Plasma lipidome variation during the second half of the human lifespan is associated with age and sex but minimally with BMI.
Abstract
Recent advances in mass spectrometry-based techniques have inspired research into lipidomics, a subfield of ‘–omics’, which aims to identify and quantify large numbers of lipids in biological extracts. Although lipidomics is becoming increasingly popular as a screening tool for understanding disease mechanisms, it is largely unknown how the lipidome naturally varies by age and sex in healthy individuals. We aimed to identify cross-sectional associations of the human lipidome with ‘physiological’ ageing, using plasma from 100 subjects with an apolipoprotein E (APOE) E3/E3 genotype, and aged between 56 to 100 years. Untargeted analysis was performed by liquid chromatography coupled-mass spectrometry (LC-MS/MS) and data processing using LipidSearch software. Regression analyses confirmed a strong negative association of age with the levels of various lipid, which was stronger in males than females. Sex-related differences include higher LDL-C, HDL-C, total cholesterol, particular sphingomyelins (SM), and docosahexaenoic acid (DHA)-containing phospholipid levels in females. Surprisingly, we found a minimal relationship between lipid levels and body mass index (BMI). In conclusion, our results suggest substantial age and sex-related variation in the plasma lipidome of healthy individuals during the second half of the human lifespan. In particular, globally low levels of blood lipids in the ‘oldest old’ subjects over 95 years could signify a unique lipidome associated with extreme longevity.
Introduction
In recent times, mass spectrometry-based lipidomics techniques have emerged as important technological platforms enabling the identification of hundreds to thousands of lipids in plasma and tissue extracts [1]. Lipids play an important role in cellular metabolism by maintaining structural integrity, and acting as signalling molecules, and may have important implications in health and disease. Lipidomics is commonly used to identify and quantify metabolic changes associated with age related disorders such as cardiovascular disease, diabetes, metabolic syndrome [2], cancer [3], and neurological disorders, such as Alzheimer’s disease [4–6]. It therefore forms a strong and relatively novel starting point for the study of disease mechanisms or disease-related biomarkers. However, before investigating pathological changes to the lipidome involved in disease states, it is important to understand how the human lipidome naturally varies in normal healthy individuals based on anthropometric variables such as age, sex and BMI. This knowledge is not only of intrinsic interest to better understand the biology of ageing, but will also aid in appropriate experimental design and subject selection to address major research questions.
In this study, we focused on blood as an important source of biomarkers and which is already widely used for both clinical and research purposes [6, 7]. Furthermore, venepuncture is a relatively safe, minimally invasive procedure and blood is easy to collect (even for repeat analyses) and store and therefore represents a convenient medium for investigating lipidomics [6, 8].
We applied a recently described technique [9] to extract lipids from human plasma samples. Plasma lipid extracts were then analysed using liquid chromatography electrospray ionisation tandem mass spectrometry (LC-ESI MS/MS) to investigate how major lipid classes were altered as a function of age. We also wished to avoid the minor APOE allele variants ε2 and ε4, which are frequently reported disease modulators [10, 11], and given the known APOE association with plasma lipids, we particularly wished to eliminate this confounder. We therefore selected exclusively APOE ε3 homozygous individuals to explore relationships between plasma lipids and other anthropomorphic variables such as sex, BMI and cholesterol levels (HDL-C and LDL-C). In younger age groups (aged 20 to 50 years), it has previously been reported that plasma lipid levels are associated with age [8, 12], sex [8, 13] and BMI [14, 15]. We therefore hypothesised that lipid profiles in normal healthy individuals will be associated with age, sex and BMI during the second half of the human lifespan, and these relationships will be different in the ‘oldest old’ who exemplify exceptional ageing.
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