A group of scientists from Colorado State University has discovered that repetitive elements (REs) in our DNA increase with aging and react to known longevity-promoting interventions [1].
Are REs genomic parasites?
At the dawn of genomic research scientists were stunned to learn that as much as 95% of our genome is non-coding: it does not code for proteins that our body needs in order to operate. A lot of what initially had been labeled as “junk DNA” was later revealed to carry out multiple important functions, such as regulating gene expression. However, up to two-thirds of our genome consists of REs, which are patterns of DNA that have multiple copies across the genome. Of these, retrotransposable elements (RTEs) comprise the majority. As their name suggests, RTEs can multiply via a process reminiscent of “copy and paste”, inserting their new copies back into the genome at various locations. Using intricate molecular machinery, RTEs transcribe themselves into RNA and back into a fresh copy of their DNA sequence, which is then inserted at a new location. Although RTEs, being under constant evolutionary pressure, tend to balance their need for propagation with the host’s survival [2], they can still disrupt genes and influence gene expression, and they have been linked to multiple disorders, some of which are age-related [3]. These short sequences of DNA, which are clearly acting as units of natural selection, may be the best illustration of Richard Dawkins’ “selfish gene” theory.
Still, under normal conditions, most REs are inactive. They reside in genomic regions that are chromatinized (wound into a tight structure called chromatin), whereas for a DNA sequence to be transcribed, the region it resides in has to be unwound. But the volume of RE transcriptions seems to rise with age, probably due to chromatin instability that is a major aging-related phenomenon. It may seem that increased RE transcriptions are a consequence rather than a cause of aging, but the authors of the paper note that REs have been linked to other hallmarks of aging, such as oxidative stress and cellular senescence, and hence may play a causative role. Notably, at least one study showed that inhibiting retrotransposition extends lifespan in mice [4].
REs react to interventions
The researchers hypothesized that if the increase in RE transcriptions is indeed age-related, it should react to known longevity-promoting interventions. To test their hypothesis, they first analyzed an RNA-sequencing dataset from an experiment in which mice were subjected to lifelong caloric restriction (CR), which is probably the most effective life-prolonging intervention that we know of. The researchers found a statistically significant increase in RE transcripts with age, which was largely attenuated by CR. They proceeded to analyze the effect of a set of somewhat shorter, but still long-term in mouse years, 8-month interventions that included CR, rapamycin, and acarbose treatments. All treatments brought about significant, global reductions in RE transcripts. This is consistent with the notion that rapamycin and acarbose mimic CR and work via similar pathways. Using a separate dataset, the authors found that a high-fat diet, which is known to reduce lifespan, also significantly promotes RE transcription.
Yet another interesting experiment that the authors conducted involved transgenic mice with the growth hormone receptor knocked out, a known way to increase longevity. The animals, as expected, showed less RE activity than their genetically unmodified peers.
Although various interventions resulted in somewhat different patterns of RE reduction, there was a significant overlap: 518 specific RE transcripts were downregulated and 92 were upregulated in all of the experiments.
Exercise lowers RE expression
The RNA-sequencing data on long-term anti-aging interventions in humans is scarce, so the researchers opted for the next best thing: a dataset that included young and older sedentary adults as well as older adults that have been habitually exercising for at least 5 years. In line with their hypothesis, the researchers found that sedentary older adults showed a much larger volume of RE expressions than young adults, but this effect seemed to be attenuated by regular exercise. Maximal aerobic exercise capacity (VO2 max), which is a major physiological predictor of longevity, also correlated heavily with RE transcription levels.
Collectively, our results support the growing idea that global RE dysregulation may be an important mechanism of aging (and not simply an adverse effect of the process). Reversing age-related RE transcript accumulation may be necessary for healthy aging, as our present findings show that health/lifespan-enhancing interventions consistently reduce RE expression.
Conclusion
REs may be the “orphans” of longevity research compared to coding sequences, but there is a growing body of evidence that their increased transcription with age may play a role in aging-related diseases. The current research seems to reinforce this notion. Though more work should be done to clarify the connection between REs and aging, the general idea that RE transcripts increase in volume mainly due to aging-related chromatin destabilization, and consequently contribute to various adverse effects, seems plausible.
Literature
[1] Wahl, D., Cavalier, A. N., Smith, M., Seals, D. R., & LaRocca, T. J. (2020). Healthy aging interventions reduce non-coding repetitive element transcripts. bioRxiv.
[2] Bourque, G., Burns, K. H., Gehring, M., Gorbunova, V., Seluanov, A., Hammell, M., … & Mager, D. L. (2018). Ten things you should know about transposable elements. Genome biology, 19(1), 1-12.
[3] Prudencio, M., Gonzales, P. K., Cook, C. N., Gendron, T. F., Daughrity, L. M., Song, Y., … & Baker, M. C. (2017). Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients. Human molecular genetics, 26(17), 3421-3431.
[4] Simon, M., Van Meter, M., Ablaeva, J., Ke, Z., Gonzalez, R. S., Taguchi, T., … & Neretti, N. (2018). Inhibition of retrotransposition improves health and extends lifespan of SIRT6 knockout mice. bioRxiv, 460808.
