Aging is a consequence of complex molecular changes, but whether a single microRNA (miRNA) can drive aging remains unclear. A miRNA known to be upregulated during both normal and premature aging is miR-29. We find miR-29 to also be among the top miRNAs predicted to drive aging-related gene expression changes. We show that partial loss of miR-29 extends the lifespan of Zmpste24-/- mice, an established model of progeria, indicating that miR-29 is functionally important in this accelerated aging model. To examine whether miR-29 alone is sufficient to promote aging-related phenotypes, we generated mice in which miR-29 can be conditionally overexpressed (miR-29TG). miR-29 overexpression is sufficient to drive many aging-related phenotypes and led to early lethality. Transcriptomic analysis of both young miR-29TG and old WT mice reveals shared downregulation of genes associated with extracellular matrix organization and fatty acid metabolism, and shared upregulation of genes in pathways linked to inflammation. These results highlight the functional importance of miR-29 in controlling a gene expression program that drives aging-related phenotypes. A miRNA screen identifies miR-29 as a driver for aging. Expression of miR-29 is sufficient to accelerate aging while its reduction delays aging in mouse models and transcriptomics reveals miR-29-regulated pathways associated with aging.

miR-29 is an important driver of aging-related phenotypes