Endocrine-exocrine miR-503-322 drives aging-associated pancreatitis via targeting MKNK1 in acinar cells.
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abstract
Aging is the risk factor for chronic pancreatitis and severity determinant for its acute attack, yet the underlying cause is unclear. Here, we demonstrate that senescent β-cells of endocrine pancreas decide the onset and severity of chronic and acute pancreatitis. During physiological aging, senescent β-cells increase the expression of miR-503-322 which is secreted as small extracellular vesicles to enter exocrine acinar cells, driving a causal and reversible role on aging-associated pancreatitis. Mechanistically, miR-503-322 targets MKNK1 to inhibit acinar-cell secretion leading to autodigestion and repress proliferation causing repair damage of exocrine pancreas. In the elderly population, serum miR-503 concentration is negatively correlated with amylase, prone to chronic pancreatitis due to increased miR-503 and decreased MKNK1 in the elderly pancreas. Our findings highlight the miR-503-322-MKNK1 axis mediating the endocrine-exocrine regulatory pathway specifically in aged mice and humans. Modulating this axis may provide potential preventive and therapeutic strategies for aging-associated pancreatitis.