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Generic HIV drug significantly reduces age-related inflammation in old mice and senescent human cells

hiv aids generic drug inflammation senescent lamivudine

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#1 Engadin

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Posted 07 February 2019 - 05:02 PM


Researchers find that generic HIV drug Lamivudine significantly reduces age-related inflammation in old mice and senescent human cells by halting the activity of retrotransposons – DNA sequences able to replicate and jump around the genome providing hope for treating age-associated disorders.

 

 

MouseCells_new.jpg?itok=BKal-zLF

 

Photo: HIV medication Lamivudine treats signs of ageing in mouse tissue.

Two weeks of treatment reduced the signs of chronic inflammation -- white blood cells stained pink amongst green fat cells -- in old mice fat tissue.

Lamivudine is the generic alternative to Epivir.

 

 

 

“This holds promise for treating age-associated disorders including Alzheimer’s,” said John Sedivy, professor of medical science and biology at Brown University. “And not just Alzheimer’s but many other diseases: Type 2 diabetes, Parkinson’s, macular degeneration, arthritis, all of these different things. That’s our goal.” Age-related inflammation is an important component of age-associated disorders.

 

The findings were published on Wednesday, Feb. 6, in the journal Nature. The collaborative research project included researchers at Brown, New York University, the University of Rochester, Université de Montréal, the University of Virginia School of Medicine and Leiden University Medical Centre in The Netherlands.

 

According to Sedivy, the HIV drug acts by halting retrotransposon activity in old cells. Retrotransposons — DNA sequences able to replicate and move to other places — make up a substantial fraction of the human genome. Retrotransposons are related to ancient retroviruses that, when left unchecked, can produce DNA copies of themselves that can insert in other parts of a cell’s genome. Cells have evolved ways to keep these “jumping genes” under wraps, but as the cells age, the retrotransposons can escape this control, earlier research from Sedivy’s lab showed. 

In the Nature paper, the research team showed that an important class of retrotransposons, called L1, escaped from cellular control and began to replicate in both senescent human cells — old cells that no longer divide — and old mice. Retrotransposon replication, specifically the DNA copies of L1, is detected by an antiviral immune response, called the interferon response, and ultimately triggers inflammation in neighboring cells, the researchers found.

 

These retrotransposons are present in every type of tissue, which makes them a compelling suspect for a unified component of cellular aging, Sedivy said. Understanding that, the team uncovered the interferon response, the potential mechanism through which these jumping genes may cause cellular inflammation without necessarily causing damage to the genome. 

“This interferon response was a complete game changer,” Sedivy said, noting that it is hard to track where newly inserted transposable elements may have inserted themselves in a genome that contains a vast number of inactive and active retrotransposon sequences.

 

The interferon-stimulating copies of L1 DNA require a specific protein called reverse transcriptase. HIV and other retroviruses also require reverse transcriptase proteins to replicate, Sedivy said. In fact, AZT, the first drug developed to treat HIV/AIDS, halts HIV reverse transcriptase. Current multi-drug cocktails used to treat or prevent HIV/AIDS still contain specific reverse transcriptase inhibitors. Sedivy and his colleagues thought that this class of drugs may keep the viral-like L1 retrotransposon from replicating and thereby prevent the inflammatory immune response.  

The team tested six different HIVreverse transcriptase inhibitors to see if they could block L1 activity and the interferon response.One generic HIV drug, lamivudine, stood out because of its activity and low side effects. (and reduced price too -- Not in the original --).

 

Growing human cells in the presence of lamivudine did not impact when the cells reached senescence or kill the senescent cells, Sedivy said. But lamivudine did decrease the interferon response and the late-stage senescence-associated secretory phenotype (SASP) — the important characteristics of senescent cells that promote inflammation in their neighbors. 

“When we started giving this HIV drug to mice, we noticed they had these amazing anti-inflammatory effects,” Sedivy said. “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.” Treating 26-month-old mice (roughly equivalent to 75-year-old humans) with lamivudine for as little as two weeks reduced evidence of both the interferon response and inflammation. Treating 20-month-old mice with lamivudine for six months also reduced signs of fat and muscle loss as well as kidney scarring. The results were encouraging, Sedivy said, but there’s more work to be done.

 

“If we treat with lamivudine, we make a tangible dent in the interferon response and inflammation,” he said. “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.”

