Intervertebral disc degeneration and aging: Shared molecular mechanisms and therapeutic interventions

Abstract

Disc degeneration is closely associated with aging and shares similar pathological mechanisms. With advancing age, intervertebral discs undergo structural, biochemical, and biomechanical degeneration, leading to functional impairment and symptoms such as low back pain. During the aging process, factors including extracellular matrix degradation, apoptosis, inflammatory responses, and oxidative stress drive disc degeneration, forming a vicious cycle that accelerates spinal degenerative changes. Recent studies suggest that multi-target pharmacological interventions may slow degenerative progression and alleviate disc-related pathological changes in preclinical models, although clinical evidence remains limited. This review summarizes the shared mechanisms linking disc degeneration and aging, discusses their bidirectional interactions, and evaluates recent advances in pharmacological interventions, with the aim of providing a framework for early intervention and translational research.

Key Words: Intervertebral disc degeneration; Aging; Oxidative stress; Cellular senescence

Core Tip: This review highlights the shared molecular mechanisms between intervertebral disc degeneration and aging, such as extracellular matrix degradation, apoptosis, inflammation, and oxidative stress. It explores their bidirectional relationship and discusses multi-target pharmacological interventions that show promise in slowing degeneration with favorable safety. The insights provide a theoretical basis for early intervention and precision treatment.

INTRODUCTION

Intervertebral disc degeneration (IVDD) is a central pathological driver of lumbar degenerative disease (LDD) and a major cause of low back pain and related spinal disorders. Both the incidence and severity of IVDD increase with advancing age, and accumulating evidence suggests that cellular senescence, oxidative stress (OS), and extracellular matrix (ECM) dysregulation are key mechanisms underlying disease progression[1,2]. As a load-bearing structure of the spine, the intervertebral disc undergoes progressive degenerative alterations during aging, leading to impaired spinal biomechanics. Hallmarks of IVDD include ECM degradation, persistent inflammatory signalling, OS, metabolic dysfunction, and excessive apoptosis[1,3,4].

As the population progresses toward aging, the prevalence of LDD is still on the rise and has become a major global health burden. Through their multi-targeted effects, natural compounds have become a focus of increasing attention in recent years for the alleviation of aging and IVDD, particularly bioactive phytochemicals and polyphenols [e.g., curcumin, resveratrol, and epigallocatechin-3-gallate (EGCG)]. However, the literature is still dominated by preclinical studies, and the reported benefits have been tested in different cell systems and animal models at different doses and with different outcome measures, making direct comparison difficult. To this end, this review not only outlines common mechanisms that underlie changes in aging and disc degeneration but also juxtaposes representative compounds along convergent pathways, major biological effects, and the stage of evidence in order to better delineate translational potential as well as current limitations of these therapeutic strategies.

COMMON MECHANISMS OF IVDD AND AGING

To provide a clearer conceptual structure, the shared mechanisms between IVDD and aging can be interpreted within the “hallmarks of aging” framework. Genomic instability and telomere attrition are regarded as upstream damage-related drivers, whereas epigenetic alterations modulate regulatory function. Mitochondrial dysfunction, OS, cellular senescence, and chronic inflammation act as highly connected processes that integrate and synergize degeneration. These traits are not mutually exclusive, but dynamically interact in IVDD, with some acting as primary driving forces and others as downstream effects that modulate an increasingly self-sustaining degenerative cycle.

Genomic instability

During the aging process, the accumulation of DNA damage caused by endogenous and exogenous genotoxic agents leads to genomic instability, a key hallmark of aging. DNA damage can promote cellular senescence and impair proliferative capacity[5,6]. In a hydrogen peroxide-induced OS model, human nucleus pulposus (NP) cells showed increased senescence-associated β-galactosidase activity and cell-cycle arrest. Mechanistically, OS induced DNA damage and activated the ATM-Chk2-p53-p21 (WAF1)-pRb pathway, leading to G1 phase delay and decreased cell proliferation[7]. Research by Nasto et al[8] demonstrated that DNA repair-deficient Ercc1−/Δ mice are more vulnerable to genotoxic stress-induced IVDD. Sub-toxic exposure to nitrogen mustard accelerated disc proteoglycan loss, cellular senescence, and apoptosis, and these degenerative changes were markedly more severe in Ercc1−/Δ mice than in wild-type littermates.

