Response to Dr. Buschard and Colleagues’ Letter to the Editor: Sulfatide and Longevity

To the Editor:

We thank Dr. Buschard et al. for their interest in our study (1) and for sharing their results. In our study, we defined three groups of the healthy populations (adults, old, and centenarians) to characterize changes in centenarians versus mature and old people focusing on sphingolipidome. Sphingolipids are a relatively little-studied type of lipids probably because they are in low abundance (<20% of their glycerolipid counterparts) in the body (2) and this is a technical limitation for its detection and quantification. The fact that centenarians show a characteristic profile in this specific family of lipids allows us deepen into the factors that are involved in the high longevity of this population. The panel of lipids analyzed included 7 sphingosines (Sph) with 4 of them conjugated with phosphate (S1P), 56 ceramides (Cer), including one ceramide-1-phosphate (Cer1P) and 5 dihydroceramides (dhCer), 44 sphingomyelins (SMs), 14 monohexosylceramides (HexCer), 10 dihexosylceramides (Hex2Cer), 6 trihexosylceramides (Hex3Cer), 8 gangliosides (GM) one of them GM1 and the rest GM3, and 6 sulfatides. We tested whether general differences according to the analyzed lipid subclasses existed among the experimental groups (adults, aged, and centenarians). The results showed that the subclass dhCer was decreased in centenarians with respect to adults and aged participants. Glycosphingolipid subclasses showed differences in HexCer, statistically higher in centenarians with respect to adults and aged participants and Hex3Cer, statistically higher in centenarians with respect to adults and aged subjects. Gangliosides showed an increased level in the centenarian group with respect to the adults and aged. Finally, Sph, Cer, SM, Hex2Cer, and sulfatide subclasses remained unaltered among the different groups. According to these results, we cannot conclude that low blood concentrations of sulfatide is a characteristic trait of centenarians and is associated with low mortality and high longevity, as pointed out by Buschard et al. in their letter to the editor. More specifically, we analyzed the concentrations of a limited number of sulfatide species (n = 6), and we only found statistically significant differences in one, the sulfatide (d18:1/24:0 (OH), which is decreased in the centenarian group (this lipid species is presented in Figure 4) (1). The weight of this particular sulfatide species represents about 12% of the total concentration for sulfatides and less than 1% of the sphingolipidome analyzed in our work. Currently, we do not know whether this change expresses a specific adaptative mechanism in this population, and the biological meaning of this molecular species. In contrast, the sulfatide determination using ELISA-methods used by Buschard et al. in their study population offers a global view of the sulfatide concentration but does not allow to discriminate among particular sulfatide species. Therefore, to understand the biological significance of these molecules it is necessary to expand the number of sulfatide species analyzed to achieve a more concise view of the state of the sulfatides under both physiological and pathological conditions. Consequently, we understand that our results do not contradict the findings expressed by Buschard et al. in relation to the concentration of sulfatides in the diabetic population and its positive effect on longevity.

We must also be honest and express the limitations of our study. (a) Our study has been performed with a limited number of participants from a specific geographical region. Thus, it is imperative to extend our approach not only to a larger, but also to a different population sample, to confirm or refute our findings. (b) Plasma and tissues show very different lipid profiles, and changes in tissue lipid metabolism are necessarily reflected in plasma, so it is key to explore the sphingolipidome (in fact, the lipidome) in tissues from centenarians. Furthermore, in our study, we analyzed the noncellular fraction of blood. Therefore, the lipid fraction analyzed comes from the lipoprotein fractions, free lipids, and extracellular vesicles, and we do not know whether specific changes in sphingolipidome are general or can be ascribed to specific fractions and, consequently, differ in their biological origin.

In conclusion, although the role of sphingolipids in insulin resistance and related disorders is a research field under intense study (2), more studies are needed to clarify the role of sphingolipids in general, and sulfatides in particular, in longevity.

Funding

None declared.

Conflict of Interest

None declared.

References