 

Sedivy is eager to translate the findings to humans. Specifically, he would like begin clinical trials of lamivudine for various age-associated conditions such as frailty, Alzheimer's disease and arthritis. Lamivudine was approved by the Food and Drug Administration in 1995, has been used to treat HIV/AIDS for decades, and its pharmacological activity and safety are well established, Sedivy said. The new clinical trials could be streamlined and focused on lamivudine’s efficacy in treating age-associated disorders, he added.

 

He would also like to develop a new reverse transcriptase inhibitor specifically for the L1reverse transcriptase. To aid in developing a specific therapeutic with minimal side effects, the molecular structure of theL1reverse transcriptase needs to be determined, he added. Researchers could also develop other types of drugs that target the L1 retrotransposons.

 

In addition to Sedivy, Marco De Cecco, now an assistant professor (research) at Brown, was involved in the research since its inception seven years ago. Other authors from Brown include graduate students Takahiro Ito, Anna Petrashen, Amy Elias, Nicholas Skvir, and Steven Criscione; visiting students from the University of Bologna Alberto Caligiana and Greta Brocculi; and collaborating faculty Nicola Neretti and Stephen Helfand.

 

 

 

 

 


Edited by Engadin, 07 February 2019 - 05:44 PM.

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#2 xEva

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Posted 08 February 2019 - 02:09 AM

That's very interesting. For a long time already I've had an inkling brewing that transposons may be central to the epigenetic drift of aging. They just seem to fit the bill so well. If indeed their  activity results in aberrant methylation patterns of old age, lamivudine may turn out the antiaging drug that goes beyond the mere inflammation control.

my first thought, too good to be true.. .. and yet.. I vaguely recall hearing about some HIV people looking surprisingly well for their age despite heavy-duty drugs they had to take. I assumed that was because they were making a concerted effort to maintain their health. But what if it's due to lamivudine?

 

 

Ten things you should know about transposable elements, 2018. Examples of how TEs can impact genomes in direct and indirect ways.  Note #5 and #9, that's gene expression vs repression

 

 

13059_2018_1577_Fig2_HTML.jpg
 

 

 

some notable quotes:

 

reduced DNA methylation often promotes TE expression

 

the effects of TEs on a host can vary considerably among tissue types and stages of an organism’s life cycle.

 

there is abundant evidence that TEs are active in somatic cells in many organisms. In humans, L1 expression and transposition have been detected in a variety of somatic contexts, including early embryos and certain stem cells

 

Somatic activity has also been observed in human cancers, where tumors can acquire hundreds of new L1 insertions. Just like for human polymorphisms, somatic activity in human cancers is caused by small numbers of so-called ‘hot’ L1 loci. The activities of these master copies varies depending on the individual, tumor type, and timeframe in the clonal evolution of the tumor. Some of these de novo L1 insertions disrupt critical tumor suppressors and oncogenes and thus drive cancer formation, although the vast majority appear to be ‘passenger’ mutations. Host cells have evolved several mechanisms to keep TEs in check. However, as the force of natural selection begins to diminish with age and completely drops in post-reproductive life, TEs may become more active.

 

Reactivated transposons harm the host in multiple ways. First, de-repression of transposon loci, including their own transcription, may interfere with transcription or processing of host mRNAs through a myriad of mechanisms. Genome-wide transcriptional de-repression of TEs has been documented during replicative senescence of human cells and several mouse tissues, including liver, muscle, and brain. De-repression of LTR and L1 promoters can also cause oncogene activation in cancer. Second, TE-encoded proteins such as the endonuclease activity of L1 ORF2p can induce DNA breaks and genomic instability. Third, accumulation of RNA transcripts and extrachromosomal DNA copies derived from TEs may trigger an innate immune response leading to autoimmune diseases and sterile inflammation. Activation of interferon response is now a well-documented property of transcripts derived from endogenous retroviruses [the OP is about this]

 

there is now mounting evidence that TEs have been a rich source of material for the modulation of eukaryotic gene expression. Indeed, TEs can disperse vast amounts of promoters and enhancers, transcription factor binding sites, insulator sequences, and repressive elements.

 

TE sequences harbor all the necessary features of a ‘classical’ gene regulatory network. They are bound by diverse sets of transcription factors integrate multiple inputs (activation/repression), respond to signals in both cis and trans, and are capable of co-ordinately regulating gene expression.

 

 

more reading:

Sleeping dogs of the genome. Retrotransposable elements may be agents of somatic diversity, disease and aging. 2014

 

Regulatory activities of transposable elements: from conflicts to benefits, 2017

 


Edited by xEva, 08 February 2019 - 02:13 AM.

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