Lipid Players of Cellular Senescence

Abstract

Lipids are emerging as key players of senescence. Here, we review the exciting new findings on the diverse roles of lipids in cellular senescence, most of which are enabled by the advancements in omics approaches. Senescence is a cellular process in which the cell undergoes growth arrest while retaining metabolic activity. At the organismal level, senescence contributes to organismal aging and has been linked to numerous diseases. Current research has documented that senescent cells exhibit global alterations in lipid composition, leading to extensive morphological changes through membrane remodeling. Moreover, senescent cells adopt a secretory phenotype, releasing various components to their environment that can affect the surrounding tissue and induce an inflammatory response. All of these changes are membrane and, thus, lipid related. Our work, and that of others, has revealed that fatty acids, sphingolipids, and glycerolipids are involved in the initiation and maintenance of senescence and its associated inflammatory components. These studies opened up an exciting frontier to investigate the deeper mechanistic understanding of the regulation and function of these lipids in senescence. In this review, we will provide a comprehensive snapshot of the current state of the field and share our enthusiasm for the prospect of potential lipid-related protein targets for small-molecule therapy in pathologies involving senescence and its related inflammatory phenotypes.

Keywords: fatty acids; glycerolipids; lipids; senescence; sphingolipids.

Figure 1

Different roles of lipids. (A) Phosphatidylcholine and cholesterol are major structural lipids. (B) Cholesterol esters and triacylglycerols are used to stored excess fatty acids in cells. They are stored within lipid droplets and endoplasmic reticulum-derived vesicular structures. (C) Diacylglycerol and sphingosine-1-phosphate are signaling lipids. Diacylglycerols affect protein kinase C activity, and sphingosine-1-phosphate promotes proliferation through its interactions with cell surface receptors.

Figure 2

Metabolites of a particular lipid can have different bioactivities. (A) Hydrolysis products of phosphatidylinositol 4,5-bisphosphate, inositol-1,4,5-trisphosphate, and diacylglycerol are involved in protein kinase C and calcium signaling. (B) Sphingomyelin and sphingosine-1-phosphate, sphingolipids synthesized from ceramide, are important membrane lipids and promote cellular proliferation, respectively. (C) Arachidonic acid products prostaglandin D2 and E2 can exhibit anti- and pro-inflammatory activities.

Figure 3

Mechanisms of establishing growth arrest. Growth arrest is established and maintained by two major tumor suppressor pathways, p53 and p16, during senescence. In proliferating cells, cyclin-dependent kinase (CDK)–cyclin complexes phosphorylate retinoblastoma (RB) proteins and promote cell cycle progression. In senescent cells, activated p16 and p21 inhibit these CDK–cyclin complexes from phosphorylating RB. Hypophosphorylated RB represses cellular proliferation.

Figure 4

Simplified sphingolipid biosynthesis scheme. Condensation of serine (red) and palmitoyl-CoA produces 3-ketosphinganine, which is reduced to sphinganine and acylated, resulting in dihydroceramide. The trans double bond is introduced to the fourth carbon to yield ceramide, which serves as the precursor for more complex sphingolipids and sphingosine. Ceramide can be incorporated into glucosylceramide or sphingomyelin through the respective pathways. Ceramide can also be hydrolyzed to form sphingosine, which can then be phosphorylated to produce sphingosine-1-phosphate. Alternatively, alanine can be utilized (blue) rather than serine, resulting in the production of 1-deoxy-dihydroceramide and 1-deoxy-ceramide. Abbreviations: SPT (serine palmitoyl transferase); KSR (3-keto-sphinganine reductase); CerS (ceramide synthase); DEGS (dihydroceramide desaturase); CDase (ceramidase); GCS (glucosylceramide synthase); SMS (sphingomyelin synthase); (SMase (sphingomyelinase); SK (sphingosine kinase).