Role of Longevity Assurance (Lass) Genes in Membrane Senescence: Tissue-specific changes of ceramide species composition in aged mice

Cell membranes are complex and dynamic systems consisting of numerous types of lipids and integral membrane proteins. Many membrane-associated cellular processes such as cell surface receptor signaling or the uptake of pathogens occur at ceramide-enriched membrane platforms and are regulated by the abundance of ceramide and higher sphingolipids within these membrane domains. Since alterations in ceramide production seem to follow a development-aging continuum, we hypothesize that the impairment of membrane functionality in the elderly is due to age-related changes of the sphingolipid composition of membranes.

The last step of the ceramide biosynthesis is catalyzed by enzymes belonging to the Lass (Longevity assurance) protein family, which includes six mammalian members (Lass 1-Lass 6). Strikingly, the first protein of the Lass family was identified in a screen for longevity-regulating genes in yeast. The Lass family members are expressed in a tissue-specific manner and show preferences for fatty acyl-CoAs of distinct chain lengths. Thus, the regulation of Lass genes represents an important mode of regulating membrane physiology through controlling the fatty acid composition of ceramides and ceramide-derived sphingolipids.

In order to obtain insights into general changes of sphingolipid expression over age, we analyzed the ceramide species composition in different tissues of aged mice using a LC-MS/MS method which allows the simultaneous quantification of ceramide, glucosylceramide, and sphingomyelin species. Compared to six weeks old mice, aged mice showed tissue-specific alterations of ceramides species composition indicating differential expression of Lass 1-6 proteins, which may impact on the functionality of aged membranes.