Aging Rhesus Macaque show tissue and sex-specific balance of drifting and coordinated miRNA programs

Rishik, S.; Nutma, E.; Ludwig, N.; Fischer, U.; Tänzer, T.; Rheinheimer, S.; Hart, M.; Gröger, L.; Meerjanssen, J.; Flotho, M.; Esteban, M. A.; Middeldorp, J.; Keller, A.

doi:10.64898/2026.04.27.720577

bioRxiv · 10.64898/2026.04.27.720577

Aging Rhesus Macaque show tissue and sex-specific balance of drifting and coordinated miRNA programs

Rishik, S.·Nutma, E.·Ludwig, N.·Fischer, U.·Tänzer, T.·Rheinheimer, S.·Hart, M.·Gröger, L.·Meerjanssen, J.·Flotho, M.·Esteban, M. A.·Middeldorp, J.·Keller, A.

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Abstract

Macaques research centrality makes it critical to study their molecular aging. We accomplish this for their non-coding transcriptome by sequencing small RNA from 11 organs, with special focus on brain by including 24 brain regions, sampling males and females between ages 3-35 years. Heart, adrenal gland, corpus callosum and caudate putamen showed the most age-deregulated miRNA trajectories. The MIR-154 family, inside the imprinted, rejuvenation-associated Dlk1-Dio3 cluster, was particularly vulnerable. Known age-associated miRNA families LET-7, MIR-29, MIR-17 and MIR-92 were strongly deregulated, with heavy dependence on tissue and sex. MiRNA genomic clusters deregulation was concordant within tissue-sex combinations, implicating upstream regulation rather than random noise. Cross-species comparison with mouse showed ancient miRNAs dominating age-deregulated trajectories. Deregulation direction in tissues-sex was conserved between species at family/cluster levels, but conservation substantially weakened at individual miRNA level. Thus, we mark a decisive step in translating miRNA aging trajectories between two heavily used model organisms. Key FindingsO_LIHeart, adrenal gland, corpus callosum, caudate putamen are hotspots of miRNA age deregulation, with dramatic influence from sex. C_LIO_LINon-brain organs show tissue specific miRNA change, with inconsistent overlap between tissues. C_LIO_LIGenomic clusters of miRNAs were found to be concordant in their age deregulation direction, dependent on tissue and sex, suggesting upstream regulation. C_LIO_LIThe MIR-154 family, housed inside the heavily imprinted Dlk1-Dio3 cluster and processed from the rejuvenation associated MEG3-MIRG host gene is prominently involved in both non-brain organs and brain regions. C_LIO_LIConcentration of age deregulation in evolutionarily ancient miRNAs across species implies regulatory program rather than epigenetic drift, involving MIR-154, LET-7, MIR-29, MIR-17 and MIR-92 families. C_LIO_LIDirection of change conserved between species at the family / genomic cluster level but diminished substantially at individual miRNA level. C_LI

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Rishik, S., Nutma, E., Ludwig, N., Fischer, U., Tänzer, T., Rheinheimer, S., Hart, M., Gröger, L., Meerjanssen, J., Flotho, M., Esteban, M. A., Middeldorp, J., Keller, A.. 2026-04-30. Aging Rhesus Macaque show tissue and sex-specific balance of drifting and coordinated miRNA programs. https://doi.org/10.64898/2026.04.27.720577

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