Fatty acid desaturation controls cellular fate decisions between senescence and ferroptosis.

Chisaka Kuehnemann, Samantha T Jezak, Bronwyn A Mogck, Niharika Kura, Rushmeen Tariq, Yuheng Che, Maija Vaittinen, Ioannis Siokas, Sharvari Deshpande, Carlyn Guthrie, Xuejuan Tan, Eliezer Aimontche, Aleksandra Aljakna Kahn, Peter Reifsnyder, Gung Lee, Amene Majidipur, Andrew H Kung, Qiaoling Wang, Diana Jurk, Tong Zheng, Andrew S Greenberg, Xiang-Dong Wang, Koji Kitazawa, Gregory Dolnikowsi, Yong Cheng, Nirupa R Matthan, Arvind Ramanthan, Jennifer Lee, Daniel Roh, Howard H Chen, Jussi Pihlajamaki, Ron Korstanje, Christopher D Wiley

Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA. · pubmed

Paper

Abstract

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.

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Research summary

The paper claims that the specific reduction of the polyunsaturated fatty acid DGLA in senescent cells drives the cellular decision toward senescence rather than ferroptosis, and that restoring DGLA levels can reverse senescence markers and improve age-related functional outcomes. This is highly relevant to longevity research because it identifies a specific metabolic mechanism (PUFA desaturation) that acts as a switch between two distinct cell fates, offering a potential therapeutic target to prevent or reverse cellular senescence, a core driver of biological aging, rather than merely treating downstream symptoms.

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