Unraveling the longitudinal effects of lifelong inulin supplementation on the metabolic pathophysiology of aging

/ABSTRACT This project aims to decipher the efficacy of a lifespan inulin-supplemented diet on the metabolic pathophysiology of aging and elucidate what major biochemical pathways mediate inulin’s effects. In my preliminary studies, I have discovered that lifespan inulin feeding decreases multiple aging markers. Isotope tracing revealed that inulin feeding enhances glucose clearance through both increased catabolism (oxidation via TCA cycle) and anabolism (fatty acid and amino acid synthesis). Also, inulin-fed mice exhibited enhanced oxidation of dietary fatty acids, indicating improved usage of available nutrients. Finally, inulin-fed old-aged mice showed markedly reduced arachidonic acid (ARA) levels while increasing its downstream metabolites, including anti-inflammatory prostaglandin (PG) species. Thus, I hypothesize that lifespan inulin supplementation invigorates tissue macronutrient usage and alters ARA metabolism to preserve metabolic fitness and mitigate aging-associated inflammation. Therefore, Aim 1 is to determine the effect of lifelong inulin provision on tissue glucose metabolism in old-aged mice. To decipher which organ(s) mediate inulin’s effect on improving systemic glucose homeostasis, I will perform a 13C-glucose tracing coupled with comprehensive metabolomics analysis across key organs utilizing our in-house quadrupole-orbitrap mass spectrometer (Q-Exactive Plus Orbitrap LC-MS, Thermo Fisher) in young and old-aged mice exposed to lifelong inulin supplementation. I will also employ indirect calorimetry to determine the effect of lifelong inulin supplementation on metabolic flexibility. My proposed Aim 2 is to determine whether arachidonic acid metabolism and inflammation regulation mediate inulin’s anti-aging effects. I aim to quantitatively measure the impact of inulin feeding on ARA synthesis and utilization for PG production using dual stable isotope tracing techniques. Also, I will determine the changes in systemic inflammatory cytokine profiles across the lifespan using longitudinally sampled blood samples every 2-3 months from 3 months to 24 months of age. Third, a successive nutritional intervention will be conducted with simultaneous administration of lifespan inulin and ARA supplementation to decipher how ARA metabolism and its bioactive lipid-derived metabolites influence the inulin’s anti-aging effects. Collectively, these studies will determine how lifelong inulin supplementation improves macronutrient usage for metabolic health and whether the ARA-PG axis regulating inflammation contributes to such anti-aging effect of inulin. Project Number: 1R36AG097777-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Miranda Lopez | Institution: UNIVERSITY OF CALIFORNIA-IRVINE, IRVINE, CA | Award Amount: $76,848 | Activity Code: R36 | Study Section: Special Emphasis Panel[ZRG1 F03B-W (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11289162