PROJECT SUMMARY Aging is the strongest risk factor for cognitive decline and dementia. Targeting fundamental aging mechanisms offers promising new strategies to counter brain dysfunction. Recent breakthroughs have demonstrated that proteins in aged blood circulation mechanistically contribute to accelerated brain aging, and senescent cells (SCs) accumulate in aging and may drive tissue deterioration, in part, through the proinflammatory senescence associated secretory phenotype (SASP). This research is designed to test whether progeronic SASP proteins produced by systemic SCs mechanistically contribute to accelerated brain aging through blood circulation. This premise is based on published findings establishing that aged blood circulation and/or direct administration of progeronic plasma proteins that are putative SASP factors are sufficient to transfer an accelerated aging phenotype to young mouse brain and our research demonstrating that systemic SC clearance attenuates the SASP in circulation, which is associated with improvements in brain inflammatory parameters and cognitive decline. To test our central hypothesis, we will combine circulatory exchange methods with mouse models in which SCs can be eliminated or production of the SC proteome can be precisely monitored, which will enable us to study whether reducing the circulating SASP is sufficient to ameliorate the adverse influence of aged blood on brain homeostasis. We will develop an innovative transgenic mouse model that will enable bioorthogonal labeling of the nascent p16+ SC proteome. This will empower our discovery of the age- and tissue-specific p16+SC-proteome, its contribution to the circulating progeronic proteome, and its responsivity to SC clearance. Administration of bioorthogonally labeled aged plasma +/- SC clearance to young mice will facilitate discovery of candidate SASP proteins responsible for accelerated aging brain phenotypes for further mechanistic interrogation. Modifying aged blood composition and targeting SCs are therapeutics actively being pursued for ameliorating age-related decline. This project is designed to mechanistically synergize and advance these two promising concepts. Our research may preclinically implicate systemic SC clearance as an option to deplete the progeronic influence of aged blood, ultimately revealing a novel approach for treatment or prevention of age-dependent cognitive decline and dementia.
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