How ancient viruses make us live longer, or not: The pros and cons of Retrotransposons control in health and disease

The question "When does aging start?" is one of the most fascinating and yet unresolved questions in Biology. The recent years have seen the identification of several biomarkers, some of which turned out to be instrumental for devising potential ameliorating strategies to preserve younger, more resilient physiological conditions. However, while the application in the clinics awaits for validation, these advances contributed, not surprisingly, to raise the bar of our comprehension of aging complexity and so we are still far from a universally accepted answer.

In this context we focused our attention of two main hallmarks of aging process:  the progressive loss of cell identity programs and inflammation and in particular about the emerging, dual role of the repeat portion of our genome: the retrotransposon. Neglected for long time relics of ancient viruses and carriers of genetic instability, recent evidence shed instead light on the key function of their RNA output in two fundamental aspects on adaptation capacity linked in particular to stress: epigenome and cell identity plasticity and innate immune response.

Progressive loss of epigenetic repression, chromatin remodeling, mitochondrial dysfunction, DNA damage, and cellular senescence—all hallmarks of aging—can increase retrotransposon expression and reduce the efficiency with which these transcripts are degraded or contained. Persistent accumulation of retrotransposon RNA may then drive chronic activation of innate immune pathways, sustaining low-grade sterile inflammation, often referred to as inflammaging. Instead of supporting adaptation, retrotransposon-derived inflammatory signals become self-amplifying, contributing to tissue dysfunction, stem cell exhaustion, immune dysregulation, fibrosis, and age-associated diseases.

In contrast, during development, tissue remodeling, wound healing, or acute cellular stress, transient retrotransposon expression may contribute to adaptive inflammation. In this context, retrotransposon-derived RNAs act as endogenous danger-associated molecular patterns that alert the immune system, stimulate repair programs, promote tissue regeneration, and enhance the organism's capacity to respond to environmental perturbations. Their regulated activation may therefore constitute an intrinsic component of physiological resilience rather than merely a pathological consequence of genomic instability. However, the same signaling pathways may become maladaptive when regulatory control deteriorates.

Based on these evidence, we investigate mechanisms and devised strategies based on retrotransposons RNA regulation aimed at impacting the start and progression of the aging process and related pathologies.