91av

鈥淲HAT bugs you about your face?鈥� demands Dr Arnold Klein, dermatologist to
Michael Jackson, Dolly Parton and now 91av鈥檚 Los
Angeles office. There is plenty to choose from. He鈥檚 already pointed out that my
upper lip is discoloured, the mark of a past pregnancy. The skin sags more on
the left side of my face than the right. There are blackheads on my nose, specks
of dandruff in my eyebrows, to say nothing of a dimple in my chin due to
age-related bone resorption. By the end of the consultation in his brightly-lit,
mirror-filled Beverly Hills clinic, I am covering my face with my hands.

But it鈥檚 the wrinkles I want treating. They, after all, are the 鈥渉arbingers
of decline, signalling that one is `over the hill鈥�, sliding downward toward
decay and death鈥�, as dermatologist Albert Kligman at the University of
Pennsylvania poetically puts it. Nor am I the only one so preoccupied: 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 鈥渟cientific testing鈥�.

Wrinkle repair

Most skin researchers agree that much of the 鈥渟cience鈥� 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鈥檚 Renova鈥攚hich contains an active ingredient
related to vitamin A called tretinoin鈥攂ecame 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 鈥淣ew-age
creams鈥�), others are spending hours at the bench, usually with drugs company
funding, trying to understand tretinoin鈥檚 modus operandi.

Most of the evidence shows that Renova really does help repair
wrinkles鈥攁t least fine ones鈥攁s 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鈥攁nd, as an added bonus, they鈥檒l 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鈥攖he
dermis鈥攖hat 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鈥檛 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鈥攖here 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鈥檛 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鈥檇 been using Retin-A (which contains tretinoin) for acne, a
standard treatment for the disorder in Britain and the US since the 1970s.

鈥淭hey told me that their wrinkles were going down and their faces looked much
smoother,鈥� says Albert Kligman. 鈥淚 didn鈥檛 see a hell of a lot but finally I got
it into my thick head that they were saying something that was interesting.鈥�
Kligman published his anecdotal evidence in 1986. And within months, Voorhees鈥檚
team began the first controlled test of tretinoin鈥檚 anti-wrinkle properties.

Skin craters

But it was last year鈥檚 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鈥檚 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 鈥渆valuators鈥� 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
鈥渘egative鈥� of each person鈥檚 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 鈥渂efore鈥� and 鈥渁fter鈥� 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鈥檚
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.

Smooth as a . . .

But they can鈥檛 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鈥攁bout
twice the intensity needed to trigger barely perceptible skin reddening鈥攐n
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.

鈥淚t鈥檚 a very interesting result,鈥� says Christopher Griffiths, professor of
dermatology at the University of Manchester. 鈥淚t鈥檚 saying that tretinoin might
not just repair photodamage, but actually prevent it in the first place.鈥�

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鈥攖hey are found in many
sites besides the skin鈥攔eflects 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鈥檚 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鈥攅ven though the
higher concentration caused much more irritation.

Looking good

Unlike scientists, consumers don鈥檛 really care how tretinoin works鈥攁s
long as they鈥檙e 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 鈥攑ossibly
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.

鈥淪o now you have a 43-year-old person who鈥檚 very worried about their wrinkles
and they start using Renova,鈥� he says. 鈥淎nd 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?鈥�

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 鈥渃ure鈥�
skin cells that have taken the first step towards cancer (see 鈥淐ancer
肠谤耻蝉补诲别蝉鈥�).

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鈥檛
create crease-free skin. This shouldn鈥檛 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.

鈥淚t鈥檚 like watching a kid learn to walk,鈥� he says. 鈥淚t鈥檚 rare that someone
goes from total lack of understanding to having the solution鈥攅ach step is
generally a modest improvement over the last. If you evaluate the products in
that light, then they鈥檙e very interesting, promising, encouraging,
蝉耻肠肠别蝉蝉蹿耻濒.鈥�

Which may be all very wise and true, but you won鈥檛 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鈥檛 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鈥攐r even cure鈥攃ancer.

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 鈥渦ndifferentiated鈥�, 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鈥檚 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鈥� responsiveness to the body鈥檚 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 鈥渕arkedly鈥� in
  12 cases, and 鈥渕oderately鈥� 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 Ch茅rie 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.
• Antioxidants
  Vitamin E and other antioxidants are showing up on the skin-care counters. In
  theory, they mop up damaging 鈥渇ree radicals鈥� 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鈥檚 advertising literature includes a picture of a man with the
  treated half of his face dramatically less wrinkled than the untreated
  side鈥攆ar more impressive than the 鈥渂efore鈥� and 鈥渁fter鈥� pictures in the
  literature describing Renova. But since Renova has won the official seal of
  approval, it is subject to stringent advertising laws鈥攗nlike Cellex-C.
  Clinical trials of Cellex-C are scheduled to begin this year, so we may soon
  know more.

Don鈥檛 expect all anti-wrinkling products to be tested as well as Renova. 鈥淭o
prove the benefits of Renova took millions of dollars,鈥� says Dan Piacquadio, a
dermatologist at the University of California in San Diego. 鈥淎 businessman鈥檚
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
颈苍蝉迟别补诲鈥�.鈥