Lipids in Senescent Cells
Fibroblasts have long been a staple in research on cellular senescence, and the exploration of lipid metabolism within these cells has gained significant traction. As researchers delve deeper, they're uncovering a complex relationship between lipids and aging, one that's not only fascinating but critical to understanding cellular decline. A striking hallmark of aging, lipofuscin, accumulates over time due to lysosomal dysfunction. This buildup represents more than just a waste product; it's a sign of the cell's struggle, a mixture of proteins, sugars, and lipids clinging to the aging structure.
Within senescent cells, lipid droplets—those little storage bubbles—seem to take on an even more prominent role, accumulating as the cell ages. But it's not just the presence of lipids that's interesting; it's the profound transformation of lipid components as cells age. Phospholipids, for example, begin to break down into more specialized forms: glycerophospholipids and sphingolipids. Fatty acids and cholesterol undergo shifts as well, often pointing to underlying changes in cell function. The lipids in these senescent cells aren't just passive bystanders—they are actively involved in keeping the cell afloat, ensuring survival as the cell slowly deteriorates. Their roles are intricate, complex, and absolutely essential to the aging process, drawing researchers deeper into the cell's lipid landscape.
Figure 1. Features of senescent cells.
The roles of key lipids in cellular senescence.
| Key lipids | Types of cellular senescence (cell lines) | Roles | References |
|---|---|---|---|
| PG | OIS (MCF-7) | Increase membrane fluidity and protect cells from stress | (Cadenas et al. 2012) |
| CA | RS (TIG-7) | Induce mitochondrial damage | (Arivazhagan et al, 2004) |
| LPC | RS/SIPS (primary HDF) | Elicit chemokine release and inhibit phagocytic capacity in macrophages | (Narzt et al. 2021) |
| CER | RS (WI-38) | Inhibit DNA synthesis and mitogenesis | (Venable et al. 1995) |
| CIP | TIS (HCT-116) | Activate transcription of pro-survival genes | (Millner et al., 2022) |
| SIP | NA (A549) | Prevent telomere damage | (Panneer Selvam et al., 2015) |
| Long chain fatty acids | OIS (IMR-90) | Support mitochondrial oxidation and energy production | (Quijano et al., 2012) |
| EVs (contains FAs) | OIS (HDF) | Affect metabolism and cell signaling to nearby tissue as SASP | (Sagini et al. 2018) |
| Oxylipins | TIS/RS (IMR-90) | Involved in the inflammation response | (Wiley et al., 2021) |
| Cholesterol | RS/SISP (TIG-1) | Lead to a deficiency in raft-mediated signaling | (Nakamura et al, 2003) |
| Lysosomal cholesterol | OIS (MCF-7) | Improve survival ability of the cells under stress conditions | (Cadenas et al., 2012) |
Glycerophospholipids and Cellular Senescence
Glycerophospholipids (GPLs) encompass a diverse range of lipids, including cardiolipin (CA), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidylcholine (PC), and lysophospholipids (LPL). Research indicates that in senescence induced by doxycycline, mitochondrial lipids, particularly PG and PI, undergo modifications that enhance membrane fluidity. In senescent fibroblasts, cardiolipin (CA) accumulates and has been shown to trigger early senescence. The mitochondrial dysfunction observed in these cells is associated with the pro-inflammatory properties of CA. The senescence-associated secretory phenotype (SASP) involves not only soluble factors but also extracellular vesicles (EVs). In fibroblasts senescent due to h-ras, alterations in lipid composition, particularly an increase in lysophosphatidylcholine (LPC), are believed to contribute to skin aging. Phospholipase A2 (PLA2), a pivotal enzyme in the metabolism of phospholipids, plays a significant role in aging by facilitating the release of both pro-inflammatory and anti-inflammatory bioactive lipids. As such, glycerophospholipids are integral to the process of cellular senescence and aging.
