Sirtuins in intervertebral disc degeneration: current understanding

Abstract

Background

Intervertebral disc degeneration (IVDD) is one of the etiologic factors of degenerative spinal diseases, which can lead to a variety of pathological spinal conditions such as disc herniation, spinal stenosis, and scoliosis. IVDD is a leading cause of lower back pain, the prevalence of which increases with age. Recently, Sirtuins/SIRTs and their related activators have received attention for their activity in the treatment of IVDD. In this paper, a comprehensive systematic review of the literature on the role of SIRTs and their activators on IVDD in recent years is presented. The molecular pathways involved in the regulation of IVDD by SIRTs are summarized, and the effects of SIRTs on senescence, inflammatory responses, oxidative stress, and mitochondrial dysfunction in myeloid cells are discussed with a view to suggesting possible solutions for the current treatment of IVDD.

Purpose

This paper focuses on the molecular mechanisms by which SIRTs and their activators act on IVDD.

Methods

A literature search was conducted in Pubmed and Web of Science databases over a 13-year period from 2011 to 2024 for the terms “SIRT”, “Sirtuin”, “IVDD”, “IDD”, “IVD”, “NP”, “Intervertebral disc degeneration”, “Intervertebral disc” and “Nucleus pulposus”.

Results

According to the results, SIRTs and a large number of activators showed positive effects against IVDD.SIRTs modulate autophagy, myeloid apoptosis, oxidative stress and extracellular matrix degradation. In addition, they attenuate inflammatory factor-induced disc damage and maintain homeostasis during disc degeneration. Several clinical studies have reported the protective effects of some SIRTs activators (e.g., resveratrol, melatonin, honokiol, and 1,4-dihydropyridine) against IVDD.

Conclusion

The fact that SIRTs and their activators play a hundred different roles in IVDD helps to better understand their potential to develop further treatments for IVDD.

Novelty

This review summarizes current information on the mechanisms of action of SIRTs in IVDD and the challenges and limitations of translating their basic research into therapy.

Introduction

Lower back pain (LBP) is a common pathologic condition of the musculoskeletal system. Approximately 80% of the global population experience acute or chronic LBP (Khan et al. 2017). The findings of several epidemiologic studies indicated that LBP is one of the leading causes of disability worldwide. This pain adversely affects the quality of life of patients and is a major economic burden for families and society worldwide (Zhang et al. 2020; Urits et al. 2019). Intervertebral disc degeneration (IVDD), which leads to disc herniation, spinal instability, vertebral slippage, and osteophytes, is considered the most important etiologic factor for LBP (Navone et al. 2017). However, the specific pathologic mechanisms of IVDD have not been elucidated, and the therapeutic effects of conservative treatment and surgery are not satisfactory (Vedicherla and Buckley 2017). Therefore, new treatment methods for IVDD are urgently required.

Silent information regulator 2 (Sir2)—a class of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase—was first identified in Saccharomyces cerevisiae (Michishita et al. 2005). Seven mammalian Sir2 homologous proteins (SIRT1–7), called Sir2-related enzymes (sirtuins), have been identified to date (Priyanka et al. 2016). The sirtuin family is characterized by highly conserved NAD+ -binding and catalytic structural domains and contains N- and C-terminals outside the catalytic core. Sirtuins are involved in the pathogenesis of various aging-related diseases by regulating inflammation, oxidative stress, and mitochondrial function (Priyanka et al. 2016; Yang et al. 2022). It is because of these powerful functions of SIRTs that they have now become a research hotspot for aging-related diseases. In recent years, a large number of studies on the role of SIRTs in IVDD have been reported, such as SIRTs can regulate autophagy, myeloid apoptosis, and extracellular matrix degradation, in addition to SIRTs can exert anti-inflammatory and anti-oxidative stress to alleviate IVDD, it is evident that the role of SIRTs in the pathogenesis of IVDD has become an active area of research. However, there is no literature that systematically summarizes the possible roles of the family of SIRTs in IVDD and organizes an effective pathway for the treatment of IVDD through the regulation of SIRTs. Therefore, the main objective of this paper is to review the current research on the mechanisms of SIRTs modulating disc degeneration and, based on this, to summarize the relevant aspects of treating IVDD by modulating SIRTs, including the challenges and limitations of translating basic research on SIRTs into therapy, which will provide new ideas for future research and clinical research areas to further contribute to the development of therapeutic potential for treating IVDD.

Sirtuins: cellular regulators with multifaceted functions

Overview of the sirtuin protein family and its role in cellular processes

Sir2 was first discovered during transcriptional silencing in Saccharomyces cerevisiae cells in the 1970s. It belongs to a highly conserved family of proteins that affect genome stability (Frydzinska et al. 2019), and their over-activation prolongs the lifespan in yeast (Kane and Sinclair 2018). The proteins homologous to Sir2 in eukaryotes were later called Sirtuins, which are class III histone deacetylases with NAD+ -dependent deacetylase activity. Sirtuins have a wide range of enzymatic activities as deacetylases, ADP ribosyltransferases, deglycosylases, and desuccinylases. Notably, binding to NAD+ is essential to all these functions (Vargas-Ortiz et al. 2019). Members of the sirtuin family regulate diverse cellular functions by acting on the post-translational modification of various proteins in organelles (Kanwal et al. 2019).

Role of sirtuins in cellular senescence, metabolism, and stress response

SIRT1–7 are the seven isoforms in the sirtuin protein family, widely distributed in cells. SIRT1 and SIRT2 are localized in the cytoplasm. SIRT1, SIRT6, and SIRT7 are distributed in the nucleus, whereas SIRT3, SIRT4, and SIRT5 are found in the mitochondria (Taneja et al. 2021). SIRT1 is most closely related to Sir2 and has been extensively investigated. It is involved in numerous biological processes, such as the regulation of gene transcription, apoptosis, survival, inflammation, oxidative stress, cellular senescence, and tumor formation (Kuno et al. 2023). SIRT1 can be directly or indirectly involved in the regulation of adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling pathway. SIRT1 can deacetylate not only histone proteins but also various non-histone proteins and transcription factors to influence multiple cellular processes, including DNA repair, stress response, and cell survival, to delay aging. SIRT1 is often referred to as the "longevity protein" because of its association with lifespan extension (Chen et al. 2020).

SIRT2 migrates to the nucleus during the G2/M phase, where it is involved in cell cycle regulation and intracellular transport (Lin et al. 2023) (Table 1). The activation of SIRT2 decreases reactive oxygen species (ROS) concentrations, deacetylates hepatic kinase B1, and promotes the activation of the AMPK pathway (Wu et al. 2021) involved in the regulation of cellular oxidative stress, autophagy, and apoptosis (Wang et al. 2019a). SIRT3 maintains mitochondrial energetic homeostasis by inducing the deacetylation and nuclear translocation of forkhead box O3a (FOXO3a) transcription factor to reduce ROS concentrations in cells (Tao et al. 2023). SIRT3 is also involved in tumorigenesis. SIRT4 plays a role in regulating energy metabolism and insulin secretion, and SIRT4 inhibits fatty acid oxidation in muscle and liver cells (Min et al. 2018).

Table 1 Sirtuins: cellular regulators with multifaceted functions

SIRT5 is the least known member of the sirtuin family and is involved in the urea cycle, glycolysis, fatty acid oxidation, and other processes that regulate malonylation of cytosolic and mitochondrial proteins (Fabbrizi et al. 2023). It is also involved in the development and progression of various cancers (Lagunas-Rangel 2023). SIRT6, highly similar in function to SIRT1, is an intracellular energy sensor and a major regulator of intracellular homeostasis (Chang et al. 2020). SIRT6 regulates genome integrity by participating in DNA repair and telomere maintenance. It modulates intracellular homeostasis by modulating glucose and lipid metabolism and inflammatory responses. In addition, SIRT6 is involved in various biological processes, such as immune response and cancer cell differentiation (Chen et al. 2021). SIRT7 is involved in gene regulation, genome stability, aging, and tumorigenesis (Tang et al. 2021). Moreover, it has also been recognized as a regulator of metabolism and stress responses (Bi et al. 2020).

Link between sirtuins and IVDD

Current understanding of IVDD pathogenesis and risk factors

The intervertebral disc consists of the nucleus pulposus (NP), annulus fibrosus, cartilaginous endplates, and capillary beds supplying nutrients. The disc is located between two adjacent vertebrae, where it serves as a weight-bearing device and maintains the stability and mobility of the vertebral body. The periphery of the NP is surrounded by a fibrous ring, and the extracellular matrix is rich in type II collagen and proteoglycans. The intervertebral disc is the largest avascular structure in the body and exchanges material through the surrounding capillary tissue. Therefore, it is highly susceptible to degenerative lesions (Kos et al. 2019). Various factors, such as nutritional deficiencies, hyperglycemia, excessive stress, hypoxia, stress, genetics, and low immunity, contribute to disc degeneration (Vergroesen et al. 2015) (Fig. 1A). This review mainly discusses the effects of related factors on the pathogenesis of IVDD from the metabolism (aging and apoptosis), inflammation, ECM degradation and oxidative stress of NP cells (Fig. 1B).

