A team of researchers have found that a generic HIV medication could be a candidate in combatting Alzheimer’s and other age-related disorders. Published this week in Nature, the collaborative project featured scientists from Brown, New York University, Université de Montréal, the University of Virginia School of Medicine, and the University of Rochester.
The drug, lamivudine, is commonly prescribed as a generic medication for HIV/AIDS patients. According to John Sedivy, professor of medical science and biology at Brown University, the drug functions by inhibiting retrotransposon activity in old cells. These retrotransposons, or DNA sequences that can self-replicate, account for a large portion of the human genome and can potentially be problematic. Cells have evolved mechanisms to keep these sequences from replicating and inserting themselves into different areas of the genome, but as the cells age these mechanisms lose efficiency.
In their published paper, these researchers showed that the L1 class of retrotransposons evade this cellular defense mechanism and replicate in both senescent, or old non-dividing, human cells and in older mice. Once this L1 replication is detected by antiviral immune responses, called interferon responses, an inflammation process is triggered in neighboring cells.
Sedivy claims that because these retrotransposons are present in all tissue types, they are an area of interest in conditions associated with cellular aging. Using this knowledge, Sedivy and his team identified the interferon response that these ‘jumping genes’ may utilize to cause inflammation without causing genomic harm.
“This interferon response was a complete game changer,” stated Sedivy. He also noted that it can be difficult to locate where transposable elements have inserted themselves in a genome with many retrotransposon sequences.
The process by which retrotransposons incorporate themselves into the genome requires the reverse transcriptase enzyme, which is also utilized by HIV and other retroviruses. Many HIV treatments function by targeting reverse transcriptase, with existing drug cocktails containing specific inhibitors to the enzyme. Being that the L1 retrotransposon identified to cause inflammation in their studies uses the same enzyme as HIV, the team saw antiretrovirals as a potential candidate to prevent this inflammatory response.
Testing six different reverse transcriptase inhibitors used to treat HIV, the team identified lamivudine as a potential option based on effectiveness and low side effects. Sedivy noted that human cells grown in the presence of lamivudine did not affect when cells reached senescence nor did it kill them when they did, but the drug did take effect. It decreased both the interferon responses and late-stage senescence-associated secretory phenotype (SASP), each playing important roles in the inflammation response.
The researchers treated mice that were 26 months of age, equivalent to humans at age 75, with the drug for two weeks and saw reduction of interferon responses and inflammation. When treating mice at 20 months of age, they noted that a six month course of treatment reduced loss of muscle and fat as well as kidney scarring.
“When we started giving this HIV drug to mice, we noticed they had these amazing anti-inflammatory effects,” said Sedivy. “Our explanation is that although L1s are activated relatively late in senescence, the interferon response reinforces the SASP response and is responsible for age-associated inflammation.”
“If we treat with lamivudine, we make a tangible dent in the interferon response and inflammation,” he continued. “But it doesn’t quite go back down to normal. We can fix part of the problem, but we don’t actually understand the whole aging problem yet. The L1 reverse transcripts are at least an important part of this mess.”
The team has plans to translate their findings to humans with clinical trials of lamivudine in treated age-associated conditions like dementia and Alzheimer’s, arthritis, and frailty. Sedivy also noted interest in creating a reverse transcriptase inhibitor specific to the L1 enzyme, adding that the enzymes molecular structure would need to be determined first.
Researchers have found that blocking retrotransposon activity with a generic HIV/AIDS medication significantly reduces age-related inflammation in old mice & senescent human cells, providing hope for treating age-associated disorders. HIV drug could treat #Alzheimer‘s pic.twitter.com/5fN7327T6K
— American Researchers🇺🇸 (@AmericanResear1) February 6, 2019
Source: Science Daily