Against HIV and aging
Beware of "molecular parasites" that cause aging and disease
Transposons are mobile genetic elements that, if their regulation is disrupted, can accelerate aging and cause age–related diseases, including oncological, neurodegenerative and autoimmune.
In the process of evolution, transposons developed together with the genomes of their hosts, but it was more of a competitive existence than a peaceful one, which is why they received the nicknames "junk DNA" and "molecular parasites" from researchers.
Transposons were first discovered in corn by Nobel Prize-winning geneticist Barbara McClintock in the 1940s. She also showed that, depending on where they are inserted into the chromosome, transposons can reversibly alter the expression of other genes. Currently, it is known that the genomes of almost all organisms, including humans, contain repeating sequences generated by the activity of transposons. When these elements move from one chromosome or part of it to another, they increase their number in the genome, sometimes to a critical level. According to some estimates, about half of the human genome is caused by the activity of molecular parasites. Their uncontrolled activity can bring long-term benefits in the form of an increase in the genetic diversity of organisms, but in most cases local chaos disrupts cell functions, for example, changing the expression of "useful" genes.
Most of the accumulated knowledge about transposons is derived from genome sequence data that show their activity in germ lines, and then over the next generations. However, recent studies, including those conducted by Professor John Sedivi from the Center for the Biology of Aging at Brown University, USA, have provided a large amount of information about the activity of transposons during the life of one person.
In an interview with the Brown University press Center, Sedivi spoke about the mechanisms governing transposons, how their activity contributes to age-related tissue degeneration and diseases, and what can be done to prevent them.
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Transposons are mobile genetic elements. How and at the expense of what they move?
There are two main groups: DNA transposons are moved using the DNA intermediate in the "cut and paste" mechanism, and retrotransposons are moved using the "copy and paste" mechanism, which includes the RNA intermediate. 35% of the human genome consists of retrotransposon DNA sequences. They move in order to survive; this allows them to increase their presence in their host. You can compare transposons with viruses – there are some viruses that are actually transposable elements. HIV (human immunodeficiency virus) is a perfect example because it uses a retrotransposition mechanism to infiltrate the genome and then allows the host cell to replicate for it. This means that if you do not kill all the cells infected with HIV, it is impossible to get rid of it. Retrotransposons do the same. They live in the genome, including the germ line, so that eggs and spermatozoa carry these genetic elements and pass them on to future generations.
Scientists have long been aware of these parasitic genetic elements, but transposons are becoming an increasingly important area of research. In recent years, the National Institutes of Health (NIH) has been actively funding projects to study the activity of retrotransposons and their effects on aging and Alzheimer's disease. What is the reason for this renewed interest?
Transposons have been studied in some detail, and one of the important achievements is their role in the spread of antibiotic resistance genes in bacteria. The level of activity in a single human body in one lifetime was considered to be quite low and carrying minimal consequences. Now it has become quite obvious that this is an incomplete picture.
What role do transposons play in the aging process?
First of all, it is important to understand that aging is not an active process. Although it may seem that a person is programmed to "deteriorate", in fact, aging is a consistent series of failures. Cellular processes and mechanisms become increasingly error-prone over time. Cancer, for example, is a disease of aging, because at some point a fatal mistake is made, which then spreads and leads to the disease. Biologists studying aging have applied the error theory to retrotransposable elements and found that it works. It is now widely recognized that over the course of life these elements become more active in somatic tissues. There are many regulatory mechanisms that cells use to keep transposons under control and suppress their activity. These are several levels of active protection necessary to keep retrotransposons "in check". It turns out that aging cells lose part of their ability to control the activity of retrotransposons.
What is the relationship between retrotransposons and Alzheimer's disease?
The aging brain of a person with Alzheimer's disease accumulates a significant amount of damage. There is also strong evidence that the brain, for some unknown reason, is a particularly favorable place for retrotransposon activity.
What have studies shown about pharmaceutical interventions to suppress the activity of retrotransposons in the brain?
The first class of HIV drugs/AIDS, called reverse transcriptase inhibitors, are effective against retrotransposons in humans. As mentioned earlier, HIV is essentially a retrotransposon. The key enzyme that the virus uses for replication is reverse transcriptase, which is also the enzyme that all other retrotransposons use, this is an important component of their life cycle. However, despite the fact that these enzymes are evolutionarily related, this does not mean that a drug against one will work against the other. However, a small subset of HIV reverse transcriptase inhibitors/AIDS is actually quite effective against an important class of retrotransposons LINE-1: the universal HIV drug lamivudine significantly reduces age-related inflammation and other signs of aging in mice. The next step would be to study the effects on humans.
A randomized double-blind clinical trial is currently being conducted to evaluate the effectiveness of a daily oral dose of the antiretroviral drug emtricitabine in patients with mild dementia caused by Alzheimer's disease. The drug under study is a new generation reverse transcriptase inhibitor, and it demonstrates better tolerability and fewer side effects in humans than lamivudine. Emtricitabine is approved and is currently being used to treat HIV/AIDS affects millions of people, but it is necessary to test its safety and tolerability in elderly people with mild dementia caused by Alzheimer's disease. This is the main purpose of this study.
In the development of what other diseases or conditions can retrotransposons be involved?
The body's immune system recognizes retrotransposons as viruses and produces an immune response. This immune response is incorrect, given that retrotransposons are part of the genome, and there is strong evidence that retrotransposons are associated with autoimmune diseases. The pro-inflammatory role of retrotransposons has been noted in rheumatoid arthritis, systemic lupus erythematosus and Sjogren's syndrome.
What are the next steps?
There is still much to be studied to understand the mechanisms and consequences of retrotransposon activation in humans. There is also a need for a more holistic understanding of how the mechanisms of aging contribute to diseases, and vice versa. Quite a lot is known about the activation of retrotransposons in aging cells, but much less about the degree and mechanisms of activation in most mature cells of the human body. As for potential therapy, nucleoside reverse transcriptase inhibitors have shown the first prospects, and there is hope that they can be used to treat Alzheimer's disease and dementia, as well as other diseases.
Article V.Gorbunova et al. The role of retrotransposable elements in aging and age-associated diseases is published in the journal Nature.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Brown University: Beware the 'molecular parasites' involved in aging and disease.