Fig. 1

Correlation between SIRT and IVDD. A Risk factors for IVDD. Various factors such as nutritional deficiencies, hyperglycemia, stress, hypoxia, stress, genetics, and immunocompromise contribute to disc degeneration. B Pathogenesis of IVDD, which mainly involves NP cell metabolism (senescence and apoptosis), inflammation, ECM degradation, and oxidative stress. C Role of SIRT in NP cell survival and activity.SIRT mainly activates autophagy, maintains intracellular homeostasis, and inhibits apoptosis

Rationale for investigating sirtuins in IVDD

The function and number of NP cells or endplate chondrocytes are decreased in degenerated disc tissues. In addition, the production of extracellular matrix components, such as type II collagen and proteoglycans, is reduced, and their degradation is enhanced. This results in the secretion of matrix metalloproteinases (MMPs) by NP cells to maintain the homeostasis of the microenvironment (Dowdell et al. 2017). This process affects the development, metabolism, proliferation, and apoptosis of NP cells, which reduces the resistance of the disc to compression and leads to structural destruction. Various proteins of the sirtuin family promote intracellular anabolism, regulate apoptosis and autophagy, reduce the degradation of functional components of the extracellular matrix, and decrease the response of the intervertebral disc to stress and inflammatory factors, slowing down the process of disc degeneration (Guo et al. 1976).

Presence and activity of sirtuin in intervertebral disc cells

The sirtuin family proteins ameliorate IVDD by promoting autophagy of NP cells and inhibiting apoptosis (Miyazaki et al. 2015) (Fig. 1C). Apoptosis and autophagy in NP cells are regulated by interrelated and interacting mechanisms. The sensitivity of NP cells to apoptosis increases when autophagic processes are blocked in NP cells (Guo et al. 1976). SIRT1 significantly inhibits apoptosis of NP cells through the Akt anti-apoptotic signaling pathway in the early stage of IVDD, slowing down IVDD (Wang et al. 2013).

Butein treatment of rats with hyperglycemia-induced disc degeneration induced an increase in Sirt1 and a decrease in acetylated p53. Therefore, butein may inhibit the acetylation of p53 by activating SIRT1 and protect NP cells from hyperglycemia-induced apoptosis and senescence (Zhang et al. 2019a). Quantitative real-time polymerase chain reaction (qRT-PCR)-based analysis revealed that resveratrol (3,5,4′ -trihydroxy-trans-stilbene) activates autophagy through the AMPK/SIRT1 signaling pathway, which attenuates TNF-α-induced MMP-3 expression in human cells (Wang et al. 2016a). SIRT1 increased the number of autophagosomes in NP cells by phosphorylating Erk1/2, thereby promoting autophagy and inhibiting apoptosis (Jiang et al. 2014). In addition, by evaluating the characteristics of the different disc degeneration stages, the early stage of disc degeneration was determined to be Pfirrmann grade III with normal disc height. The authors suggested that mildly degenerated NP cells may be a key target for molecular biological intervention therapy for disc degeneration. Notably, SIRT1 activates autophagy through the Akt/ERK signaling pathway and protects mildly degenerated human NP cells from apoptosis (He et al. 2021a).

SIRT2 overexpression significantly ameliorates ROS-induced IVDD and increases the concentrations of SOD1/2, type II collagen, and aggregated proteoglycans. In addition, SIRT2 overexpression in NP cells significantly downregulates the expression of p53 and p21. SIRT2 plays an important role in maintaining homeostasis by promoting anabolic metabolism and inhibiting catabolism in vivo (Yang et al. 2019). HSP70 can inhibit mitochondrial fission by upregulating SIRT3 expression, thereby attenuating compression-induced apoptosis in NP cells (Hu et al. 2022). SIRT5 is involved in maintaining mitochondrial homeostasis through its desuccinylase activity, and its expression was decreased in rat NP tissues under mechanical loading. Overexpression of Sirt5 effectively alleviated apoptosis and dysfunction of NP cells under mechanical stress, whereas its knockdown exacerbated apoptosis and dysfunction (Mao et al. 2023). Overexpression of SIRT6 inhibits apoptosis, replication of NP cells, and stress-induced premature senescence (Chen et al. 2018) (Table 2).

Table 2 Link between Sirtuins and IVDD

Sirtuins and cellular senescence in IVDD

Cellular senescence as a hallmark of aging and IVDD

Cellular senescence refers to an irreversible proliferative arrest of cells in the G0/G1 phase. It is morphologically characterized by cell enlargement, pigment accumulation in the cytoplasm, vacuole formation, decreased mitochondrial count, increased nuclear size, nuclear invagination, and chromatin condensation, ultimately leading to cell death (Sikora et al. 2014; Calcinotto et al. 2019). Another important feature of senescent cells is the secretion of various inflammatory factors, chemokines, growth factors, and tissue reconstruction proteases, which constitute the senescence-associated secretory phenotype. These factors are extensively involved in multiple biological processes, such as inflammatory response, cell proliferation, and cell migration (Calcinotto et al. 2019).

The local metabolic state changes when intervertebral NP cells undergo aging. This change is manifested as a decrease in anabolism and an increase in catabolism, resulting in pathologic changes such as increased extracellular matrix degradation and decreased NP water content (Stich et al. 2020). The number of SA-β-gal staining-positive cells significantly increases in the NP tissues of patients with IVDD, and their number correlates positively with the Pfirrmann grade on magnetic resonance imaging of the intervertebral disc and negatively with the number of Ki67-positive (proliferating) cells (Li et al. 2019a; Novais et al. 2019; Che et al. 2019). Therefore, NP cell senescence is positively correlated with the severity of IVDD.

SIRT1-mediated regulation of senescence pathways

Aging involves the loss and degradation of various physiologic functions in the organism, and these changes are mainly reflected in the loss of cells and constitutive substances in the tissues and slowing down of the metabolic rate. Therefore, maintaining the normal function of mitochondria to ensure optimal metabolism is critical to slow down the aging process (You and Liang 2023).

Oxidative metabolism occurs through the peroxisome proliferator-activated receptor γ coactivator 1 (PGC1)-α-dependent and PGC1-α non-dependent pathways in mitochondria, and Sirt1 plays an important role in regulating these pathways. PGC1-α and cytoplasmic Sirt1 are localized in the mitochondrial matrix (Aquilano et al. 2013). Sirt1 activates PGC1-α by acetylation, and both of them further co-activate mitochondrial transcription factor A (TFAM). The activated TFAM binds to the D-loop region of mtDNA to form a complex, which regulates mitochondrial DNA replication and transcription, thereby affecting mitochondrial biosynthesis (Yuan et al. 2016). The key protein in the PGC1-α non-dependent pathway is hypoxia-inducible factor 1 (HIF1)-α, which blocks TFAM transcription. The protein also binds to and inhibits PGC1-β activity (Yu et al. 2018). This is another positive regulator of mitochondrial biosynthesis. However, reduced Sirt1 expression increases the stabilization of HIF1-α, which downregulates mitochondrial bioactivity (Bellafante et al. 2014).

FOXO3 has multiple biological effects, including resistance to oxidative stress damage. The expression of Sirt1 and FOXO3 decreases in cardiac microvascular endothelial cells of aging mice (Lin et al. 2014). Sirt1 regulates ROS generation under oxidative stress by activating the expression of the manganese-containing superoxide dismutase (MnSOD; an antioxidant-acting superoxide dismutase in mammals) transcription factor through the deacetylation of FOXO3 (Emidio et al. 2014). Sirt1 deacetylates FOXO3 to restore and enhance its transcriptional activity and upregulates the expression of MnSOD to achieve antioxidant effects (Emidio et al. 2014). In addition, activated FOXO3 induces the transcription of PGC1-α and regulates mitochondrial function. Sirt1 acts as a deacetylase and has a delaying effect on aging. However, the regulatory pathway is affected by various factors, and the current studies on its role in aging-related pathways are in the speculative stage. (Fig. 2).

