Xi Ren, PhD; Albert Hofman, MD, PhD; Lewis Lipsitz, MD
Competition Sponsor: US National Academy of Medicine
When a car is zigzagging, it may be due to the car being compromised, or the road being slippery, or both. Aging is a result of chronic, system-level changes of almost all organs within the body, and affects not only the cells (“car”) but also their microenvironment, the extracellular matrix (ECM, “road”). Prevailing anti-aging therapeutic development focuses on targeting cellular signaling but remains ineffective. Despite being one of the most significant pathological hallmarks of aging and end-stage organ failure, the ECM itself has rarely been explored for direct drug targeting. This research will lay the foundational work to promote a transformation in aging research and therapeutic development by cataloging for the first time how aging modulates the ECM synthetic programs and identify common aging ECM signatures that are shared across different organs (the lung, heart and liver) in the mouse model. In particular, this research will develop a newly synthesized ECM (newsECM) profiling strategy for selective labeling, enrichment and ultrasensitive detection of nascent ECM proteins synthesized over defined short time spans with unprecedented daily temporal resolution, irrespective of the complex pre-existing ECM background. In the short term, this research will inspire interventions targeting key aging ECM molecular signatures to slow down aging progression on cell and tissue levels, and thereby promote longevity of organs and individuals. In the long term, this research will enable investigation of the extracellular mechanism underlying the interplay of aging and chronic diseases, such as organ fibrosis, and thereby promote healthier longevity.