Demographic and clinical variables affecting mid- to late-life trajectories of plasma ceramide and dihydroceramide species.

Michelle M Mielke,Yang An,Luigi Ferrucci,Susan M Resnick,Veera Venkata Ratnam Bandaru,Norman J Haughey,Dingfen Han

doi:10.1111/acel.12369

Abstract

It has been increasingly recognized at the basic science level that perturbations in ceramide metabolism are associated with the development and progression of many age-related diseases. However, the translation of this work to the clinic has lagged behind. Understanding the factors longitudinally associated with plasma ceramides and dihydroceramides (DHCer) at the population level and how these lipid levels change with age, and by sex, is important for the clinical development of future therapeutics and biomarkers focused on ceramide metabolism. We, therefore, examined factors cross-sectionally and longitudinally associated with plasma concentrations of ceramides and DHCer among Baltimore Longitudinal Study of Aging participants (n = 992; 3960 total samples), aged 55 years and older, with plasma at a mean of 4.1 visits (range 2-6). Quantitative analyses were performed on a high-performance liquid chromatography-coupled electrospray ionization tandem mass spectrometer. Linear mixed models were used to assess the relationships between plasma ceramide and DHCer species and demographics, diseases, medications, and lifestyle factors. Women had higher plasma concentrations of most ceramide and DHCer species and showed steeper trajectories of age-related increases compared to men. Ceramides and DHCer were more associated with waist-hip ratio than body mass index. Plasma cholesterol and triglycerides, prediabetes, and diabetes were associated with ceramides and DHCer, but the relationship showed specificity to the acyl chain length and saturation. These results demonstrate the importance of examining the individual species of ceramides and DHCer, and of establishing whether intra-individual age- and sex-specific changes occur in synchrony to disease onset and progression.

Highlights

Ceramides, the central molecular species of the sphingolipid pathway, function both as structural lipids and as second messengers for intraand intercellular signaling affecting cellular growth, proliferation, differentiation, senescence, and apoptosis
The homeostasis of ceramide metabolism may be critical in regulating lifespan and age-associated diseases (Cutler & Mattson, 2001; Rao et al, 2007)
It has been increasingly recognized, from the cellular to human level, that perturbations in ceramide metabolism are associated with longevity (Yu et al, 2012; Gonzalez-Covarrubias et al, 2013; Cutler et al, 2014; Huang et al, 2014) and the development and progression of many age-related diseases including cancer (Alberg et al, 2013), atherosclerosis (Ichi et al, 2006), insulin resistance and diabetes (Holland et al, 2007; Holland & Summers, 2008; Boon et al, 2013), Alzheimer’s disease (Mielke et al, 2012), and Parkinson’s disease (Mielke et al, 2013)

Summary

Introduction

The central molecular species of the sphingolipid pathway, function both as structural lipids and as second messengers for intraand intercellular signaling affecting cellular growth, proliferation, differentiation, senescence, and apoptosis. The homeostasis of ceramide metabolism may be critical in regulating lifespan and age-associated diseases (Cutler & Mattson, 2001; Rao et al, 2007). Each sphingolipid species has multiple chain lengths that are regulated by specific biochemical pathways and contribute to distinct cell functions (Hannun & Obeid, 2011). With improved understanding of ceramide chain lengths at the cellular level, and of their role in disease mechanisms, there is a need to quantify and translate this knowledge to clinical and population studies. Compared to other lipids (e.g., cholesterol, triglycerides), there are little data on ceramides at the population level and the intra- and interindividual changes in levels of specific carbon chain lengths by age, sex, race, and disease status. To further understand the relationship between individual ceramide species and disease risk, it is important to understand intraindividual changes with age and onset of disease in people over 50 years

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Conclusion