PATHWAY OF 'JUMPING DNA': A PROMISING ROUTE TO DELAY AGEING
Transposable elements (TEs) are mobile genetic elements or jumping genes, stretching 0.1–20 kilobase-long DNA has the function of changing their genomic position which results in insertion mutations in the new locations. In the case of the new location is functional-coding or regulatory sequences, these insertions can lead to phenotypic consequences.
TEs can be broadly classified as relocating DNA transposons and self-replicating retrotransposons. In the case of relocating DNA transposons, where the element moves from site to elsewhere in genomic positions, whereas in self-replicating retrotransposons, the element is copied by reverse transcription and then the duplicate jumps into a new genomic position. Some TEs lose their ability to mobilize due to accumulating mutations, but they can still be activated by intact TEs known as autonomous elements.
The functionality of the TEs is so significant as they constitute a large portion of the eukaryotic genome, 47% of the human genome consists of TE-related repetitive sequences and 97% of these elements are identified as retrotransposons, among which several thousand copies are estimated to be transcriptionally active even though most cannot actively jump. Whether the progressively increasing mobilization of TEs is a cause or a consequence of ageing remains a fundamental problem in biology.
In previous research conducted by scientists at Eötvös Loránd University (ELTE) in Hungary, studies published in 2015 and 2017 had put forward theories regarding the role of the Piwi-piRNA pathway contributed to ageing by helping to control TEs. Now, in their most recent study, they have presented experimental evidence to support and demonstrate the functioning of this pathway.
The piwi-piRNA (P element-induced wimpy testis in Drosophila-Piwi-interacting RNA) pathway is a specific RNA silencing mechanism that protects eukaryotic genomes from the mutagenic effects of TEs. These basically are present in non-ageing cells like germline and cancer stem cells, as well as certain animal species such as freshwater hydra and flatworm planaria, but not in ageing somatic cells. This raises the intriguing possibility that TEs may play a substantial role in the ageing process itself. Accumulating evidence suggests that TEs become more active during the lifespan of various eukaryotic species. However, it remains unclear whether TE activation is a cause or consequence of ageing. Some data suggest that TEs become more active as organisms age, while others suggest that ageing results from increased TE mobilization.
To date, genetic inhibition of entire TE families within eukaryotic genomes has been challenging due to the large number of TE copies. Recent findings have revealed that in mice, LINE-1 retrotransposons, also known as L1 retrotransposons, experience increased transcriptional activity during cellular senescence. Additionally, it was observed that substances inhibiting the reverse transcriptase enzyme of L1 retrotransposons can disrupt age-related inflammation. A comparable beneficial impact of reverse transcriptase inhibitors on extending lifespan had been noted earlier in Drosophila.
In the present study, researchers successfully downregulated specific TE families in the nematode Caenorhabditis elegans, a species with a compact genome containing a relatively small fraction of TE-derived sequences, primarily DNA transposons. This genetic intervention resulted in an extended lifespan for the nematodes. Additionally, when Piwi proteins were ectopically expressed in somatic cells of transgenic nematodes, they also exhibited a longer lifespan compared to controls. Furthermore, the study found that adenine nucleobases within active TE regions progressively became methylated as the nematodes aged, and this change was associated with increased TE transcriptional activity. This research highlights the significant role TEs play in driving the ageing process in nematodes and suggests that TEs may have a similar role in other organisms, providing new insights into the functions of eukaryotic genomes.
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