Aging is the single greatest risk factor for many chronic diseases and thus is a major contributor to morbidity in the VA population. Our broad research goal is to understand how chromatin regulatory mechanisms influence nuclear and epigenetic programs, and how de-regulation of these mechanisms contributes to aging and disease. The work proposed here will focus on elucidating the functions of SIRT7, a chromatin regulatory enzyme in the Sirtuin family of aging-regulatory factors. Inactivation of SIRT7 in mice leads to shortened lifespan and phenotypes associated with aging, cancer, and metabolic disorders. Thus, studying the molecular mechanisms and physiologic functions of SIRT7 promises to elucidate central molecular pathways that impact on aging and health span. This project will study novel mechanisms of SIRT7 in protecting against genomic instability and cellular senescence, fundamental aging mechanisms that are implicated in age-related diseases and are a significant cause of tissue dysfunction. Recent studies indicate that elimination of senescent cells in mice can prevent or reverse a wide range of aging-related pathologies, from cancer to fatty liver disease. By elucidating the SIRT7 signaling pathways that control cellular senescence, the proposed work can provide insights for developing therapeutic strategies for aging-related diseases that impact Veterans' health. The central hypothesis of the study is that genomic instability at repetitive ribosomal DNA (rDNA) sequences is a driver of senescence in mammalian cells, and that SIRT7 guards against such instability by maintaining rDNA chromatin silencing via novel mechanisms. Molecular, cellular, and genetic approaches will be taken to (1) study the molecular mechanisms and biological contexts of SIRT7 in controlling rDNA chromatin dynamics; (2) elucidate the functional interplay of SIRT7 with a newly described rDNA silencing pathway that is mutated in numerous cancers; and (3) characterize downstream chromatin signaling mechanisms of SIRT7 at rDNA sequences. Accumulating evidence indicates that rDNA instability may be an oncogenic driver in many cancers, and senescent cells can have pathogenic effects in tumor malignancy and myriad aging-associated pathologies. By elucidating the SIRT7 signaling pathways that control rDNA instability and cellular senescence, our proposed work can provide insights for developing therapeutic strategies for aging-related diseases that impact Veterans' health.