If course, chronic overexposure to ultraviolet (UV) light is one of the major causes of older-looking skin and, as a result, many skin rejuvenation procedures focus on correcting photo-aging effects. But according to one expert, future skin rejuvenation modalities may also include efforts to repair the DNA damage induced by UV rays — and here immunomodulation is key.

"It has become common knowledge that sun exposure causes direct damage to the DNA in our skin cells," says Elma Baron, M.D., assistant professor and director of the Skin Study Center, Department of Dermatology, Case Western Reserve University, Cleveland, Ohio. "Aside from the direct cancerous effects of unrepaired DNA damage, DNA damage also plays a major role in UV-induced immunosuppression. It is this DNA damage and the inadequate repair of this damage that lead to a suppression of the skin's immune system, which opens up Pandora's box in terms of the development of cutaneous carcinomas, as well as the photo-aging effects of the skin," Dr. Baron tells Cosmetic Surgery Times .

SUNSCREEN SUPPLEMENTS Although many skin care products are available to help rejuvenate the skin with pro-active enzymes, antioxidants and other "fountain of youth-like" ingredients, novel over-the-counter cosmeceuticals are also being developed that contain DNA repair enzymes to prevent UV suppression. These enzymes may also reverse the detrimental skin effects of overexposure to UV rays. But just how efficacious are such topicals?

"We found that with the use of this product that contains DNA repair ingredients, the participants were significantly less prone to the suppressive effects of UV light, compared to the study group who underwent the UV exposure without prior use of the product," Dr. Baron relates. "Essentially, those who received an application of the moisturizer containing DNA repair ingredients were able to recognize the allergen better than the control group."

According to Dr. Baron, the use of topical products that contain DNA repair enzymes such as that used in this study appears to be beneficial in shielding the skin from the harmful effects of UV radiation and is able to prevent the suppression of the skin's immune system. This important finding is particularly useful in those individuals who expose themselves to harmful UV radiation, as the application of such a moisturizer offers an added protection of the skin in addition to commonly used sunscreens.

A DELICATE BALANCE The main purpose of the skin's immune system is to provide immuno-surveillance, which increases the skin's resistance to the development of skin cancer, not necessarily to prevent photoaging. This is perhaps best illustrated in transplant patients who receive iatrogenic immunosuppression and who are much more susceptible to the development of cutaneous cancers than normal populations.

However, some of the mechanisms of UV-induced photoaging overlap with the development of skin cancer because as we age and receive more photo-damage, we also develop more skin cancers. In the process of mounting an adequate immune response to the harmful UV radiation, though, the skin defense systems begin to recruit and muster inflammatory cells such as macrophages, neutrophils and other cellular immune components that release enzymes that also have the potential to cause the degradation of various skin components such as collagen.

"There is a very delicate balance as to whether we want more of an immune response or less of an immune response to take place and keeping this fine balance is key in cutaneous homeostasis," Dr. Baron says. "Just where this fine line lies and how much of an immune response is good to hold that fine balance is currently still unknown. In terms of UV-induced aging, whether a decreased immune response is more beneficial or, contrarily, having a very avid immune response where inflammatory cells release hydrogen peroxide and other enzymes that can eventually degrade the skin's matrix (causing wrinkling and other signs of skin aging) is still a gray area."

Cosmetic surgeons know well the fine line that exists between marketing spin and what has been scientifically proven to work. The same goes for cosmetic skin care: While there is no shortage of products promising to diminish signs of skin aging, only a few ingredients have actual science to back their claims, experts say.

MAKING THE CUT

Dermatologists agree the gold standard is the retinoid — first and foremost, prescription tretinoin. Over-the-counter retinoid derivatives include retinaldehyde and retinol.

Retinoids are the tried and true molecules that not only help increase collagen production, but also enhance cell turnover, normalization of the stratum corneum, remove pigment in the skin, normalize epidermal cells and make pores smaller, according to Kathy Fields, M.D., dermatologist and assistant clinical professor at University of California, San Francisco's department of dermatology.

