Transposable Elements in Aging

Transposable elements are parasitic DNA sequences that have attached themselves to the genome over the course of evolutionary history. They are rigorously suppressed in normal cellular operation, but that suppression appears to fail with age, leading more cells to suffer replication of these transposable elements. This activity shows up in senescent cells, for example.

Some researchers, such as the authors of the paper linked here, argue that rising activity of retrotransposons - or transposable elements - in our DNA are a cause of aging. This is a subgroup of those who think that, more generally, accumulated stochastic nuclear DNA damage is a cause of aging above and beyond paving the way to higher levels of cancer. It is thought to disarray the activities of cells to a large enough degree to disrupt tissue function. As for transposable elements, the data can be argued either way: while the correlations are strong and DNA damage is shown to raise cancer risk, there is no good experimental evidence to demonstrate that nuclear DNA damage in isolation significantly contributes to aging in other ways across the current length of a human life span, nor to definitively answer the question of whether transposable element mobilization is closer to being a root cause or closer to being an end consequence in aging.

As in many of these mechanisms, the best and fastest approach to obtaining that answer would be to repair the damage and see what happens - assuming that repair to be feasible. For stochastic DNA damage, this is becoming somewhat more practical as a future possibility with the falling cost of gene therapy and improved techniques such as CRISPR, but the challenge here is substantial: how to fix different forms of damage in every cell. Short of full-blown molecular nanotechnology, the development of complex programmable machines built of DNA or similar, capable of figuring out what to fix in situ inside a cell, I see few options.

Understanding the molecular basis of ageing remains a fundamental problem in biology. In multicellular organisms, while somatic tissue undergoes a progressive deterioration over the lifespan, the germ line is essentially immortal as it interconnects the subsequent generations. Genomic instability in somatic cells increases with age, and accumulating evidence indicates that the disintegration of somatic genomes is accompanied by the mobilisation of transposable elements (TEs) that, when mobilised, can be mutagenic by disrupting coding or regulatory sequences. In contrast, TEs are effectively silenced in the germ line by the Piwi-piRNA system.

Here, we propose that TE repression transmits the persistent proliferation capacity and the non-ageing phenotype (e.g., preservation of genomic integrity) of the germ line. The Piwi-piRNA pathway also operates in tumorous cells and in somatic cells of certain organisms, including hydras, which likewise exhibit immortality. However, in somatic cells lacking the Piwi-piRNA pathway, gradual chromatin decondensation increasingly allows the mobilisation of TEs as the organism ages. This can explain why the mortality rate rises exponentially throughout the adult life in most animal species, including humans.



As I said in another recent thread, stochastic DNA damage can be amenable to conventional SENS approaches if it is located in cells that undergo periodic turnover and renewal. You can replenish the stem-cell pools with known-good cell lines. Increasingly cheap and available sequencing technology can enable checking to make sure that stem cells are free from stochastic DNA damage.

Even in organs with terminally-differentiated long-lived cells, wholesale replacement of the organ affected by stochastic DNA damage remains a possibility.

Neurons are the real obstacle. They pose a unique problem IF in fact the stochastic DNA damage is relevant other than for cell loss.

Even there, where some radical new technology seems to be required, rigid molecular machines making atomically-precise movements probably are not. A more bio-mimetic nanotechnology would suffice. How about the mother of all gene therapies? I mean wholesale genome replacement. Doesn't matter if there's stochastic damage if you can replace the whole genome.

Just getting something the size of a human genome imported into a cell seems like a tremendous challenge. Fortunately it can be simplified. If only neurons need such treatment, one could edit out of the genome every gene that never needs to be expressed in neurons, as well as junk DNA and transposable elements. The more compact replacement neuronal genome could be imported by mimicking an apicomplexan intracellular parasite.

Parasitoid nucleus therapy may be a little more well-grounded or near-term than Drexlerian molecular machines? If we're going to go so far as to entertain the possibility of nanomachines, maybe it is worth some attention?

Posted by: José at October 14th, 2015 2:01 PM

The big potential problem I see with whole genome replacement is that you would in effect be wiping out all of a neuron's specific epigenetic information. This would be disastrous if done to a large number of neurons at one, but might be able to be worked around if the replacement is done -really- slowly, so that any neurons effectively reverted to a blank state will be able to recreate the appropriate epigenetic settings by responding to the signals from their unaffected neighbours.

Posted by: Arcanyn at October 15th, 2015 10:36 AM
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