Exploring the links between cyclin D1, metabolism and aging - PROJECT SUMMARY Aging is a fundamental driver of many chronic conditions, including obesity, type II diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as fatty liver disease). Numerous aging-related pathologies are promoted by overnutrition and are associated with dysregulation of key metabolic pathways, particularly those related to lipid metabolism and energy homeostasis. We have previously found that the cell cycle protein cyclin D1 is induced in hepatocytes in response to feeding and overnutrition, and that it unexpectedly regulates key metabolic pathways in the liver, independently of its role in proliferation. In particular, we find that cyclin D1 represses several steps of lipid catabolism, which play an important role in health and lifespan. We now find that cyclin D1 increases with age in hepatocytes of mice and humans, suggesting a link between cyclin D1 and age-related metabolic dysfunction. However, the mechanisms by which age and overnutrition promote cell cycle-independent expression of cyclin D1 have not been defined. In addition, we have significant gaps in our understanding of how this protein modulates downstream metabolic events. Using the nematode C. elegans, we have established that the links between cyclin D1 and repression of lipid catabolism are fundamental biological responses conserved between species. Using the auxin-induced degron (AID) system, we have developed a new genetic tool in C. elegans that allows visualization of the worm ortholog of cyclin D1, encoded by the cyd-1 gene, as well as a means of reducing expression in a temporal and spatial manner. Preliminary studies indicate that genetic manipulation of cyclin D1/CYD-1 alters lipid metabolism in the worm and targets pathways involved in lipid catabolism. We will now use this powerful genetic model system as a discovery platform to define the mechanisms by which cyclin D1/CYD-1 influences lipid metabolism, aging and age-related metabolic dysfunction. Our proposed studies will establish a mechanistic foundation for further translational work, focusing on identifying strategies to inhibit cyclin D1 expression or manipulate its downstream targets as therapeutic approaches to combat age-related metabolic dysfunction.
