Thursday, January 2, 2025
1/2/2025
PROJECT SUMMARY: In this project, we seek to test the hypothesis that age-related perturbation of interorgan communication signals emanating from the hematopoietic (blood-forming) system may be a common driver of age-associated dysfunction across the body’s major organ systems. This possibility is based on recent human studies, which document an unexpected increase in the likelihood of diseases affecting non-blood organs in individuals with clonally expanded, mutant blood cells. To test our hypothesis, we will apply a novel in vivo gene editing system to introduce into mouse blood cells specific somatic mutations that are frequently associated with clonal hematopoiesis in aging humans. Mutations will be induced in situ, in discrete subsets of endogenous blood cells of otherwise normal young or aging mice, using a lineage-selective, virus-based gene editing system. We will then monitor these animals over time for the emergence of mutant blood cell clones and of well- characterized, age-associated pathologies in three different non-hematopoietic organ systems – the skeletal muscle, heart and brain. Each of these organs shows profound and well-defined alterations with advancing age, and prior studies demonstrate that aging pathologies that arise in each of these non-blood organs shows responsiveness to blood-borne (systemic) signals. Our proposed studies also will compare the possible differential effects of different mutations occurring in distinct target genes, each associated with aging of the human blood system, and evaluate whether the lineage restriction (cell type) or timing (age of onset) of the mutagenic event has any impact on subsequent organismal pathology. Finally, we will apply rigorous single cell sequencing, heterochronic parabiosis and serum analyte assays to uncover the molecular mediators of aging-relevant blood-to-non-blood organ communication networks. In this way, our experiments will directly test the hypothesis that age-associated clonal mutagenesis is a mechanistic driver of aging pathologies that disrupts interorgan communication between the hematopoietic system and other tissues, identifying the specific cellular contexts and mutagenic events occurring in the aging blood system that can drive dysfunction in the cardiovascular, neurologic and skeletal muscle systems through cell non- autonomous signals. Ultimately, the results of these studies will offer new guidance for the clinical interpretation and management of individuals identified to harbor clonal hematopoiesis, estimated to represent more than 20% of individuals over the age of 70 (and potentially nearly all individuals who reach very old age) and important new insights into the significant interorgan communication mechanisms that contribute to aging and disease.
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