Date Published: January 15, 2019
Publisher: Impact Journals
Author(s): Valentina Vozella, Abdul Basit, Fabrizio Piras, Natalia Realini, Andrea Armirotti, Paola Bossù, Francesca Assogna, Stefano L. Sensi, Gianfranco Spalletta, Daniele Piomelli.
Circulating ceramide levels are abnormally elevated in age-dependent pathologies such as cardiovascular diseases, obesity and Alzheimer’s disease. Nevertheless, the potential impact of age on plasma ceramide levels has not yet been systematically examined. In the present study, we quantified a focused panel of plasma ceramides and dihydroceramides in a cohort of 164 subjects (84 women) 19 to 80 years of age. After adjusting for potential confounders, multivariable linear regression analysis revealed a positive association between age and ceramide (d18:1/24:0) (β (SE) = 5.67 (2.38); p = .0198) and ceramide (d18:1/24:1) (β (SE) = 2.88 (.61); p < .0001) in women, and between age and ceramide (d18:1/24:1) in men (β (SE) = 1.86 (.77); p = .0179). In women of all ages, but not men, plasma ceramide (d18:1/24:1) was negatively correlated with plasma estradiol (r = -0.294; p = .007). Finally, in vitro experiments in human cancer cells expressing estrogen receptors showed that incubation with estradiol (10 nM, 24 h) significantly decreased ceramide accumulation. Together, the results suggest that aging is associated with an increase in circulating ceramide levels, which in post-menopausal women is at least partially associated with lower estradiol levels.
The ceramides are key lipid constituents of mammalian cells. They regulate the structural properties of the lipid bilayer  along with its interaction with cellular proteins , and control many signalling processes, including cell survival , growth and proliferation , differentiation , senescence  and apoptosis [7,8]. Dysfunctions in ceramide-mediated signalling may contribute to the initiation and progression of a variety of age-dependent diseases. Human studies have shown the existence of abnormal plasma levels of various ceramide species – including ceramide (d18:1/18:0), (d18:1/22:0), (d18:1/24:0) and (d18:1/24:1) – in several conditions such as obesity , type-2 diabetes , hypertension , atherosclerosis  and other cardiovascular diseases . Furthermore, elevated serum levels of long-chain ceramides have been linked to the increased risk of memory deficits  and may be predictive of hippocampal volume loss and cognitive decline in patients affected by mild cognitive impairment . Other studies have reported the existence of sex-dependent differences in circulating ceramides, albeit with apparently contrasting results [16–18]. For example, in a study of a large cohort of Mexican-Americans of median age 35.7 years, plasma ceramides were found to be higher in men than in women . By contrast, in the Baltimore Longitudinal Study of Aging, whose participants were aged 55 or older, plasma ceramide concentrations were shown to be higher in women than in men . These discrepancies may reflect across-study differences in design and participation.
In the present study, we investigated the age- and sex-dependent trajectories of plasma ceramides in 80 men and 84 women aged 19-80 years. The results show that, in women, plasma levels of two ceramide species – (d18:1/24:0) and (d18:1/24:1) – increased with age, and that this change cannot be ascribed to confounding factors such as obesity, diabetes, and other health conditions. In men, the analysis revealed an association between age and ceramide (d18:1/24:1). Further analyses identified a significant negative correlation between circulating levels of estradiol and ceramide (d18:1/24:1) in women of all ages, but not in men. Finally, in vitro experiments showed that estradiol lowers ceramide levels in human cells expressing estradiol receptors. The findings suggest that aging is accompanied, in men and women, by an increase in the plasma concentrations of two ceramide species, (d18:1/24:0) and (d18:1/24:1), which are also known to be elevated in age-dependent pathologies such as atherosclerosis and cardiovascular disease [23,24]. The results also point to the intriguing possibility that estradiol might control circulating ceramide levels in a sexually dimorphic manner.