Upregulation of miR-29 Appears to Promote Degenerative Aging
Researchers here show that upregulation of a specific microRNA, miR-29, occurs during aging. When induced artificially, increased expression of miR-29 produces an aging-like disruption of metabolism and early mortality. The research community doesn't have a good understanding of why miR-29 expression increases with age, with most research focused on downstream consequences. Aging as a whole no doubt includes many maladaptive changes in gene expression, some of which are likely to be more important than others. How large a gain in healthy life span can reasonably be achieved by blocking only a select few of these changes with suitable drug technologies? That remains to be determined.
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 wild type 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.