Beware the ‘molecular parasites’ involved in aging and disease – Brown University

PROVIDENCE, R.I.[Brown University] If youve ever seen a petunia with artfully variegated petals, then youve seen transposons at work. The flowers showy color patterns are due to transposable elements, or DNA sequences that can move locations within a genome. Yet when it comes to transposons effects on humans, the results might not be as lovely or desirable.

As researchers learn more about these so-called mobile genetic elements, theyve found increasing evidence that transposons influence and even promote aging and age-related diseases like cancer as well as neurogenerative and autoimmune disorders, says John Sedivy, a professor of biology and director of the Center on the Biology of Aging at Brown. Sedivy is the corresponding author of a new review article in Nature that discusses the latest thinking and research around transposons.

The splotches and specks of this variety of flower, petunia hybrida W138, are due to the activity of transposons. (Photo: The Petunia Platform, ENS de Lyon)

Lets put it this way: These things can be pretty dangerous, said Sedivy. If they are uncontrolled, and there are many examples of that, transposons can have profound consequences on most forms of life that we know of.

Since the dawn of life, the researchers noted, transposons have coevolved with their host genomes, but its been more of a competitive existence than a peaceful one, earning them the nicknames of junk DNA and molecular parasites. Transposons were first discovered in corn by the Nobel prize-winning geneticist Barbara McClintock in the 1940s, who also found that depending on where they inserted into a chromosome, they could reversibly alter the expression of other genes.

It is now quite apparent that the genomes of virtually all organisms, including humans, contain repetitive sequences generated by the activity of transposons. When these elements move from one chromosome or part of a chromosome to another, they amplify and increase their presence in genomes, sometimes to dramatic levels. According to Sedivy, about half of the human genome is due to the activity of these molecular parasites. Their unregulated activity can have long-term benefits by increasing genetic diversity in organisms, but in most cases the chaos degrades cell function, such as by disrupting useful genes.

Most of what is known about transposons, said Sedivy, comes from genome sequence data that shows their activity in the germline, or throughout successive generations of an organism. However, recent research, including from Sedivy and other scientists at Brown, has revealed a wealth of information on transposon activity during the lifetime of a single individual, as well.

In an interview, Sedivy discussed the mechanisms driving transposons, how their activity influences and promotes age-related tissue degeneration and disease and what can be done to fight back.

There are two main groups: 'DNA transposons' move using a DNA intermediate in a 'cut and paste' mechanism, and retrotransposons move using a 'copy and paste' mechanism that involves an RNA intermediate. Thirty five percent of the human genome is comprised of retrotransposon DNA sequences. The reason they move is to survive; it allows them to relocate to and increase their presence in their hosts. You can think of transposons as viruses there are some viruses that are, in fact, transposable elements. HIV (human immunodeficiency virus) is a perfect example because it uses the retrotransposition mechanism to insert itself into the genome, and then lets the host cell do the replication for it. This means that unless you kill all the cells that HIV has infected, you cant get rid of it. Thats what retrotransposons do, too. They live in the genome, including the germline so that eggs and sperm carry these genetic elements and pass them along to future generations.

Transposons have been studied quite extensively, one important impact in medicine being their role in propagating antibiotic-resistance genes in bacteria. The level of activity in an individual human body, over a single lifetime, was thought to be quite low and of minimal consequence. Its now become quite obvious thats not the full story.

First of all, its important to realize that aging is not an active process. While it might seem that youre programmed to deteriorate, aging is in fact a successive sequence of failures. Cellular processes and mechanisms become more error-prone over time. Cancer, for example, is a disease of aging because at some point, a fatal error is committed which then propagates and leads to disease. As biologists who study aging, we applied the error and failure theory to retrotransposable elements and discovered thats exactly what was happening. Its now widely appreciated that over a lifespan, these elements become more active in somatic tissues theres very good evidence that this is happening. There are multiple surveillance mechanisms that our cells use to keep these elements under control and suppress their activity; several layers of active defense that are necessary to keep the retrotransposons under wraps, so to speak. It appears that aging, or senescent, cells lose some of their ability to control the activity of retrotransposons. The defense mechanisms no longer work as well.

The aging brain of a person with Alzheimer's already shows a significant amount of damage. There's also reasonably good evidence that the brain, for some reason, is a particularly permissive site for retrotransposon activity, so the retrotransposons can basically have a field day in that tissue because theres very little that can stop them. So they promote further damage. This is a major topic in our recent review article in Nature. The question becomes: What can be done to limit the activity of these elements?

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Beware the 'molecular parasites' involved in aging and disease - Brown University