THE IMMORTALITY SWITCH Essays - Ageing, Telomeres, Gerontology

THE IMMORTALITY SWITCH: TURNING TELOMERASE FUNCTIONALITY ON AND OFF Abstract: A role of telomeres in the aging process and cancer has long been known to exist. Furthermore, telomerase a reverse transcriptase enzyme, has been well characterized as a polymerizing agent of the 3' hydroxy end of DNA strands. The specifics of the roles of telomeres and telomerase and their relations to other cellular processes, however, still need to be better defined. Given the current level of understanding of telomerase, however one deduction can be made with certainty. The most useful information research will be able to provide regarding telomerase's applicability as a clinical treatment tool, is information on how to regulate the production of telomerase, rather than how to either stimulate or inhibit production alone. Fundamentally, how to turn the telomerase production switch on and off is critical given this enzyme's paradoxical nature. Key Words: Senescence, telomeres, telomerase, reverse transcriptase, leading strand, lagging strand, hematopoietic cells, lymphocytes, endometrial cells Conventional replication of linear eukaryotic chromosomes has a well-documented deficiency. During replication, the two strands of the DNA template separate such that a growing fork moves from the 5' to the 3' end of the DNA (7). One of the strands, the leading strand is synthesized continuously. The other strand, the lagging strand, requires a discontinuous method of synthesis from multiple primers, given that continuous replication would have to occur in the 3' to 5' direction and DNA polymerase will only add in the opposite 5' to 3' direction (7, 11). The deficiency in this combination of methods is apparent when the growing replication fork reaches the 3' end of the leading strand. Upon completion of replication of the leading strand, the daughter chromatid is released. This, however, occurs before the lagging strand parts have been completely copied and pieced together. Consequently, the daughter chromatid resulting from synthesis of the lagging strand would theoretically be sh ortened with each replication (7). The cell has derived a mechanism to prevent the loss of the critical nucleotide message in a chromosome. Linear DNA strands have nucleotide caps at each end called telomeres that consist of repeating oligomeric sequences (11). Although telomere data is lost from the lagging strand with each successive replication, this genetic information can be replaced by the enzyme telomerase, which polymerizes the DNA strand from the 3'-hydroxyl end. An RNA template directs the synthesis of telomeric repeats onto DNA substrates (1). Usually, if telomerase does not replace the lost telomeres, the cell reaches senescence after a finite number of cell divisions (7). Senescence marks the end of a cells replicative cycle and indicates imminent cell death (10). Telomerase, therefore, has an apparent ability to prolong cell life. Research has pursued the roles of telomeres and telomerase in two different cellular phenomena: cancer and aging (1-11). The concept of cell immortality, brought on by telomerase activity, gives rise to paradoxical connotations (8). Eternal youth and cancer - could a single enzyme restore beauty and vitality while causing a cellular disaster? Conversely, inhibiting telomerase could curb the growth of rapidly proliferating cancer cells, but that would bring about premature aging according to current research and accepted theory (3,6). The extreme positive and negative effects that come about with either stimulating or repressing the production of telomerase cast doubt on the applicability of telomerase science in a clinical setting (1, 4,5). After all, the role telomerase plays in cancer development suggests that telomerase production should be repressed while the anti-aging benefits of telomerase imply that cells should be coaxed into producing more telomerase (1,9). There is a resolution to this apparent paradox. The discovery that would allow for the application of telomerase as a clinical tool is not the single determination of how to either stimulate or repress telomerase production. Rather the critical discovery in telomerase science is that which will allow clinicians to turn telomerase functionality on and off at will, at specific localities or at specific stages in the cell cycle (10). More than 20 years ago, Olovnikov showed that the loss of telomere sequences, because of the end replication problem, might play a role in regulating cellular life span (9). Telomere shortening was at that time assigned the role of mitotic clock, determining when a cell