Fig. 2

SIRT in IVDD cell metabolism.SIRT1 alleviates cellular senescence and apoptosis by regulating PGC-α,FOXO3, IL-β, Akt, mTOR AMPK, and NF-KB.SIRT2 regulates ERK.SIRT3 is activated by p11k/Akt and AMPK/PGC-1α and releases SOX5 and ARID5B.SIRT4 activates FOXO1 to maintain ECM homeostasis, thereby maintaining disc integrity.SIRT5 and SIRT6 inhibit the release of inflammatory factors.SIRT5 and SIRT6 inhibit the release of inflammatory factors.SIRT6 inhibits the release of inflammatory factors. SIRT4 activates FOXO1 to maintain ECM homeostasis, thereby maintaining disc integrity.SIRT5 and SIRT6 inhibit the release of inflammatory factors. Some miRNAs can also activate SIRT to regulate cellular metabolism

Potential implications for delaying or reversing disc degeneration

High-intensity stress inhibits mitochondrial function and promotes ROS production. ROS damage intracellular DNA and other important biomolecules, promoting premature cell death (Benkafadar et al. 2019) and accelerating IVDD (Fearing et al. 2018). Consequently, the NF-κB pathway is activated, which exacerbates the senescence of NP cells. The Akt/FOXO1 pathway acts upstream of SIRT1 to modulate its expression and regulate H₂O₂-induced senescence in rat bone marrow cells (Wu et al. 2022). Deficiency of PTEN-induced kinase 1 (PINK1), a key mitotic regulator, impairs mitosis and diminishes the protective effect of SIRT1 against compression-induced senescence in myeloid cells. Wang et al. (2020a) reported that SIRT1 diminishes high-intensity compression-induced senescence in human NP cells through the PINK1/Parkin axis, a central mitotic mechanism. Furthermore, SIRT1 inhibits apoptosis by promoting autophagy (Jiang et al. 2014). SIRT1 overexpression attenuates decrease in autophagy and increase in NP cell senescence induced by high stress. In addition, SIRT1 overexpression significantly increases the LC3B/Fas complex formation, which rapidly inhibits the activation of the NF-κB pathway and thus CASP3 cleavage. LC3B silencing attenuates the inhibition of the NF-κB signaling pathway, partially promoting CASP3 cleavage and inhibiting NP cell senescence under high-intensity stress conditions (Zhuo et al. 2021). Overexpression of p300 promotes NP cell proliferation and autophagy. P300 enhances FOXO3 expression by binding to the SIRT1 promoter, leading to inactivation of the Wnt/β-cyclin pathway. Moreover, p300 disrupts the Wnt/β-linker pathway through the FOXO3/SIRT1 axis, thereby delaying the progression of IVDD (Hao et al. 2022).

Oxidative stress-induced myeloid cell senescence and apoptosis are mediated by the dysregulation of SIRT3 and the secondary imbalance of mitochondrial redox homeostasis. SIRT3 expression decreases with the progression of IVDD in humans. Wang et al. reported that in vitro silencing of SIRT3 expression reduces cellular resistance to oxidative stress and promotes senescence and apoptosis in rat myeloid cells. In contrast, activation of SIRT3 significantly inhibits oxidative stress-induced myeloid cell senescence and apoptosis and delays IVDD (Wang et al. 2018a). Lin et al. (2021a) reported a similar effect of SIRT3 on oxidative stress-induced myeloid cell senescence (Fig. 2).

Anti-inflammatory effects of sirtuins in IVDD

Role of inflammation in IVDD progression

Inflammation is a pathologic process initiated in response to infection or tissue damage. Inflammation is a key factor in the process of IVDD (Jin et al. 2019; Han et al. 2019). The concentrations of various pro-inflammatory cytokines, including interleukin (IL)-1α, IL-1β, IL-6, IL-17, and tumor necrosis factor (TNF)-α, significantly increase in the degenerated discs with the progression of IVDD (Cai et al. 2017; Mouser et al. 2019). These cytokines generate local autoimmune inflammatory reactions and enhance the catabolism of extracellular matrix in the intervertebral disc, leading to disc dysfunction and structural changes. IL-1β concentration increases in degenerated intervertebral discs and is directly proportional to the severity of IVDD. IL-1β directly inhibits extracellular matrix synthesis and forms a positive feedback loop. The loop stimulates the release of other inflammatory mediators and the synthesis of MMPs, increasing local catabolism in the intervertebral disc (Jin et al. 2019). IL-1β stimulation of human NP and annulus fibrosus cells substantially increases the secretion of IL-6, IL-8, and IL-17. Therefore, IL-1β may act as a key initiator of the inflammatory cascade by promoting the release of IL-6, IL-8, and IL-17 (Cai et al. 2017).

COX-2 plays an important role in inflammation. COX-2 is induced in many cell types in response to stimulation by inflammatory cytokines such as IL-1β and tumor necrosis factor alpha (TNF-α), as confirmed in IVDD (Miyamoto et al. 2000). COX-2 is the gene that produces PGE₂ in cells, and when stimulated, activation of COX-2 leads to the production of PGE₂ in IVDD and causes deleterious pathophysiologic effects such as inflammation20839316. PGE₂ inhibits the synthesis of aggregated glycans in NPCs, leading to extracellular matrix disruption in IVDD (Lowe et al. 1996). It has been reported Propionibacterium acnes-induced activation of iNOS/NO and COX-2/PGE₂ via the ROS-dependent NF-κB pathway may be responsible for the pathology of IVDD (Lin et al. 2018a). As IVDD progresses, the presence of COX-2 gradually increases (Lin et al. 2018a). Therefore, COX-2 is not only a cell signaling factor, but also a well-known pathogen for IVDD.

Chen et al. (2017) performed enzyme-linked immunosorbent assay (ELISA) and found that serum IL-21 concentration in patients with lumbar disc herniation was significantly higher than that in patients without disc herniation. Gorth et al. (2019) investigated the role of IL-1 in age-associated IVDD and found that IL-1α/β double knockout mice showed a significant reduction in blood concentrations of interferon-γ, IL-5, and IL-15. The number of SA-β-gal-positive cells significantly increased after TNF-α and IL-1β treatment of rat NP cells (Li et al. 2019b). Circ-FAM169A promotes IDD by regulating NF-κB pathway-induced IL-1β and TNF-α production via the miR-583/BTRC signaling pathway, upregulating the expression of MMP13 and ADAMTS5, and downregulating the expression of collagen II and aggrecan (Guo et al. 2020). In addition, some inflammatory factors, such as IL-1β, IL-6, and TNF-α, stimulate the sinusoidal nerve endings that grow into the intervertebral discs, which, in turn, trigger the clinical symptoms of radicular pain (Feng et al. 2016). Overall, inflammatory factors are powerful pro-cellular senescence factors, leading to IVDD and chronic lower back pain.

Effect of sirtuins on the NF-κB signaling and inflammatory responses

Classical NF-κB is a P50–P50/ P60–P60 homodimer or a P50–P65 heterodimer formed by P50 and RelA/P65. The P50–P65 heterodimer plays a major physiologic role in vivo. NF-κB mostly binds to its inhibitory proteins in the cytosol to form inactive complexes (Capece et al. 2022). NF-κB inhibitory protein disassociates from the complex after cell stimulation and translocates into the nucleus to regulate the transcriptional activation of the target genes. However, NF-κB heterodimer must undergo some post-translational modification before exerting the regulatory effect (Maubach et al. 2022). Reversible acetylation/deacetylation is an important post-translational modification of NF-κB, which can regulate a variety of physiologic activities, including chromatin aggregation and gene transcription (Zhao et al. 2023). NF-κB transcription factors including P65, can precisely regulate NF-κB transcriptional activation through histone acetyltransferases and deacetylases (Guldenpfennig et al. 2023).

Yeung et al. (2004) evaluated the effect of SIRT1 on NF-κB signaling and inflammatory response and suggested that SIRT1 directly deacetylates the P65/RelA subunit of NF-κB and decreases the level of its acetylation, inhibiting the transcriptional function of downstream factors. SIRT1 directly acts on P65/RelA and reduces the acetylation level of Lys310, inhibits its transcriptional activity, and downregulates the expression of downstream genes. They used the luciferase reporter gene system and detected that the intracellular SIRT1 overexpression inhibited the transcriptional activity of NF-κB. These results were similar to those reported by Yeung et al. (2011). The knockdown of SIRT1 can lead to NF-κB hyperacetylation. Therefore, SIRT1 is a key enzyme that catalyzes the deacetylation of NF-κB (Yu and Auwerx 2010).

