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    Understanding mechanisms of aging in skin

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    Dr. Nishigori
    Singapore — To understand the aging process and its effect on the skin, it is useful to consider three categories of aging: the normal aging process, premature aging associated with genetic disorders and aging resulting from.environmental damage, according to Chikako Nishigori, Ph.D., M.D., professor and chairman of the division of dermatology, Kobe University Graduate School of Medicine, Hyogo, Japan. Among environmental causes of premature aging, the long-term effects of repeated exposure to UV are the most significant, leading to photoaging.

    Defective DNA repair or replication may be responsible for the complex process of aging.

    "One theory to explain the aging process is that aging is caused by the imbalance between the formation of DNA damage caused by daily life and the ability of the cells to repair the DNA damage,"Dr. Nishigori says. Evidence of the role that DNA repair plays in the aging process comes in part from studies of genetic disorders such as Werner's syndrome, an autosomal recessive disorder characterized by the premature appearance of many features of normal aging. In tissue culture, the lifespan of fibroblasts from individuals with Werner's syndrome is markedly reduced compared to that of fibroblasts from normal individuals. Patients with Werner's syndrome have a mutation that abolishes the function of a helicase enzyme essential for DNA repair and for maintenance of telomeres at the end of chromosomes.

    "Telomere shortening may be the molecular clock that triggers senescence," Dr. Nishigori says.

    Photoaging differs Damage from ultraviolet light impairs skin function and causes coarse wrinkling, thickening and roughness, sebaceous hyperplasia and uneven pigmentation in the exposed skin. Decreased levels of type I and type III collagen and increased levels of elastic fiber are among the histological features that characterize the dermal changes in photoaged skin. By contrast, the normal aging process causes atrophy, dryness and fine wrinkles in skin. Although sebaceous hyperplasia and uneven pigmentation occur with normal aging, these features appear less striking than in photoaged skin.

    Ultraviolet radiation includes UVA, UVB and UVC radiation. UVA has the lowest energy and causes cellular damage indirectly through an endogenous photosensitizer. UVB irradiation can directly crosslink DNA at dipyrimidine sites to produce cyclobutane-pyrimidine dimers and (6-4) photoproducts. UVB irradiation can also produce cellular damage indirectly in the presence of a photosensitizer, either with or without the involvement of oxygen. UVC radiation has high energy and leads directly to pyrimidine dimmer formation.

    One of many structures formed by UV irradiation, 8-hydroxyguanine (8-OHG) serves as a sensitive marker of oxidative DNA damage. UVB radiation can form 8-OHdG directly via an electron or hydrogen transfer reaction or via reaction with an oxygen molecule in the presence of a photosensitizer. Formation of 8-OHdG can lead to a G:C to T:A transversion as a consequence of 8-OHdG pairing with adenine instead of cytosine.

    Inflammation plays role Dr. Nishigori and colleagues measured the amount of 8-OHdG in skin samples from chronically UV-irradiated mice and found that the levels of 8-OHdG were not completely UV-dose-dependent, indicating that additional components were likely to be involved in the formation of reactive oxygen species. Additional research indicated that reactions with nitric oxide and superoxide from neutrophils recruited in an inflammatory response also generate 8-OHdG. Repeated inflammation appears to play a significant role in the photoaging process.

    "Both intrinsic aging and photoaging are related to oxidative stress," says Dr. Nishigori, "but despite the fact that both aging processes can share the same consequences, such as skin cancer, the events occurring in these two processes are very much different."

    Disclosure: Dr.Nishigori reports no conflicts of interest.

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