Metformin (MET) and nicotinamide riboside (NR) have both been reported to exert geroprotective effects in multiple species. However, the mechanism by which MET and NR reconnect the aging program and delay aging in multiple tissues remains unclear. Here, we demonstrated that MET and NR attenuate aging features in human mesenchymal stem cells. Moreover, by systematically investigating the pathophysiological changes in different tissues from aged rats after oral administration of MET and NR, we showed that both MET and NR treatment alleviated various aging-related characteristics in multiple tissues, including inflammation, fibrosis, and protein aggregates. Consistently, MET or NR treatment partially rescued aging-related gene expression changes in aged rats. Collectively, we report that both MET and NR attenuate senescence phenotypes in human stem cells in vitro and in a variety of rodent tissues in vivo, thus providing a valuable resource and foundation for further evaluation of these two compounds against aging.