Overexpression or activation of SIRT1 can inhibit the inflammatory response, whereas its deletion can enhance the inflammatory response (Yoshizaki et al. 2010). Inflammatory stimuli can phosphorylate P300 through the mitogen-activated protein kinase (MAPK) signaling pathway and activate its histone acetyltransferase activity. The phosphorylated P300 catalyzes the acetylation of NF-κB, increases the binding of NF-κB to κB sequences, and initiates the NF-κB-mediated transcription of pro-inflammatory genes (Yang et al. 2022). SIRT1 catalyzes the deacetylation of NF-κB and restricts the overactivation of NF-κB, thereby reducing the inflammatory response. The results of transgenic animal experiments were consistent with those of cell culture experiments in this context. Lipopolysaccharide-induced NF-κB activation and the expression of various pro-inflammatory cytokines were significantly increased in SIRT1-excluded mouse RAW264.7 macrophages (Yoshizaki et al. 2009). Myeloid cell-specific SIRT1 knockout mice are highly sensitive to local or systemic endotoxin challenges (Schug et al. 2010). Reduced SIRT1 expression leads to inflammation and macrophage accumulation in the adipose tissue. The knockdown of SIRT1 in the adipose tissue stimulates the activation of NF-κB and highly acetylated H3K9 in histones, which, in turn, promote the activation of inflammatory genes (Gillum et al. 2011). The levels of SIRT1 protein in lung cells were significantly decreased in patients with COPD. This decrease was accompanied by increased levels of NF-κB acetylation and a corresponding increase in the concentrations of NF-κB-dependent pro-inflammatory cytokines (Rajendrasozhan et al. 2008).

SIRT6 is also closely related to the NF-κB signaling pathway. Cells transfected with a vector expressing SIRT6 showed suppressed NF-κB transcriptional activity (Lim et al. 2013), and SIRT6 deletion upregulated toll-like receptor 4 (TLR4) and enhanced the activation of the NF-κB signaling pathway (Wu et al. 2019). Mechanistically, SIRT6 inhibits the NF-κB signaling pathway in different ways. On the one hand, SIRT6 directly mediates the deacetylation of H3K9 near the promoters of the NF-κB target genes, which significantly inhibits transcription (Liu et al. 2017; Ashburner et al. 2001). On the other hand, the NF-κB inhibitor IκBα tightly binds to NF-κB in the cytoplasm. Stress activates IκB kinase, which separates IκBα from the complex, promotes the translocation of NF-κB into the nucleus, and ultimately regulates target gene expression (Ma et al. 2014). SIRT6 induces cysteine monoubiquitination of the methyltransferase SUV39H1 leading to its removal from the IκBα gene. The consequent increase in the expression of IκBα inactivates the NF-κB pathway (Santos-Barriopedro and Vaquero 2018) (Fig. 3).

Fig. 3

Anti-inflammatory effects of SIRT in IVDD.SIRT1 and SIRT6 mainly exert anti-inflammatory effects in IVDD.SIRT1 and SIRT6 can inhibit the NF-κB signaling pathway as well as the release of inflammatory factors through various pathways to exert anti-inflammatory effects

Considering sirtuin-based strategies for reducing inflammation in IVDD

IL-10 and TGF-β inhibit the release of inflammatory factors from degenerating disc cells. IL-1β is commonly used as an inducer of disc inflammation to mimic degenerating disc tissue (Li et al. 2014a). Inhibition of nuclear translocation of NF-κB through SIRT1 deacetylation of RelA/p65 suppresses inflammation. IL-1β downregulates the expression of SIRT1 by activating TLR2, and SIRT1 inhibits IL-1β-mediated inflammatory responses through the TLR2/SIRT1/NF-κB pathway (Li et al. 2014a). Resveratrol, which acts as a SIRT1 activator, can decrease the concentrations of pro-inflammatory cytokines in vitro and has considerable potential in the treatment of myeloid cell-mediated pain (Wuertz et al. 1976).

1,4-Dihydropyridine, a novel activator of SIRT1, has antioxidant properties. It inhibits ROS-mediated inflammation and extracellular matrix degradation through the activation of SIRT1 in human NP cells (Song et al. 2020a). Monocyte chemoattractant protein 1 (MCP1) activation is involved in the initial inflammatory response associated with degenerating discs. SIRT1 inhibits MCP1 production in degenerating NP cells by inhibiting the phosphorylation of c-Fos and c-Jun factors in activator protein 1 and thus inhibits disc degeneration (Cai et al. 2020). Peroxisome proliferator-activated receptor β/δ (PPARβ/δ), which enhances IL-1β-induced COX-2 expression and PGE2 production in human thylakoid cells through the SIRT1 pathway (Li et al. 2022a). Red ginseng inhibits hypoxia-induced COX-2 expression through SIRT1 activation (Lim et al. 2015). Melatonin treatment upregulates testicular SIRT1 expression to inhibit Lipopolysaccharide (LPS)-induced inflammatory proteins, namely NF-kB/COX-2/iNOS expression (Kumar et al. 2021). It has been reported that SIRT1 inhibits activator protein-1 transcriptional activity and COX-2 expression in macrophages (Zhang et al. 2010). The regulation of COX-2 expression by SIRT1 in IVDD has not been reported yet and needs further confirmation.

Activation of the NF-κB signaling pathway promotes matrix-degrading enzyme activity in the NP and promotes extracellular matrix degradation in IVDD. SIRT6 overexpression significantly inhibits human NF-κB-dependent transcriptional activity in NP cells. Inhibition of NF-κB signaling is essential for SIRT6-mediated maintenance of extracellular matrix homeostasis in the NP (Kang et al. 2017). Moreover, 3-methyladenine and chloroquine-mediated autophagy inhibition partially reverses the anti-aging and anti-apoptotic effects of SIRT6 (Chen et al. 2018). Luteolin inhibits TNF-α-induced inflammatory damage and senescence in human NP cells through the SIRT6/NF-κB pathway (Xie et al. 2022a). Chen et al. (Chen et al. 2018) reported that IL-1β increases the levels of senescence-associated proteins (e.g., p16, p21, and p53) to promote cell death and senescence, which, in turn, reduces NP cell population and aggravates IVDD. SIRT6 overexpression downregulates the expression of senescence-associated proteins and inhibits IL-1β-induced senescence and apoptosis in NP cells.

Sirtuins and extracellular matrix regulation

Role of extracellular matrix in disc health and degeneration

The rates of extracellular matrix synthesis and degradation are in equilibrium in a healthy intervertebral disc. IVDD usually occurs when extracellular matrix degradation exceeds its synthesis, and type II collagen and proteoglycans are the important components lost in this process. This results in a loss of water in the disc tissue and a decrease in the cushioning and compression resistance (Emanuel et al. 2018). MMPs, the main degradative enzymes, are highly expressed in degenerated discs (Perez-Garcia et al. 2019).

Influence of sirtuins on extracellular matrix synthesis and maintenance

SIRT maintains extracellular matrix homeostasis, regulates chondrocyte metabolism, inhibits chondrocyte apoptosis and autophagy, and prevents cellular senescence through its deacetylation activity (Sun et al. 2022) (Fig. 2). SIRT1 regulates the expression of extracellular matrix-related proteins and promotes mesenchymal stem cell differentiation. Moreover, it exerts anticatabolic, anti-inflammatory, anti-oxidative stress, and anti-apoptotic effects and participates in autophagy (Deng et al. 2019). FGF21 administration alleviated tert-butyl hydroperoxide (TBHP)-induced extracellular matrix catabolism by mediating autophagy flux through the activation of the SIRT1/mTOR signaling pathway (Lu et al. 2021). Echinacoside, the active substance of Cistanche, possesses potent anti-oxidative stress properties. It can inhibit endoplasmic reticulum stress and extracellular matrix degradation by upregulating SIRT1 in the chondrocytes of TBHP-treated mice (Lin et al. 2021b). Notably, safranal has the same effect (Liu et al. 2022). Melatonin (Zhao et al. 2022) and paeonol (Shang et al. 2022) enhanced SIRT1 expression to inactivate the NF-κB signaling pathway, which ameliorated inflammatory cytokine secretion and extracellular matrix degradation.

PEP-1–SIRT2 promote MMP-induced dedifferentiation through ERK signaling in articular chondrocytes (Eo et al. 2016). Early activation of SIRT3 in 1D sedimentation cultures significantly increased the gene expression of type II collagen, aggregated collagen, and the cartilage transcription factors SOX5 and ARID5B in extracellular matrix (Smith et al. 2022). Evodiamine upregulates SIRT3 and inhibits extracellular matrix degradation and inflammation through the activation of the PI1K/Akt pathway (Kuai and Zhang 2022). Deacetylation of FOXO1 by SIRT4 activates SOX9 expression, thereby maintaining cartilage stability in ECM (Ma et al. 2021). Circ_0022383 protects chondrocytes from IL-1β-induced apoptosis, inflammation, and degeneration through the miR-1-3619p/SIRT5 axis (Qian et al. 2022). Overexpression of SIRT6 prevents IL-1-induced NP extracellular degradation (Kang et al. 2017).

