It is common knowledge that aging is a part of life, but a recent study aims to further unravel the mechanisms behind it.
The study, published Feb. 6 in the journal Nature, indicates that remnants of ancient viruses with DNA in the human genome may be actively pushing humans toward the wrinkles and difficulties that manifest with old age.
Promising results from a joint study between researchers at Brown and numerous other universities suggest an HIV drug, Lamivudine, could hinder these inherited molecules. This research has applications in potentially treating age-associated neurological diseases and other disorders, according to the study’s authors.
Findings from this experiment indicated that LINE-1 — long interspersed nuclear elements and a type of retrotransposon — can lead to age-related inflammation, said Marco De Cecco, research assistant professor and the first author of the study. The study showed that cells recognize retrotransposons as foreign DNA and consequently prompt a response from the immune system to eliminate the supposed invaders, which leads to inflammation, he said. Unlike a typical virus, these out-of-place DNA molecules are not a one-time occurrence; They keep triggering the immune response, heightening the level of inflammation over time, he added.
Seeing “the (retrotransposable) elements (become) active in senescent cells was brand new,” De Cecco said, adding that “this was very, very exciting … and kind of opened the door for (a) hypothesis that we called aging by retrotransposition.” The team then wondered if the retrotransposons are not only correlated with age but if they cause signs of aging, he said. Silencing of these retrotransposons so that they wouldn’t be expressed minimized the immune response and inflammation, suggesting that the two were in fact interdependent, he added.
Previously, De Cecco and other researchers at the University discovered that senescent cells — which are cells that do not divide — start to lose their order and compactness as pieces of their DNA drift out of the confines of the nucleus, which normally encapsulates all of the DNA in the cell, he said. These strands of DNA — called retrotransposons — are repetitive elements, meaning they are repeated throughout the genome. They are unique because of their origins in our genome, he added.
Retrotransposons are essentially parasites on a molecular level, De Cecco said. They spread from one segment of DNA to another within the same cell by utilizing an enzyme called reverse transcriptase. This enzyme permits the retrotransposon’s RNA to be copied into DNA, he added. The RNA serves as a template for creating an identical DNA sequence for insertion elsewhere in the genome. It also produces proteins inside the cytoplasm of a cell that facilitate retrotransposon’s transportation back into the nucleus, he said.
After identifying a potential culprit for age-related inflammation, the next step was to find a potential way to stop the retrotransposons and their effects in their tracks. For that task, an HIV drug offered a promising solution. Lamivudine combats HIV by blocking the activity of the reverse transcriptase enzyme on the body’s own LINE-1 retrotransposons, said principal investigator of the study and Professor of Medical Science John Sedivy. Retrotransposable elements and HIV bear a close resemblance to each other as they both use reverse transcriptase to incorporate into the genome. As a result, researchers wanted to use the drug to try and block the activity of retrotransposons.
Lamivudine — a nucleotide reverse transcriptase inhibitor — renders DNA synthesized by reverse transcriptase useless, De Cecco said.
The team believes Lamivudine, which has successfully attacked LINE-1 in senescent cells, could be used in aging-related treatments, but “no drugs are completely safe (and) every drug is going to have some side effects,” Sedivy said, adding that Lamivudine is deemed safer for patients than some other alternatives.
If researchers could have a model with only one target to “specifically pinpoint a trigger of inflammation … that would be super exciting for so many applications,” De Cecco said. Identifying a possible way of accomplishing this is “a bit of a dream come true,” though “there’s a lot of work to be done,” he added.
“What we are proposing is one of the many potential unifying models for an aging theory,” De Cecco said. “We finally have one target,” which “allows everybody to try to take a step forward and now exploit that target to make life better for a lot of people,” he added.
Taking the project from cells to complete organisms, the team then specifically tested the Lamivudine drug on mice under two treatment lengths: two weeks and six months. They were excited to see that short-term treatment was “highly, highly effective in dropping this inflammation,” De Cecco said.
Due to the connection between LINE-1 retrotransposons, inflammation and senescent cells, which can build up in the brains of individuals with Alzheimer’s, the findings point to the possibility of applying HIV treatments to some neurological diseases, according to De Cecco. Nevertheless, De Cecco said the team will likely try to first explore possibilities of treating other burdens that come with age-related cellular senescence, such as pain and difficulty walking, as well as autoimmune disorders like arthritis. “We’re actively pursuing several avenues, trying to design the most appropriate study” and “would love to start testing something by the end of the year,” De Cecco said.
The researchers hope to continue conducting experiments using mice and to perform tests on factors such as different tissues or age-associated diseases, Sedivy said.
Furthermore, Sedivy thinks “it would be entirely feasible to do a study in humans,” but figuring out the exact method and logistics could be a challenge.
James Kirkland, a professor at the Mayo Clinic who has also looked into treatments for age-associated diseases but was not involved in the study, said the results were interesting, novel and important. He added that it fosters questions about drug and diagnostic test development specifically regarding “whether agents that target senescent cells based on this kind of approach would be beneficial in experimental animal models and also … people.”
The experiment has helped to clarify knowledge of how the immune system responds to DNA that leaves the nucleus, making it a “beautiful piece of work,” said Judith Campisi, a professor at the Buck Institute for Research on Aging and Senior Scientist at the Lawrence Berkeley National Laboratory. Campisi was not involved in the project but has studied cellular senescence, its connection to diseases associated with aging and anti-retroviral drugs.
The research also provides “more mechanistic clarity in the origins of those pieces of DNA” and how retrotransposons could be harmful from an aging perspective, she added.
According to Campisi, not all HIV drugs are identical, and some are known to actually increase aging in patients and result in the early onset of senescence. She added that it would be “terrible if people lump all anti-HIV drugs into the same category. ... Some of them will have extra benefits,” like Lamivudine, whereas others will not, she said.
