Development and Validation of a Plasmalogen Score as an Independent Modifiable Marker of Metabolic Health: Population Based Observational Studies and a Placebo-Controlled Cross-Over Study

Abstract

Background: Decreased levels of circulating ethanolamine plasmalogens [PE(P)], and a concurrent increase in phosphatidylethanolamine (PE) are consistently reported in various cardiometabolic conditions. Here we devised, a plasmalogen score (Pls Score) that mirrors a metabolic signal that encompasses the levels of PE(P) and PE and captures the natural variation in circulating plasmalogens and perturbations in their metabolism associated with disease, diet, and lifestyle.

Methods: We utilized, the Australian Obesity, Diabetes and Lifestyle study (AusDiab; n = 10,339, plasma) a nationwide cohort, to devise the Pls Score and validated this in the Busselton Health Study (BHS; n = 4,492, serum) and in a placebo-controlled crossover trial involving Shark Liver Oil (SLO) supplementation. We examined the association of the Pls Score with cardiometabolic risk factors, type 2 diabetes mellitus (T2DM), cardiovascular disease and all-cause mortality (over 17 years).

Findings: In a model, adjusted for age, sex and BMI, individuals in the top quintile of the Pls Score (Q5) relative to Q1 had an OR of 0.31 (95% CI 0.21– 0.43), 0.39 (95% CI 0.25 – 0.61) and 0.42 (95% CI 0.30 – 0.57) for prevalent T2DM, incident T2DM and prevalent cardiovascular disease respectively and a decreased mortality risk (HR=0.66; 95% CI: 0.56 – 0.78). Significant associations between diet and lifestyle habits and Pls Score exist and these were validated through dietary supplementation of SLO that resulted in a marked change in the Pls Score.

Interpretation: The Pls Score as a measure that captures the natural variation in circulating plasmalogens, was not only inversely related to cardiometabolic risk and all-cause mortality but also associate with diet and lifestyle. Our results support the potential utility of the Pls Score as a biomarker for metabolic health and its responsiveness to dietary interventions. Further research is warranted to explore the underlying mechanisms and optimize the practical implementation of the Pls Score in clinical and population settings.

Funding: National Health and Medical Research Council (NHMRC grant 233200), National Health and Medical Research Council of Australia (Project grant APP1101320), Health Promotion Foundation of Western Australia, and National Health and Medical Research Council of Australia Senior Research Fellowship (#1042095).

Declaration of Interest: The Baker Institute has filed a provisional patent on the Plasmalogen Score. Application number: 2023900769; Title: Methods of assessing metabolic health. PJM consults for Juvenescence Ltd.

Ethical Approval: This study used datasets from the AusDiab biobank (project grant APP1101320) approved by the Alfred Human Research Ethics Committee, Melbourne, Australia (project approval number, 41/18) and the BHS cohort (informed consent obtained from all participants, and the study was approved by the University of Western Australia Human Research Ethics Committee [UWA-HREC; approval number, 608/15]). The current study was also approved by UWA HREC (RA/4/1/7894) and the Western Australian Department of Health HREC (RGS03656). Both studies were conducted in accordance with the ethical principles of the Declaration of Helsinki. No participant compensation was provided. The SLO trial study received approval from the Alfred Hospital Ethics Committee (approval number: 436/15).

Keywords: Pls Score, Metabolic health, Diet, Lifestyle Intervention