Preserving disc integrity through sirtuin modulation

Hypoxia and a significant increase in inflammatory cytokines are common features of IVDD, and these events disrupt the normal balance between extracellular matrix degradation and synthesis in degenerative discs. SIRT1 inhibits the mRNA expression of proteases that degrade TNF-α-induced extracellular matrix (Wang et al. 2016b). SIRT1 was upregulated by tyrosol, and SIRT1 silencing inhibits the Akt phosphorylation in NP cells. SIRT1 knockdown attenuates the effect of tyrosol on IL-1β-induced apoptosis, inflammation, and extracellular matrix remodeling in NP cells (Qi et al. 2020). Overexpression of SIRT1 mediated by lentiviral vectors inhibits IL-1β-induced extracellular matrix degradation and apoptosis. In contrast, siRNA knockdown of the gene encoding SIRT1 increases IL-1β-induced MMP expression and apoptosis (Shen et al. 2016). Orientin downregulates oxidative stress-mediated endoplasmic reticulum stress and mitochondrial dysfunction through the AMPK/SIRT1 pathway in rat NP and attenuates disc degeneration (Zhang et al. 2022). Hyperoside upregulates SIRT1 and nuclear factor E2-related factor 2 (Nrf2) protein expression and ameliorates TNF-α-induced inflammation and extracellular matrix degradation (Xie et al. 2022b).

The activation of the AMPK/PGC-1α pathway partially alleviates oxidative stress, senescence, and degeneration induced by the knockdown of SIRT3 in NP cells (Lin et al. 2021a). SIRT6 prevents the degradation of the NP extracellular matrix in vitro by inhibiting the NF-κB-dependent transcriptional activity, thereby ameliorating disc degeneration (Kang et al. 2017) (Fig. 2).

Regulation of apoptosis by sirtuins in IVDD

Apoptosis contributes to cell death and degeneration in intervertebral discs

Apoptosis refers to the genetically controlled, autonomous, and orderly death of cells to maintain the stability of the internal environment. Apoptosis, also known as type I programmed death, is involved in many physiologic processes, such as growth, development, and prevention of malignant transformation of cells. The reduction in the number of cells in the intervertebral disc due to apoptosis and a decrease in extracellular matrix synthesis and alteration of its composition are the key features of disc degeneration (Fine et al. 2023).

Anti-apoptotic effects of SIRT1 and its potential relevance

SIRT1 regulates many important genes through deacetylation, such as p53, FOXO, PGC-1α, and protein kinase B (PKB/Akt). These downstream genes, in turn, regulate disc cell apoptosis by modulating apoptotic factors, neuroinflammation, oxidative stress, and mitochondrial development.

P53 is a tumor suppressor protein that belongs to the family of p63 and p73. P53 is a key component of the cellular stress response. The protein is regulated by modulating its gene expression and stability, as well as various reversible post-translational modifications. P53 is induced or undergoes rapid reversal of post-translational modifications for stabilization and activation in response to DNA damage, oncogene expression, hypoxia, increased ROS, and nutrient deficiencies. P53 transcriptional activation in the nucleus is involved in apoptosis, cell cycle, autophagy, and metabolism (Kruiswijk et al. 2015). In contrast, cytoplasmic p53 acts in a transcription-independent manner and directly binds to cytoplasmic apoptosis and autophagy effectors (Saldana-Meyer and Recillas-Targa 2011). P53 mainly interacts with the Bcl family proteins, including the anti-apoptotic protein Bcl-2, which induces Bak oligomerization, permeabilizes mitochondrial membranes, induces cytochrome C release, and activates apoptotic protease cascades, thereby regulating apoptosis. Several lysine residues of p53, including K320, K373, and K382, can be acetylated in vivo. The acetylation of different residues induces different aspects of the p53-mediated stress response. Acetylation of the K382 residue activates p53 to trigger the transcription of apoptosis-associated target genes (Wang et al. 2014). SIRT1 deacetylates the lysine residue at the K382 position to reduce the transcriptional activity of p53 and inhibit apoptosis (Li et al. 2014b). P53 is ubiquitinated at the C-terminal position, and SIRT1 deacetylates these residues during cellular stress to block proteolytic degradation and ensure stabilization of p53 (Liu et al. 2018a).

FOXO1 and FOXO3 are two of the most widely studied isoforms of FOXO transcription factors, which are involved in the pathogenesis of several diseases and stem cell activity (Liu et al. 2018a). FOXO1/3 upregulates several cell cycle inhibitors and pro-apoptotic targets and plays important roles in cell proliferation, differentiation, and apoptosis in the heart, vasculature, skeletal muscle, liver, and brain (Zhang et al. 2017). Transcriptional activation of FOXO can be regulated by acetylation/deacetylation or phosphorylation/dephosphorylation. Lysine residues in the DNA-binding region of the FOXO protein can be acetylated by cytosolic proteins with histone acetyltransferase activity, decreasing its transcriptional activation. The FOXO family of proteins is a common target of SIRT1, essential for mediating apoptosis. SIRT1 has a dual effect on the function of FOXO3a. It enhances the ability of FOXO3a to promote cell cycle arrest and resistance to oxidative stress and inhibits its ability to induce cell death through SIRT1-mediated deacetylation (Brunet et al. 2004).

PGC-1α is a nuclear transcriptional co-activator of nuclear receptors and several other transcription factors. PGC-1α is involved in the positive regulation of oxidative metabolism and counteracts ROS to enhance cellular antioxidant capacity (Khan et al. 2012). Histone acetyltransferase complex directly acetylates multiple lysine residues of PGC-1α, leading to a decrease in its levels and transcriptional activity. In contrast, SIRT1 deacetylates PGC-1α to enhance its activity, promote mitochondrial biosynthesis, and maintain mitochondrial function to reduce apoptosis (Zhou et al. 2017).

Akt is a serine-threonine kinase activated by phosphorylated phosphatidyl kinase-3-kinase products. The movement of Akt from the cytoplasm to the plasma membrane induces the activation of the kinase and regulates the phosphorylation of Akt substrates, ultimately influencing various physiologic and pathologic processes. Expression of SIRT1 increases Akt activity and inhibits apoptosis (Iaconelli et al. 2017). Histone acetyltransferases acetylate Akt at Lys-14 and Lys-20; phosphorylation of acetylated Akt decreases, inhibiting its activity. In contrast, SIRT1 deacetylates Akt at the same positions to promote its activation. Activated Akt phosphorylates its substrates, such as Bad, FOXO, and glycogen synthase kinase 3β to inhibit apoptosis (Li et al. 2018a). The non-phosphorylated Bad translocates to mitochondria and triggers cytochrome C release, cystatinase-3 activation, and apoptosis in the absence of activated Akt. Non-phosphorylated FOXO proteins translocate to the nucleus and act as transcription factors to increase the protein levels of Bim and Fas ligands. Bim also triggers cytochrome C release, whereas Fas triggers the extrinsic apoptotic pathway (Iaconelli et al. 2017) (Fig. 2).

Exploring avenues for enhancing cell survival through sirtuin modulation

CircRNAs and miRNAs are the intracellular regulators that modulate iodine deficiency disorders (Yang et al. 2021). miR-34a-5p binds to SIRT1 mRNA, and its overexpression inhibits miR-34a-5p-induced cell cycle arrest and senescence (Zhu et al. 2021). CircRNA-CIDN acts as a miR-34a-5p sponge to inhibit compression-induced apoptosis and extracellular matrix degradation in NP. The combination of CircRNA-CIDN and miR-34a-5p diminishes compressive loading-induced myeloid cell injury by targeting SIRT1 (Xiang et al. 2020). Xie et al. (2019) demonstrated that circERCC2 promotes filamentophagy response by regulating apoptosis, mitosis, and extracellular matrix degradation in NP and decreases apoptosis and extracellular matrix degradation to alleviate IVDD. In contrast, circRNA_0000253 is highly upregulated in degenerate myeloid exosomes and can promote IVDD by adsorbing miRNA-141-5p and downregulating SIRT1 (Song et al. 2020b).

