Piwi-piRNA: a pathway to biological immortality?

Many studies seem to confirm that a gene regulation pathway, the Piwi-pi-RNA pathway, displays anti-aging properties that can be found in most biological systems. There could potentially be a biological pathway to immortality.

Piwi-piRNA in the fight against aging

The main function of this signaling pathway is to inhibit the activity of transposable elements, which are mobile genetic elements. Those transposable elements are DNA sequences that can move from one genomic locus to another, and cause spontaneous mutations. In aged organisms, transposable elements seem to be more and more active [1] which results in more genomic mutation in somatic cells. This characteristic of transposable elements comes to show how important they are for mutagenesis and in the progressive degradation of genetic information. However, genome instability is relevant when it comes to aging. Could these transposable elements be molecular “markers” of aging?

A recent study, « The Piwi-piRNA pathway : road to immortality » delves into the hypothesis and demonstrated that these transposable element-induced genomic instabilities contribute to the aging process, and could be inhibited by the Piwi-piRNA pathway [2]. This discovery could allow us to better understand the mechanisms of aging, which remain a complex and fascinating mystery for biologists.

Biological mechanisms affected by the Piwi-pi-RNA pathways

Genome instability, triggered by irrevocable DNA mutations, is fundamental to cellulair aging [2]. However, some cell types could resist aging. Researchers defined in this study the concept of “aging-resistant cells”. This would be cells that do not experience aging and constitute a tissue that could result in a line of “immortal” cells. In these age-resistant cells, the whole genome seems preserved throughout the life of the subject. Therefore, the tissue itself does not experience aging, and does not deteriorate with time. Without genome instabilities, it remains capable of proliferating and surviving [2].

This seems to originate from one biological mechanism: the Piwi-piRNA pathway (“P-element-induced wimpy testis in drosophila” – Piwi-interacting noncoding RNA). It is a gene-regulating pathway, where non-coding ARNs, ARNpis, interact with Piwi proteins. Piwi proteins are originally know for repressing stem cell differentiation and maintain genomic stability in the germinal line. This “molecular machine” seems to be responsible for the processes that maintain genetic material integrity [2]. It works mostly in aging-resistant cells, by repressing the activity of genetically mobile elements, the transposable elements.

It is active in germinal cells as well as in the primary phases of embryo development. This study also shows that outside of the germinal line, the Piwi-piRNA pathway is active in all types of somatic cells that don’t show signs of aging. These cells can be found in many organisms:   with somatic stem cells in poriferans (“sponges”), medusas, planarias, sea slugs, drosophiles and in some mammals [2].

The role of Piwi-piRNA during aging

In aged somatic cells, the Piwi-piRNA pathway in mostly inactive. With time and in the absence of components to allow the pathway to function properly, a progressive loss of heterochromatin can be observed.  Heterochromatin normally inhibits the transcription of transposable elements [2].

That is how, in adult subjects, transposable elements mobility increases, which in turn increases the risk to develop important molecular damage that could prevent DNA repair systems from maintaining the cells. It was proved that depending on their location, transposable elements can induce the inactivation of genes that are indispensable to the repair and maintenance systems of the DNA. Through all adult life, they contribute to the accumulation dysfunctioning cells. The affected cells cannot be fixed and are eliminated through programmed cell death, in order to maintain tissue integrity. However, the increase in dead cells leads to tissue deterioration, associated to aging-related diseases, potentially leading to the death of the organism. Transposable elements then play a leading role in the aging process.

By acting on transposable elements activity, the Piwi-piRNA pathway seems to have an impact on cell life expectancy. This study showed that this pathway protects germinal cells and somatic cells from aging via transposable elements-mediated mutagenesis [2]. Thanks to their mechanisms, the only occasional mutations triggered by physical or chemical mutagens are eliminated through cell maintenance and repair mechanisms.

These cells benefit from a genome that remains mostly intact and stable, and thus don’t experience aging symptoms. In other words, the Piwi-piRNA pathway could play a critical part in cell immortality, and transposable elements could be the primary genetic determinants of aging [2].

Sources :

[1] Li, W., Prazak, L., Chatterjee, N., Grüninger, S., Krug, L., Theodorou, D., & Dubnau, J. (2013). Activation of transposable elements during aging and neuronal decline in Drosophila. Nature neuroscience, 16(5), 529-531.

[2] Sturm, Á., Perczel, A., Ivics, Z., & Vellai, T. (2017). The Piwi‐piRNA pathway: road to immortality. Aging Cell.

[3] Clarke, M. F., & Fuller, M. (2006). Stem cells and cancer: two faces of eve. Cell, 124(6), 1111-1115.