Decreased extracellular-signal-regulated kinase and increased stress-activated MAP kinase activities in aged human skin in vivo

The ability of human skin to rejuvenate itself diminishes with the passage of time, resulting in increased fragility. This increased fragility reflect s both reduced growth of skin cells and loss of collagenous connective tiss ue. Oxidative damage plays a central role in cellular aging. Cellular respo nses to growth signals and oxidative stress are mediated, in part, by growt h-factor-activated and stress-activated MAP kinases. We report here that th e extracellular-signal-regulated MAP kinase pathway is reduced and the stre ss-activated MAP kinase pathway is increased in old, compared with young, h uman skin in vivo. Extracellular-signal-regulated kinase activity was 45% l ower in old skin (mean age 84.3 y) relative to young skin (mean age 23.8 y) . This lower extracellular- signal-regulated kinase activity resulted from reduced activation, since total extracellular-signal-regulated kinase prote in levels did not differ between young and old skin, whereas phosphorylated (i.e., activated) extracellular-signal-regulated kinase protein was reduce d 60% in old skin. Cyclin D2, which is regulated by extracellular-signal-re gulated kinase and functions to promote cell cycle progression, was reduced 50% in old skin compared with young skin. In contrast, stress-activated MA P kinase activity was elevated 3.4-fold in old skin compared with young ski n. This increased activity resulted from enhanced activation, since total s tress-activated MAP kinase protein levels were similar in old and young ski n. Transcription factor c-Jun, which is activated by stress-activated MAP k inases and promotes expression of connective-tissue-degrading matrix metall oproteinases, was elevated 2-fold in old skin compared with young skin. Tre atment of old skin with vitamin A (retinol) for 7 d stimulated extracellula r-signal-regulated kinase activity, consistent with its demonstrated abilit y to stimulate cell growth in old human skin. Taken together, these data in dicate that alterations in MAP kinase activities play a key role in the pat hophysiology of human skin aging.