"That is square one," Dr. Fields says.

IN THE WORKS

Peptides, growth factors, botanicals and even stem cells are making headlines in skin care.

"This would be...inclusive of all aspects including stem cells (adult and embryonic); growth factors; engineered proteins (proteonomics); recombinant DNA products to fight/halt/reverse aging; the next wave of human growth hormone, or HGH; and a better understanding and control of immune system function, along with the relative and absolute declines in hormonal balances," Dr. Werschler says. While some of these mechanisms of action might pan out, others might not.

The latest news in stem cell technology, according to Dr. Fields, is in retrieving the cells from plants.

"[The theory is that] you get all the ingredients to create new life from a cell ... such as growing skin," she says.

"Peptide technology...works on so many levels. Peptides can be anticancer, antimicrobial, antibacterial, stimulate collagen, stimulate growth factor," she says.

But dermatologists also question the viability of some active ingredients.

"...growth factors on the market, which are huge molecules that are very unlikely to penetrate the skin, ...would make terrific moisturizers," Dr. Spencer says. "We have penta-peptides and hexa-peptides [but again] penetration is the issue. I do not mean to be too skeptical but...you put these molecules on the outside of the skin and they have to get in to work. That does not mean that they do not work, it is just that they have not been shown to work."

CARY, N.C. Botulinum toxin type A (Botox; Allergan) has proven to be a powerful tool in facial rejuvenation and is readily used in aesthetic medicine for the treatment of lower eyelid lines and wrinkles. Just how much botulinum A toxin and precisely where the injections should be placed when treating these areas clearly differs from patient to patient, but according to one study, botulinum A toxin for the treatment of infraorbital lines and wrinkles can achieve better cosmetic results when the lower eyelid orbicularis oculi muscle is treated concomitantly with the lateral orbital area, resulting in a more youthful widening of the eye.

Dr. Flynn

"One of the major endpoints of this kind of facial rejuvenation is to try to give the patient a more youthful, wider eye. In my experience, I have seen that this can be best achieved when treating not only the orbicularis oculi muscle, but also the lateral orbital area," he tells Cosmetic Surgery Times.

PEEPER PROTOCOL In the study, each patient received two units of botulinum A toxin in the lower eyelid subdermally in the midpupillary line precisely 3 mm below the ciliary margin. The opposite periocular area received two units of botulinum A toxin in the lower eyelid, and 12 units of botulinum A toxin injected into the lateral orbital area (crow's feet). The lateral orbital area injections were divided into three injections consisting of four units each, and were placed 1.5 cm from the lateral canthus (located 1 cm outside the lower orbital rim), each 1 cm apart.

"Clinically, most patients who seek botulinum A toxin treatment for their fine lines and wrinkles usually have several different areas treated simultaneously, and one common site of treatment is the lateral orbital area or crow's feet area," Dr. Flynn says.

According to Dr. Flynn, the results of this study show that while only a slight improvement of rhytids is achieved when using two units alone in the lower eyelid, when these two units are combined with 12 units of botulinum A toxin in the lateral orbital area, a moderate improvement of the rhytids can be achieved.

"Furthermore, the concomitant treatment of both these areas in one visit proves to be safe and has few if any complications," he adds.

This patient received Botox to the lower eyelid and concomitant treatment of the crow's feet. The treatment effect can best be observed when the patient exhibits a full smile, as she is in both pre- (left) and post-procedure (right) photos. (Photo credit: Timothy C. Flynn, M.D.)

According to Dr. Flynn, an increased palpebral aperture was noted for both two units in the lower eyelid (6 of 15 patients; 40 percent) and also for two units in the lower eyelid plus 12 units in the lateral orbital area. However, a significant increase in the palpebral aperture was seen when both the lower eyelid and the lateral orbital area were concomitantly treated (12 of 15 patients; 86 percent), and this could best be observed when the patients exhibited a full smile.

