Lipidomics – the global assessment of lipids – can be performed using a variety of mass spectrometry (MS)-based approaches. However, choosing the optimal approach in terms of lipid coverage, robustness and throughput can be a challenging task. Here, we compare a novel targeted quantitative lipidomics platform known as the Lipidyzer to a conventional untargeted liquid chromatography (LC)-MS approach. We find that both platforms are efficient in profiling more than 300 lipids across 11 lipid classes in mouse plasma with precision and accuracy below 20% for most lipids. While the untargeted and targeted platforms detect similar numbers of lipids, the former identifies a broader range of lipid classes and can unambiguously identify all three fatty acids in triacylglycerols (TAG). Quantitative measurements from both approaches exhibit a median correlation coefficient (r) of 0.99 using a dilution series of deuterated internal standards and 0.71 using endogenous plasma lipids in the context of aging. Application of both platforms to plasma from aging mouse reveals similar changes in total lipid levels across all major lipid classes and in specific lipid species. Interestingly, TAG is the lipid class that exhibits the most changes with age, suggesting that TAG metabolism is particularly sensitive to the aging process in mice. Collectively, our data show that the Lipidyzer platform provides comprehensive profiling of the most prevalent lipids in plasma in a simple and automated manner.

The lifespan of an organism is strongly influenced by environmental factors, including diet, and by internal factors, notably reproductive status. Lipid metabolism is critical for adaptation to external conditions or reproduction. Interestingly, specific lipid profiles are associated with longevity and increased uptake of certain lipids extends longevity in C. elegans and ameliorates disease phenotypes in humans. How lipids impact longevity, and how lipid metabolism is regulated during aging, is just beginning to be unraveled. This review describes recent advances in the regulation and role of lipids in longevity, focusing on the interaction between lipid metabolism and chromatin states in aging and age-related diseases.

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.

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