Overexpression of miR-199a-5p promotes apoptosis and IVDD in myeloid cells. The effects of miR-199a-5p overexpression were diminished upon SIRT1 overexpression, whereas its silencing diminished the effects of p21 overexpression. Furthermore, miR-199a-5p promoted myeloid apoptosis and IVDD by inhibiting SIRT1-dependent p21 deacetylation (Sun et al. 2021a) (Fig. 2). The downregulation of miR-138-5p upregulated SIRT1 expression by directly targeting its 3'-untranslated region, and mutations in the miR-138-5p binding site inhibited this effect. The inhibition of miR-138-5p decreased the PTEN protein expression and promoted the PI3K/AKT activation. In contrast, inhibition of SIRT1 or PI3K/AKT inhibitor treatment eliminated the effect of miR-138-5p on NP cell apoptosis. miR-138-5p knockdown protects human NP cells from apoptosis by upregulating SIRT1, and this effect may be mediated through the PTEN/PI3K/Akt signaling pathway (Wang et al. 2016c). miR-22-3p protects human NP cells from apoptosis by targeting SIRT1 and plays a mechanistic role in the development of IVDD. SIRT1, in turn, activates the JAK3/STAT22 signaling pathway. Delivery of miR-22-3p inhibitors and mimics through nanoparticles synthesized in the IVDD model alleviated and exacerbated IVDD, respectively. The nanocarriers enhanced miR-22-3p translocation to myeloid NP cells, which led to in vivo inhibition of miR-22-3p, thereby facilitating the development of miRNA-specific drugs for IVDD (Chen et al. 2023a). miR-141 promotes IVDD by targeting and depleting SIRT1, a negative regulator of the NF-κB pathway (Ji et al. 2018). miR-106b-5p overexpression decreases cell growth, induces apoptosis, impairs extracellular matrix formation, and increases the expression of matrix-degrading enzymes in NP cells through the SIRT2/MAPK/ERK signaling pathway (Meng et al. 2023).

NP mesenchymal stem cells (NPMSCs) in the intervertebral disc can promote regeneration due to their endogenous repair function and differentiation potential (Liao et al. 2019). Liao et al. (2019) demonstrated that overexpression of SIRT1 diminishes IVDD by inactivating the MCP1/chemokine receptor 2 axis, which promotes chondrogenic differentiation and reduces apoptosis of NPMSCs. Liu et al. (2020a) demonstrated that high-glucose culture significantly decreased the stem cell gene expression and the mRNA and protein expression of SIRT1, SIRT6, HIF-1α, and glucose transporter protein type 1, while increasing apoptosis, senescence, and caspase-3 expression in NPMSCs. The high sugar concentration significantly decreased the cell proliferation, colony-forming ability, migration, and wound-healing ability of NPMSCs. Notably, NPMSCs cultured in high glucose concentrations had a significantly low expression of stemness gene-related mRNAs and proteins.

Oxidative stress management by sirtuins

Effect of oxidative stress on IVDD development

Oxidative stress is a pathologic condition characterized by an imbalance between the generation of ROS and the corresponding antioxidant system (Xian et al. 2021). ROS are incompletely reduced oxygenated molecules with strong reactivity, which can diffuse in the cells to destroy nucleic acids, proteins, lipids, and other molecules (Cheung and Vousden 2022). The human body has an antioxidant system that scavenges ROS, and a homeostasis of oxidative and antioxidant systems exist under normal conditions. However, excessive ROS production or decline in the function of the antioxidant system leads to an imbalance, i.e., oxidative stress, which ultimately destroys critical molecules or cells in the body (Endale et al. 2023). The accumulation of cells damaged by ROS activity further accelerates the production of ROS, forming a vicious cycle.

ROS are extensively involved in signaling, metabolic regulation, programmed cell death, senescence, and phenotypic transformation of intervertebral disc cells. Notably, IVDD is a disc cell-mediated pathologic process, and disc degeneration is closely related to the viability and function of disc cells (Li et al. 2022b). Oxidative stress induced by excessive ROS activates multiple signaling pathways in disc cells, prompting a phenotypic shift from a matrix anabolic phenotype to a catabolic and pro-inflammatory phenotype, leading to matrix loss and enhanced inflammation in the disc microenvironment. In addition, chemokines secreted by disc cells recruit more immune cells to the disc, further exacerbating inflammation. These immune cells secrete more cytokines and chemokines, which again reduce the viability and function of the disc cells (Risbud and Shapiro 2014).

Oxidative stress is a potent trigger of autophagy, apoptosis, and senescence in NP cells. Autophagy protects NP cells from oxidative damage by providing metabolic substrates for recycling under oxidative stress. However, excessive autophagy induced by persistent oxidative stress will lead to autophagic death of NP cells (Zheng et al. 2019). Moreover, oxidative stress directly induces apoptosis in NP cells. Therefore, the activity and function of NP cells are significantly reduced under sustained oxidative stress, and this reduction cannot be compensated by cell proliferation due to NP cell senescence. Moreover, senescent NP cells secrete pro-inflammatory cytokines that promote the death or senescence of neighboring NP cells, further reducing the count of viable and functional cells (Chen et al. 2019).

Role of sirtuins in enhancing antioxidant defenses

SIRT1 regulate NF-κB (Li et al. 2018b), FOXO1 (Yao et al. 2018), P53 (Lin et al. 2018b), PGC-1α (Tang 2016), AMPK (Wang et al. 2019b), Nrf2 (Tang et al. 2014), HIF-1α (Shin and Lee 2017), endothelial nitric oxide synthase (eNOS) (Ding et al. 2015), Ku70 (Jeong et al. 2007), and other target genes/ proteins, which play an important role in oxidative stress injury(Fig. 4A). Activated NF-κB factors activate inflammatory mediators that damage the body and simultaneously promote ROS production, which damages tissues and organs and further promotes the expression of inflammatory factors. NF-κB binds to its inhibitor IκBα in the cytoplasm to form an inactive complex under normal conditions. IκB kinase phosphorylates IκBα and releases NF-κB upon stimulation, which then enters the nucleus and binds to the corresponding promoter gene target to enhance transcription. SIRT1 deacetylates RelA/p65, binds NF-κB to IκBα, and inhibits NF-κB transcriptional activity, thereby reducing the expression of inflammatory factors (Li et al. 2018b).

Fig. 4

SIRT is associated with the management of oxidative stress associated with IVDD. A SIRT1 can regulate a variety of target genes and target proteins, for example, SIRT1 can activate Nrf2, FOXO1, PGC-1α, LKB1, and RelA/p65, and SIRT1 can inhibit p53 and HIF-1α, etc., and thus plays an important role in oxidative stress injury. B SIRT3 is associated with the management of oxidative stress associated with IVDD.SIRT3 regulates the expression of antioxidant enzymes through activating FOXO3, PGC-1α, E2, and CREB.SIRT3 is associated with the management of oxidative stress associated with IVDD. SIRT3 is associated with the management of oxidative stress associated with IVDD.SIRT3 regulates the expression of antioxidant enzymes through the activation of FOXO3, PGC-1α, E2 and CREB

FOXO1 can scavenge excessive ROS by regulating downstream target genes, such as MnSOD and catalase, thereby reducing cellular oxidative stress damage (Meng et al. 2017). SIRT1 activates FOXO1 through deacetylation, attenuates H₂O₂-induced cellular oxidative stress injury, and inhibits osteoblast apoptosis. Xiong et al. (2011) reported that FOXO1 increases the expression level of SIRT1. This suggests that a feedback mechanism may be involved in FOXO1-dependent SIRT1 transcription and SIRT1-mediated deacetylation of FOXO1.

P53 promotes oxidative stress damage and induces apoptosis by regulating different target proteins, such as P53-inducible protein, reduced nicotinamide adenine dinucleotide phosphate cytoplasmic subunit NCF2/p67phox, p66Shc, and Bax (Liu et al. 2020b). The H₂O₂-induced oxidative stress environment increases the expression and accumulation of the p53 gene, whereas activation of SIRT1 decreases its activity (Kim et al. 2015). Lin et al. (2018b) confirmed that SIRT1 can protect renal tubular cells from oxidative stress injury and reduce apoptosis by deacetylating p53 and inhibiting its activation. Overall, SIRT1 can inhibit p53 activation through deacetylation and apoptosis, thereby resisting oxidative stress injury.

PGC-1α may play an anti-oxidative role by scavenging excessive ROS, inducing the expression of antioxidant enzymes, and maintaining mitochondrial function (Iacovelli et al. 2016). SIRT1 can regulate metabolic disorders through deacetylation of PGC-1α and decrease cellular damage caused by external stimuli (Tang 2016). Liang et al. (2020) showed that SIRT1 activates PGC-1α through deacetylation, scavenges ROS generated by oxidative stress, and attenuates intestinal oxidative stress injury. Therefore, SIRT1 can activate the expression of PGC-1α through deacetylation and ameliorate oxidative stress injury.

AMPK can be activated by liverkinase B1, and activated AMPK ameliorates oxidative stress injury by promoting insulin sensitivity, fatty acid oxidation, and mitochondrial biosynthesis to produce ATP. Overexpression of SIRT1 can lead to deacetylation of liverkinase B1 and changes its localization from the nucleus to the cytoplasm, where it activates AMPK (Vancura et al. 2018). Wang et al. (2019b) showed that SRT1720 (a SIRT1 agonist) increased the expression of AMPK and improved the antioxidant capacity in type 2 diabetic rats. In addition, SIRT1 and AMPK can regulate each other, and both of them can directly affect the activity of PGC-1α through acetylation and phosphorylation, respectively. This series of events eventually ameliorates the oxidative stress injury (Canto et al. 2009).

