Unlike ageing, longevity is sexually transmitted

Abstract

In the invitation to write this article, I am asked to describe my “…contributions… to cell aging and the telomere story”. My research on the phenomenon of cell senescence began more than 50 years ago. From that time until today, the work done on this subject in my laboratory, and that of hundreds of other researchers, can only be described in the allotted space by a few generalizations and even fewer details. From the birth of cell culture technology in 1907, it was believed that all cultured cells, if provided with the proper conditions, would replicate indefinitely. Fifty-three years later, we overthrew this dogma by finding that, in the best conditions, normal cells have a finite capacity to replicate and that only abnormal or cancer cell populations can replicate indefinitely. We interpreted these findings to impact on our understanding of the aging process. If, as had been thought prior to our work, that normal cultured cells released from in vivo controls can replicate indefinitely, then age changes could not have an intracellular origin. Our findings demonstrated that, on the contrary, age changes do have an intracellular origin. The hundreds of changes that were subsequently found to precede the loss of replicative capacity have been interpreted to be age changes and the finitude of replication to be an expression of longevity determination. Age changes are the result of the inexorable dissipation of energy that occurs in complex biomolecules and that, unless repaired, causes their dysfunction. The positive balance of repair and synthetic processes over accumulating dysfunctional substrate molecules shifts after reproductive success to favor the increase in more dysfunctional molecules over repair capability as the repair processes succumb to the same Second Law of thermodynamics. The processes that control longevity, or how long repair and synthesis processes remain functional and retain their balance over dysfunctional molecules, are governed by the genome. Hence, the information that governs longevity determination is sexually transmitted whereas the aging process is a stochastic or random process governed by the laws of probability that are embodied in the Second Law of thermodynamics. Our search for the location of the molecular mechanism that controls the number of cell, or DNA replications, that occur in normal cells ended with our finding that the mechanism was located in the nucleus. Years later, and as the result of the confluence of studies done by others in several unrelated fields, the molecular mechanism was discovered. It was found that telomere attrition governs the limit on DNA replications in normal cells and that the expression of telomerase can circumvent this limit, thus explaining our discoveries of the phenomena of normal cell mortality and cancer cell immortality.