Small RNA profiling reveals inflammatory and mitochondrial changes in aging β cells and islet macrophages

Abstract Aging is associated with functional decline and senescence of pancreatic β-cells. Modulation of post-transcriptional mechanisms is a hallmark of aging. Here we analyze the small non-coding RNA (sncRNA) repertoire of FACS-sorted β-cells and islet-resident macrophages (iMACs) from 3-, 12-, and 22-month-old mice, and of senescence-associated β-galactosidase–positive β-cells from 8-month-old mice. We show that senescent β-cells display distinct sncRNA signatures partially overlapping with aging-associated ones. MiRNAs linked to diabetic conditions and islet inflammation are commonly modulated in both contexts. Cytokine exposure followed by washout partially recapitulates the aging sncRNA profile in vitro. Upregulation of inflammatory miR-146a-5p and downregulation of proliferative miR-181a-5p are shared across aged metabolic tissues, whereas upregulation of the miR-143-3p/miR-145-5p cluster, which is associated with insulin responses, is β-cell specific. Aging also remodels the tRNA-derived fragment (tRF) repertoire, with mitochondrial tRFs markedly increased. iMACs from aged mice show elevated anti-inflammatory associated miRNAs and mitochondrial tRFs, suggesting adaptive reprogramming. Overall, our findings reveal extensive sncRNA remodeling during islet aging.