Genomic instability in IVDD, viewed through the lens of aging hallmarks, can act as a relevant upstream driver rather than just a consequence of degeneration because such unresolved DNA damage triggers canonical senescence pathways and decreases NP cells’ proliferative and reparative ability. On the other hand, the hypoxic and oxidative disc microenvironment can further exacerbate DNA injury therein, thus indicating that genomic instability could also be secondarily triggered in the course of disease progression[9].

Telomere attrition

Because of the end-replication problem, telomeres progressively shorten with each round of DNA replication, which can eventually trigger replicative senescence or growth arrest[10]. Telomere attrition is widely linked to cellular senescence and age-related disease processes[11]. In IVDD, telomere shortening has been associated with impaired proliferative capacity and senescence-related changes in disc cells. In support of this, overexpression of human telomerase reverse transcriptase has been shown to extend the replicative capacity of human NP cells and protect against apoptosis and cell-cycle arrest, suggesting an important role of telomere maintenance in disc cell homeostasis[12]. Compared with healthy controls, patients with IVDD exhibited significantly shorter relative telomere length, supporting an association between telomere attrition and disc degeneration[13]. Chronic inflammation accelerates cellular aging by exacerbating telomere dysfunction through reactive oxygen species (ROS)-induced DNA damage[14]. The combination of telomere shortening and decreased activity of the protective enzyme telomerase strongly correlates with NP cell senescence and disc degeneration. These processes may be further influenced by OS, chronic inflammation, and cell-cycle regulatory pathways, thereby eventually leading to the progression of IVDD. Telomere attrition in IVDD may include a dual role from the perspective of aging hallmarks: It can limit the proliferative reserve of disc cells, and is probably linked with accumulated stress exposure within the degenerative microenvironment.

Epigenetic alterations

Epigenetic dysregulation plays an important role in aging and IVDD. Among these mechanisms, ncRNAs, including miRNAs, lncRNAs, and circRNAs, participate in disc degeneration by modulating inflammatory mediators and related signaling pathways. For example, miR-194 suppresses lipopolysaccharide (LPS)-induced inflammatory responses in NP cells by targeting tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling[15]. MiR-181a exerts anti-inflammatory effects by targeting TNF-related apoptosis-inducing ligand and suppressing ERK pathway activation[16]. In addition, miR-495-3p alleviates TNF-α-induced apoptosis and inflammation in human NP cells by targeting interleukin (IL)-5 receptor alpha subunit[17], whereas miR-140 inhibits TLR4-mediated inflammatory signaling and reduces the expression of TNF-α, IL-1β, and IL-6[18].

LncRNAs and circRNAs also contribute to IVDD through competitive endogenous RNA networks. HCG18 promotes IVDD by sponging miR-146a-5p and regulating TRAF6 expression, thereby influencing NF-κB-related inflammatory responses[19]. Similarly, circ_0005918 aggravates IVDD by sponging miR-622 and enhancing inflammatory and catabolic changes[20], while circ_0134111 promotes IVDD progression through suppression of miR-578[21].

Beyond ncRNA regulation, histone methylation-related mechanisms also participate in IVDD. Enhancer of zeste homolog 2 (EZH2) is upregulated in patient specimens and LPS-stimulated NP cells, where it suppresses miR-129-5p via H3K27me3 modification and subsequently upregulates MAPK1, thereby promoting inflammation, senescence, and IVDD progression[22].

Emerging evidence suggests that several ncRNA-regulated pathways may have translational relevance in IVDD, particularly those involved in inflammation and matrix catabolism. In particular, miRNA-mediated modulation of NF-κB-related inflammatory signaling has attracted increasing attention because these pathways are central to IVDD progression. LncRNA-mediated ceRNA networks and upstream epigenetic regulators such as EZH2 also appear to have therapeutic potential, although their clinical application remains limited by delivery challenges, network complexity, and insufficient in vivo validation.