NATIONAL REPORT With the high patient demand for liposuction comes an equally high interest in developing new, more effective, and less invasive methods for achieving the same — or better — results. While Gregory Roche, M.D., in private practice in Bloomfield Hills, Mich., touts the new Zerona laser (Erchonia Medical) as such an alternative, other cosmetic surgeon experts await additional data. "The laser works by dragging the fatty content of the cells out of the cells through the cell membrane into the extracellular space, resulting in deflation of the adipose cells," Dr. Roche, who recently studied the effects of the Zerona laser, tells Cosmetic Surgery Times . "This has been proven by histology and scanning microscopy," he adds.

Dr. Roche

A total of 62.86 percent of patients in the treatment group and 6.25 percent of patients in the placebo group achieved a total decrease of three inches or more in combined circumference measurements from pre-procedure to study endpoint. Additionally, patients in the treatment group lost an average of 2.837 inches more than patients in the placebo group. Compared with baseline, total circumference measurements were statistically lower at week 1, week 2, and 2 weeks post-procedure. Patients in the treatment group achieved an overall decrease of 3.22 inches in total circumference measurements between baseline and two weeks after the procedure, which was statistically significant. Patients in the placebo group achieved an overall decrease of 0.62 inches in total circumference measurements during the same time period.

This histological series depicts the Zerona lasers purported effect; the thinning of the cell wall (Fig. 6) allowing lipid passage into the extracellular space and the cells subsequent collapse. (All photos credit: Gregory Roche, M.D.)

Dr. Nir

THE WHOLE TOMATO The small pilot study showed that Lyc-O-Mato, a tomato extract formulation, reduced sunburn cell formation and slowed depletion of Langerhans cells after exposure to a UVB/UVA solar simulator. The unpublished study was conducted by the extract's developer, Israeli-based company, LycoRed Ltd.

In the study, 10 male and female subjects over 18 years of age were randomized into two groups of five. For 10 weeks, group 1 consumed 85mg of Lyc-O-Mato 6 percent capsules twice daily, and group 2 consumed a placebo twice daily. Each Lyc-O-Mato capsule contains 5 mg of pure lycopene, as well as a mixture of other tomato-derived phytonutrients, such as phytoene, phytofluene, beta-carotene, tocopherols and phytosterols. At the end of the 10 weeks, subjects were exposed to two minimal erythemal doses (MED) of UV radiation from a solar simulator, and 24 hours later skin cells were biopsied and assessed. The Lyc-O-Mato group showed a sunburn cell count six times lower than that in the placebo group as well as evidence of reduced depletion of Langerhans cells, according to Zohar Nir, Ph.D., Chemistry, Weizmann Institute of Science in Rohovot, Israel, and vice president of new product development for LycoRed. These findings are important on two fronts, according to Dr. Nir. "First, sunburn cell formation is indicative of photo-damage to the skin, and, second, depletion of Langerhans cells negatively affects the important immune function of the skin." The Lyc-O-Mato mechanism is simple, he says: "The interaction of radiation with the skin creates reactive oxygen species (ROS), and lycopene is the most effective quencher of the ROS free radicals responsible for oxidative stress and hence, damage of the skin."

Dr. McDaniel

"Oral supplements such as this mixture of lycopene and related carotenoids need further studies like this one to expand our understanding of how oral antioxidants impact our skin — both for health and beauty," states Dr. McDaniel. "It would be interesting," he adds, "to understand better what biochemical pathways are being impacted by this product. Meanwhile, we already know that carotenoids are some of the most potent antioxidants for interacting with singlet oxygen, one of the important free radicals involved in premature aging and other diseases."

If there is no normal, what is abnormal? This existential question is one issue in the medical debate surrounding vitamin D and sunlight. It is also a question the Institute of Medicine (IOM) has set out to answer. The organization has formed a committee to assess the current relevant evidence and update its dietary reference intakes for vitamin D and calcium.

