On the role of intracellular physicochemistry in quantitative gene expression during aging and the effect of centrophenoxine. A review

Abstract

The turnover of proteins in biological systems is due mostly to an ever-occuring damaging (cross-linking) effect of the OH' free radicals. The replacement of the damaged proteins requires a continuous gene expression. A key issue of experimental gerontology is why the gene expression maintains the fidelity but loses the speed during aging. The membrane hypothesis of aging (MHA) proposes a cellular mechanism based on the fact that the more compact cellular structures (e.g., membranes) are damaged faster than the more diluted ones (e.g., cytosol). In addition, the cell membrane is exposed also to the residual heat-induced damage deriving from a frequent discharge of its electric polarity. Therefore, one can assume that even an extremely small incompleteness of the replacement of the damaged membrane components per turnover cycle may result in an error accumulation, which may be responsible first for the inhibition of growth, then for aging of cells. In agreement with this hypothesis, neurons display a life-long, gradual loss of the passive potassium permeability of the cell membrane, resulting in a continuous dehydration of the intracellular mass, i.e., an increase of physical density. Theory and experimental models show that this latter process causes a slowing down of all enzyme functions including those realizing the gene expression and the elimination of the damaged components. Increase of-the dry mass content of cells and tissues is an obligatory process for maturation; however, later on it leads to aging. The known nootropic effects of centrophenoxine (CPH) can be interpreted on the basis of the OH' radical scavenger properties of dimethylaminoethanol (DMAE) which is incorporated in the neuronal membranes of the brain in form of phosphatidyl-DMAE. The protective effects of CPH (and of similar, newly synthesized other drugs) on the membrane components can slow down the age-dependent deteriorations of the intracellular physicochemistry, in agreement with the predictions of the MHA.