Mechanism' therapy: Reversing the effects of environmental, genetic factors in aging skin

Key Points

Boston - Over the past four decades, a great deal has been learned about the mechanisms of aging in general, and skin aging in particular, says Barbara Gilchrest, M.D., professor and chairman emeritus of dermatology, Boston University, Boston.

Genetic and environmental factors are the two major components of skin photoaging, and the major environmental culprit is ultraviolet radiation from the sun. Photoaging is responsible for dyspigmentation, wrinkling, laxity and other visible changes in the skin. It also contributes to functional losses, such as reduced wound-healing capacity, thermoregulation and immune competence. These become increasingly compromised as we age, she says.

Older skin is also more prone to skin cancer. In fact, there is an exponential increase in skin cancer risk starting at about age 50, according to Dr. Gilchrest.

Improving appearance

Not so long ago, the belief that photoaging was irreversible was universally held, but this began to change after a landmark study by John Voorhees and colleagues at the University of Michigan (JAMA. 1988;259(4):527-532), performed in follow-up to clinical observations by Albert Kligman, M.D., at the University of Pennsylvania, showed that retinoic acid applied to the skin could diminish wrinkles and improve the appearance of photoaged skin.

"This was a real watershed in skin aging. Up to that point, it was thought that moisturizers were nice and all that, but the thought that anything could reverse any part of the aging process was so against the dogma that, even though the study was beautifully done and published in a stringently peer-reviewed journal, everybody wanted not to believe it," Dr. Gilchrest says.

Disbelief was so strong that the New York Times sent a team of reporters to search for evidence that Dr. Voorhees and colleagues had somehow falsified their results. "They were absolutely convinced that the Michigan group had doctored their photos and went to search for evidence of cheating," Dr. Gilchrest says. They found none.

Retinoic acid

Retinoic acid is the active metabolite of vitamin A and is a critical morphogen during embryonic development that must be available to the fetus at the right level in order for normal development to occur. It is also an important regulator of development and homeostasis in tissues, including skin, and is essential for normal skin throughout life.

Importantly, retinoic acid appears to be involved in the production of collagen. But, with age, functional retinoic acid levels in the skin decline. Treating photoaged skin topically with retinoic acid corrects this deficiency, Dr. Gilchrest says.

"Ultraviolet radiation activates matrix metalloproteases, a group of enzymes that degrade collagen and other matrix components. The amount of light that is required to do that is very modest. When you go out in the sun, you are just chewing up the matrix in your dermis," she says.

Retinoic acid treatment blocks this process, and can prevent the UV-induced breakdown of collagen in the dermis.

Topical retinol, which is metabolized to retinoic acid in the skin, corrects even intrinsic aging changes when applied to sun-protected skin of elderly subjects. Over a period of months, retinol reduces wrinkling and increases collagen and glycosaminoglycans.

"An important message here, which is very consistent with other work being done in the aging field, generally, is that aging and photoaging have many things in common and will respond similarly to the same interventions. Things that work to fix photoaging changes can also fix intrinsic aging changes," Dr. Gilchrest says.

Other products, such as antioxidants and alpha hydroxy acids, are touted as improving the appearance of photoaged skin, but these have not been as rigorously studied as the retinoids, and there are no data from rigorously done trials to prove they reverse aging changes in skin.

CO₂ laser resurfacing can improve skin texture, even out pigmentation irregularities and reduce wrinkling. Another alternative is photodynamic therapy (PDT) using aminolevulinic acid, Dr. Gilchrest says.

Photodynamic therapy

"When aminolevulinic acid is applied to the skin, it is metabolized to a protoporphyrin. Radiating the skin with visible blue or red light activates the protoporphyrin molecule, which kills off the more damaged cells near the surface, thus allowing younger cells to move up to the surface and make new skin. A similar effect occurs with fibroblasts, to produce dermal changes that improve skin as well," Dr. Gilchrest explains.

"The group from the University of Michigan has shown that PDT accelerates epidermal turnover, increases epidermal thickness and collagen production, both at the message level and at the protein level. These are very similar to the changes that you observe after a CO₂ laser resurfacing," she says.

PDT and topical retinoid therapy appear to decrease skin cancer risk. "The aging process makes skin cancer-prone," Dr. Gilchrest says. "PDT gets rid of the cells that are already halfway to being cancerous. Improving the quality of the matrix and the dermis also seems to have the effect of decreasing cancer risk."

Oligonucleotides

A future weapon in the fight against photoaging may be oligonucleotides - small pieces of DNA, specifically those with the same TTAGGG repeat sequence as the cell's own telomeres. Currently experimental, oligonucleotides increase pigment production - a major defense against UV damage - and increase DNA repair capacity when applied to skin cells in vitro or to mice in vivo. They also activate the telomerase complex and increase telomere length in cultured cells.