Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY As we age, our organs experience molecular and physiological damage that prevents them from functioning properly, which ultimately leads to disease. In the case of the heart, age-associated dysfunction causes the top killing and most expensive diseases to treat worldwide. Over the years, it has been established that cardiac dysfunction is largely dependent on the interaction between the exposome and genetics; however, accumulating evidence indicates that aging in distant organs such as the lung, muscle, and kidneys can also accelerate heart age. In this proposal, we will use deep learning and deep phenotyping data from large longitudinal cohorts (BLSA, UK Biobank) to generate sex-specific clinical-based estimators of the biological age of different organs and define the complete network of organs that affect each other’s aging across populations in different sexes. A mechanism that is known to drive age-related dysfunction in the heart is the accumulation of senescent cells, which are growth-arrested cells that secrete pro-inflammatory cytokines, chemokines, growth factors, and proteases known as the Senescence-Associated Secretory Phenotype (SASP). SASP proteins can induce senescence in healthy cells, and their components have been shown to increase with age in the blood, suggesting that they could mediate the propagation of aging between organs. In fact, experiments in animal models indicate that induction of cellular senescence in an organ, via transplantation or genetics, induces cellular senescence in distant organs. Using blood multi-omics data from individuals with clinical-based estimations of age in different organs and non-linear machine learning methods, we will generate an atlas of the SASP-linked blood biomarkers associated with biological age in different organs. By performing interventional studies in human-derived heart organoids combined with high-throughput functional electrophysiological and imaging analysis and multi-omics, we will study the causal effects of SASP-associated proteins on cardiac function. This will indicate the SASP-associated molecules secreted by each organ that impact cardiac health and enable the discovery of new targets to ameliorate heart-related diseases. Finally, we will apply our novel signature-based drug repurposing method (GCEA) to identify compounds that reverse the molecular changes induced by multiple SASP-associated proteins in the heart. We will study in mice the effect of these compounds on maintaining cardiac function during aging and the molecular mechanisms involved using multi-omics. The experimentally validated compounds will hold great potential to slow down and reverse the aging process in the heart and delay the onset of cardiovascular diseases.
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