Reviewing What is Known of the Role of Transposable Element Activity in Aging
Transposable elements make up a sizable portions of the genome, capable of copying themselves to other locations in the genome under the right circumstances. This activity is suppressed in youth, but increases in older individuals for reasons that are still being explored. Transposable element activity is thought to contribute to aging in a similar way to the effects of mutational damage to DNA, setting aside the risk of cancer, meaning a growing disarray in cellular metabolism due to altered genes and gene expression. When this occurs in stem cells or progenitor cells, this disarray might propagate to a sizable fraction of cells in a tissue.
It is still a little early to say to what degree transposable element activity is a problem, in comparison to the other contributing mechanisms of aging, and what the best approach to suppress it might be. Nonetheless, it is worth considering the recent research suggesting that the operation of DNA repair processes that address double-strand breaks in the nuclear genome causes epigenetic changes characteristic of aging. The LINE-1 retrotransposons have been shown to increase the pace at which double-strand breaks occur once they become active. Joining the dots, perhaps this is a plausible mechanism for cellular disarray. It is an interesting connection, but one that needs further exploration and validation, however.
Transposable elements (TEs) are mobile genetic elements able to change their position within a genome, often resulting in a duplication of their sequences. There are two main classes of these genetic elements: DNA transposons, which encode a transposase required for a cut-and-paste mechanism of transposition, and retrotransposons, which transpose by reverse transcription of an RNA intermediate. Mobilization of TEs may have deleterious effects on genomes, such as the induction of chromosome rearrangements and, when inserted in the coding region of a gene, the destruction or alteration of the normal gene functions. For this reason, TEs are normally repressed by specific silencing mechanisms guided by small non-coding RNAs (sncRNAs).
Beyond the deleterious effects, TEs have an important impact on genome-wide gene regulation. In fact, TEs and TE-derived sequences represent a consistent part of the genome of eukaryotic cells and comprise about 46% of the human genome. TE-derived sequences act as transcriptional regulatory regions in a substantial proportion of human genes, contributing to determining the regulation of the controlled genes. In fact, there is clear evidence that regulatory regions of TEs in mammalian cells have been domesticated to modulate the regulation of nearby genes. Transposition of TEs can deposit regulatory sequences across the genome, modifying the regulation of genes located nearby. Some of these events seem to have had evolutionary advantages.
The transposon theory of aging proposed that the increased activation of TEs in somatic tissues during the aging process leads to a shortening of the lifespan. Activation of TEs is a consequence of the loss of repressive structure that occurs gradually with aging in constitutive heterochromatin regions. Since TEs are highly enriched in these domains, loss of heterochromatin induces an increase in TE expression and a consequent increase in transposition rate. While there are different studies that confirm the upregulation in the expression of TEs during aging, it is not clear to which extent this activation is associated to production of de novo TE mutations in somatic tissues.
It is possible that the contribution of TEs to aging does not depend only on the production of de novo mutations. In fact, activation of LINE-1 retrotransposons leads to a high level of DNA double-strand breaks (DSB), while the predicted numbers of successful retrotransposition events appears lower. Since DNA damage is considered a cause of aging, the mechanism by which LINE-1 contributes to aging could depend on the significant degree of inefficiency in the LINE-1 integration process, which, however, produces a progressive increase of DSBs. Given these findings, LINE-1 element activation during the lifetime in somatic tissues has been considered a possible key factor in human aging.