Mitochondrial dysfunction

Mitochondria serve as a key signaling hub for cellular stress responses and metabolic homeostasis. Mitochondrial dysfunction is widely recognized as an important feature of aging and has been strongly implicated in IVDD[23]. It is characterized by excessive ROS production, mitochondrial DNA (mtDNA) damage, impaired oxidative phosphorylation, disturbed energy metabolism, and defective mitochondrial quality control. These factors ultimately disrupt mitochondrial integrity and exacerbate age-related pathological changes. Mitochondrial dysfunction represents not only a distal metabolic derangement, but, in the context of aging-hallmark biology, also an important mechanism. Because mitochondrial damage potentiates ROS production, compromises adenosine triphosphate (ATP) supply, and renders cells more susceptible to apoptosis and senescence, it serves as a master effector linking primary damage signals to manifest tissue degeneration. However, mitochondrial dysfunction is simultaneously reinforced by inflammatory and nutritional stress in the avascular disc, indicating its bi-directional link with IVDD progression.

The role of OS in IVDD and aging: Mitochondria are the primary source of ROS. Under normal physiological conditions, mitochondria maintain ROS levels through a dynamic equilibrium of “production and clearance”. However, when this balance is disrupted, excessive ROS generation triggers OS, leading to mitochondrial membrane depolarization, electron leakage, release of apoptotic factors, Ca²⁺ overload, and impaired ATP synthesis[24,25]. In the hypoxic and nutrient-poor disc microenvironment, opening of the mitochondrial permeability transition pore (mPTP) leads to a decrease in mitochondrial membrane potential (ΔΨm), mitochondrial swelling, and cristae damage. This establishes a vicious cycle of mitochondrial dysfunction and ROS accumulation. Excessive ROS damage DNA, lipids, proteins, and the ECM, inducing apoptosis and disrupting the mechanical homeostasis of the intervertebral disc[26]. Advanced glycation end products (AGEs) also contribute to age-related disc degeneration. AGEs accumulate in long-lived matrix proteins and promote matrix stiffening and degeneration through non-enzymatic cross-linking. In addition, AGEs can enhance OS and inflammatory responses and have been reported to activate the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in NP cells, thereby accelerating IVDD progression[26,27]. OS-related pathways, including MAPK and NF-κB signaling, have also been implicated in cartilage endplate (CEP) cells apoptosis and calcification, which may further compromise disc nutrition[28]. In NP cells, ROS promotes cellular senescence and apoptosis through multiple stress-responsive and inflammatory pathways, including NF-κB and NLRP3 signaling[29]. Senescent cells exhibit a senescence-associated secretory phenotype (SASP), which upregulates ROS levels via NADPH oxidase 4, thereby forming a cycle of OS and senescence.

Age-related oxidative damage in IVDD is further reflected by the accumulation of AGEs, which arise from non-enzymatic glycation and oxidative modification of proteins and lipids[27]. With advancing age, disc anabolic activity declines while catabolic activity increases. Disc cellularity decreases, and age-related structural alterations may further impair nutrient transport and metabolite exchange, thereby aggravating matrix degeneration[30]. Collectively, these findings indicate that mitochondrial dysfunction regulates cellular metabolism, apoptosis, and aging processes through ROS production, thereby promoting the development of IVDD.

The role of mitophagy in IVDD and aging: Autophagy dysfunction, particularly impaired mitochondrial autophagy, is associated with aging and various degenerative diseases such as IVDD[31]. Defective mitophagy promotes cellular senescence and accelerate the onset and progression of IVDD by inducing mitochondrial dysfunction. Appropriate regulation of mitophagy may attenuate aging-related cellular changes by preserving mitochondrial quality control and limiting senescence. This process is primarily achieved through two pathways: Receptor-mediated autophagy and non-receptor-mediated autophagy. Receptor-mediated autophagy involves multiple outer mitochondrial membrane proteins, including BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), NIX, and FUN14 domain-containing protein 1 (FUNDC1). Under stress conditions such as hypoxia or nutrient deprivation, these receptors interact with microtubule-associated protein 1 light chain 3 (LC3) to promote autophagosome formation[32]. By contrast, non-receptor-mediated autophagy is classically mediated by the PINK1/parkin pathway. Upon mitochondrial depolarization, PINK1 accumulates on the outer mitochondrial membrane and recruits Parkin, which promotes ubiquitination of mitochondrial substrates and facilitates the recruitment of autophagic adaptors, thereby linking damaged mitochondria to LC3-positive autophagosomes[33].

