Novel Insight into the Serum Sphingolipid Fingerprint Characterizing Longevity

Barbacini, Pietro; Torretta, Enrica; Arosio, Beatrice; Ferri, Evelyn; Capitanio, Daniele; Moriggi, Manuela; Gelfi, Cecilia

doi:10.3390/ijms23052428

Cited by 3 publications

(2 citation statements)

References 68 publications

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“…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 ].…”

Section: Resultssupporting

confidence: 81%

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

Staab

McIntyre

Wang

et al. 2023

Aging

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Lipid metabolism affects cell and physiological functions that mediate animal healthspan and lifespan. Lipidomics approaches in model organisms have allowed us to better understand changes in lipid composition related to age and lifespan. Here, using the model C. elegans, we examine the lipidomes of mutants lacking enzymes critical for sphingolipid metabolism; specifically, we examine acid sphingomyelinase (asm-3), which breaks down sphingomyelin to ceramide, and ceramide synthase (hyl-2), which synthesizes ceramide from sphingosine. Worm asm-3 and hyl-2 mutants have been previously found to be long-and short-lived, respectively. We analyzed longitudinal lipid changes in wild type animals compared to mutants at 1-, 5-, and 10-days of age. We detected over 700 different lipids in several lipid classes. Results indicate that wildtype animals exhibit increased triacylglycerols (TAG) at 10-days compared to 1-day, and decreased lysophoshatidylcholines (LPC). We find that 10-day hyl-2 mutants have elevated total polyunsaturated fatty acids (PUFA) and increased LPCs compared to 10-day wildtype animals. These changes mirror another shortlived model, the daf-16/FOXO transcription factor that is downstream of the insulin-like signaling pathway. In addition, we find that hyl-2 mutants have poor oxidative stress response, supporting a model where mutants with elevated PUFAs may accumulate more oxidative damage. On the other hand, 10-day asm-3 mutants have fewer TAGs. Intriguingly, asm-3 mutants have a similar lipid composition as the long-lived, caloric restriction model eat-2/mAChR mutant. Together, these analyses highlight the utility of lipidomic analyses to characterize metabolic changes during aging in C. elegans.

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Section: Resultssupporting

confidence: 81%

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

Staab

McIntyre

Wang

et al. 2023

Aging

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“…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.…”

Section: Estrogens and Sphingolipidsmentioning

confidence: 60%

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

Arosio

Corbi

Davinelli

et al. 2022

IJMS

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The medical community recognizes sex-related differences in pathophysiology and cardiovascular disease outcomes (CVD), culminating with heart failure. In general, pre-menopausal women tend to have a better prognosis than men. Explaining why this occurs is not a simple matter. For decades, sex hormones like estrogens (Es) have been identified as one of the leading factors driving these sex differences. Indeed, Es seem protective in women as their decline, during and after menopause, coincides with an increased CV risk and HF development. However, clinical trials demonstrated that E replacement in post-menopause women results in adverse cardiac events and increased risk of breast cancer. Thus, a deeper understanding of E-related mechanisms is needed to provide a vital gateway toward better CVD prevention and treatment in women. Of note, sphingolipids (SLs) and their metabolism are strictly related to E activities. Among the SLs, ceramide and sphingosine 1-phosphate play essential roles in mammalian physiology, particularly in the CV system, and appear differently modulated in males and females. In keeping with this view, here we explore the most recent experimental and clinical observations about the role of E and SL metabolism, emphasizing how these factors impact the CV system.

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Phenotypic upregulation of hexocylceramides and ether‐linked phosphocholines as markers of human extreme longevity

Fernàndez‐Bernal,

Sol,

Galo‐Licona

et al. 2024

Aging Cell

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Centenarians and their relatives possess a notable survival advantage, with higher longevity and reduced susceptibility to major age‐related diseases. To date, characteristic omics profiles of centenarians have been described, demonstrating that these individuals with exceptional longevity regulate their metabolism to adapt and incorporate more resilient biomolecules into their cells. Among these adaptations, the lipidomic profile stands out. However, it has not yet been determined whether this lipidomic profile is specific to centenarians or is the consequence of extreme longevity genetics and is also present in centenarians' offspring. This distinction is crucial for defining potential therapeutic targets that could help delay the aging process and associated pathologies. We applied mass‐spectrometry‐based techniques to quantify 569 lipid species in plasma samples from 39 centenarians, 63 centenarians' offspring, and 69 noncentenarians' offspring without familial connections. Based on this profile, we calculated different indexes to characterize the functional and structural properties of plasma lipidome. Our findings demonstrate that extreme longevity genetics (centenarians and centenarians' offspring) determines a specific lipidomic signature characterized by (i) an enrichment of hexosylceramides, (ii) a decrease of specific species of ceramides and sulfatides, (iii) a global increase of ether‐PC and ether‐LPC, and (iv) changes in the fluidity and diversity of specific lipid classes. We point out the conversion of ceramides to hexosylceramides and the maintenance of the levels of the ether‐linked PC as a phenotypic trait to guarantee extreme longevity. We propose that this molecular signature is the result of an intrinsic adaptive program that preserves protective mechanisms and cellular identity.

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Novel Insight into the Serum Sphingolipid Fingerprint Characterizing Longevity

Cited by 3 publications

References 68 publications

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

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

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

Phenotypic upregulation of hexocylceramides and ether‐linked phosphocholines as markers of human extreme longevity

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