburn, vitamin A, retinoids, UV radiation, cancer, alpha-hydroxy acids, fruit acids, antioxidants, free radicals, anti-wrinkling products

Date: April 2001

Category: Macronutrients

Type: Article

Author: Rosie Mestel


Retinoids and wrinkles

The big guns of research are being brought to bear on the wrinkle. Rosie Mestel investigates the latest claims in cosmetics

Each year in the US alone, people spend a cool $850 million on anti-ageing skin products. Cosmetics counters are overflowing with impressive-looking potions stuffed with liposomes, vitamins, fruit acids and skin proteins. The ads imply that every one of them has undergone bona fide "scientific testing".

Wrinkle repair

Most skin researchers agree that much of the "science" surrounding anti-wrinkle preparations is pure hype, but they also acknowledge that rigorous research is finally entering the war against wrinkles. Last December, for example, Ortho Pharmaceutical's Renova-which contains an active ingredient related to vitamin A called tretinoin-became the first prescription-only wrinkle treatment to win approval from the US Food and Drug Administration, after clinical trials of a scale and rigor usually reserved for drugs designed to fight life-threatening diseases. (In Britain, tretinoin is called Retinova. It was approved as a prescription wrinkle treatment in 1994.)

Now, while some scientists are gearing up to run clinical trials on at least one other of the new generation of anti-wrinkle elixirs (see "New-age creams"), others are spending hours at the bench, usually with drugs company funding, trying to understand tretinoin's modus operandi.

Most of the evidence shows that Renova really does help repair wrinkles-at least fine ones-as well as fade age spots, and smooth the skin. But it remains debatable whether the drug works by acting as a mild irritant or by activating specific receptors that control, among other things, the production of key skin proteins. And at least one dermatologist is concerned that long-term use of Renova may increase the doses of ultraviolet radiation that reach the deeper layers of the skin and so actually worsen wrinkles and increase the incidence of skin cancer.

But by far the most important finding of this new era of dermatological research is that the vast majority of wrinkles and other signs of ageing are caused by sunshine rather than simply getting old. By slapping on a sunscreen, people can ward off those wrinkles-and, as an added bonus, they'll ward off skin cancer, too. Which may sound back-to-front, but dermatologists have learnt to their chagrin that the threat of looking old and wrinkly is by far the stronger motivation for using a sunscreen.

When it comes to wrinkles, it is down in the lower skin region-the dermis-that the sun takes its toll. For a start, UV-B (and UV-A to some extent) wreak havoc with two essential skin proteins called elastin and collagen. Elastin and collagen fibres, which are manufactured by cells called fibroblasts, form a dense mesh that makes the skin tough and stretchy.

In the past few years, researchers have concentrated their efforts on tracking the effect of UV light on elastin and collagen, and on the way wrinkles form, often using a peculiar strain of hairless mice. While both mouse and human skin go through very similar changes when they are zapped with UV, the changes in the mouse occur far more rapidly. Irradiate a hairless mouse at a level equivalent to less than one hour of sunlight a day for up to 20 weeks and it wrinkles across its pink back, while it accumulates a malformed type of elastin in its dermis, and the amount of collagen falls, suggesting that damage to those two proteins underlies the wrinkle process.

In humans, the amount of normal collagen in the skin can fall by a massive 20 per cent following the level of sun exposure typical of a life-long beach bum, says dermatologist Lorraine Kligman, of the University of Pennsylvania in Philadelphia, who pioneered the use of the hairless mouse.

And one doesn't need to fry on the beach for hours to set the whole process in motion. In an article in Nature (vol 379, p 335), in January, dermatologist John Voorhees and his colleagues at the University of Michigan in Ann Arbor reported that UV-B doses far lower than those that cause actual sunburn activate the enzymes that chew up collagen and elastin, raising the possibility that even small, but repeated, doses of UV-B can trigger wrinkles.

So much for why wrinkles form: most people simply want to know how to get rid of them. Staying out of the sun may help-there is evidence both from rodents and humans that the skin can repair itself to some degree if given half a chance. But sunscreen-after-the-fact won't work miracles. Neither, for that matter, will Renova.

