The Mechanism of Phenoptosis: 2. The Hayflick Limit Is Caused by Programmed Decrease of the Bioenergetics Level

This paper continues an early attempt at substantiation of the programmed aging mechanism (phenoptosis). The concept underlying this mechanism is that life represents many interrelated physical and chemical processes propelled by bioenergetics. The gradual programmed decrease of the bioenergetics level causes slow and coordinated weakening of all physiological functions, i.e., aging. For a convincing substan tiation of such a mechanism, it is necessary to show how the bioenergetics decrease causes the basic harmful processes accompanying aging. It has been shown earlier that the agedependent decrease of the bioenerget ics level causes an increase of reactive oxygen production by mitochondria and decrease of the overall level of protein synthesis. Evidence that termination of cell proliferation after a certain number of doublings (the Hayflick limit) is also caused by the agerelated decrease of the bioenergetics level is presented in this paper. Old cells stop dividing because decrease of the bioenergetics level below a certain critical level deprives a cell of its ability to pass the G1phase restriction point of the proliferative cycle. The cyclindependent kinase inhibitor p27 prevents a cell (except embryonic and cancer cells) from passing through this critical point. During division of normal somatic cells, p27 is removed by the active cyclin ECdk2 complex in response to mitogen stimulation. Interaction of p27 with the cyclin ECdk2 complex can have two consequences. At the normal physiological level of bioenergetics, the cyclin ECdk2 phosphorylates p27. After that the latter is destroyed by proteolytic enzymes and the cell enters the Sphase. If the bioenergetics level decreases below a certain level, the cyclin ECdk2 becomes a target for p27. As a result the inhibitor elimination stops and a restriction point becomes closed—a cell enters an irreversible proliferative rest.