Fatty acid desaturation controls cellular fate decisions between senescence and ferroptosis

When subject to damage or stress, cells develop responses in order to maintain tissue homeostasis. Two such responses are ferroptosis and cellular senescence, but how cells decide between these outcomes remains unclear. Here, we show that senescent cells increase import and membrane levels of multiple polyunsaturated fatty acids (PUFAs), but a specific intermediate PUFA, dihomo-gamma-linolenic acid (DGLA, 20:3ω-6), is reduced. Exogenous repletion of DGLA instead results in cell death by ferroptosis. Senescent cells manifest additional features associated with ferroptosis, including labile iron and expression of lipoxygenases as well as low-level membrane peroxidation. Oral DGLA supplementation lowers markers of senescence in aged mice and improves age-related functional outcomes. Finally, obese humans with lowered DGLA desaturation rates have lower markers of adipose tissue senescence. Together, our data implicate shifts in PUFA metabolism as a driver of decisions between senescence and ferroptosis.