MiR-29-driven Regulation of Epigenetic Aging and Plasticity Unlocks Translational Potential

Aging is characterized by progressive epigenetic alterations that reshape chromatin organization and gene expression programs. In aged tissues, DNA methylation patterns progressively diverge from the youthful state, a phenomenon known as epigenetic drift, which contributes to transcriptional changes, reduced regenerative capacity, and increased vulnerability to disease. In the first part, a multi-tissue transcriptomic screen in humans identified the ectodysplasin-A2 receptor (EDA2R) as a ubiquitous, age-associated gene. Functional experiments demonstrated that EDA2R activation in muscle cells triggers parainflammatory responses and recapitulates features of aging-related decline. These findings established the EDA2R/EDA-A2 axis as a conserved hallmark and potential therapeutic target to mitigate systemic effects of aging. Building on this initial discovery of biological features associated with aging, the second part of this work shifts from observation to causation, moving from the identification of age-associated markers to the search for molecular drivers that actively define the progression of aging. Through integrative transcriptomic and DNA-methylation analyses, miR-29 was identified as a key regulator of the epigenetic landscape. Indeed, miR-29 expression increases with aging in normal tissues and decreases during rejuvenation. Its modulation in fibroblasts revealed a bidirectional control of epigenetic age and chromatin state: the inhibition rejuvenated the methylome, reduced biological age, and enhanced cellular plasticity, whereas overexpression induced a rigid and non-editable chromatin configuration. Given that many tumors are characterized by epigenetic reprogramming and enhanced cellular plasticity during disease progression, particularly hormone-dependent cancers, such as prostate cancer. In this context, miR-29 upregulation was tested as a strategy to reinforce rigidity and constrain adaptive reprogramming. Preliminary results show that miR-29 mimic treatment suppresses proliferation and induces apoptosis selectively in TP53-mutated prostate cancer models. These findings support that enforcing miR-29 could be a therapeutic strategy to counteract tumor progression. Together, this work delineates a coherent progression from the identification of systemic aging features to the discovery of molecular regulators and their translational application, positioning miR-29 as a crucial node connecting aging and cancer through epigenetic remodeling.