A growing body of evidence suggests that changes in fat metabolism may have a significant effect on lifespan. Accumulation of lipid deposits in non-adipose tissue appears to be critical for age-related pathologies and may also contribute to the aging process itself. We established a model of lipid storage in muscle cells of C. elegans to reveal a mechanism that promotes longevity non-cell-autonomously. Here, we describe how muscle-specific activation of adipose triglyceride lipase (ATGL) and the phospholipase A2 (PLA2) ortholog IPLA-7 collectively affect inter-tissular communication and systemic adaptation that requires the activity of AMP-dependent protein kinase (AMPK) and a highly conserved nuclear receptor outside of the muscle. Our data suggest that muscle-specific bioactive lipid signals, or “lipokines,” are generated following triglyceride breakdown and that these signals impinge on a complex network of genes that modify the global lipidome, consequently extending the lifespan. Display omitted •Muscle-specific lipid catabolism extends lifespan in a non-cell-autonomous manner•Depletion of IMLDs via the PKA/ATGL pathway remodels the global lipidome•Muscle-specific PLA2 generates “lipokines” that signal to tissues outside of the muscle•Regulators of metabolic homeostasis in neurons are required to promote longevity Schmeisser et al. describe a longevity pathway that originates in muscle tissue through PKA-mediated ATGL-dependent depletion of intramyocellular lipid droplets. This, together with the PLA2 ortholog IPLA-7, affects inter-tissular signaling through the formation of “lipokines,” modulating metabolic homeostasis and extending the lifespan via neuronal AMPK and NHR-80.