In NP cells, impaired PINK1/parkin-mediated mitophagy has been associated with increased ROS accumulation, mitochondrial damage, and cellular senescence[34-36]. Mechanical loading has also been reported to disturb autophagic/mitophagic flux in disc cells, thereby aggravating mitochondrial injury, although the precise lysosomal mechanisms may vary across models. Moreover, mitophagy can also be mediated by Parkin-independent mechanisms involving BNIP3/NIX and other regulators. During these events, receptor proteins including FUNDC1, NIX, and BNIP3 are recruited to the damaged mitochondria[32], and directly interact with LC3 to stimulate autophagic degradation. Thus, it is suggested that impaired mitophagy is a significant contributor linking mitochondrial dysfunction to aging-related IVDD.

Cellular senescence and chronic inflammation

Cellular senescence is a relatively stable cell-cycle arrest state induced by diverse stressors, including DNA damage, telomere dysfunction, oncogenic signaling, and metabolic stress, and is commonly accompanied by macromolecular damage, metabolic dysfunction, and alterations in the secretory profile[37-39]. One of the most characteristic features of senescent cells is the SASP, which comprises pro-inflammatory cytokines and chemokines, growth factors, matrix-remodeling enzymes, ROS, and ncRNAs. The composition and intensity of the SASP vary depending on cell type, senescence inducer, and the surrounding microenvironment[39,40]. Cellular senescence is closely linked to chronic inflammation, with the SASP serving as a major mediator of this interaction[40]. SASP can reinforce senescence through autocrine and paracrine signaling, thereby establishing a positive feedback loop between senescence and chronic inflammation[41]. Inflammasome-related signaling has also been implicated in the establishment and amplification of inflammatory senescence phenotypes. Activation of the NLRP3 inflammasome promotes caspase-1 activation and the maturation and release of IL-1 family cytokines, including IL-1β and IL-18. In addition, inflammasome-associated IL-1 signalling is increasingly recognized as an important regulator of the SASP, contributing to the persistent inflammatory state of senescent cells[42,43].

The relationship between IVDD and the inflammatory microenvironment is bidirectional. The inflammatory microenvironment contributes to IVDD progression by promoting matrix catabolism, fibrosis-related remodeling, and disc cell dysfunction. Conversely, degenerative disc tissues further amplify local inflammation through increased production of inflammatory mediators such as TNF-α, IL-1β, and IL-6, which are closely associated with cellular senescence, apoptosis, and ECM degradation. Among these mechanisms, NLRP3 inflammasome activation has emerged as an important contributor to IVDD, and its inhibition has been reported to attenuate matrix degradation and delay degenerative progression[44]. Furthermore, mtDNA can induce NP cell pyroptosis via activation of the TLR9-NF-κB-NLRP3 signaling axis, thereby further promoting IVDD development[44]. Because OS promotes mitochondrial damage and mtDNA release, it may further amplify this inflammatory cascade.

Epigenetic and epitranscriptomic regulation also contributes to IVDD and NP cell senescence. Li et al[45] reported that increased WTAP expression enhances N6-methyladenosine (m6A) modification of lncRNA NORAD, promoting its degradation through YTHDF2-mediated recognition. Reduced NORAD weakens its sequestration of PUM1/2, thereby facilitating repression of E2F3 and accelerating senescence in NP cells. These findings indicate that chronic inflammation, cellular senescence, mitochondrial dysfunction, and epigenetic dysregulation are closely interconnected in IVDD. Figure 1 summarizes the common mechanisms linking IVDD and aging.

Figure 1 Diagram of the common mechanisms driving intervertebral disc degeneration and aging. The figure illustrates the principal mechanisms shared by intervertebral disc degeneration (IVDD) and aging, including mitochondrial dysfunction, cellular senescence and chronic inflammation, telomere loss, genomic instability, and epigenetic alterations. These processes are closely interconnected and collectively contribute to disc cell senescence, apoptosis, extracellular matrix imbalance, and progressive disc degeneration. Mitochondrial dysfunction involves oxidative stress, impaired mitophagy, mitochondrial swelling, and reduced mitochondrial membrane potential. Senescence-associated inflammation is amplified through the NLRP3 inflammasome and downstream inflammatory mediators. Genomic instability and telomere attrition further promote cellular dysfunction, whereas epigenetic dysregulation, including abnormal non-coding RNA expression and DNA methylation changes, modulates multiple pathogenic pathways. Overall, these shared aging-related hallmarks accelerate the onset and progression of IVDD. IVDD: Intervertebral disc degeneration; ECM: Extracellular matrix; ΔΨm: Mitochondrial membrane potential; IL: Interleukin; TNF-α: Tumor necrosis factor-alpha; AGE: Advanced glycation end.