It was just a decade ago that researchers discovered that people who rubbed tretinoin all over their faces had fewer wrinkles and age spots. The news came from women who'd been using Retin-A (which contains tretinoin) for acne, a standard treatment for the disorder in Britain and the US since the 1970s.

"They told me that their wrinkles were going down and their faces looked much smoother," says Albert Kligman. "I didn't see a hell of a lot but finally I got it into my thick head that they were saying something that was interesting." Kligman published his anecdotal evidence in 1986. And within months, Voorhees's team began the first controlled test of tretinoin's anti-wrinkle properties.

Skin craters

But it was last year's FDA approval of Renova for treating wrinkles and other marks of age and weather ravaged skin, such as age spots, that changed the face of cosmetics for ever. It was based on the results of a large clinical trial sponsored by Johnson & Johnson's Ortho division, conducted at eight research centres in the US, and published in the Archives of Dermatology and The Journal of the American Academy of Dermatology. The first of those reports tells how three hundred people aged between 29 and 50, with either mild or moderate amounts of wrinkling and other signs of photodamage such as age spots, rubbed one of two concentrations of Renova, or a control lotion, onto their faces once a day for between six months and a year.

Every few weeks, trained "evaluators" rated faces for qualities such as roughness, wrinkling and age spots, on a 0 (the best) to 9 (the worst) scale. The subjects also rated their own faces. And optical profilometry, a NASA technique for mapping the craters on the Moon, was used to obtain an objective assessment of the degree of wrinkling. The researchers made a silicone rubber "negative" of each person's skin and measured the length of the shadows cast by the wrinkles when it was illuminated at an angle.

In total, 79 per cent of the volunteers who received the high dose of tretinoin (the dose that is now in the commercially available Renova) showed some type of improvement. Skin became less rough almost immediately, improving by 29.3 per cent after six months. Age spots started to fade after two months, and had faded by 37 per cent after six months. Wrinkling had improved as well, by as much as 27.1 per cent after six months.

At six months, however, the effects began to level out. In appearance terms, which is what really counts, they were never particularly dazzling anyway, as the "before" and "after" photos in the Renova press kit amply illustrate. What is more, 48 per cent of the control group, who were instructed to apply sunscreen and moisturisers religiously, showed some type of improvement.

The multi-centre study, as well as experiments by the Kligmans, Voorhees's group and others have also begun to piece together how tretinoin does what it modestly does. Initially, in both humans and mice, tretinoin causes the stratum corneum, the outermost layer of the epidermis, the outer part of the skin, to flatten, and the rest of the epidermis to thicken. These are the short-lived changes which may account for the initial plumping and smoothing of the skin.

But they can't account for the fact that as treatment carries on the wrinkles continue to improve for at least six months. In the long-term, the only change that truly correlates with wrinkle effacement is increased levels of collagen in the dermis. In humans and hairless mice, tretinoin both stimulates the production of collagen and stops it from being destroyed, effects that continue for several years of tretinoin treatment (even although, in the Johnson & Johnson trials, the visible improvements in the skin reach a plateau).

And tretinoin might do more than simply repair wrinkles: it might also stop them happening in the first place. Voorhees refuses to discuss his findings with journalists, but in his Nature paper he reported how several dozen male and female volunteers received a single, quick mild dose of UV-B-about twice the intensity needed to trigger barely perceptible skin reddening-on their bare buttocks. The researchers then sliced off both the irradiated portions of skin and the adjacent, non-irradiated patches, and compared them. In less than a day after irradiating the buttocks, the levels of three enzymes that degrade collagen and elastin had increased roughly fourfold in the skin samples. Within just 15 minutes, the levels of AP1 and NF-kB, proteins that switch on the genes for those enzymes, had more than doubled. When tretinoin was applied before irradiation, however, the increase in AP-1 and NF-kB, and in the collagen and elastin-chewing enzymes was greatly reduced.

