Cellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities

Abstract

Closely associated with aging and age-related disorders, cellular senescence (CS) is the inability of cells to proliferate due to accumulated unrepaired cellular damage and irreversible cell cycle arrest. Senescent cells are characterized by their senescence-associated secretory phenotype that overproduces inflammatory and catabolic factors that hamper normal tissue homeostasis. Chronic accumulation of senescent cells is thought to be associated with intervertebral disc degeneration (IDD) in an aging population. This IDD is one of the largest age-dependent chronic disorders, often associated with neurological dysfunctions such as, low back pain, radiculopathy, and myelopathy. Senescent cells (SnCs) increase in number in the aged, degenerated discs, and have a causative role in driving age-related IDD. This review summarizes current evidence supporting the role of CS on onset and progression of age-related IDD. The discussion includes molecular pathways involved in CS such as p53-p21^CIP1, p16^INK4a, NF-κB, and MAPK, and the potential therapeutic value of targeting these pathways. We propose several mechanisms of CS in IDD including mechanical stress, oxidative stress, genotoxic stress, nutritional deprivation, and inflammatory stress. There are still large knowledge gaps in disc CS research, an understanding of which will provide opportunities to develop therapeutic interventions to treat age-related IDD.

Keywords: aging; cellular senescence; intervertebral disc degeneration; senescent cells; senolytics; senotherapy.

Figure 1

Overview of cellular senescence during intervertebral disc degeneration. The reported pathways of stressors, signaling molecules, and consequences of cellular senescence (CS) during intervertebral disc degeneration (IDD) are depicted. During aging, disc CS can be caused by mechanical, genotoxic, oxidative, metabolic, and inflammatory stress which activate signaling cascades such as NF-kB, mitogen activated protein kinases (MAPKs), Sirtuins, PI3K/Akt/mTOR, etc., and cellular mechanisms such as autophagy and mitophagy or they directly activate the DNA damage response to induce the senescence pathway. The senescence signals and DNA damage responses activate the ATM-p53-p21^CIP1 and p16^INK4a-pRb pathways, which work reciprocally with each other to induce cell cycle arrest and senescence. Disc CS associated secretory phenotype (SASP) produces and secretes pro-inflammatory and catabolic factors such as MMPs to further amplify the process of disc degeneration. As a consequence of changed cellular phenotype, extracellular matrix (ECM) catabolism is increased, and anabolism is reduced leading to degradation of the disc tissue. (Figure created with BioRender.com, accessed on 8 March 2023).

Figure 2

Proposed mechanisms of cellular senescence activation in the intervertebral disc by mechanical stress from reported findings. Chronic abnormal mechanical stress is a major contributor of age-associated for IDD. Mechanical stress including compression or tensile forces can induce DNA damage leading to activation of the p53-p21^CIP1 senescence pathway. Mechanical stress also increases expression of Piezo1 ion channel resulting in an increase in intracellular calcium level which leads to NF-κB activation, mitochondrial damage, and endoplasmic reticulum (ER) stress. NF-κB activation mediates secretion of periostin by NP cells and promotes cellular senescence (CS) and catabolic processes, creating a NF-κB-periostin activation loop to further amplify the senescence process. Mitochondrial damage on the other hand, inhibits autophagy and induces apoptosis which leads to disc CS. The ER stress activates GRP78 and CHOP, which induce apoptosis and senescence of disc cells. Mechanical stress also induces ROS production regulating the disc cell senescence directly or through ER stress. It is reported that mechanical stress activates ROS production through p38 MAPK or G protein-coupled receptor 35 (GPR35) mediated rise in intracellular calcium level or via sirtuin1 (SIRT1) inhibition. The SIRT1 expression is reduced during mechanical stress thereby inhibiting mitophagy. Mitophagy is activated via macrophage migration inhibitory factor (MIF) or direct activation of PTEN-induced kinase 1 (PINK1). The MIF1 is upregulated by moderate compression stress but downregulated with chronic mechanical compression. Inhibition of autophagy or mitophagy upregulates disc CS. Additionally, actin cytoskeleton reorganization is involved in disc CS. Compression stress activates the RhoA-ROCK1-pMLC pathway to inhibit F-actin interaction with myosin IIA and induce its interaction with myosin IIB leading to an imbalance, which activates senescence. The actomyosin cytoskeleton remodeling is dependent on nuclear translocation of myocardin-related transcription factor A (MRTF-A) in the disc cells. (Figure created with BioRender.com, accessed on 8 March 2023).

Figure 3

Proposed signaling pathways during cellular senescence activation in intervertebral discs based on reported findings. Oxidative stress is one of the major factors inducing cellular senescence (CS) in intervertebral disc. Accumulation of reactive oxygen species (ROS) occurs from oxidative stress, metabolic stress such as hyperglycemia, or inflammatory stress signaling mediated through toll like receptors (TLRs) or cytokine receptors. An increase in ROS activates MAPK signaling or NF-kB signaling to induce CS and senescence associated secretory phenotypes (SASPs). Secretion of SASP factors further amplify the senescence process through cytokine receptor mediated signaling. Arginase II increases ROS production and activates NF-kB signaling. The AOPPs activate the MAPK and NF-kB signaling pathways through NOX4 to drive disc CS. The levels of sirtuins are reduced in IDD whereas activation of sirtuins is beneficial against disc degenerative changes. The SIRT1 modulates senescence through c-Myc-LDHA mediated glycolysis. The SIRT3 modulates senescence through the AMPK-PGC1α pathway or deacetylation of SOD2. Furthermore, increase in ROS modulates the autophagic pathway thereby affecting CS. Autophagy is downregulated in IDD and several autophagy related genes (ATGs) and other signaling molecules such as noncoding RNAs (ncRNAs), transcription factor EB (TFEB), TANK binding kinase 1 (TBK1) mediated autophagy or mitophagy activation, can reduce senescence of disc cells. Genotoxic and metabolic stressors induce DNA-damage response mediated CS activation via the ATM-p53 pathway. Additionally, cytosolic DNA is sensed by cGAS leading to activation of the cGAS-STING pathway in which activation and nuclear translocation of IRF3 contributes to senescence of the disc cells. In addition, activated IRF3 induces the Bax-mediated apoptotic pathway. Change in pH activates the p38 MAPK mediated senescence pathway or is sensed by ASIC1 or ASIC3, which then directly activates the senescence pathway. For clarity, not all signaling pathways relating to disc CS are included in this figure. Please refer to text for details. AOPPs; Advanced oxidation protein products, ASIC; Acid-sensing ion channels, AMPK; AMP-activated protein kinase, IDD; intervertebral disc degeneration, PGC1α; Peroxisome proliferator-activated receptor-γ coactivator 1 alpha, IRF3; Interferon regulatory factor 3. (Figure created with BioRender.com, accessed on 8 March 2023).