STRATEGIES AGAINST IVDD AND AGING

Strategies targeting DNA damage

Defective DNA repair and persistent DNA damage accumulation are increasingly recognized as important drivers of aging across multiple organ systems, including the intervertebral disc[46]. Consistent with this concept, DNA repair-deficient Ercc1-/Δ mice accelerated IVDD compared with wild-type mice, as evidenced by proteoglycan loss, reduced disc height, and increased cellular senescence within disc tissues[47]. These findings support a mechanistic link between impaired genome maintenance and age-related IVDD.

Targeting telomere-associated DNA damage responses has also been proposed as a potential anti-senescence strategy. In a mouse model of premature aging, inhibition of telomeric DNA damage response signaling using telomeric antisense oligonucleotides attenuated persistent DNA damage response activation, reduced senescence-associated markers and SASP-related alterations, and improved tissue homeostasis[48]. Although this approach has not yet been directly evaluated in IVDD models, it provides a conceptual basis for exploring whether suppression of telomere-associated DNA damage may alleviate disc degeneration associated with cellular senescence.

Anti-OS

Natural compounds that attenuate OS and mitochondrial dysfunction: OS is closely involved in IVDD and contributes to senescence-related changes in NP cells. For this reason, antioxidant interventions have been widely investigated as a potential therapeutic approach for disc degeneration. Many antioxidants and mitochondria-protective compounds act on overlapping pathways, particularly NF-κB/MAPK, PI3K/Akt, and Nrf2-related signaling. However, the main biological effects and the level of supporting evidence vary across compounds. Among these agents, curcumin has been consistently reported to exert anti-inflammatory and anti-oxidative effects in disc cells, partly through modulation of MAPK-related signaling, autophagic flux, and mitochondrial homeostasis[49-51].

Polyphenolic compounds are plant secondary metabolites with potent antioxidant properties. Resveratrol (3,5,4'-trihydroxy-styrene) is a natural polyphenol that can modulate mitochondrial function, ROS generation, and cellular energy metabolism[52,53]. In NP cells, resveratrol prevents the loss of ΔΨm, preserves intracellular ATP levels, reduces OS-induced apoptosis, and promotes matrix biosynthesis[54,55]. Its protective effect is also associated with autophagy activation through the PI3K/Akt pathway[55]. In addition, polydatin, a natural glucoside precursor of resveratrol, has been reported to attenuate IVDD by activating the Nrf2 signaling pathway, thereby promoting matrix homeostasis and cell survival[26]. OS-related mitochondrial injury in disc cells can also be attenuated through antioxidant defenses linked to Parkin- and Nrf2-related pathways[56].

Naringin, a flavanone glycoside, exerts anti-apoptotic and mitochondria-protective effects primarily through activation of the PI3K/Akt signalling pathway[57,58]. Research indicates that naringin can prevent stress-induced mitochondrial damage and energy depletion in NP-derived stem/progenitor cells through this pathway[58]. EGCG, a catechin abundant in green tea, protects ΔΨm under OS conditions[59]. Compared with curcumin and resveratrol, however, the evidence for both naringin and EGCG remains largely limited to cell-based studies, and their relative in vivo efficacy, disc pharmacokinetics, and long-term safety remain insufficiently defined.

