Using RNA Regulation to Argue for the Relevance of Transposons in Aging

Of late a number of research groups have argued that transposon activity is a contributing cause of dysfunction. Transposons are sections of genetic material that can move around within the genome, and more of this moving around occurs with advancing age, taking place in a more or less random manner within individual cells. The discussion over whether and why this can be a significant cause of aging is similar to that for stochastic mutational damage in nuclear DNA. Here researchers point to a comparative lack of transposon activity in lower organisms such as hydra that exhibit exceptional regeneration and minimal aging as a point to consider in this debate.

Intense investigation in aging research has led to the identification of over five hundred evolutionarily conserved genes, the mutational or RNA interference-mediated inactivation of which slows down the rate of the aging process in divergent eukaryotic species. While many of these genetic interventions can significantly promote longevity, they are unable to halt aging. Even mutant animals with extreme longevity continue to age, albeit at a diminished rate when contrasted with their corresponding controls. A related problem in aging research is that of the mortality rate, which displays an exponential growth throughout the adult life in numerous animal species. As the accumulation of mutations and harmful metabolic factors, such as reactive oxygen species, causing cellular damage, is known to occur at a nearly constant rate during the lifespan, this has bred speculations regarding potential genetic or metabolic components that are likely to be generated exponentially, and to primarily contribute to aging.

Triggered by unrepaired mutations, genomic instability is a key feature of aging cells. Nonaging biological systems however show either no or only limited signs of genome disintegration. Such potentially immortal systems involve the germline that genetically interconnects the subsequent generations, somatic cancer stem cells with indefinite proliferation capacity, and certain organisms from some ‘lower’ animal taxa, somatic cells of which display stem cell-like features. The term of ‘nonaging cells’ refers to cells constituting a tissue that traces an essentially immortal lineage. Nonaging tissues display an indefinite renewal capacity. In nonaging cells, genome integrity remains largely stable during the lifespan.

Genomic instability in aging cells progressively increases during adulthood, thereby limiting their capacity to proliferate and survive. A molecular machinery primarily responsible for maintaining the integrity of genetic material is the Piwi-piRNA pathway. This small RNA-based gene regulatory system operates predominantly in nonaging cells. The pathway was originally discovered in the Drosophila male germline, and established to function in repressing the activity of mobile genetic elements, also called transposable elements (TEs), transposons, or ‘jumping genes’. In addition planarian flatworms and freshwater hydra somatically express components of the Piwi-piRNA pathway, rendering the self-renewal ability of their somatic cells apparently unlimited.

In the absence of active Piwi-piRNA pathway components, aging somatic cells tend to increasingly lose heterochromatin, which normally maintains TEs under transcriptional repression. Thus, during adulthood, the gradual release of TEs may generate considerable levels of molecular damage that overwhelm the capacity of the cellular maintenance and DNA repair systems. In addition to their increasing mobilization during adult life, TEs can inactivate genes that function in the repair and maintenance systems, further contributing to the age-associated accumulation of cellular damage. In contrast, the Piwi-piRNA pathway protects the germline and nonaging somatic cells from TE-mediated mutagenesis. Occasional mutations generated by chemical and physical mutagens are effectively recognized and eliminated by cellular maintenance and repair mechanisms.

Alternatively, the Piwi-piRNA pathway may have a different, TE-independent, but as of yet unexplored function to ensure genomic integrity in nonaging cells. For example, the pathway may regulate the transcription of certain key genes via modulating chromatin organization. It is also possible that besides the Piwi-piRNA system, another molecular mechanism operates in nonaging cells to preserve the stability of their genomes. Such a mechanism however has not yet been identified. Nevertheless, the activity of the Piwi-piRNA pathway is a shared feature of all nonaging cells identified so far.




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