Sphingolipids and Cellular Senescence
Sphingolipid metabolism involves ceramide, sphingosine-1-phosphate, and sphingosine. Ceramide and sphingosine-1-phosphate play key roles in cell survival and proliferation, with ceramide also promoting cellular senescence. Sphingomyelinase converts sphingolipids into ceramide and phosphorylated choline. In cellular senescence models, ceramide levels and neutral sphingomyelinase activity significantly increase, leading to cell growth arrest. Ceramide, sphingosine, and their metabolic enzymes are associated with cellular senescence. The expression of ASAH1, an enzyme involved in sphingolipid metabolism, is elevated in senescent cells, and its silencing can reduce senescence marker levels. Ceramide kinase phosphorylates ceramide, and its inhibitor can suppress senescence. Sphingosine kinase phosphorylates sphingosine to form sphingosine-1-phosphate, maintaining a balance. The deletion of SK1 can increase ceramide levels and protect mice from tumors, while the inhibition or depletion of SK2 can lead to cellular senescence.
Fatty Acids, Oxylipins, and Cellular Senescence
Fatty acids are key components of many lipids and are crucial for energy storage, membrane function, and the production of signaling molecules. They are also the primary energy source for mitochondrial β-oxidation. As aging progresses, levels of saturated fatty acids, polyunsaturated fatty acids, and monounsaturated fatty acids in plasma rise, and senescent fibroblasts release more vesicles enriched with fatty acids. Metabolomics analysis indicates that intracellular lipids, particularly long-chain free fatty acids, play an important role in cellular senescence.
During aging, polyunsaturated fatty acid levels significantly increase, including linoleic acid, α-linolenic acid, EPA, AA, DGLA, and DHA. Oxylipins are oxidative metabolites of polyunsaturated fatty acids (PUFAs) produced by specific enzymes like LOX, COX, and CYP, which increase in senescent cells. Specifically, the increase in 15d-PGJ2 can serve as a biomarker to assess the efficacy of anti-aging drugs. Oxylipins also include prostaglandin E2, thromboxane, and leukotrienes, which are involved in the inflammatory response of cellular senescence. COX2 is a key regulatory factor in oncogene-induced senescence (OIS), and it is associated with tumor suppression in the early stages of cancer development. Senescent PanIN cells promote carcinogenesis by activating pro-inflammatory signaling, while the clearance of senescent cells and intermittent short-term treatments can inhibit carcinogenesis progression.
Cholesterol and Cellular Senescence
Cholesterol serves as a key precursor for cellular membranes and a variety of biomolecules, and disruptions in its metabolism have been linked to a range of diseases. While research in this area is still limited, available evidence points to a potential connection between cholesterol levels and cellular senescence. For instance, chemotherapy treatments and oxidative stress can modify intracellular cholesterol concentrations, which seem to correlate with aging processes. Lipid analyses have shown an increase in cholesterol production in senescent cells, and recent studies suggest a possible link between cholesterol biosynthesis pathways and cellular aging. However, the precise cause-and-effect relationship between cholesterol and cellular senescence remains to be fully elucidated.
Figure 2. Major lipid species involved in senescence.
Metabolism of Key Lipids During Cellular Senescence
Lipid metabolism imbalance can increase the risk of metabolic diseases. Cellular senescence involves the uptake, transport, synthesis, oxidation, and storage of lipids, all of which are closely associated with the survival of senescent cells and the secretion of the senescence-associated secretory phenotype (SASP).
Increased Lipid Uptake as a Key Cause of Lipid Accumulation in Senescent Cells
Studies indicate that the uptake of sphingolipids, ceramides, and fatty acids is notably elevated during stress-induced cellular senescence (TIS). Several proteins are involved in the uptake and transport of lipids, including CD36, FATP, FABP, ABCA1, and CAV-1. CD36 plays a role in fatty acid metabolism, promotes inflammation, and is upregulated in senescent cells. Its overexpression has been linked to the induction of cellular senescence. Additionally, research has shown that CD36 facilitates the secretion of the senescence-associated secretory phenotype (SASP), particularly the inflammatory cytokines IL-6 and IL-8, through the Src-p38-NF-κB signaling pathway. Lipid rafts, specialized microdomains on the plasma membrane, are closely tied to cellular senescence, with CAV-1 being a key protein in these rafts, contributing to cell signaling and the aging process. For instance, in bleomycin-induced senescence, CAV-1 expression increases, and reducing CAV-1 levels can prevent senescence. Further research suggests that CAV-1 is involved in cholesterol uptake and its accumulation in lysosomes, although it remains uncertain whether disruptions in lipid uptake and transport are essential for sustaining cellular senescence and the secretion of SASP factors.
