Abstract
Aging is a multifactorial process involving a gradual decline in cellular and tissue functions, making it a major risk factor for aging-related degenerative diseases. In this study, we utilized the senescence-accelerated mouse prone 8 mice model, which mimics pathological characteristics of Alzheimer's disease, fatty liver disease, and cardiac fibrosis, to construct a heterochronic parabiosis model and systematically investigate the rejuvenating effects of heterochronic parabiosis on the brain, liver, and heart. Our findings revealed that heterochronic parabiosis promotes synaptic plasticity and neuronal communication, restores hepatocyte metabolic functions, and reduces chronic inflammation and fibrosis in the heart. Notably, heterochronic parabiosis significantly downregulates the expression of age-related disease risk genes. In addition, endothelial cells, as cell types directly exposed to the circulatory environment, demonstrated the highest sensitivity to heterochronic parabiosis across three organs, and exhibited significantly reduced inflammation after intervention, suggesting that they may play an early and central role in the rejuvenation process. Overall, our study increases the understanding of the molecular and cellular mechanisms of aging and its related diseases, highlights the multiorgan and multitarget potential of heterochronic parabiosis in delaying aging and mitigating aging-related diseases, and provides new therapeutic targets for achieving healthy aging.