The principal component-based clinical aging clock (PCAge) identifies signatures of healthy aging and provides normative targets for clinical intervention

Clinical healthy aging recommendations are disease-centric and reactive rather than focusing on holistic, organismal aging. In contrast, biological age (BA) estimation informs risk stratification by predicting all-cause mortality, however current BA clocks do not pinpoint aging mechanisms making it difficult to intervene clinically. To generate actionable BA clocks, we developed and validated a principal component (PC)-based clinical aging clock (PCAge) that identifies signatures (PCs) associated with healthy and unhealthy aging trajectories. We observed that by intervening in PC-specific space, angiotensin-converting-enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) normalize several modifiable clinical parameters, involved in renal and cardiac function as well as inflammation. Proactive treatment with ACE-I/ARBs appeared to significantly reduce future mortality risk and prevented BA acceleration. Finally, we developed a reduced BA clock (PC_mAge), based directly on PCAge, which has equivalent predictive power, but is optimized for immediate application in clinical practice. Our Geroscience approach points to mechanisms associated with BA providing targets for preventative medicine to modulate biological process(es) that drive the shift from healthy functioning toward aging and the eventual manifestations of age-related disease(s).