Novel Insight into the Serum Sphingolipid Fingerprint Characterizing Longevity

Abstract

Sphingolipids (SLs) are structural components of the lipid bilayer regulating cell functions. In biological fluids, their distribution is sex-specific and is at variance in aging and many disorders. The aim of this study is to identify SL species associated with the decelerated aging of centenarians. SLs, extracted from serum of adults (Ad, 35–37 years old), aged (Ag, 75–77 years old) and centenarian (C, 105–107 years old) women were analyzed by LC-MS/MS in combination with mRNA levels in peripheral blood mononuclear cells (PBMCs) of SL biosynthetic enzymes. Results indicated in Ag and C vs. Ad a comparable ceramides (Cers) increase, whereas dihydroceramide (dhCer) decreased in C vs. Ad. Hexosylceramides (HexCer) species, specifically HexCer 16:0, 22:0 and 24:1 acyl chains, increased in C vs. Ag representing a specific trait of C. Sphingosine (Sph), dihydrosphingosine (dhSph), sphingosine-1-phosphate (S1P) and dihydrosphingosine-1-phosphate (dhS1P), increased both in Ag and C vs. Ad, with higher levels in Ag, indicating a SL fine-tuning associated with a reduced physiological decline in C. mRNA levels of enzymes involved in ceramide de novo biosynthesis increased in Ag whereas enzymes involved in sphingomyelin (SM) degradation increased in C. Collectively, results suggest that Ag produce Cers by de novo synthesis whereas C activate a protective mechanism degrading SMs to Cers converting it into glycosphingolipids.

The lipidomes of C. elegans with mutations in asm-3/acid sphingomyelinase and hyl-2/ceramide synthase show distinct lipid profiles during aging

“…Together, these data support a model where increased abundance of sphingolipid precursors and sphingomyelin may contribute to poor aging phenotypes. Indeed, our findings support lipidomic analyses of human longevity suggesting that centenarians upregulate mechanisms to upregulate sphingomyelins to ceramide-containing glycosphingolipids [ 56 , 57 ].…”

Sex Differences in Cardiovascular Diseases: A Matter of Estrogens, Ceramides, and Sphingosine 1-Phosphate

“…Notably, depletion of Es resulted in a significant increase in total Cer levels while S1P decreased significantly, further strengthening the role of Es as a bridge between SLs and CV system homeostasis. The importance of the aging process on SL release in women has been recently reported by our group [ 170 ]. In particular, we characterized for the first time the serum SL profile in adults (35–37 years old) vs. aged (75–77 years old) vs. long-lived (centenarians; 105–107 years old) women and in accordance with previous results we observed that Cer levels increased with age.…”