Importance and Meaning of TERRA Sequences for Aging Mechanisms.

Any theory suggesting an adaptive meaning for aging implicitly postulates the existence of specific mechanisms, genetically determined and modulated, causing progressive decline of an organism. According to the subtelomere-telomere theory, each telomere is covered by a hood formed in the first cell of an organism having a size preserved at each subsequent duplication. Telomere shortening, which is quantitatively different for each cell type according to the telomerase regulation, causes the hood to slide on the subtelomere repressing it by the telomeric position effect. At this point, the theory postulates existence of subtelomeric regulatory sequences, whose progressive transcriptional repression by the hood should cause cellular alterations that would be the likely determinant of aging manifestations. However, sequences with characteristics of these hypothetical sequences have already been described and documented. They are the [sub]TElomeric Repeat-containing RNA (TERRA) sequences. The repression of TERRA sequences causes progressively: (i) down- or up-regulation of many other regulatory sequences; (ii) increase in the probability of activation of cell senescence program (blockage of the ability to replicate and very significant alterations of the cellular functions). When cell senescence program has not been triggered and the repression is partial, there is a partial alteration of the cellular functions that is easily reversible by telomerase activation. Location of the extremely important sequences in chromosomal parts that are most vulnerable to repression by the telomeric hood is evolutionarily unjustifiable if aging is not considered adaptive: this location must be necessarily adaptive with the specific function of determining aging of the cell and consequently of the whole organism.