Factors affecting longitudinal trajectories of plasma sphingomyelins: the Baltimore Longitudinal Study of Aging

Abstract

Sphingomyelin metabolism has been linked to several diseases and to longevity. However, few epidemiological studies have quantified individual plasma sphingomyelin species (identified by acyl-chain length and saturation) or their relationship between demographic factors and disease processes. In this study, we determined plasma concentrations of distinct sphingomyelin species in 992 individuals, aged 55 and older, enrolled in the Baltimore Longitudinal Study of Aging. Participants were followed, with serial measures, up to 6 visits and 38 years (3972 total samples). Quantitative analyses were performed on a high-performance liquid chromatography-coupled electrospray ionization tandem mass spectrometer. Linear mixed models were used to assess variation in specific sphingomyelin species and associations with demographics, diseases, medications or lifestyle factors, and plasma cholesterol and triglyceride levels. We found that most sphingomyelin species increased with age. Women had higher plasma levels of all sphingomyelin species and showed steeper trajectories of age-related increases compared to men. African Americans also showed higher circulating sphingomyelin concentrations compared to Caucasians. Diabetes, smoking, and plasma triglycerides were associated with lower levels of many sphingomyelins and dihydrosphingomyelins. Notably, these associations showed specificity to sphingomyelin acyl-chain length and saturation. These results demonstrate that longitudinal changes in circulating sphingomyelin levels are influenced by age, sex, race, lifestyle factors, and diseases. It will be important to further establish the intra-individual age- and sex-specific changes in each sphingomyelin species in relation to disease onset and progression.

A Lipidomics Approach to Assess the Association Between Plasma Sphingolipids and Verbal Memory Performance in Coronary Artery Disease Patients Undertaking Cardiac Rehabilitation: A C18:0 Signature for Cognitive Response to Exercise

“…Plasma was immediately isolated and stored at −80°C until analysis. Quantification of 45 individual sphingolipid species was accomplished by high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry (LC/MS/MS) using multiple reaction monitoring and processed by the Analyst 1.4.2 software package as previously described[63]. Briefly, a crude lipid extraction from plasma was performed using a modified Bligh and Dyer procedure (Avanti Polar Lipids, Alabaster, AL, USA).…”

Peripheral sphingolipids are associated with variation in white matter microstructure in older adults

“…The lipid extractions and methods for measuring plasma ceramide and sphingomyelin levels in the BLSA have previously been described in detail, including the inter- and intra-day coefficients of variation (Mielke et al, 2015a, 2015b). Briefly, a crude lipid extraction of plasma was conducted using a modified Bligh and Dyer procedure with ceramide or sphingomyelin C12:0 included as an internal standard (Avanti Polar Lipids, Alabaster, Alabama) (Bandaru et al, 2013; Haughey et al, 2004).…”

“…The covariates for multiple regression models were selected because they significantly correlated with FA or MD in large WM regions (age, sex, ratio of WML to ICV), have been shown to affect sphingolipid levels (i.e., diabetes, BMI), or to control for limitations in data collection (i.e., multiple scanners and variable follow-up interval between blood sample and DTI). As previous work has shown levels of peripheral ceramides and sphingomyelins increase with age (Mielke et al, 2015a, 2015b), we also examined models including age X sphingolipids. However, we only present models without the addition of this interaction as the simpler model yielded similar results.…”

“…While ceramides do act as structural lipids, they are important bioactive lipids necessary for regulating signaling cascades involved in cellular senescence, apoptosis, and inflammation (Hannun and Obeid, 2008; Kolesnick, 1998). Both sphingomyelins and ceramides increase with age (Cutler et al, 2004; Mielke et al, 2015a, 2015b). Further, these lipids, individually and the ratio of sphingomyelin to ceramide, have been implicated in the development and progression of neurodegenerative diseases (Ben-David and Futerman, 2010; Cutler et al, 2004; Haughey, 2010).…”

The Association Between Plasma Ceramides and Sphingomyelins and Risk of Alzheimer’s Disease Differs by Sex and APOE in the Baltimore Longitudinal Study of Aging

“…We recently reported sex-specific trajectories of increasing plasma ceramides and sphingomyelins with aging [21, 22], and sex differences in the risk factors for AD are well known [23]. The APOE gene encodes the lipid/cholesterol carrier apolipoprotein E and the APOE ε4 allele may have a greater deleterious effect for women versus men with regards to hippocampal pathology, functional connectivity changes in the default mode network, cortical thickness, memory performance and risk of dementia in women compared with men [24–28].…”