High-coverage plasma lipidomics reveals novel sex-specific lipidomic fingerprints of age and BMI: Evidence from two large population cohort studies

PLoS Biol. 2020 Sep 28;18(9):e3000870. doi: 10.1371/journal.pbio.3000870. eCollection 2020 Sep.


Obesity and related metabolic diseases show clear sex-related differences. The growing burden of these diseases calls for better understanding of the age- and sex-related metabolic consequences. High-throughput lipidomic analyses of population-based cohorts offer an opportunity to identify disease-risk-associated biomarkers and to improve our understanding of lipid metabolism and biology at a population level. Here, we comprehensively examined the relationship between lipid classes/subclasses and molecular species with age, sex, and body mass index (BMI). Furthermore, we evaluated sex specificity in the association of the plasma lipidome with age and BMI. Some 747 targeted lipid measures, representing 706 molecular lipid species across 36 classes/subclasses, were measured using a high-performance liquid chromatography coupled mass spectrometer on a total of 10,339 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), with 563 lipid species being validated externally on 4,207 participants of the Busselton Health Study (BHS). Heat maps were constructed to visualise the relative differences in lipidomic profile between men and women. Multivariable linear regression analyses, including sex-interaction terms, were performed to assess the associations of lipid species with cardiometabolic phenotypes. Associations with age and sex were found for 472 (66.9%) and 583 (82.6%) lipid species, respectively. We further demonstrated that age-associated lipidomic fingerprints differed by sex. Specific classes of ether-phospholipids and lysophospholipids (calculated as the sum composition of the species within the class) were inversely associated with age in men only. In analyses with women alone, higher triacylglycerol and lower lysoalkylphosphatidylcholine species were observed among postmenopausal women compared with premenopausal women. We also identified sex-specific associations of lipid species with obesity. Lysophospholipids were negatively associated with BMI in both sexes (with a larger effect size in men), whilst acylcarnitine species showed opposing associations based on sex (positive association in women and negative association in men). Finally, by utilising specific lipid ratios as a proxy for enzymatic activity, we identified stearoyl CoA desaturase (SCD-1), fatty acid desaturase 3 (FADS3), and plasmanylethanolamine Δ1-desaturase activities, as well as the sphingolipid metabolic pathway, as constituent perturbations of cardiometabolic phenotypes. Our analyses elucidate the effect of age and sex on lipid metabolism by offering a comprehensive view of the lipidomic profiles associated with common cardiometabolic risk factors. These findings have implications for age- and sex-dependent lipid metabolism in health and disease and suggest the need for sex stratification during lipid biomarker discovery, establishing biological reference intervals for assessment of disease risk.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / blood*
  • Body Mass Index
  • Cohort Studies
  • Female
  • Humans
  • Lipid Metabolism
  • Lipidomics*
  • Lipids / blood*
  • Male
  • Menopause / blood
  • Middle Aged
  • Obesity / metabolism*
  • Sex Characteristics*
  • Waist Circumference


  • Lipids

Grants and funding

This research was supported by the National Health and Medical Research Council of Australia (Project grant APP1101320). This work was also supported in part by the Victorian Government’s Operational Infrastructure Support Program. JSS and DJM are supported by Senior Research Fellowships from the National Health and Medical Research Council of Australia. HBB was supported by the Baker institute and Monash University Scholarships. The 1994/95 Busselton health survey was supported by a grant from the Health Promotion Foundation of Western Australia, and the authors acknowledge the generous support for the 1994/1995 Busselton Health Study follow-up from Western Australia and the Great Wine Estates of the Margaret River region of Western Australia. Support from the Royal Perth Hospital Medical Research Foundation is also gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.