Transposable elements in aging: From biomarkers to effectors

This chapter reviews the current understanding of the role of transposable elements (TEs) in the aging process. TEs represent a significant proportion of mammalian genomes and, far from being "junk DNA", they harbor important functions as regulators of gene expression and important drivers of evolution. Their classification, epigenetic mechanisms that control their silencing, and the evidence for their progressive activation during physiological aging across multiple species are discussed.Aging is associated with a global loss of heterochromatin, which triggers TE derepression, and unleashes two major pathological consequences. First, the increased activity of these elements generates genomic instability through insertional mutagenesis, DNA damage, and changes in genome organization. Second, TE-derived nucleic acids are recognized by DNA sensors such as cGAS-STING and RNA sensors including RIG-I and MDA5, perpetuating interferon responses that contribute to the age-associated functional decline. Diverse therapeutic strategies to control TE dysregulation are presented, including reverse transcriptase inhibitors (NRTIs), lifestyle interventions, genetic approaches, and SIRT6 activation. These interventions have demonstrated efficacy in extending lifespan, suppressing TE expression, reversing inflammatory phenotypes, ameliorating age-related decline, and restoring TE epigenetic silencing in experimental models. Finally, the significance of TE-based biomarkers is highlighted, emphasizing their vital role as both effectors and indicators of biological age and their utility in assessing disease risk. Together, these findings position TE dysregulation as a fundamental aging mechanism and a promising therapeutic target for promoting healthy aging.