"It's a very interesting result," says Christopher Griffiths, professor of dermatology at the University of Manchester. "It's saying that tretinoin might not just repair photodamage, but actually prevent it in the first place."

The skin researchers suspect that tretinoin, a type of retinoid, causes these molecular changes by seeping into the skin and binding to retinoid receptors in cells that, once activated, have profound effects on gene regulation. The widespread presence in the body of the receptors-they are found in many sites besides the skin-reflects the importance of the naturally occurring retinoids such as vitamin A.

For instance, people who are deprived of vitamin A may go blind and their immune systems become suppressed, while too high a dose of retinoids during pregnancy causes defects in rodent pup's limbs and other organs. That is why pregnant women are advised not to use retinoid-containing creams.

But rather than activating specific retinoid receptors, tretinoin could work in a more trivial way. Many people who rub it on their skin develop mild dermatitis, which itself induces some degree of skin repair that could conceivably smooth out wrinkles.

Arguing against this theory, though, are the latest studies by Lorraine Kligman in which tretinoin but not mildly irritating detergents triggered mice with sun-damaged skins to repair collagen. And in a study last year, Griffiths, Voorhees, and their colleagues tested two concentrations of tretinoin on human skin, and found the same degree of improvement with both-even though the higher concentration caused much more irritation.

Looking good

Unlike scientists, consumers don't really care how tretinoin works-as long as they're sure that it does. A more nagging concern for consumers and scientists alike is the possibility that tretinoin treatment may, in the long run, actually increase exposure to UV radiation, and hence wrinkles and even skin cancer.

People using tretinoin are certainly more prone to sunburn -possibly because when the stratum corneum flattens temporarily it lets more light into the epidermis. This bothers John DiGiovanna, a dermatologist at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, in Bethesda, Maryland.

"So now you have a 43-year-old person who's very worried about their wrinkles and they start using Renova," he says. "And the question is, are they going to get more wrinkles because of the increased light that penetrates, and are they going to put themselves at an increased risk of developing skin cancer?"

So far, there has been no bad news, even among the many people who have used tretinoin on acne for years. And tretinoin lotions have even been used to "cure" skin cells that have taken the first step towards cancer (see "Cancer crusades").

Nonetheless, there have been no study specifically looking for changes in the skin cancer rates or in the amount of wrinkles in healthy long-term users of tretinoin-containing lotions, and studies on rodents have been contradictory. Mice that are smeared with tretinoin throughout life do not develop more skin tumours than control mice. But when the treated mice are also exposed to UV radiation, half the studies find an increase in the number of skin tumours, and half a decrease, says Lorraine Kligman.

When it comes to those nagging wrinkles, meanwhile, hopeful consumers must face up to the fact that even the most scientifically tested of remedies won't create crease-free skin. This shouldn't come as much of a surprise, says Dan Piacquadio, director of clinical research at the University of California, San Diego. After all, despite all its lofty achievements to date, science has only just started to tackle the wrinkle problem.

"It's like watching a kid learn to walk," he says. "It's rare that someone goes from total lack of understanding to having the solution-each step is generally a modest improvement over the last. If you evaluate the products in that light, then they're very interesting, promising, encouraging, successful."

Which may be all very wise and true, but you won't stop me from vainly wishing for the Moon each time I smear some of that prescription from Arnold Klein, dermatologist to the stars, on my face. And that, of course, is why cosmetics companies don't need rigorous scientific studies to make as much money as they do.

Cancer crusades

Tretinoin, and other vitamin A-like chemicals that are collectively called retinoids, promise to do more than simply make us look younger. They may also help prevent-or even cure-cancer.

When tretinoin is applied to the skin not only do wrinkles fade, but cells in the epidermis that are on their way to becoming malignant disappear. They do so, the theory goes, because cells that are becoming cancerous must lose all their specialised features and become "undifferentiated", while retinoids remind those cells of what they should be.

