GSK3beta and aging liver.

The loss of regenerative capacity of tissues is one of the major characteristics of aging. Liver represents a powerful system for investigations of mechanisms by which aging reduces regenerative capacity of tissues. The studies within last five years revealed critical role of epigenetic silencing in the inhibition of liver proliferation in old mice. These studies have shown that a number of cell cycle proteins are silenced in livers of old mice by C/EBPalpha-HDAC1-Brm complex and that old liver fails to reduce the complex and activate these genes in response to proliferative stimulus such as partial hepatectomy. The complex modifies histone H3 on the promoters of c-myc and FoxM1B in the manner which prevents expression of these genes. Despite this progress, little is known about mechanisms by which aging causes this epigenetic silencing. We have recently discovered signal transduction pathways which operate upstream of the C/EBPalpha-HDAC1-Brm complex. These pathways involve communications of growth hormone, GSK3beta and cyclin D3. In addition to the liver, GH-GSK3beta-cyclin D3 pathway is also changed with age in lung, brain and adipose tissues. We suggest that other age-associated alterations in these tissues might be mediated by the reduced levels of GSK3beta and by elevation of cyclin D3. In this review, we summarize these new data and discuss the role of such alterations in the development of aging phenotype in the liver and in other tissues.