A sizable fraction of any mammalian genome is the made up of transposable elements, largely the debris of ancient viral infections, sometimes repurposed, sometimes of dubious benefit. Many of these sequences retain the ability to hijack the machinery of gene expression to copy themselves, or to generate particles that are sufficiently virus-like to provoke an innate immune reaction. In youth, transposable elements are suppressed. Regions of the genome containing transposable elements are folded away, given epigenetic decorations that ensure that these regions are inaccessible to the protein machinery that carries out transcription of sequences into RNA. The epigenetic changes that occur with age alter this situation for the worse, and transposable element sequences are unfolded to become accessible and active. This is thought to cause inflammation and genetic damage at the very least, contributing in some yet to be established degree to degenerative aging.
In today's open access review paper, researchers discuss what is known of the relationship between transposable element activity and aging. It is by no means straightforward. Transposable element activity doesn't seem to be a root cause of aging, in that it is downstream of epigenetic changes characteristic of aging and will not emerge absent those changes. But one can argue for a range of possibly bidirectional interactions between transposable element activation and other mechanisms and outcomes in aging. Any disruptive influence on cells that results in epigenetic dysregulation to expose transposable elements may in turn be accelerated by transposable element activity, particularly via inflammatory signaling resulting from innate immune reactions.
Exploring the relationship of transposable elements and ageing: causes and consequences
Modern theories of ageing, which seek to explain its underlying mechanisms, are divided into two main categories: the error/damage and the programmed perspective. The error/damage model proposes that ageing results primarily from the accumulation of cellular and molecular damage over time. This theory emphasises that environmental factors, lifestyle choices, and metabolic processes contribute to this damage. In contrast, the programmed model views ageing as an inherent and essential part of the life cycle, driven by genetic and hormonal mechanisms rather than simply being a consequence of accumulated damage over time.
Advances in whole-genome sequencing techniques have enabled the study of the genetic mechanisms involved in ageing. Among various genomic components, transposable element (TE) effects have been repeatedly linked to ageing due to their capacity to generate mutations with potential to disrupt normal cellular functions. TEs are repetitive DNA sequences capable of moving (transpose) within the genome, which are commonly classified into two main classes based on their mechanism of transposition. Class I elements, or retrotransposons, transpose via an RNA intermediate through a "copy and paste" mechanism. In contrast, Class II elements, or DNA transposons, move using a DNA intermediate and typically follow a "cut and paste" mechanism.
To capture the diversity within these broad categories, TEs are further classified in subclasses, orders, and superfamilies based on mechanistic and enzymatic criteria. TEs are present in virtually all eukaryotic and prokaryotic genomes, and they typically represent a considerable fraction of the genomes, although their abundance is highly variable from one species to another. Due to their mobile and repetitive nature, TEs are a source of genomic variation. The DNA breaks and insertions associated with transposition events lead to obvious alterations to the genome. The consequences of TE expression and mobilisation can also have widespread effects, altering gene expression and structure, chromosome dynamics, as well as the epigenetic landscape of the genome.
The idea that TEs can contribute to ageing processes through mutations (associated with the error/damage theory of ageing) was first proposed in the 1980s. Building up on the same idea, the transposon ageing model, introduced in 1990, postulates that an exponential increase of TE copy number with time could eventually kill the cell or organism by inactivating essential genes. Indeed, the activation of TEs has been demonstrated to affect lifespan associated with DNA damage in several organisms like fruit flies and mice. Similarly, TE activation has been recently associated with neurodegenerative, autoimmune, and cancer diseases which can in turn affect organismal lifespan.
To mitigate detrimental TE-related effects, TE activity (expression and/or transposition) is normally repressed by epigenetic mechanisms that can involve DNA methylation, histone modifications and/or production of small RNAs. Ageing disrupts these TE silencing mechanisms, increasing their activity. Examples of that have been documented in several organisms, where TE expression and sometimes TE transposition increased with age in different somatic tissues. In this review, we explore current literature demonstrating that TE activity can be associated with both the causes and consequences of ageing, leading to a more complex hypothesis regarding the role of TEs in ageing processes.
View the full article at FightAging
