Fatty acid desaturation controls cellular fate decisions between senescence and ferroptosis
Summary When subject to damage or stress, cells develop responses in order to maintain tissue homeostasis. Two such decisions are ferroptosis and cellular senescence, but how cells decide between these outcomes remains unclear. Here we show that senescent cells increase levels of multiple membrane-bound polyunsaturated fatty acids (PUFAs), but a specific PUFA, dihomo-gamma-linolenic acid (DGLA, 20:3 ω -3) is reduced. Exogenous repletion of DGLA or inhibition of delta-5-desaturase, the enzyme that metabolizes DGLA, instead results in cell death by ferroptosis. Senescent cells had elevated levels of other fezzroptosis sensitizers, including labile iron and expression of lipoxygenases – but also increased Gpx4 levels to prevent ferroptosis. Oral DGLA lowered senescent cell burden in aged mice and improved age-related functional outcomes. Finally, obese humans with lowered DGLA desaturation rates showed lower markers of adipose tissue senescence. Together, our data implicate DGLA and its desaturation as a major driver of decisions between senescence and ferroptosis.
Authors
- Ioannis Siokas (ORCID: https://orcid.org/0000-0003-0363-0027)
- Nirupa Rachel Matthan (ORCID: https://orcid.org/0000-0002-7037-9779)
- Diana Jurk (ORCID: https://orcid.org/0000-0003-4486-0857)
- Sharvari Deshpande
- Xuejuan Tan (ORCID: https://orcid.org/0000-0003-1926-9686)
- Koji Kitazawa (ORCID: https://orcid.org/0000-0003-2203-5776)
- Maija Vaittinen (ORCID: https://orcid.org/0000-0002-7423-557X)
- Bronwyn A. Mogck
- Gung Lee (ORCID: https://orcid.org/0000-0002-0223-7955)
- Ron Korstanje (ORCID: https://orcid.org/0000-0002-2808-1610)
- Samantha T. Jezak
- Jussi Pihlajamäki (ORCID: https://orcid.org/0000-0002-6241-6859)
- Arvind Ramanthan
- Amene Majidipur (ORCID: https://orcid.org/0000-0003-0925-5563)
- Chisaka Kuehnemann (ORCID: https://orcid.org/0000-0001-7977-3257)
- Christopher D. Wiley (ORCID: https://orcid.org/0000-0002-7699-6866)
- A. H. Kung
- Andrew S. Greenberg (ORCID: https://orcid.org/0000-0001-5062-387X)
- Niharika Kura (ORCID: https://orcid.org/0000-0003-2008-6879)
- Eliézer Aïmontché (ORCID: https://orcid.org/0000-0001-7774-3257)
- Rushmeen Tariq
- Yuheng Che
- QiaoLing Wang
- Yong Cheng
- Aleksandra Aljakna Kahn
- Peter Reifsnyder
- Howard H. Chen
- Carlyn Guthrie
- Gregory Dolnikowsi
- Daniel Roh
- Tong Zheng
- Xiang-Dong Wang
- Jennifer Lee
Institutions
- Oklahoma State University (US)
- Tufts University (US)
- Buck Institute for Research on Aging (US)
- University of Eastern Finland (FI)
- Kyoto Prefectural University of Medicine (JP)
- Jean Mayer Human Nutrition Research Center on Aging (US)
- Jackson Laboratory (US)
- VIR Biotechnology (United States) (US)
Publication Details
- Journal
- Cell
- Published
- 2026-11-01
- DOI
- https://doi.org/10.1016/j.cell.2026.09.036
- Citations
- 1
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 4.65
Funders
- U.S. Department of Agriculture
- Glenn Foundation for Medical Research
- SENS Research Foundation
- Fondation pour la Recherche Médicale
- Agricultural Research Service
- National Institute of Diabetes and Digestive and Kidney Diseases