Lipids as Regulators of Cellular Senescence

The senescence-associated secretory phenotype (SASP), which accumulates over the course of normal aging and in age-related diseases, is a crucial driver of chronic inflammation and aging phenotypes. It is also responsible for the pathogenesis of multiple oral diseases. However, the pathogenic mechanism underlying SASP has not yet been fully elucidated. Here, relevant articles on SASP published over the last five years (2017–2022) were retrieved and used for bibliometric analysis, for the first time, to examine SASP composition. More than half of the relevant articles focus on various cytokines (27.5%), growth factors (20.9%), and proteases (20.9%). In addition, lipid metabolites (13.1%) and extracellular vesicles (6.5%) have received increasing attention over the past five years, and have been recognized as novel SASP categories. Based on this, we summarize the evidences demonstrating that SASP plays a pleiotropic role in oral immunity and propose a four-step hypothetical framework for the progression of SASP-related oral pathology—1) oral SASP development, 2) SASP-related oral pathological alterations, 3) pathological changes leading to oral immune homeostasis disruption, and 4) SASP-mediated immune dysregulation escalating oral disease. By targeting specific SASP factors, potential therapies can be developed to treat oral and age-related diseases.

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“…Abnormal lipid accumulation induces pro-inflammatory genes activation and senescence phenotype ( 15 ). Ni et al.…”

Section: Discussionmentioning

confidence: 99%

Senescence-associated secretory phenotype and its impact on oral immune homeostasis

et al. 2022

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“…Mechanistically, different cellular stressors have been shown to provoke senescence, including oxidative and metabolic stress ( Campisi, 2013 ; Wiley et al, 2016 ; Nacarelli et al, 2017 ). How certain individual lipids regulate senescence and how senescence changes the cellular lipidome has been excellently reviewed recently ( Hamsanathan and Gurkar, 2022 ). Oxidized lipids particularly promote the development of cellular senescence ( Hamsanathan and Gurkar, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…How certain individual lipids regulate senescence and how senescence changes the cellular lipidome has been excellently reviewed recently ( Hamsanathan and Gurkar, 2022 ). Oxidized lipids particularly promote the development of cellular senescence ( Hamsanathan and Gurkar, 2022 ). Higher amounts of oxidised CL, used here as a representative marker for lipid oxidation, were detected in C6-TAZ cells.…”

Section: Discussionmentioning

confidence: 99%

Re-Expression of Tafazzin Isoforms in TAZ-Deficient C6 Glioma Cells Restores Cardiolipin Composition but Not Proliferation Rate and Alterations in Gene Expression

Jagirdar

Scheffold²,

Simm³

et al. 2022

Front. Genet.

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Tafazzin—an acyltransferase—is involved in cardiolipin (CL) remodeling. CL is associated with mitochondrial function, structure and more recently with cell proliferation. Various tafazzin isoforms exist in humans. The role of these isoforms in cardiolipin remodeling is unknown. Aim of this study was to investigate if specific isoforms like Δ5 can restore the wild type phenotype with respect to CL composition, cellular proliferation and gene expression profile. In addition, we aimed to determine the molecular mechanism by which tafazzin can modulate gene expression by applying promoter analysis and (Ingenuity Pathway Analyis) IPA to genes regulated by TAZ-deficiency. Expression of Δ5 and rat full length TAZ in C6-TAZ- cells could fully restore CL composition and—as proven for Δ5—this is naturally associated with restoration of mitochondrial respiration. A similar restoration of CL-composition could not be observed after re-expression of an enzymatically dead full-length rat TAZ (H69L; TAZMut). Re-expression of only rat full length TAZ could restore proliferation rate. Surprisingly, the Δ5 variant failed to restore wild-type proliferation. Further, as expected, re-expression of the TAZMut variant completely failed to reverse the gene expression changes, whereas re-expression of the TAZ-FL variant largely did so and the Δ5 variant to somewhat less extent. Very likely TAZ-deficiency provokes substantial long-lasting changes in cellular lipid metabolism which contribute to changes in proliferation and gene expression, and are not or only very slowly reversible.

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“…This fuels cancer progression, suggesting PP2A inhibition as a therapeutic approach to combat metabolic disorders and cancer progression [ 150 ]. Many of these increased synthesised fatty acids are senescence-associated lipid changes that give rise to therapy resistant persister cancer cells [ 151 ].…”

Section: Role Of Pp2a In Cellular Processesmentioning

confidence: 99%

Pleiotropy of PP2A Phosphatases in Cancer with a Focus on Glioblastoma IDH Wildtype

Kashani

Vassella

2022

Cancers

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Serine/Threonine protein phosphatase 2A (PP2A) is a heterotrimeric (or occasionally, heterodimeric) phosphatase with pleiotropic functions and ubiquitous expression. Despite the fact that they all contribute to protein dephosphorylation, multiple PP2A complexes exist which differ considerably by their subcellular localization and their substrate specificity, suggesting diverse PP2A functions. PP2A complex formation is tightly regulated by means of gene expression regulation by transcription factors, microRNAs, and post-translational modifications. Furthermore, a constant competition between PP2A regulatory subunits is taking place dynamically and depending on the spatiotemporal circumstance; many of the integral subunits can outcompete the rest, subjecting them to proteolysis. PP2A modulation is especially important in the context of brain tumors due to its ability to modulate distinct glioma-promoting signal transduction pathways, such as PI3K/Akt, Wnt, Ras, NF-κb, etc. Furthermore, PP2A is also implicated in DNA repair and survival pathways that are activated upon treatment of glioma cells with chemo-radiation. Depending on the cancer cell type, preclinical studies have shown some promise in utilising PP2A activator or PP2A inhibitors to overcome therapy resistance. This review has a special focus on “glioblastoma, IDH wild-type” (GBM) tumors, for which the therapy options have limited efficacy, and tumor relapse is inevitable.

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Lipids as Regulators of Cellular Senescence

Cited by 57 publications

References 194 publications

Senescence-associated secretory phenotype and its impact on oral immune homeostasis

Senescence-associated secretory phenotype and its impact on oral immune homeostasis

Re-Expression of Tafazzin Isoforms in TAZ-Deficient C6 Glioma Cells Restores Cardiolipin Composition but Not Proliferation Rate and Alterations in Gene Expression

Pleiotropy of PP2A Phosphatases in Cancer with a Focus on Glioblastoma IDH Wildtype

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