Transposable elements, or transposons, are DNA sequences capable of directing the protein machinery surrounding nuclear DNA to haphazardly insert copies of the transposon elsewhere in the genome, potentially breaking other necessary sequences. Transposons are thought to be the remnants of ancient viral infections, but given that transposon activities are most likely an important mechanism of evolution, driving functional changes that can then be selected, that may not be universally true.
Transposons are suppressed in youth, the structure of DNA managed by epigenetic mechanisms to package away transposon sequences into heterochromatin structures and thus hide them from transcription machinery in the cell nucleus. With advancing age the epigenetic control of DNA structure changes in a variety of ways, altering the expression of many genes to contribute to loss of function, but also unleashing transposons to an ever greater degree.
Beyond mutational damage, transposon activity generates molecules that the cell has evolved to recognize as foreign and react to with inflammatory signaling. The activity resembles a viral infection, in essence. It may be that the greatest harm done by transposon activation is not in fact the mutational damage to DNA, but rather the contribution to a state of systemic sterile inflammation that is characteristic of aging, disruptive to tissue structure and function.
Ageing and age-related diseases are the result of complex biological processes that progressively cause deterioration of cellular and tissue function. Among the key hallmarks of ageing are epigenetic alterations and genomic instability, both of which are closely interconnected and significantly contribute to the ageing process. The epigenome, encompassing both DNA and histone modifications, regulates gene expression and maintains genomic integrity throughout life. With age, these regulatory systems become dysregulated, leading to genome-wide changes in chromatin structure, histone modifications, and the reactivation of transposable elements (TEs).
TEs, typically silenced in heterochromatic regions, become active in aged cells, contributing to genomic instability, mutagenesis, inflammation, and metabolic disruption. Despite their significant implications, the role of TEs in the ageing process remains underexplored, and the interplay between epigenomic remodelling and TE activity remains poorly understood. In this review, we explore the molecular mechanisms underlying epigenetic alterations and TE reactivation during ageing, the impact of these changes on genomic stability and the potential therapeutic interventions targeting this interplay. By deciphering the role of epigenetic modifications and TE derepression in the ageing process, we aim to highlight novel avenues for anti-ageing and pro-longevity strategies.
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