Aging and Cellular Defense Mechanisms

The quest for increasing the life span of men and women on earth is not a recent issue. FIGURE 1 is the front page of the Italian translation of a book by Hufeland, which appeared in 1798. The book describes methods to increase the life span and discusses and refutes statements by authors such as Cohausen, Boerhaave, Cagliostro, Mesmer, and Paracelsus, who were active in Europe between the fifteenth and eighteenth centuries. In my opinion, however, the most thought-provoking way to improve life span is still the one designed by Eos to increase the life expectancy of her lover, Tithonos. According to Greek mythology, Eos, the pink-fingered goddess of dawn, was in love with Tithonos, a mortal human male. Afraid that Tithonos’s death might bring their happiness to an end, Eos asked Zeus to allow Tithonos to become immortal. Zeus agreed, and Tithonos grew older and older and became worn and torn and used by consumption, so that eventually only his voice was left: Eos had forgotten to ask for eternal youth! Besides the poetic meaning of the myth, Eos’s drama might lead one to attempt a definition of eternal youth. One might define youth by comparing it to old age. Senescence might therefore be defined as the sum of the time-dependent phenomena associated with modifications and impairment of cellular function, and aging is the sum of the phenomena related to the time-dependent impairment of the physiological functions of an organ or organism. With these definitions in mind, for an individual at the end of development, that is, when all his genetic potential is expressed, eternal youth is the capability to not grow old, that is, to remain unchanged, despite the interaction with the environment. A reductionistic point of view might suggest that eternal youth is the capability to replace exactly the accidentally modified molecular components of the organism, that is, the ability of all the cells, when necessary, to reproduce strictly identical copies of themselves and to synthesize and deliver molecules everywhere in the organism when an accidental modification has occurred. Incidentally, this definition bears the not unexpected consequence that eternal youth be associated with complete unfitness for learning. One tenet of molecular biology is that a cell knows how to get rid of damaged cellular components and that the information stored in DNA allows the reconstitution of the molecular pool necessary to perform the physiological functions of the cell. With this hypothesis, it is expected that only the accumulation of unfaithfully repaired DNA damages (mutations) will play a role in promoting cellular wear and tear; in replacement of accidentally modified cellular components, in mutated cells, an ever growing number of molecules will be synthesized, which will differ from the original design. The accumulation of mutations might lead to cell death because of the loss of functional activities, as expected in a nonviable mutation of an enzyme implicated in the respiratory chain. It is also possible that the accumulation of mutations will lead to the synthesis of outer-membrane proteins that are so different from the originally