Modulation of complex lipids to promote healthy aging

Aging has long been considered a passive process that could not be reverted. Fortunately, it is now clear from genetic and pharmacological intervention studies that aging is actively regulated and can be influenced to reduce the burden of age-related diseases, such as neurodegenerative and metabolic diseases. Studies in various organisms established the importance of dysregulated lipids in the development of aging and age-related diseases. It remains unclear, however, how complex lipids and lipid metabolism causally affect aging, and the mechanisms are poorly understood. In my preliminary lipidomics analysis in ten different tissues of aged mice, I found a striking accumulation of bis(monoacylglycero)-phosphate (BMP) in all tissues. While little is known about BMPs, one lysosomal enzyme that has been described to contribute to its production is PLA2G15. Remarkably, knocking down Pla2g15 in worms leads to a significant lifespan extension. Together, these findings suggest a causal involvement of Pla2g15 in aging. I hypothesize that targeting complex lipid metabolism could promote healthy aging. Therefore, the main goal of LipidAge is to unravel the role of complex lipids, specifically BMPs in the development of aging, and how these pathways and their downstream effects impinge on lysosomal functions and healthy aging. I will use human and mouse lipid data profiles, worm C. elegans, and apply a combination of molecular, biochemical and phenotypic experiments with a focus on lipids and aging. These experiments will lead to a better understanding of conserved complex lipid changes, and the role of Pla2g15 in the BMP synthesis cascade relevant for health and disease during aging.