Dysfunctional lipid metabolism and peroxidation in chronic pain and neurodegeneration

National Institute On Aging

Investigators

Linked publications & trials

Abstract

The mission of the Lipid Peroxidation Unit (LPU) is to (1) discover new mediators and mechanisms linking lipids and lipoproteins and their peroxidation to age-related diseases, with a focus on chronic pain and Alzheimer's disease, and (2) to translate advances into targeted, safe, and effective diet and drug treatments. Our long-term goal is to develop and advance non-addictive diet and drug-based interventions to prevent and treat age-related diseases. We apply an interdisciplinary, translational approach comprising randomized controlled trials, postmortem studies, synthetic and analytical chemistry, antibody development, advanced immunohistochemistry, and cellular assays to achieve these objectives. Randomized controlled trials Our team is leading or collaborating on several randomized controlled trials testing the clinical efficacy and biochemical effects of targeted alterations in dietary fatty acids, which are precursors to bioactive lipid mediators including oxylipins and endocannabinoids. These trials have included a total of more than 500 randomized participants, including 350 suffering with chronic pain syndromes that are refractory to conventional medical management. Five trials grew out of the promising results of small randomized trial conducted at UNC-Chapel Hill testing targeted dietary manipulation as an adjunct strategy for managing treatment-resistant chronic headaches in collaboration with Doug Mann, M.D., and the Department of Physical Medicine and Rehabilitation Medicine. We published the results of a follow-up randomized controlled trial in 2021 demonstrating clinical efficacy and biochemical effects of a targeted dietary intervention in n=182 patients with frequent migraines (https://www.bmj.com/content/374/bmj.n1448). In 2023, we published the results of an NIH intramural RCT testing the effects of targeted alterations in dietary fatty acids on endocannabinoids, craving, satiety, and body composition. The primary endpoints of this trial, which was led by NIAAA and includes investigators from NIA, NIDDK, the NIH Clinical Center, and UNC-Chapel Hill. In 2025, we published results of a multi-site randomized controlled trial demonstrating clinical efficacy and biochemical effects of a targeted dietary intervention in n=120 military personnel (SP) with persistent post-traumatic headaches. We are currently working with collaborators to extend this novel adjunct approach for treating chronic pain to participants with chronic lumbosacral radicular (neuropathic) pain and chronic axial (nociceptive) low back pain. Mediators and mechanisms linking lipids to disease Our team has identified new oxidized derivatives of fatty acids and is investigating the potential roles of these and other oxidized lipids that are present in human tissues in pain, itch, and age-related diseases. Synthetic chemistry and drug discovery Our team uses the interdisciplinary, translational approach described above to inform the design and total synthesis of stable analogs and small molecules as potential drug candidates. Our Unit used this approach to synthesize two classes of compounds that are designed to mimic the beneficial effects of our diet interventions. A lead compound has demonstrated anti-nociceptive (pain relieving) effects in blinded testing in three outside labs. The long-term goal of these efforts is to develop targeted, effective, non-addictive drugs to treat chronic pain and neurodegenerative diseases. Analytical chemistry Our team applies liquid chromatography-tandem mass spectrometry and related techniques to identify and quantify protein and lipid compounds in human and rodent tissues. These approaches provide key biochemical insights into potential mechanisms linking proteins and lipids to inflammation, pain, and related clinical endpoints in randomized controlled trials and other studies. These assays also used to identify potential mechanism-based biomarkers for Alzheimers disease. Immunohistochemistry Our team applies advanced immunohistochemistry techniques to characterize lipid and lipoprotein-related derangements in human neurological tissues. We are currently investigating lipid-related derangements in postmortem hippocampus, entorhinal cortex, amygdala, frontal cortex, and brainstem nuclei specimens from cases with Alzheimer's disease, Mild Cognitive Impairment, and matched non-AD controls, and frontal cortex of cases and controls with and without chronic traumatic encephalopathy. Cellular assays Our Unit expanded use of iPSC derived human neuron and astrocyte cell lines which to model and investigate lipid-related molecular mechanisms relevant for neuroinflammatory and neuro-degenerative diseases. These collective efforts are directed toward discovery of new mediators and mechanisms underlying age-related diseases, and the translation of findings to identify novel mechanism-based biomarkers and develop effective, non-addictive treatments for chronic pain and neurodegenerative diseases.