In a paper published in Aging Cell, researchers have described how older cells send long interspersed nuclear element-1 (LINE-1) RNA to other cells in extracellular vesicles (EVs), spurring inflammation.
Evil EVs
In the literature, EVs are often discussed in a therapeutic context, as they can be used to send beneficial signals. However, EVs are the natural communications method of cells; their contents can consist of nearly any molecular information, not all of which is beneficial.
EVs can even pass through the blood-brain barrier (BBB), the protective layer between the brain’s vasculature and its cells, and previous work has found that this can indeed spur inflammation [1] and even Parkinson’s disease [2]. However, what these harmful EVs contain and where they come from are questions that have not been thoroughly answered.
These researchers focus on LINE-1, a series of mobile genetic elements that comprise a full sixth of the human genome and whose activation has been associated with mutation [3] and aging [4]. LINE-1 RNA is known to be reverse transcribed into DNA [5], and previous work had found that this RNA can be transmitted through EVs [6]. These researchers, therefore, sought to determine the effects of these EVs on microglial inflammation and brain aging.
LINE-1 dramatically increases with aging
First, the researchers purified and quantified the EVs derived from 185 people between 20 and 95 years old. As expected, EVs containing distinctly identifiable LINE-1 elements were far lower in younger people; 20- to 45-year-olds had roughly a third of the LINE-1 elements of 46- to 65-year-olds, who themselves had roughly a quarter of the LINE-1 elements in people over 65. There was a significant correlation between LINE-1 elements in EVs and markers of brain aging, including amyloid beta, even when adjustments were made for age and other possibly confounding factors such as heart disease and diabetes.
To find out where these harmful EVs were coming from, the researchers studied 3-month-old and 21-month-old mice. The older animals had many more EVs coming from the brain and heart, but there was no significant upregulation in the kidney and liver. In the older animals, LINE-1 elements were significantly upregulated in the brain and lung but not in other tissues.
Harmful in younger animals
The researchers then confirmed that these older EVs were harmful by administering them to 10-month-old mice. Compared to a control group, the mice that had received these EVs suffered significant cognitive impairment, including depressive behaviors, a lack of interest in novel objects, and poorer results on the Y-maze test. However, if the mice were injected with EVs derived from older animals that had been previously treated with a LINE-1 inhibitor, the harmful effects were considerably blunted.
These findings were recapitulated in an examination of the mice’s brains. Older EVs without LINE-1 had very limited harmful effects that did not always rise to the level of statistical significance, but LINE-1 EVs significantly increased markers of both microglial activation and cellular senescence, and they decreased the number of healthy neurons in the hippocampus as well.
These effects were found to be due to the well-known cGAS/STING pathway, which promotes inflammation. Its downstream effects, such as an increase in the pro-inflammatory cytokine TNF-α, were readily apparent. Alongside the LINE-1 EVs, the researchers injected the treated mice with inhibitors of either LINE-1 retrotranscription or STING. Both approaches were found to be effective; these treated animals had microglial effects and inflammation levels that were much more like the control group, compared to animals that had received LINE-1 EVs alone.
As it is extremely difficult to intercept EVs in transit, the researchers suggest investigating both LINE-1 and STING inhibition as possible treatments. However, this was only a mouse study, and much more work needs to be done to determine whether such approaches can be developed into safe therapies for human beings.
Literature
[1] Ramos-Zaldívar, H. M., Polakovicova, I., Salas-Huenuleo, E., Corvalán, A. H., Kogan, M. J., Yefi, C. P., & Andia, M. E. (2022). Extracellular vesicles through the blood–brain barrier: a review. Fluids and Barriers of the CNS, 19(1), 60.
[2] Guo, M., Wang, J., Zhao, Y., Feng, Y., Han, S., Dong, Q., … & Tieu, K. (2020). Microglial exosomes facilitate α-synuclein transmission in Parkinson’s disease. Brain, 143(5), 1476-1497.
[3] Cordaux, R., & Batzer, M. A. (2009). The impact of retrotransposons on human genome evolution. Nature reviews genetics, 10(10), 691-703.
[4] Miller, K. N., Victorelli, S. G., Salmonowicz, H., Dasgupta, N., Liu, T., Passos, J. F., & Adams, P. D. (2021). Cytoplasmic DNA: sources, sensing, and role in aging and disease. Cell, 184(22), 5506-5526.
[5] Thawani, A., Florez Ariza, A. J., Nogales, E., & Collins, K. (2024). Template and target-site recognition by human LINE-1 in retrotransposition. Nature, 626(7997), 186-193.
[6] Kawamura, Y., Sanchez Calle, A., Yamamoto, Y., Sato, T. A., & Ochiya, T. (2019). Extracellular vesicles mediate the horizontal transfer of an active LINE-1 retrotransposon. Journal of Extracellular Vesicles, 8(1), 1643214.
View the article at lifespan.io
