Salehi, FahimehKavoosi, GholamrezaJacobs, Paul JuanBennett, Nigel CharlesAhmadian, ShahinBastani, BabakGholami, Mahdi2025-07-222025Salehi, F., Kavoosi, G., Jacobs, P.J. et al. The road to a long lifespan in the Persian squirrel, a natural model for extended longevity: resisting free radical stress and healthy phospholipids. GeroScience (2025). https://doi.org/10.1007/s11357-025-01668-9.2509-2715 (print)2509-2723 (online)10.1007/s11357-025-01668-9http://hdl.handle.net/2263/103501DATA AVAILABILITY : The corresponding author will deliver the information assisting the findings of this study upon reasonable request.Longevity is influenced by various factors, including fatty acid composition and free radical stress, which relate to the membrane pacemaker and rate of living hypotheses. While these aspects are well-documented in some long-lived species, they remain largely unexplored in tree squirrels. This study aimed to compare oxidative stress, antioxidant activity, nitrosative stress, and lipid composition between the long-lived Persian squirrel (Sciurus anomalus) and the short-lived Wistar rat across age cohorts (younger and older). Tissue homogenates from skin, liver, skeletal muscle, spleen, lung, and kidney were analysed for lipid composition (monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), arachidonic to linoleic acid ratio, peroxidation index, and unsaturation index. Oxidative, nitrosative, and antioxidant markers were assessed, including NADPH oxidase, superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase (GST), nitric oxide synthase, superoxide, hydrogen peroxide, nitric oxide, malondialdehyde, 4-hydroxynonenal, and total antioxidant capacity (TAC). Squirrels demonstrated higher GST activity, lower free radical stress, lower PUFA, and higher MUFA compared to rats. Antioxidant activities, except for TAC were negatively correlated with longevity. Older squirrels exhibited similar oxidative, nitrosative, and antioxidant profiles to younger squirrels, whereas younger rats displayed highly susceptible fatty acids, similar to older rats. The Persian squirrel’s longevity appears closely linked to fatty acid composition and free radical resistance, likely due to increased GST activity. We propose GST’s multifunctional role in reducing inflammation, enhancing immune response, providing disease resistance, and antioxidant activity contributes significantly to the longevity of the Persian squirrel.en© The Author(s), under exclusive licence to American Aging Association 2025. The original publication is available at : https://link.springer.com/journal/11357.Persian squirrel (Sciurus anomalus)AgeingLipidsFree radicalOxidative stressTree squirrelGlutathione-S-transferasePostprint Article