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.
Just eyeballing the curve it looks like median survival for the male mice on DANA+rapamycin was about 42 weeks/994 days, which is a slight extension compared to long-lived controls. Unlike many treatments that just extend median lifespan, this also extended maximum lifespan by a good margin, and the combination with rapamycin extended lifespan even moreso. Exact final results pending, but it looks like the DANA+rapa combination would surpass 1200 days, which is approaching rapa+acarb territory.