Kinsenoside inhibits tert-butyl hydroperoxide-induced NP cell senescence and mitochondrial dysfunction while enhancing antioxidant capacity through activation of the Akt-ERK1/2-Nrf2 pathway[60]. Apigenin also protects NP cells against degeneration-associated injury, in part by restoring autophagic flux and attenuating oxidative damage[61]. The Akt-FoxO1-sirtuin 1 (SIRT1) axis is closely associated with OS-induced cellular senescence. In a model of H₂O₂-induced senescence in rat NP cells, activation of SIRT1 reduced senescence-associated protein expression, lowered proinflammatory cytokine levels, and alleviated G0/G1 arrest, indicating that SIRT1 modulates OS-induced NP cell senescence through the Akt-FoxO1 pathway[62]. Heat shock protein 70 (HSP70) alleviates OS-induced senescence in NP cells by inhibiting the c-Jun N-terminal kinase (JNK)/c-Jun signaling pathway[63]. In addition, mitochondrial-targeted metal-phenolic nanoparticles (PGA-Mn-TP04) have been shown to restore mitochondrial function by modulating mitochondrial dynamics, thereby improving NP cell survival; in a rat IVDD model, they preserved disc height and NP hydration[64].

Honokiol (HKL) effectively suppresses apoptosis-related proteins, OS markers, inflammatory mediators, and ECM-degrading enzymes in oxidatively stressed NP cells, while promoting ECM anabolic protein expression[65]. Mechanistically, HKL inhibits the NF-κB/JNK pathway and suppresses activation of the TXNIP/NLRP3/caspase-1/IL-1β cascade. In addition, SIRT3-dependent mitochondrial antioxidant regulation via the AMPK-peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) axis has been implicated in the protection of NP cells against oxidative damage[66]. These studies indicate that the majority of candidate compounds act through common therapeutic mechanisms; specifically, by preventing ROS accumulation and mitochondrial dysfunction while reducing senescence-induced inflammation, rather than acting via completely independent pathways. At present, most evidence remains preclinical, and the lack of standardized head-to-head comparisons and clinical studies limits conclusions regarding superiority, optimal dosing, disc penetration, and durability of benefit.

Redox modulators and mitochondria-targeted antioxidants: Pyrroloquinoline quinone (PQQ), fullerene-derived antioxidants, and fullerol have all been investigated as redox modulators that alleviate excessive ROS-related damage[67-69]. PQQ is a redox-active quinone with ROS-scavenging capacity and can protect NP cells against H₂O₂-induced apoptosis by inhibiting mitochondria-mediated oxidative injury[70]. Fullerenes have attracted attention because of their potent free-radical scavenging properties and their ability to reduce lipid peroxidation in experimental systems[68,71]. Fullerol, a hydroxylated fullerene derivative, has been reported to protect human NP cells and experimental discs by reducing ROS production, promoting matrix synthesis, and inhibiting ectopic ossification-related changes[72].

Glutathione exerts a protective role in human NP cells by inhibiting H₂O₂-induced apoptosis and matrix degradation while reducing ROS generation[69]. Estrogen influences multiple physiological systems, and estrogen deficiency has been associated with accelerated disc degeneration and calcification[73,74]. In a menopause-related rat model, estradiol alleviated IVDD partly by modulating antioxidant enzymes and autophagy-related pathways[74].

Coenzyme Q (ubiquinone) is an endogenous electron carrier in the inner mitochondrial membrane that transfers electrons from complexes I and II to complex III. MitoQ, a mitochondria-targeted derivative of coenzyme Q, protects disc cells by rebalancing mitochondrial dynamics, upregulating fusion-related proteins such as Mfn1 and Mfn2, and Drp1. In addition, MitoQ activates the Nrf2 pathway and downstream antioxidant enzymes, including SOD2 and NQO1, thereby enhancing cellular antioxidant defenses. In experimental IVDD models, MitoQ ameliorated mitochondrial dysfunction and redox imbalance and attenuated degenerative structural changes in disc tissue[75].

Piperidinium nitroxides, including 2,2,6,6-TEMPO and its derivatives, function as superoxide dismutase mimetics and ROS scavengers[76]. In NP cells exposed to AGEs, MitoTEMPO mitigates mitochondrial ROS accumulation, inflammatory activation, and mitochondrial dysfunction[26]. In the same general context of mitochondria-targeted antioxidation, plastoquinonyl-decyl-triphenylphosphonium has also shown marked anti-apoptotic and mitochondrial protective effects in AGEs-treated NP cells[77]. XJB-5-131, a mitochondria-targeted nitroxide, improved matrix content in NP tissue and restored CEP cellular architecture in an aged ERCC1-/Δ mouse model[78]. Collectively, these studies support the concept that mitochondria-targeted antioxidants may protect disc cells and disc structure by alleviating oxidative damage and preserving mitochondrial homeostasis.

