Age-driven miR-29 trades youthful plasticity for epigenetic fidelity
- 1Institute of Oncology Research (IOR)
Abstract
Throughout life, somatic cells must preserve their identity while retaining the capacity to adapt. How this balance shifts with ageing and rejuvenation remains unclear. Here we identify miR-29 as a central point of convergence between the transcriptional programmes of physiological ageing and two routes to rejuvenation: induced reprogramming and the natural reset of early development. miR-29 rises with ageing, falls in both rejuvenation settings and shows the most conserved age-associated increase across vertebrates. miR-29 inhibition opposes transcriptional ageing, whereas mimics promote an older transcriptional state. Methylome analysis reveals a broader function: inhibition releases the miR-29 brake on remodelling, and mimic treatment reinforces it. This release increases methylation at repeat-associated CpGs and lowers epigenetic-clock estimates through unequal contributions in opposite directions. Inhibition also amplifies stimulus-induced methylation changes but reduces fidelity to lineage-specific methylation patterns. We extend this relationship to cancer, where low miR-29 expression marks tumours with younger epigenetic-age estimates yet greater methylation divergence from their tissue of origin. These findings identify miR-29 as a control point linking ageing, rejuvenation and cancer, and support a maladaptive trade-off model in which epigenetic fidelity is preserved at the expense of the plasticity needed for methylome maintenance and adaptation.
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BibTeX
@misc{craparotta2026agedriven,
title = {{Age-driven miR-29 trades youthful plasticity for epigenetic fidelity}},
author = {I. Craparotta and M. C. Barbera and G. A. Cassanmagnago and A. C. Salvatore and A. Sallemi and L. Guarrera and A. Vallerga and M. Bolis},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.18.759616},
url = {https://www.biorxiv.org/content/10.64898/2026.10.18.759616v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Age-driven miR-29 trades youthful plasticity for epigenetic fidelity
AU - I. Craparotta
AU - M. C. Barbera
AU - G. A. Cassanmagnago
AU - A. C. Salvatore
AU - A. Sallemi
AU - L. Guarrera
AU - A. Vallerga
AU - M. Bolis
PY - 2026
DA - 2026/10/18
PB - bioRxiv
DO - 10.64898/2026.10.18.759616
UR - https://www.biorxiv.org/content/10.64898/2026.10.18.759616v1
AB - Throughout life, somatic cells must preserve their identity while retaining the capacity to adapt. How this balance shifts with ageing and rejuvenation remains unclear. Here we identify miR-29 as a central point of convergence between the transcriptional programmes of physiological ageing and two routes to rejuvenation: induced reprogramming and the natural reset of early development. miR-29 rises with ageing, falls in both rejuvenation settings and shows the most conserved age-associated increase across vertebrates. miR-29 inhibition opposes transcriptional ageing, whereas mimics promote an older transcriptional state. Methylome analysis reveals a broader function: inhibition releases the miR-29 brake on remodelling, and mimic treatment reinforces it. This release increases methylation at repeat-associated CpGs and lowers epigenetic-clock estimates through unequal contributions in opposite directions. Inhibition also amplifies stimulus-induced methylation changes but reduces fidelity to lineage-specific methylation patterns. We extend this relationship to cancer, where low miR-29 expression marks tumours with younger epigenetic-age estimates yet greater methylation divergence from their tissue of origin. These findings identify miR-29 as a control point linking ageing, rejuvenation and cancer, and support a maladaptive trade-off model in which epigenetic fidelity is preserved at the expense of the plasticity needed for methylome maintenance and adaptation.
ER -