HIV therapies that block an enzyme that is essential for viruses to replicate, called reverse transcriptase, may offer a new way of treating age-related disorders like Alzheimer’s, a study suggests.
The study, “L1 drives IFN in senescent cells and promotes age-associated inflammation,” was published in the journal Nature.
Retrotransposon elements (RTE) work like “jumping genes” that are able to copy themselves and move around a cell’s chromosomes. Once these jumping genes insert into a new place in the DNA, they can modify and induce errors in nearby genes leading to genomic instability.
“Increasing evidence points to RTE activation in some cancers, in the adult brain, and during ageing,” the researchers wrote. However, the exact contribution of RTE to aging and age-related diseases, like Alzheimer’s, is not known.
Due to RTEs damaging effects, cells have developed a series of defense mechanisms to keep retrotransposons in check. Researchers at Brown University and colleagues found that one particular RTE, called LINE-1 or L1, is able to escape these control mechanisms.
As we age, our cells stop dividing, a condition called senescence. Researchers saw that in senescent human fibroblasts the levels of L1 were four to five times higher than usual. Importantly, L1 reactivation triggers an antiviral immune response mediated by a molecule called type 1 interferon (IFN-1), which is involved in inflammatory responses.
During cellular aging, cells first activate an early DNA damage-response, followed by a phase in which they secrete senescence-associated factors. Now, researchers show that a third and later phase also exists, one characterized by an increased expression of L1 and IFN-1 response.
They found that L1 reactivation in senescent cells was due to a failure in the cell’s surveillance systems, and that of three players, specifically — TREX1, RB1 and FOXA1 — in charge of keeping RTE in check.
“In normal healthy cells all three effectors have to be compromised to unleash L1 effectively,” the researchers wrote.
Working with mice, they detected L1 reactivation in several tissues as the animals aged. Old mice (26 months) showed increased activation of several genes associated with IFN-1, as well as pro-inflammatory and senescence-associated secretory phenotype (SASP) factors — molecules that can either contribute to tumor suppression or development, and to wound healing, and embryonic development. Scientists believe SASPs can be either beneficial or deleterious, depending on the biological context.
Moreover, about 10% of dermal fibroblasts isolated from human skin biopsies from older adults were positive for the p16 senescence marker, and 10.3% of p16 positive fibroblasts showed L1 activation.
Researchers then tested whether they could block the viral-like L1 activity to prevent an inflammatory immune response. Because retrotransposons like L1 need an enzyme called reverse transcriptase to replicate — an enzyme that HIV (human immunodeficiency virus) also needs to replicate inside the body — the team tested wether reverse transcriptase inhibitors currently used against HIV could block L1 activity.
They used lamivudine, a reverse transcriptase inhibitor originally developed by GlaxoSmithKline and approved by the FDA in 1995. They treated aged mice with lamivudine for two weeks, and saw a reduction in IFN response and age-associated inflammation (what the researchers called inflammaging) in several tissues.
Overall, “we propose that the activation of L1 elements (and possibly other RTEs in the mouse) promotes age-associated inflammation, and that the L1 reverse transcriptase is a relevant target for the development of drugs to treat age-associated disorders [like Alzheimer’s disease]”, the researchers concluded.
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