The most current IOM guidelines for the adequate daily intake of vitamin D were published in 1997. They recommend 200 IU for children and adults up to 50 years of age, 400 IU for adults 51 to 70 years of age and 600 IU for adults 71 years of age and older. The FDA suggests a slightly higher daily value of 400 IU for those older than four years. And vitamin D advocates believe children and adults will experience many benefits with an intake twice that, about 800 IU to 1000 IU daily.

If the IOM's results — expected May 2010 — suggest that the elevated levels are more accurate, then a significant portion of the population may be found vitamin D deficient, "at least during the winter," says Dr. Spencer. To counteract this deficiency and the subsequent negative effects, some vitamin D advocates recommend five to 30 minutes of daily unprotected sun exposure — no sunscreen, hats or umbrellas. This is another issue in the vitamin D controversy.

"On the other side of the coin is the skin cancer story. I think it's beyond debate that UV light causes skin cancer," says Dr. Spencer. The medical community has cautioned for years against unnecessary and/or extensive sun exposure to reduce the risk of melanoma.

So how can individuals incorporate these contradictory messages into their lifestyles? "There is no conflict. We can protect ourselves from sun and the development of skin cancer and wrinkles and still enjoy the benefits of vitamin D simply with a healthy diet and use of vitamin pills," says Dr. Spencer.

The Evidence

The exact benefits of vitamin D present a gap in available research. Much of the vitamin D literature focuses on the geographic variability of the incidence and/or mortality of disease. For instance, notes Dr. Spencer, the incidence of colon cancer is higher in the Northeast than the Southeast. "This latitudinal gradient is quite striking in the East and Midwest," says Dr. Spencer, adding it is not seen in the West.

Researchers have postulated the reason is linked to different vitamin D levels associated with varying climatic sun exposure. "There are 50 or so papers describing the geographic variability. They say multiple sclerosis is a rare disease near the equator, but does that prove anything?" asks Dr. Spencer.

Although the correlations have been well documented, vitamin D's role in disease incidence and progression remains unproven. "Vitamin D could be a stand-in for general nutritional status, for example," says Dr. Spencer.

Complicating the data are mixed results from prospective interventional trials examining vitamin D's impact on disease incidence. "Some studies have shown that vitamin D takers had the same incidence rate as those who didn't take vitamin pills, and some have shown vitamin D takers got less cancer," says Dr. Spencer, noting there is not a lot of literature of this type.

The lack of consistent evidence leads some to question if vitamin D is the new vitamin C. Dr. Spencer recalls the craze over ascorbic acid led by Linus Carl Pauling, a two-time Nobel winner, in the 1970s and 1980s. Research completed by Pauling and colleagues suggested very large doses of vitamin C could offer cold- and cancer-fighting benefits. This later turned out not to be true.

The IOM committee will identify where the gaps in research on vitamin D lie. Future studies will likely be designed to answer some of these questions.

Dr. Levitt

The proposed ban of its over-the-counter sales was based on controversial murine models suggesting that hydroquinone could act as a carcinogen, along with reports, also controversial, linking the product with exogenous ochronosis. The FDA's action was met with strong opposition from the largest user of hydroquinone, the aesthetic dermatologic community, which was adamant in its assertion of the product's safety, and, after the four-month period of public comment, no regulatory action was taken.

But the issue was never officially put to bed, and with hydroquinone bans currently on in the European Union, Japan and Australia, doctors and patients alike may be justified in wondering if hydroquinone remains on borrowed time in the U.S.

"The studies showed that the strain of rats that developed kidney problems also developed the problems independently, even without hydroquinone exposure, because they were genetically predisposed to do so, so it was unfair to link their tumors to hydroquinone," says Dr. Levitt, an assistant clinical professor of dermatology at the Mount Sinai Medical Center in New York.

DATA DETOUR Not only did the studies fail to prove a carcinogenic link, but with respect to the liver they could, in fact, easily be read to suggest the opposite, he adds. "There was indeed a slight increase in benign adenomas in relation to hydroquinone exposure, but there was a decrease in malignant liver carcinomas, so you could argue that hydroquinone had a protective effect." Ultimately, he holds, the "systemic exposure to hydroquinone from routine topical application is no greater than that from quantities present in common foods."

