ER-localized ceramide accumulation contributes to replicative senescence

Mar 31, 2026Cell chemical biology

Build-up of fat molecules in the cell’s protein-making area may contribute to cell aging

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Abstract

Senescent cells exhibit elevated ceramide levels and depletion of very-long-chain sphingomyelins.

Ceramide accumulation occurs despite unchanged expression of sphingomyelin synthase 1.
Impaired ceramide-sphingomyelin turnover is implicated in the observed changes.
Inhibition of the ceramide transfer protein enhances senescence and mimics sphingolipid remodeling.
Raman spectroscopy indicates that ceramide accumulation is localized to the endoplasmic reticulum (ER).
Increased ceramide levels in ER fractions of senescent cells suggest a link to ER stress.

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Ceramides regulate diverse cellular processes through compartment-specific accumulation. While mitochondrial ceramide accumulation promotes apoptosis, its regulation and function during senescence remain incompletely understood. Here, we integrate lipidomics, transcriptomics, Raman spectroscopy, and biochemical characterizations to define sphingolipid remodeling in replicative senescence. Senescent cells exhibit elevated ceramide levels and depletion of very-long-chain sphingomyelins, despite unaltered sphingomyelin synthase 1 expression, implicating impaired ceramide-sphingomyelin turnover. Pharmacological inhibition of ceramide transfer protein (CERT), the ER-to-Golgi ceramide transporter, phenocopies sphingolipid remodeling and enhances senescence, suggesting disrupted ceramide trafficking as a driver of senescence. Raman spectroscopy suggests ceramide accumulation localized to the ER. In parallel, analysis of ER-enriched fractions confirms increased ceramide levels in ER fractions of senescent cells. Mechanistically, ceramide accumulation at the ER can contribute to ER stress. These findings identify altered ceramide trafficking as a contributor to ER stress and highlight ER-localized ceramide as a critical component of senescence-associated sphingolipid remodeling.

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ER-localized ceramide accumulation contributes to replicative senescence

Abstract

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