Lipid Synthesis and Oxidation in Senescent Cells
Fatty acids (FAs) are the basic components of lipids and are essential for lipid synthesis. Key enzymes in the synthesis process include fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), and ATP-citrate lyase (ACL), which are regulated by sterol regulatory element-binding proteins (SREBPs). During cellular senescence, the expression of these enzymes increases, and FASN inhibitors can delay senescence. However, in some cases, fatty acid synthesis is suppressed, such as when stearoyl-CoA desaturase (SCDs) levels are reduced, which impacts cell division.
In senescent cells, the levels of key regulatory factors in cholesterol synthesis increase, leading to an increase in organelle mass, especially in membrane-bound organelles. Fatty acid β-oxidation provides energy to cells, with CPT1 as the rate-limiting enzyme controlling this process. Low expression of CPT1C is associated with mitochondrial dysfunction and may accelerate cellular senescence. Lipotoxicity is related to cellular senescence, and knocking down CPT1C can alleviate lipid accumulation and lipotoxicity, thereby slowing down senescence. Fatty acid β-oxidation contributes to the formation and maintenance of cellular senescence by affecting lipotoxicity, mitochondrial function, and coordinating SASP secretion. Targeting CPT1, particularly CPT1C, can reduce SASP and be beneficial for inhibiting senescent cells in tumors.
Accumulation of Lipid Droplets Storing Lipids in Senescent Cells
Cells typically store fatty acids (FAs) in cytoplasmic lipid droplets (LDs), which are located within triacylglycerol (TAG)-containing organelles, the primary organelles responsible for lipid storage. The size of LDs determines a cell's capacity for lipid storage, and their dynamic regulation is critical for maintaining energy metabolic homeostasis. During the aging process of Caenorhabditis elegans, LDs accumulate in the nuclear membrane. Studies have also found that as aging microglial cells accumulate lipid droplets in the brains of mice and humans, they secrete pro-inflammatory cytokines, which may be related to neurodegenerative diseases. The number and volume of LDs typically increase in senescent cells, with exogenous lipids preferentially incorporated into TAGs to form LDs, which may be associated with reduced SCD1 activity. The enrichment of LD-related proteins, such as DGAT1 and PLIN2, in senescent cells, along with oil red O staining to confirm the accumulation of LDs, further supports this. The interaction between LDs and mitochondria can modulate mitochondrial damage and oxidative stress in cells, suggesting that the accumulation of LDs may be a stress response to stimuli, helping to protect against cell death.
Lipid Peroxidation Drives Cellular Senescence
Lipid peroxidation (LPO) is the process of oxidizing unsaturated fatty acids in the body, producing harmful substances such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), which are biomarkers of LPO. LPO is associated with age-related diseases, mitochondrial dysfunction, and cellular senescence. Mitochondrial dysfunction can lead to lipid metabolic disorders and increased production of LPO products, which then trigger cellular senescence. Aldehyde dehydrogenases (ALDHs) metabolize aldehydes, counteracting oxidative stress. While LPO is generally harmful and promotes cell death, at low levels it may promote cellular senescence.
Studies have shown that LPO plays a significant role in cellular senescence, promoting DNA damage. LPO also mediates the production of inflammatory mediators and cell toxicity, but it can also protect cells from death. The relationship between lipid peroxidation and cellular senescence requires further investigation. Lipid metabolic reprogramming is associated with cellular senescence, particularly with SASP secretion. Interventions targeting lipid metabolism could influence the accumulation of senescent cells or the release of SASP, potentially preventing age-related diseases. Further research into the causal relationship and mechanisms between lipid metabolism and cellular senescence may help in clearing senescent cells or inhibiting the release of SASP.
References
- Zeng Q, Gong Y, Zhu N, Shi Y, Zhang C, Qin L. Lipids and lipid metabolism in cellular senescence: Emerging targets for age-related diseases. Ageing Res Rev. 2024 Jun;97:102294. doi: 10.1016/j.arr.2024.102294. Epub 2024 Apr 5. PMID: 38583577.
- Hamsanathan S, Gurkar AU. Lipids as Regulators of Cellular Senescence. Front Physiol. 2022 Mar 4;13:796850. doi: 10.3389/fphys.2022.796850. PMID: 35370799; PMCID: PMC8965560.
