The Impact of Dietary Lipids on Cellular Organelles during Aging and Longevity

• Applicant: Dr. Katharina Papsdorf
• Subject Area: Biogerontology and Geriatric Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570226551

Monounsaturated fatty acids (MUFAs) correlate with longevity, and diets rich in MUFAs protect against cardiovascular diseases. MUFAs also causally induce longevity in the nematode C. elegans. However, MUFAs fail to extend lifespan when supplemented to older individuals, and the underlying reasons are unknown. We hypothesize that MUFAs protect cells from lipotoxic stress, but the metabolic flexibility required for this protection diminishes with age. To test this, we will develop a platform to measure lipotoxicity in human intestinal epithelial cells and intestinal organoids derived from young and old mice. It will be determined whether cellular responses to MUFAs differ with age. Once these platforms are established, we will test how endosomal transport processes are involved in protection from lipotoxicity. Preliminary findings suggest that some endosomal genes are required for lifespan extension upon MUFAs in C. elegans and endosomes regulate lipid degradation. However, it is unknown whether endosomes maintain cellular lipid homeostasis with age. We hypothesize that endosomes transport beneficial lipids to their destination within the cell, and that this process becomes impaired with aging. To test this hypothesis, endosomal function in intestinal cells and organoids will be perturbed using shRNA or small molecules. The effects of these perturbations will be evaluated using the lipotoxicity assessment platform. Organoids derived from young and old mice will then be examined to determine whether age exacerbates the effects of disrupted endosomal trafficking on lipid homeostasis. Results from this aim will reveal how endosomes contribute to maintaining lipid health and how aging and dietary lipids affect this critical function. By elucidating mechanisms of lipid regulation, this study will provide fundamental insights into aging biology and metabolic flexibility. Furthermore, these findings could carry significant translational potential for promoting healthy mammalian aging through dietary or pharmacological interventions targeting lipid homeostasis.

• DFG Programme: Research Grants