Nrf2 is a leucine transcription factor composed of six structural domains NRF2 ECH homology 1–6. It plays a crucial role in the transcriptional regulation of antioxidant response element (ARE)-dependent defense genes. Nrf2 binds to the inhibitory protein Keap1 in the cytoplasm and exists as an inactive Nrf2–Keap1 complex. Nrf2 dissociates from Keap1 and enters the nucleus upon stimulation, where it interacts with ARE and regulates the expression of antioxidant genes, such as glutathione S-transferase, glucuronosyltransferase, and heme oxygenase (Zhang et al. 2013). SIRT1 can activate Nrf2 by modifying the structure of Keap1, leading to nuclear translocation of Nrf2, thereby promoting the expression of antioxidant genes (Tang et al. 2014). Huang et al. (2015) found that resveratrol directly promotes the deacetylation and subsequent activation of Nrf2 by increasing the expression of SIRT1, which ultimately upregulates the expression of target genes of Nrf2 (antioxidant genes). Chen et al. (2023b) showed that populin may exert a protective effect against ischemic encephalopathy injury by alleviating oxidative stress and apoptosis through the NRF2 signaling pathway. And it has been demonstrated that populin can prevent intervertebral disc degeneration in rats through the Nrf2/HO-1/NF-κB signaling pathway (Mao and Fan 2023). Xie et al. (2023) found that populin affected the SIRT1/PGC-1α pathway to protect mitochondrial function and alleviate cellular senescence in H₂O₂-treated myeloid MSCs. Overall, SIRT1 can directly or indirectly activate Nrf2 and regulate the expression of antioxidant genes to protect the cells from oxidative stress damage.

The HIF family consists of HIF1, HIF2, and HIF3 proteins. HIF expression increases during oxidative stress and inflammation in hypoxic tissues. HIF regulates various genes, such as erythropoietin, vascular endothelial growth factor, and glycolytic enzymes, which play an important role in vascularization, energy metabolism, cell survival, apoptosis, and the maintenance of cellular stability under hypoxic conditions (Choudhry and Harris 2018). The activation of HIF-1α is associated with oxidative stress and can directly and indirectly regulate ROS formation (Stuart et al. 2019). Shin et al. (2017) found that an increase in SIRT1 decreases the HIF-1α acetylation level. In contrast, the knock down of SIRT1 significantly increases the HIF-1α acetylation level, indicating that SIRT1 regulates HIF-1α acetylation to resist hepatic ischemia–reperfusion injury. Therefore, SIRT1 may play a regulatory role in oxidative stress by modulating HIF-1α expression.

eNOS is mainly expressed in endothelial cells and plays an important role in cardiac and vascular oxidative stress. SIRT1 plays an important role in regulating eNOS activity, and upregulation of SIRT1 can decrease eNOS acetylation (inactivated state) and increase its phosphorylation (activated state) (Ding et al. 2015). Moreover, activation of the SIRT1/eNOS pathway inhibits oxidative stress and ameliorates ischemia–reperfusion injury in the relevant animal models. Ku70 is a DNA repair protein involved in DNA damage repair and apoptosis caused by various stimuli. All types of oxidative stress damage may cause DNA damage. SIRT1 enhanced DNA repair activity after radiation exposure by deacetylating Ku70. The pro-apoptotic protein Bax binds to Ku70 under physiologic conditions. Ku70 is acetylated upon oxidation stimulation and dissociates from Bax, and the dissociated Bax is then localized to the mitochondrial membrane to promote cell apoptosis (Jeong et al. 2007). SIRT1 can deacetylate Ku70, which strengthens its interaction with Bax. Consequently, the transfer of Bax to the mitochondrial membrane is inhibited, thereby inhibiting apoptosis in rat germ cells and ultimately alleviating cellular oxidative stress injury (Liu et al. 2018b).

Several authors have evaluated the role of SIRT3 in oxidative stress (Fig. 4B). SIRT3 regulates the expression of antioxidant enzymes through FOXO3a and PGC-1α. Jocobs et al. reported for the first time that SIRT3 interacts with FOXO3a to form a complex that regulates the activity of FOXO3a. This interaction enhances the binding of FOXO3a to both promoters, altering the intracellular oxidative environment (Jacobs et al. 2008). Activation of FOXO3a by SIRT3 increased the levels of mRNA transcripts of several antioxidant genes, including MnSOD and catalase genes, consequently increasing the levels of corresponding proteins (Sundaresan et al. 2009). The deacetylation of FOXO3a by SIRT3 protects mitochondria from oxidative stress by modulating FOXO3a-dependent expression of the antioxidant genes, which is associated with the intervention of aging-related pathogenesis (Tseng et al. 2013).

SIRT3 regulates the transcriptional regulator PGC-1α to upregulate MnSOD expression. PGC-1α further regulates the expression of several mitochondrial antioxidant genes, including MnSOD and catalase (Valle et al. 2005). Transcriptional activation of PGC-1α is mainly regulated by CREB in different tissues (Lopez-Lluch et al. 2008). SIRT3 promotes the phosphorylation of CREB, which, in turn, triggers the transcriptional activation of PGC-1α (Rius-Perez et al. 2020). In addition, activation of SIRT3 in a pressure-overload hypertrophic mouse model increases the levels of PGC-1α mRNA, resulting in reduced oxidative stress and improved mitochondrial function (Pillai et al. 2015). However, PGC-1α deletion reduces SIRT3 gene expression in myocytes and hepatocytes, which is mediated by estrogen-related receptor-binding element (Kong et al. 2010). These results suggest a bidirectional regulation between SIRT3 and PGC-1α involved in mitochondrial antioxidant defense.

Sirtuin-based strategies for mitigating oxidative damage

Oxidative stress-induced senescence of NP cells is an important cause of IVDD. Regarding SIRT 1 affecting IDD action through oxidative stress, we have discussed it in detail in the aging section. Here, we mainly reviewed the effect of SIRT3 on IVDD. Dysregulation of SIRT3 and secondary imbalance of mitochondrial redox homeostasis are important mechanisms mediating oxidative stress-induced senescence and apoptosis in NP cells. SIRT3 expression was downregulated with the progression of human IVDD. In vitro silencing of SIRT3 reduced cellular resistance to oxidative stress and upregulated senescence and apoptosis in rat NP cells. In contrast, activation of SIRT3 significantly inhibited oxidative stress-induced senescence and apoptosis of NP cells and delayed IVDD (Wang et al. 2018a). Similar effects of SIRT3 on oxidative stress-induced senescence of NP cells have been reported in vitro (Lin et al. 2021a). Some authors used H₂O₂ to induce oxidative stress in NP cells, and H₂O₂ treatment upregulated the expression of SIRT3 in NP cells. The upregulated SIRT3 exerted cytoprotective effects. Therefore, SIRT3 upregulates the activity of the mitochondrial antioxidant enzyme system, scavenges intracellular ROS, and maintains cellular homeostasis and physiological functions (Wang et al. 2018a; Lin et al. 2021a). The deubiquitinating enzyme USP11 stabilizes SIRT3 by directly binding to and deubiquitinating SIRT3. Therefore, USP11 overexpression significantly ameliorates oxidative stress-induced iron-dependent cell death and alleviates IVDD through SIRT3 upregulation (Zhu et al. 2023).

Nicotinamide mononucleotide attenuates oxidative stress-induced apoptosis in NP cells by attenuating the inhibitory effect of AGEs on SIRT3 (Song et al. 2018). The activation of the AMPK/PGC-1α pathway enhanced the cytoprotective effect of SIRT3, whereas inhibition of this pathway with compound C attenuated the cytoprotective effect of SIRT3 on NP cells (Wang et al. 2018a; Song et al. 2018). SIRT3 can upregulate SOD2 expression by activating FOXO3a, thereby exerting an antioxidant effect and delaying the degenerative process in intervertebral disc (Zhou et al. 2019). Recently, Hu et al. reported that SIRT3 inhibits oxidative damage and apoptosis in NP cells by activating downstream mitochondrial autophagy to promote Nrf2-mediated antioxidant effects (Hu et al. 2021).

SIRT3 activation promotes mitochondrial autophagy in NP cells, thereby attenuating oxidative stress-induced senescence and apoptosis. In addition, SIRT3 activates mitochondrial autophagy through a BNIP3-dependent pathway after anti-staphylococcal treatment (Wang et al. 2018a). miR-494/SIRT3/mitochondrial autophagy signaling pathway promotes apoptosis and mitochondrial dysfunction in NP cells. Duhuo Jisheng Decoction protects from IVDD by regulating this signaling axis (Liu et al. 2023). Wang et al. (2019c) demonstrated that metformin protects primary chondrocytes from PINK1/Parkin-mediated mitochondrial autophagy through SIRT3 activation. However, the regulatory network of autophagy is complex. Therefore, further studies are needed to assess whether SIRT3 is associated with macroautophagy and the PINK1/Parkin-dependent classical mitochondrial autophagy pathway in intervertebral disc cells.

