Protein arginine methylation regulates anti-inflammatory programming in response to aging stress.

PRMT1 is a key enzyme responsible for protein arginine methylation, which regulates various cellular processes. However, its physiological significance at whole-body level remains unknown due to embryonic lethality of Prmt1-null mice. Despite only one amino acid difference at position 179, molecular dynamics simulations and biochemical assays showed that human PRMT1 exhibits enhanced methyltransferase activity compared to its mouse counterpart. Capitalizing on this finding, we generated humanized PRMT1 knock-in mice (huMice) carrying the H179Y substitution. Notably, huMice displayed distinct transcriptomic signatures associated with attenuated inflammatory responses compared to wild-type mice in an age-dependent manner. In particular, huMice exhibited reduced pro-inflammatory cytokines production following lipopolysaccharide (LPS) challenge at 12 months, revealing that heightened PRMT1 activity confers a physiological advantage in alleviating age-related inflammatory stress. Our findings underscore PRMT1's key role in the modulation of anti-inflammatory programming at the organismal level and open avenues for leveraging this knowledge in developing mitigation strategies against inflammaging.