Elastin-derived extracellular matrix fragments drive aging through innate immune activation
Junzhi Yi, Yixuan Wang, Hairu Sui, Zhichu Chen, Tianning Ye, Yuliang Zhong, Jingyi Qian, Bingbing Wu, Jiayun Huang, Tian Tian, Fangyuan Bao, Xuri Chen, Xiao Xiao, Jiasheng Wang, Jiajie Hu, Yujuan Xie, Hui Zhang, Pan Jin, Xiaoping Xia, Xudong Yao, Yi-Shan Chen, Zi Yin, Weiliang Shen, Jing Zhou, Xiaohui Zou, Hua Liu, Hongwei Ouyang
Abstract
The roles of cells in systemic aging have been systematically investigated, while the roles of the extracellular matrix (ECM) and its degradation have been largely overlooked. Herein, we show that the serum contents of elastin-, hyaluronic acid- and fibronectin-derived fragments are all positively correlated with age. Elastin-derived fragments exhibited the most potent lifespan-shortening effects in mice and a positive correlation with various aging indicators in a human cohort (n = 1,068). Mechanistically, the VGVAPG oligopeptide (E-motif) in elastin-derived fragments activated monocytes and macrophages through NEU1, a component of the elastin receptor complex, which consequently caused an inflammatory response. Therapeutically, a NEU1 inhibitor extended lifespan by up to 17% in wild-type naturally aged mice and alleviated aging-related phenotypes in wild-type mice, immune-humanized mice and pigs. This study uncovers that degraded ECM acts as a circulating driver of aging, providing an anti-aging intervention strategy focused on particular elastin fragment signals. The contribution of the extracellular matrix and its degradation to the aging process is not well understood. Here, the authors show that degraded elastin fragments, which increase in the circulation with age, promote aging, while counteracting elastin fragment signals alleviates inflammation, promotes healthy aging and extends lifespan.