Age-dependent changes in nervonic acid-containing sphingolipids in mouse hippocampus Molecular and cell biology of lipids

Sphingolipids have been implicated in age-related neurodegeneration. Previous studies have reported elevated ceramide levels in the brain of old rodents, but a systematic investigation of the impact of age on brain sphingolipid metabolism is still lacking. Here we quantified 17 key sphingolipid species in the hippocampus of young (3months), middle-aged (12months) and old (21months) male and female mice. Lipids were extracted and quantified by liquid chromatography/mass spectrometry; transcription of enzymes involved in sphingolipid biosynthesis was evaluated by qPCR. Age-dependent changes of multiple sphingolipid species - including ceramide (d18:1/18:0), sphingomyelin (d34:1), hexosylceramide (d18:1/16:0), ceramide (d18:1/24:0) - were found in mice of both sexes. Moreover, sex-dependent changes were seen with hexosylceramide (d18:1/18:0), ceramide (d18:1/22:0), sphingomyelin (d36:1) and sphingomyelin (d42:1). Importantly, an age-dependent accumulation of sphingolipids containing nervonic acid (24:1) was observed in 21month-old male (p=0.04) and female mice (p<0.0001). Consistent with this increase, transcription of the nervonic acid-synthesizing enzyme, stearoyl-CoA desaturase (Scd1 and Scd2), was upregulated in 21month-old female mice (Scd1 p=0.006; Scd2 p=0.009); a similar trend was observed in males (Scd1 p=0.07). In conclusion, the results suggest that aging is associated with profound sex-dependent and -independent changes in hippocampal sphingolipid profile. The results also highlight the need to examine the contribution of sphingolipids, and particularly of those containing nervonic acid, in normal and pathological brain aging.