PROJECT SUMMARY Biological systems are presumed to fail over time based on nine “hallmarks of aging,” which somehow cause a global decline in tissue function and health. Based on this paradigm, interventions, and combinations of them, are being developed to attenuate each of the hallmarks and slow the aging process. Unfortunately, a lack of insight into the interdependence among these aging hallmarks has made it difficult to develop universally effective mitigation strategies. Our lab and others have provided evidence that a loss of stored information impairs the function of cellular machinery and physical structures, leading to aging and age-related diseases. We have developed the ICE system (Yang et al. 2022, provisionally accepted by Cell) which allows for spatial and temporal control over epigenetic aging in mammals. We have also discovered that partial reprogramming using the reprogramming factors, Oct4, Sox2, and Klf4 (OSK), allows cells to retrieve a “backup copy” of youthful information that resets the epigenome, reverses multiple hallmarks of aging, and restores DNA methylation patterns to their previous youthful state (Lu et al., 2020; Yang et al., 2022, provisionally accepted by Cell). In this study, we leverage our ability to control the pace of aging in forward and reverse directions to test the hypothesis that a loss of interconnectivity between cellular information and cellular machinery and physical structures is a primary driver of the Hallmarks of Aging and a reversible cause of aging itself. To do this, we will develop the first set of fluorescent hallmark reporters to monitor hallmark progression and interactions during aging and discover ways to promote their co-reversal. This novel tool will be utilized along with advanced multi- omic approaches in novel co-biosis systems and age-programmable mice in the heterogeneous UM-HET3 genetic background. This study is important because it will provide valuable knowledge concerning the long-standing questions about interconnectivity among the aging hallmarks, such as whether hierarchies exist and if the reversal of one hallmark ensures the erasure of others. Together, this work will provide the field with a novel set of customizable tools to track and study these hallmarks and test the hypothesis that many hallmarks intersect at the informational level and are therefore co-reversible when information in the nucleus is reset to a youthful state.