Targeted Plasmalogen Supplementation: Effects on Blood Plasmalogens, Oxidative Stress Biomarkers, Cognition, and Mobility in Cognitively Impaired Persons

Dayan B Goodenowe; Jonathan Haroon; Mitchel A Kling; Margaret Zielinski; Kennedy Mahdavi; Barshen Habelhah; Leah Shtilkind; Sheldon Jordan

doi:10.3389/fcell.2022.864842

Targeted Plasmalogen Supplementation: Effects on Blood Plasmalogens, Oxidative Stress Biomarkers, Cognition, and Mobility in Cognitively Impaired Persons

Front Cell Dev Biol. 2022 Jul 6:10:864842. doi: 10.3389/fcell.2022.864842. eCollection 2022.

Authors

Dayan B Goodenowe¹, Jonathan Haroon², Mitchel A Kling^{3

4

5}, Margaret Zielinski², Kennedy Mahdavi², Barshen Habelhah², Leah Shtilkind¹, Sheldon Jordan²

Affiliations

¹ Prodrome Services USA LLC, Temecula, CA, United States.
² The Regenesis Project, Santa Monica, CA, United States.
³ Pereleman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
⁴ Crescenz VA Medical Center, Philadelphia, PA, United States.
⁵ New Jersey Institute for Successful Aging, Department of Geriatrics and Gerontology, Rowan School of Osteopathic Medicine, Stratford, NJ, United States.

Abstract

Plasmalogens are a specific type of glycerophospholipid found in especially high levels in neuronal membranes. Decreased blood and brain levels of docosahexaenoic acid (DHA) containing plasmalogens are associated with decreased cognition and neuromuscular function in humans. Administration of 1-O-alkyl-2-acylglycerol (AAG) plasmalogen precursors containing DHA at the sn-2 position dose-dependently increase blood DHA plasmalogens and are neuroprotective in animal models of neurodegeneration at doses between 10 and 50 mg/kg. We conducted an investigational clinical trial in 22 cognitively impaired persons to evaluate the effects of an escalating oral dosing regimen of DHA-AAG from 900 to 3,600 mg/day over a 4-month period on blood serum plasmalogen and non-plasmalogen phospholipids and oxidative stress biomarkers. Safety, tolerability and therapeutic effects on cognition and mobility were also evaluated. DHA plasmalogen levels increased with increasing dose and remained significantly elevated at all treatment doses and durations. DHA plasmalogen levels were positively associated with catalase activity and negatively associated with malondialdehyde (MDA) levels. DHA-AAG supplementation normalized catalase activity in persons with low baseline catalase activity, normalized MDA levels in persons with high baseline MDA levels, and normalized superoxide dismutase activity in persons with high baseline SOD activity. Cognition improved in nine participants, was unchanged in nine, and declined in four. Mobility improved in twelve, was unchanged in five and declined in four participants. Changes in cognition and mobility were statistically significant versus a random outcome. Baseline DHA-plasmalogen levels were not predictive of clinical response. DHA-AAG was well tolerated at all dosages and no adverse reactions were observed.

Keywords: alkylglycerol (AKG); catalase; dementia; malondiadehyde; oxidative stress; plasmalogen; sarcopenia; superoxide dismutase.