A lipid droplet-peroxisome network drives longevity by monounsaturated fatty acids via modulating ether lipid synthesis and ferroptosis

Abstract

Dietary mono-unsaturated fatty acids (MUFAs) are linked to human longevity and extend lifespan in several species1-12. But the mechanisms by which MUFAs promote longevity remain unclear. Here we show that an organelle hub involving lipid droplets and peroxisomes is critical for lifespan extension by MUFAs in C. elegans. MUFA accumulation increases lipid droplet number in fat storage tissues, and lipid droplet synthesis is necessary for MUFA-mediated longevity. Interestingly, the number of lipid droplets in young individuals can predict their remaining lifespan. MUFA accumulation also increases the number of peroxisomes, and peroxisome activity is required for MUFA-mediated longevity. By performing a targeted screen, we uncover a functional network between lipid droplets and peroxisomes in longevity. Interestingly, our screen also identifies ether lipids as critical components of the lipid droplet-peroxisome network. Using lipidomics, we find that the ratio of MUFAs to polyunsaturated fatty acids (PUFAs) in ether lipids is increased by MUFA accumulation. Ether lipids are involved in ferroptosis, a non-apoptotic form of cell death13-17, and MUFAs promote longevity in part via suppression of ferroptosis. Our results identify a mechanism of action for MUFAs to extend lifespan and uncover an organelle network involved in the homeostasis of MUFA-rich ether lipids. Our work also opens new avenues for lipid-based interventions to delay aging.

Lipid droplets and polyunsaturated fatty acid trafficking: Balancing life and death

“…Another mechanism employed by cells to protect from lipid (per)oxidation involves the incorporation of less harmful MUFAs in cell membranes in order to reduce PUFA content and membrane unsaturation (Figure 3). The beneficial effect of the monounsaturated OA in the protection from lipotoxicity has been observed in many studies (Listenberger et al, 2003;Ackerman et al, 2018;Chen et al, 2018;Jarc et al, 2018;Lisec et al, 2019;Pérez-Martí et al, 2022) and more recently also linked with ferroptosis resistance (Magtanong et al, 2019;Tesfay et al, 2019;Ubellacker et al, 2020;Brunet et al, 2021;Xie et al, 2022).…”

“…Despite evidence that LDs are involved in MUFA trafficking, their role in MUFA-mediated protection from ferroptosis remains unclear (Magtanong et al, 2019;Liang et al, 2022). A recent study in C. elegans provides important insights into the potential role of LDs in MUFA-regulated suppression of ferroptosis (Brunet et al, 2021). The study found that LDs are critical for MUFA-induced lifespan extension in C. elegans by forming close contact sites with peroxisomes.…”

“…In other conditions, LDs act as antioxidant organelles that sequester membrane PUFAs into their protective neutral lipid core to prevent their oxidation (Bailey et al, 2015). Accordingly, recent evidence suggests that LDs modulate ferroptosis sensitivity by regulating membrane unsaturation through the control of PUFA/MUFA trafficking between the TAG and phospholipid lipid pools (Bai et al, 2018;Brunet et al, 2021;Dierge et al, 2021) (Figure 1). These emerging mechanisms of LDmediated regulation of mitochondrial function, lipid (per)oxidation and ferroptotic cell death are discussed in the following sections.…”