The Contribution of Transposons to Differences in Life Span Between Species
Transposable elements in the nuclear genome, also called transposons, are remnant DNA sequences left over from past, often ancient viral infections. A transposon is capable of hijacking the intricate machineries of gene expression to insert further copies of itself into the genome if not suppressed, producing what is effectively DNA damage as these haphazard insertions break existing gene sequences. Further, the transcription of transposon DNA produces viral-like RNA that can provoke an inflammatory innate immune response when present in the cell. Unfortunately, the suppression of transposons weakens with age, allowing these issues to arise and contribute to degenerative aging.
It is entirely unclear as to exactly how much of aging and cancer risk can be attributed to activation of transposons. Absent a means to safely shut down transposon activity near entirely in old animals, efforts to better understand the size of the problem must rely on more indirect approaches. Thus the research community undertakes studies such as the one outlined in today's open access paper. The authors looked over the genomes of selected small mammals with short and long life spans, and compared the differing burden of transposon insertions. It appears that short-lived species at a given body mass tend to have a greater number of potentially active transposons, which might be used to apply some bounds to the degree to which transposon activation constrains life span.
Transposable element (TE) activity and accumulation can have manifold effects on genomes and biological phenotypes. Multiple studies have linked TEs to ageing and the development of several diseases including cancer. Here, we have studied the relationship between TEs and two different aspects of mammal life: longevity and cancer incidence. In rodents, the short lifespan is associated with the presence of cancer. On the other hand, bats are considered cancer-resistant species. The bats and rodents considered in this study are known to have different lifespans while sharing similar, small, body sizes (under 2 kg). H. glaber is the rodent with the longest lifespan known (31 years) and resistant to cancer while the other rodents show shorter lifespans of 12 (C. porcellus), 4 (M. musculus) and 3.8 (R. norvegicus) years.
By analysing the TE annotations, we found that the main difference between short- and long-lived species of rodents is represented by a drop in non-LTR retrotransposon accumulation at recent times. Similarly, the long-lived species of bats showed a drop in non-LTR retrotransposon accumulation at recent times while presenting an overall accumulation of class II transposons (DNA transposons and Helitrons). Previous studies hypothesised that bats have a higher tolerance for the activity of transposable elements with alternative ways to dampen potential health issues due to this activity. Given our observation on the shared drop of non-LTR retrotransposons accumulation in bats and in H. glaber, we add to the aforementioned hypothesis, that the specific repression of non-LTR retrotransposon activity may enhance cancer resistance. In fact, the non-LTR retrotransposons are the most prevalent types of TEs in rodents and the most extensively investigated by biomedical research given that they are the only active TEs in the human genome.
As expected, cancer-prone species present a higher load of recently inserted non-LTR retroelements than cancer-resistant species. While lifespan of rodents showed a strong relation with the recent activity of non-LTR retrotransposons, the same type of relation for bats is less clear. However, based on a comparison of density of insertion (DI) of retrotransposons, we noticed that the long-lived bats show a DI similar to the sole long-lived cancer-resistant rodent (H. glaber), while the sole short-lived bat (M. molossus) shows a DI value more similar to short-lived rodents. Given the pattern of DI observed in rodents, we speculate that the recent accumulation of non-LTRs may be related to the lifespan of these species.
The increased transcription of non-LTR retrotransposons in humans may contribute to so-called "sterile inflammation", a phenomenon for which a chronic state of inflammation is triggered without the presence of any obvious pathogen and that is exacerbated with age ("inflammaging"). The density of recently inserted non-LTR elements in short-lived bat M. molossus is 8269 per Gb, which is comparable to the value in the short-lived rodent Cavia porcellus (9,163 insertions per Gb). In contrast, the long-lived rodent Heterocephalus glaber has a DI of only 4,550 insertions per Gb, while the long-lived bat Myotis lucifugus has 4,531 insertions per Gb. Therefore, we speculate that the marked accumulation of non-LTR retrotransposons in M. molossus might trigger phenomena similar to the sterile inflammation and inflammaging that can cause a shortening of its lifespan. For these reasons M. molossus, together with the well-known H. glaber, may be an exceptional model for biogerontology.