Dr. Levitt also evaluated the FDA concern that hydroquinone could increase the risk for ochronosis, and found a remarkably low incidence rate in relation to hydroquinone usage.

As noted by Dr. Levitt in his paper, "A literature review of exogenous ochronosis and clinical studies employing hydroquinone (involving over 10,000 exposures under careful clinical supervision) reveal an incidence of exogenous ochronosis in the United States of 22 cases in more than 50 years."

Interestingly, the majority of ochronosis cases found were associated with lower — not higher — concentrations of hydroquinone (2 percent, as opposed to the prescription strength of 4 percent). This suggests overuse of the product at the consumer level may be a potential problem, and offers one bit of support for limiting its use to doctor-supervised prescriptions only.

"The way dermatologists use hydroquinone is to use it over a period of about three months and if it doesn't work, you stop," Dr. Levitt explains. "After six months or so, you'll probably get a plateau of effect anyway, and will also need to stop; but if people are using the product over-the-counter every day for 10 or 20 years, then there can be a problem and in that regard, I could defend keeping it as prescription only." Dr. Levitt notes that prior to its proposal for the ban, the FDA itself had already approved a hydroquinone-containing product, the melasma treatment Tri-Luma, a prescription-strength topical containing retinoid (0.5 percent tretinoin), steroid (0.01 percent fluocinolone acetonide) and hydroquinone (4 percent).

Dr. Zülli

Research indicates that CoQ10, or ubiquinone, has what it takes to counter the effects of age on the skin. Findings reviewed here explain why and how this ubiquitous enzyme can offer meaningful results to patients interested not only in staving off the appearance of advancing age, but also the deleterious effects of photoaging.

AT THE CELLULAR LEVEL In a study funded by German skin care product manufacturer Beiersdorf AG, researchers showed that aging skin is functionally anaerobic and that CoQ10 positively influences the age-affected cellular metabolism by essentially facilitating a battle against the signs of aging that start at the cellular level. "Cutaneous aging is characterized by a decline in energy metabolism of skin cells partially caused by detrimental changes in mitochondrial respiration," explains Thomas Blatt, Ph.D., human biologist, who heads up skin aging research at Beiersdorf and is one of the study authors. "The processes involved seem to be predominantly mediated by free radical actions known to be generated either by exogenous [influences] such as UV light, or by endogenous processes such as impaired mitochondrial respiration and generation of ROS [reactive oxygen species] by leakage of electrons from the respiratory chain."

The skin attempts to compensate for this loss of mitochondrial energetic capacity by getting energy from other sources. "This is either through the exploitation of intracellular energy stores for high energy demands in the short term, or the switch to anaerobic pathways for energy supply, such as glycolysis, as a last resort," he notes. In this context, glycolysis, used by a cell as a last resort, is associated with the generation of reactive glycolytic intermediates. These, Dr. Blatt says, favor the formation of advanced glycation end products (AGEs) via reactive carbonyl groups.

"These AGEs may harm a cell by processes ranging from the generation of infunctional cytoskeletal proteins up to the induction of apoptosis. Thus, it's important to keep tissues from anaerobiosis by keeping mitochondrial energy generation upright. Furthermore, it's important to supply a cell with substantial energy stores — to be filled with energy in phases of baseline activity — which can be used in situations of high energy demand without the need to switch to glycolysis," he states.

While there are several entry points to affect skin aging from an energy perspective, according to Dr. Blatt, it's important to keep in mind that active ingredients keep the respiratory chain in skin cells working in order to avoid generation of ROS. The study findings support that this can be achieved via supplementation with CoQ10, which Dr. Blatt describes as a key component of the respiratory chain.

"CoQ10 declines with age but can be effectively replenished in skin by topical formulations — as long as the appropriate formulations ensure that CoQ10 is bioavailable and fully integrates into the mitochondria," he adds.