Cell proliferation, cell death and aging.

An integrated view of the processes which most likely play a critical role in the aging process at the cellular level is proposed. Cells are continuously exposed to a variety of internal and external stressors, potentially dangerous for the maintenance of the functional integrity of the cell (UV and gamma radiation, heat, oxygen free radicals, glucose, bacteria, viruses). In the course of evolution a number of mechanisms [DNA repair, production of heat shock and other stress proteins, enzymatic and non-enzymatic antioxidant defence systems, poly(ADP-ribose) polymerase activation] have emerged which allow the cell to cope with such a variety of potentially harmful agents. These mechanisms are in fact interconnected and constitute a network of cellular defence systems. It is suggested that they play a physiological role, being involved in the control of gene expression. A failure of these mechanisms does not allow the cell to maintain homeostasis and has profound consequences as far as two of the major programs of the cell are concerned, i.e. cell proliferation and cell death. Recent data suggesting that these are two physiologically active phenomena tightly linked and regulated are examined. Thus, activation of cell cycle related genes and active inhibition of suicide genes appear to be a part of an integrated process. Conversely, deprivation of growth factors seems able to induce an active process of programmed cell death characterized by Ca++,Mg+(+)-dependent endonuclease activity and DNA fragmentation (apoptosis). Similar phenomena have been shown to accompany the terminal differentiation process in several cellular systems. The understanding of the factors which favour or prevent cell death (a phenomenon which has been recognized as one of the most important in fetal development and morphogenesis) will help to unravel and eventually to manipulate the aging process. In an evolutionary perspective, cell senescence appears to be the price paid to avoid unlimited capability of proliferation, i.e. cell transformation and cancer.