Investigating the link between propionate metabolism and aging

PROJECT SUMMARY/ ABSTRACT Aging, the gradual decline in an organism's physiological functions over its lifespan, impacts all individuals. Yet, why do some individuals age faster and show a greater susceptibility to age-related diseases, including cancer, tissue fibrosis, and diabetes, compared to others? Mounting evidence supports the idea that aging, and the associated process of cell senescence, are rooted in metabolic dysfunction. Metabolic dysfunction occurs when chemical reactions become dysregulated during aging and negatively alter the body's processing and distribution of nutrients, inducing the aberrant accumulation of certain metabolites. These metabolites can affect cellular function by altering signaling processes and protein modifications, contributing to aging progression. The link between aging and metabolism has solidified itself as one of the new challenges in understanding the complexity of aging as a systemic disease. Identifying metabolic pathways and metabolites that drive cell senescence and metabolic dysfunction is critical to understanding and treating age-related diseases. The propionate metabolism pathway is a highly conserved pathway critical for the metabolism of certain amino acids, odd chain fatty acids, cholesterol and propionate. The function of this pathway and its metabolites in cell senescence and aging remains to be identified. Previous studies and my preliminary data suggest that the activity of propionate metabolism changes with aging, and two metabolites in this pathway, methylmalonic acid (MMA) and propionyl-CoA (P-CoA), are involved in the regulation of cell senescence, lipid metabolism and protein modification. Therefore, I hypothesize that the propionate metabolism pathway plays a fundamental role in the aging process. During the K99 phase of this award, I will continue dissecting the role of MMA in cell senescence and aging-associated pulmonary fibrosis. Additionally, I will characterize a novel function of P-CoA in lipid droplet dynamics. I will also uncover the function of a novel post-translational modification (propionylation) on p53 (a key regulator for cell senescence) and catalog target proteins for propionylation. During the R00 phase of this award, I will expand on my lipid droplet studies and investigate the role or P-CoA in aging-associated ectopic fat accumulation (visceral fat deposition) and validate the target proteins for propionylation as identified during K99 phase. Furthermore, I will identify the main target genes and functions associated with histone H3 at lysine 23 (H3K23) propionylation during cell senescence. These investigations will pave the way for new research projects and serve as the basis for pursuing R01 grants and other funding opportunities. This award will allow me to expand on my training in aging physiology, metabolism and epigenetics, and gain expertise in chromatin biology, lipid droplets dynamic, and protein post-translational modification, ultimately helping me develop new niches (metabolic dysfunctions and aging) as an independent investigator. In addition to the scientific objectives outlined in this proposal, I have devised a comprehensive training plan for the K99 phase of the award to ensure a smooth transition towards independence.