This is why pills containing isotretinoin, a retinoid closely related to the active ingredient in the anti-wrinkle lotion Renova, are used to help prevent the literally hundreds of skin cancers to which people with a disease called xeroderma pigmentosum are prone.

That same ability to ensure that cells retain the characteristics of their particular type may underlie tretinoin's success in treating acute promyelocytic leukaemia (APL), a rare form of leukaemia that has a mortality rate as high as 75 per cent. APL is associated with genetic damage to a key receptor called RAR-alpha that blocks the cells' responsiveness to the body's normal retinoids. Supplying extra retinoid in pill form may have its effect by circumventing this block, nudging the diseased cells of the immune system back into becoming mature, differentiated ones.

By 1994, about 2000 people worldwide suffering from APL had taken tretinoin and had notched up a remission rate of 84 per cent. Remission typically lasts just a few months, though, and rarely longer than a year, but when tretinoin treatment is followed by chemotherapy, the long-term survival rate reaches 75 per cent, says oncologist Raymond Warrell at the Memorial Sloan-Kettering Cancer Center in New York.

And there is even evidence that isotretinoin could help cure cervical cancer or prevent head and neck cancer. In one study, scientists at the University of Texas in Houston showed that when isotretinoin was used with alpha-interferon, it shrank tumours in 26 women with cervical cancer, and completely removed them in 14 cases.

In another study by the same group, only 4 per cent of patients who had previously suffered head or neck cancer developed new tumours when they were given isotretinoin compared with 24 per cent for those given placebos. All of which is a sight more important than a drug that simply makes us look younger.

New-age creams

Tretinoin is the most rigorously tested anti-wrinkle remedy available to date and the only one with a rubber stamp from the Food and Drug Administration.

But other new-generation products that claim to be based on science are under development or already on the cosmetic shelves. Two of these are:

Alpha Hydroxy Acids

Scores of face creams contain what may be the magic ingredient in age-old remedies such as milk, wine and lemons: alpha hydroxy acids or fruit acids.

In 1984, dermatologist Eugene Van Scott, who practices in Pennsylvania, started the whole craze when he treated 27 women with dilute glycolic acid, a type of AHA, twice daily for over three months. Wrinkles improved "markedly" in 12 cases, and "moderately" in nine. Van Scott holds patents on his discovery.

AHAs may work by speeding up shedding of the outer layers of the epidermis. But in February this year, dermatologist ChÉrie Ditre, a consultant for cosmetics company NeoStrata, with Van Scott and their colleagues reported in The Journal of the American Academy of Dematology that AHAs applied for six months also causes the skin to thicken by 25 per cent; the number of water-absorbing molecules called GAGs to increase; and elastin fibres to become more like those in young skin. But AHAs have yet to be rigorously tested in a large clinical trial.


Vitamin E and other antioxidants are showing up on the skin-care counters. In theory, they mop up damaging "free radicals" that form when ultraviolet rays hit molecules inside the skin cells.

Sheldon Pinnell, chief of dermatology at Duke University Medical Center in Durham, North Carolina, thinks that a product he developed that contains a form of Vitamin C (its trade name is Cellex-C) not only acts as an antioxidant, but also stops the suppression of the immune cells in the skin associated with sunburn, so reducing the risk of cancer.

Cellex C's advertising literature includes a picture of a man with the treated half of his face dramatically less wrinkled than the untreated side-far more impressive than the "before" and "after" pictures in the literature describing Renova. But since Renova has won the official seal of approval, it is subject to stringent advertising laws-unlike Cellex-C. Clinical trials of Cellex-C are scheduled to begin this year, so we may soon know more.


Don't expect all anti-wrinkling products to be tested as well as Renova. "To prove the benefits of Renova took millions of dollars," says Dan Piacquadio, a dermatologist at the University of California in San Diego. "A businessman's perspective might be `I can market this product today without a trial, probably make more liberal claims about it, and get millions of dollars-worth of exposure instead'."

From New Scientist magazine, vol 150 issue 2031, 25/05/1996, page 42

© Copyright New Scientist, RBI Ltd 2000