Targeted mitochondrial autophagy

Autophagy plays a crucial role in maintaining the integrity and viability of intervertebral disc cells. The interplay among autophagy, apoptosis, and ROS-dependent endoplasmic reticulum stress is an important component of IVDD pathogenesis[79]. However, the role of autophagy in IVDD appears to be context-dependent: In many experimental settings, moderate autophagy or mitophagy is cytoprotective, whereas dysregulated or excessive activation may contribute to degeneration[80-82]. The JNK/MAPK pathway can be activated by inflammatory stimulation or OS and has been implicated in stress-induced autophagic responses in disc-related cells[80,82]. Fan et al[81]. reported that OS induces early JNK-dependent mitophagy in bone marrow-derived mesenchymal stem cells, in which mitophagy acts as a protective response against apoptosis. Urolithin A, a gut microbial metabolite derived from ellagitannin-rich foods such as pomegranates, exhibits anti-aging and anti-degenerative effects in NP cells and experimental IVDD models. In NP cells, Urolithin A inhibits intrinsic apoptotic signaling, restores H₂O₂-induced loss of ΔΨm, and promotes mitophagy via activation of the AMPK pathway[83]. These findings indicate that pharmacological enhancement of mitophagy may help preserve mitochondrial quality control and cellular homeostasis in disc cells.

Identifying molecules that inhibit the opening of the mPTP may represent another approach to modulating mitochondrial homeostasis in disc cells. Cyclophilin D (CypD) is an important regulator of mPTP opening, and cyclosporine A (CsA) can inhibit CypD-dependent pore opening, thereby reducing mitochondrial dysfunction under stress conditions[84]. In disc-derived cell models, CsA has been reported to attenuate compression-induced apoptosis by alleviating mitochondrial dysfunction and OS[85]. Accordingly, CsA may indirectly influence mitophagy-related mitochondrial quality control, although its effects in IVDD should not be interpreted as selective mitophagy regulation alone.

Mfn2, an outer mitochondrial membrane protein, is involved in mitochondrial dynamics and can participate in PINK1/Parkin-associated mitophagy regulation[86]. Mfn2 expression is reduced in degenerative NP tissues/cells, and its repression contributes to impaired autophagy, aggravated mitochondrial dysfunction, and apoptosis[87]. In contrast, Mfn2 overexpression attenuates apoptosis and supports mitochondrial homeostasis, at least in part through ROS-dependent PINK1/Parkin signaling[87].

NDUFA4 L2 is a hypoxia-responsive mitochondrial protein associated with regulation of complex I-related respiratory activity and ROS production. Its expression is regulated by hypoxia-inducible factor-1α (HIF-1α), a key factor in disc cell adaptation to hypoxia and maintenance of ECM homeostasis[88,89]. Under hypoxic conditions, activation of HIF-1α upregulates NDUFA4 L2 expression, suppresses excessive ROS generation, and promotes cell survival[89]. In NP cells, the protective effect of the HIF-1α/NDUFA4 L2 axis appears to be mediated, at least in part, by restraining excessive mitophagy[90]. As IVDD progresses, HIF-1α and NDUFA4 L2 expression decline. Conversely, NDUFA4 L2 overexpression reduces apoptosis- and mitophagy-related signaling, whereas carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), a mitophagy activator, partially reversed this protective phenotype[90].

PGC-1α is a key regulator of mitochondrial bioenergetics and redox homeostasis. In annulus fibrosus cells exposed to OS, excessive mitophagy has been reported to aggravate apoptosis, whereas the SIRT2/PGC-1α axis suppresses excessive mitophagy and exerts anti-apoptotic effects[91]. These findings suggest that mitophagy should not simply be enhanced or inhibited indiscriminately; instead, its level and timing must be precisely controlled to maintain mitochondrial quality without triggering additional cell loss. Small-molecule modulation of mitophagy has therefore attracted increasing attention as a potential strategy for protecting disc cells from degeneration-related mitochondrial injury[92]. Taken together, these studies support the view that mitochondria-targeted quality-control pathways, including mitophagy modulation, may represent promising therapeutic avenues for IVDD. Nevertheless, the therapeutic window for mitophagy regulation remains incompletely defined, and excessive activation may be detrimental in some OS contexts.