Therapeutic implications and future directions

Potential of sirtuin-targeted interventions in IVDD

Resveratrol is a phenolic derivative mainly found in grape skins and seeds (Bhat et al. 2001). This compound exerts anti-inflammatory, antioxidant, and aging-delaying effects in cells and can be used for treating chronic diseases, such as diabetes, obesity, cardiovascular disease, and cancer (Malaguarnera 2019; Galiniak et al. 2019). Resveratrol can reduce apoptosis and senescence of NP cells and promote the synthesis of proteoglycans in the extracellular matrix, thereby slowing down the process of IVDD (Lin et al. 2018a). Moreover, resveratrol can activate downstream signaling molecules including SIRTs (Wang et al. 2018b; Gomes et al. 2018). Therefore, resveratrol is widely used as an activator of SIRTs in several experiments.

Honokiol (C18H18O2) is a naturally occurring small molecule compound extracted from the roots and bark of Magnolia officinalis. It possesses various pharmacologic properties, including anti-inflammatory, antioxidant, analgesic, and neuroprotective effects (Lin et al. 2007; Tang et al. 2018). Notably, honokiol mediates an increase in SIRT3 activity (Kanwal 2018; Zheng et al. 2018). Wang et al. (2018a) reported that honokiol enhanced mitochondrial antioxidant capacity, mitochondrial dynamics, and mitochondrial function upon SIRT3 activation through the AMPK/PGC-1α signaling pathway, thereby rescuing oxidative stress-induced NP cells from apoptosis and senescence. Moreover, honokiol significantly ameliorated IVDD in a rat model. Naringin enhances autophagic flow through AMPK activation and SIRT1 upregulation, thereby protecting NP cells against inflammatory responses, oxidative stress, and impaired cellular homeostasis (Chen et al. 2022). Quercetin inhibits apoptosis and ameliorates IVDD through the SIRT1/autophagy axis (Wang et al. 2020b).

Melatonin is an endocrine hormone synthesized and secreted by the pineal gland in the brain and plays an important role in the maintenance of circadian rhythms (Zisapel 2018). Melatonin treatment reduces apoptosis and inhibits endplate chondrocyte calcification in a dose-dependent manner. In addition, melatonin upregulates SIRT1 expression and activity and promotes autophagy in endothelial progenitor cells. However, inhibition of autophagy using 3-methyladenine reverses the protective effects of melatonin on apoptosis and calcification. The SIRT1 inhibitor EX-527 inhibited melatonin-induced autophagy and the protective effects of melatonin on apoptosis and calcification. These findings suggest that the beneficial effects of melatonin are mediated through the SIRT1/autophagy pathway (Zhang et al. 2019b). Melatonin inhibits M1-type macrophage polarization and ameliorates inflammation-induced NP cell injury through the SIRT1/gap signaling pathway, which is important for the remission of IVDD (Dou et al. 2023).

Nimbolide, a natural compound isolated from Azadirachta indica, activates SIRT1 in NP cells during inflammation to promote cholesterol efflux and inhibit the activation of NF-κB and MAPK signaling pathways, which balance matrix anabolism and catabolism. However, SIRT1 inhibition significantly diminishes the effects of nimbolide. Furthermore, nimbolide promoted SIRT1 expression in RAW 264.7 cells, increased the proportion of M2 macrophages by promoting cholesterol homeostatic reprogramming, and impaired M1-like macrophage polarization by blocking the activation of inflammatory signals. Therefore, nimbolide can be potentially used for the treatment of IVDD (Teng et al. 2023).

Small extracellular vesicles released from induced pluripotent stem cell-derived mesenchymal stem cells (iMSC-sEVs) can restore NP cell senescence and slow down the progression of IVDD. iMSC-sEVs exert their anti-aging effects by delivering miR-105-5p to senescent NP cells and activating the SIRT6 pathway. Sun et al. (2021b) showed that iMSCs are a promising candidate for obtaining sEVs on a large scale while avoiding some of the pitfalls associated with the current applications of MSCs. Therefore, iMSC-sEVs may be a novel cell-free therapeutic tool for the treatment of IVDD. Although iMSC-sEVs are currently the main research direction in nanomedicine, a current study found that Platelet-derived extracellular vesicles (PEVs) can improve IVDD by improving mitochondrial function. PEVs can restore impaired mitochondrial function by modulating the sirtuin 1 (SIRT1)-peroxisome proliferator activated receptor γ coactivator 1α (PGC1α)-mitochondrial transcription factor A (TFAM) pathway to reduce oxidative stress. body proliferator-activated receptor γ coactivator 1α (PGC1α)-mitochondrial transcription factor A (TFAM) pathway to restore impaired mitochondrial function, reduce oxidative stress, and restore cellular metabolism; PEVs delayed the progression of IVDD in a rat model (Dai et al. 2023). Thus, this nanomaterial therapy may offer more potential therapeutic prospects in the future.

Challenges and limitations in translating basic research on sirtuins to therapies

Although some authors have reported the regulation of myeloid cells by SIRTs, studies on ex-SIRT1 are limited. Therefore, further studies are needed to assess their mechanisms of action. In addition, there are no effective drugs for the treatment of iodine deficiency disorders. Several authors have examined SIRT-mediated regulation of autophagy and apoptosis in myeloid cells but not in cartilage endplate cells. Therefore, basic and clinical studies should be conducted on the use of SIRTs for the diagnosis and treatment of IVDD. Studies have been conducted using simple and stable animal models of IVDD, such as the rat caudal pinning model. However, the stress response in the rat caudal spine is different from that in the human IVDD. Therefore, this animal model does not fully mimic the pathologic process of human IVDD. Further, the role of SIRTs in the pathogenesis of IVDD has not been evaluated using transgenic animals. Most in vivo studies have been performed using drug-induced models having poor specificity. Therefore, the use of transgenic animal models can provide reliable evidence for the role of SIRTs in the pathogenesis of IVDD.

Identifying areas for future research and clinical investigations

Compounds, such as resveratrol, honokiol, melatonin, naringin, and quercetin have therapeutic effects on IVDD. However, most of these compounds have been evaluated in only preclinical studies. Animal studies and preliminary clinical trials are needed to further validate the efficacy and safety of these compounds. In addition, the expression of SIRTs is reduced in senescent MSCs, and knockdown of SIRTs leads to an accelerated senescence phenotype in MSCs accompanied by abnormal mitochondrial function. However, abnormal mitochondrial function and delayed cellular senescence can be partially ameliorated by backfilling with SIRTs or overexpression of SIRTs in old MSCs (Diao et al. 2021). Stem cell therapy has been used for the clinical treatment of degenerated intervertebral discs (Garcia-Sancho et al. 2017; Pettine et al. 2017). Given that myeloid stem cells also exist in the NP and can repair degenerated myeloid tissues (Liao et al. 2019; He et al. 2021b), new therapeutic avenues can be explored if the aging of myeloid stem cells is closely related to SIRTs (Table 3).

Table 3 Therapeutic implications and future directions

Conclusion

Sirtuin family proteins can ameliorate the pathologic process of IVDD by regulating cellular senescence (Table 4), inflammation (Table 5), ECM (Table 6), apoptosis (Table 7), oxidative stress (Table 8), and mitochondrial function. Considering their important role in IVDD, these proteins can be explored as promising diagnostic biomarkers for IVDD. However, large-scale, multicenter prospective clinical trials are needed to validate the diagnostic value of sirtuins. These proteins are also involved in key aspects of senescence and apoptosis in myeloid cells. The continuous discovery of interacting molecules and the revelation of deep molecular mechanisms will facilitate the use of sirtuins in the prevention and treatment of IVDD in the future.

Table 4 Sirtuins and cellular senescence in IVDD

Table 5 Anti-inflammatory effects of sirtuins in IVDD

Table 6 Sirtuins and extracellular matrix regulation

Table 7 Regulation of apoptosis by sirtuins in IVDD

Table 8 Oxidative stress management by sirtuins

Although SIRTs have potential advantages in preventing and treating IVDD through the regulation of multiple pathways, they also have the following limitations: first, most of the experiments on the regulation of multiple pathways by SIRTs for the treatment of IVDD are mainly in vitro experiments, so there is a lack of in-depth understanding of the mechanism of in vivo action of SIRTs for the treatment of IVDD; second, the research on the treatment of IVDD by SIRTs-related activators is still in the experimental stage. Therefore, more high-quality animal and preclinical studies are needed to verify their efficacy and safety.