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Aging, The Molecular Concepts

7. SIGNALLING AND INTERVENTION

With aging, the human skin of Caucasian individuals becomes mottled; it has a reduced ability to tan and an increased risk of melanoma and non-melanoma skin cancers. It is frequently observed that in old skin from Caucasians, areas of hypopigmentation coexist with localized hyperpigmentation, due to the presence of solar lentigines (aging spots). These changes in skin pigmentation appear to result from a general decrease in the number of active melanocytes, starting at the third decade of life, in addition to a focal proliferation of melanocytes in sun-exposed areas (reviewed in 1, 2). Intriguingly, aging spots are not observed in old black skin, although the number of active melanocytes also appears to decrease with age.

7.1. MELANOCYTE AGING IN VIVO AND IN VITRO

Melanocytes in the skin of older individuals are a textbook example of the complexity of human aging. Older skin from Caucasians has irregular pigmentation, particularly in sun-exposed areas. This heterogeneity results from the presence of hypopigmented areas, which coexist with hyperpigmented macules known as solar lentigines. Hypopigmentation may be the result of a decrease in the number of active melanocytes, whereas an increased number of melanocytes in the dermo-epidermal junction and melanosomal complexes in surrounding keratinocytes have been observed in solar lentigines (reviewed in 3). The incidence of solar lentigines increases with age, affecting more than 90% of whites older than 50 years (4). Since inter-follicular melanocytes reside in the skin mostly in a non-proliferative state, it is difficult to hypothesize that melanocytes can exhaust their proliferative capacity during the normal lifespan of the individual. Therefore, we speculate that loss of the differentiated function of some melanocytes may be a major factor in determining hypopigmentation in older skin. This, superimposed on the focal proliferation of some melanocytes, particularly in sun-exposed areas, may contribute to alter skin homeostasis, accelerate skin aging and predispose to melanoma and non-melanoma skin cancers.

The number of population doublings achieved in vitro by human melanocytes exposed to a variety of mitogens depends on the age of the donor (5-7). Melanocytes from neonatal skin undergo 60-80 population doublings (P.D.) whereas cells from adults from 20 to 50 years of age proliferate much more slowly and have fewer P.D. It has been unsuccessful to obtain proliferating cell cultures from donors over 60 years of age. The data displayed here is supported by results obtained with melanocytes isolated from the skin of a patient affected by the Werner's syndrome (WRN), a segmental progeria disease. WRN melanocytes have a dramatically reduced proliferative lifespan compared with aged-matched controls (2-3 P.D. vs 15-20 P.D). These melanocytes show increased dendricity and dendrite arborization (Fig. 7.1B). In addition, some melanocytes show cellular atypia with enlarged nuclei and prominent nucleoli (Fig. 7.1B, inset).

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