Anti-inflammatory strategies

Inflammation serves as a key catalyst for NP cell aging. Anti-inflammatory interventions targeting IVDD primarily focus on modulating inflammatory pathways (such as the NF-κB pathway) and reducing the expression of pro-inflammatory cytokines and enzymes (such as IL-1β and TNF-α). Huang et al[93] demonstrated that delivering LINC02569 siRNA to NP cells via a cationic polymer-coated carbon nanotube delivery platform significantly suppressed IL-1β-induced inflammatory responses and delayed NP cell senescence by inhibiting the NF-κB signaling pathway. Similarly, higenamine enhances the viability of IL-1β-stimulated NP cells while reducing ECM-degrading enzymes and inflammatory mediators, including inducible nitric oxide synthase, NO, PGE2, COX-2 and NF-α. These effects are accompanied by suppression of NF-κB signalling and attenuation of NP cell senescence[94]. Additionally, omentin-1 alleviates IL-1β-induced senescence in NP cells, reduces G1 phase cell cycle arrest, and enhances ECM synthesis[95]. Additional studies indicate that dehydrocostus lactone (DHE) can mitigate TNF-α-induced ECM degradation and NP cell senescence while inhibiting the NF-κB and MAPK inflammatory signaling pathways. DHE also alleviates TNF-α-induced senescence by suppressing the STING-TBK1/NF-κB signaling pathway[96].

Molecular interventions targeting aging- and inflammation-related intracellular signaling pathways have also been explored in IVDD. Approaches such as gene therapy, modulation of mechanoreceptor signaling, supplementation with growth factors, and pharmacological targeting of mechanistic target of rapamycin (mTOR)-related pathways have shown potential therapeutic value in experimental models[97]. Pharmacological inhibition of mechanistic target of rapamycin complex 1 (mTORC1), particularly through targeting RAPTOR-associated signaling, has been reported to protect human disc cells and may represent a more clinically translatable strategy than gene-based interventions. In vitro studies comparing first-generation mTORC1-selective inhibitors, including rapamycin, everolimus, and temsirolimus, with broader-spectrum inhibitors such as INK-128 and NVP-BEZ235 showed that rapamycin, temsirolimus, and everolimus reduced mTOR and p70/S6K phosphorylation while increasing Akt phosphorylation. These agents significantly suppressed IL-1β-induced apoptosis, senescence, and matrix degradation. In contrast, the broader mTOR pathway inhibitors INK-128 and NVP-BEZ235, while reducing mTOR and Akt phosphorylation, exacerbated IL-1β-induced apoptosis, senescence, and matrix degradation[98]. These findings suggest that selective modulation of inflammation- and senescence-related signaling pathways may offer a potential therapeutic strategy for IVDD.

Clearance of senescent cells

Senolytic therapies have attracted considerable attention as a major anti-aging strategy because they can selectively eliminate senescent cells. In the context of IVDD, senolytic or senotherapeutic approaches such as dasatinib plus quercetin, RG-7112, and o-vanillin have shown promising protective effects in experimental models and human disc tissues[99-103]. These interventions are conceptually distinct from pathway-modulating agents, because their primary goal is to reduce the burden of senescent cells rather than merely suppress inflammatory signaling.

In recent years, the combination of dasatinib and quercetin has garnered increased research attention. The co-administration of dasatinib and quercetin enhances proteoglycan content in mouse intervertebral discs and facilitates the removal of senescent cells from the intervertebral disc space[99]. Novais et al[100] reported that weekly treatment with dasatinib plus quercetin prevented or attenuated age-related IVDD in 6-, 14-, and 18-month-old wild-type C57BL/6 mice. These findings suggest that combined dasatinib and quercetin therapy may attenuate IVDD progression. Recent studies have shown that o-vanillin, a senotherapeutic agent, can reduce senescent cell burden and improve matrix synthesis in human disc cells and tissues[101]. Research indicates that the cell cycle inhibitor p16INK4a plays a crucial role in inducing and sustaining intervertebral disc aging[102]. Cherif et al[103] demonstrated that RG-7112 could eliminate senescent cells when injected into the central region of intact human intervertebral discs. The importance of p16INK4a -positive senescent cells in disc aging is further supported by transgenic mouse studies. In p16-3MR mice, systemic clearance of p16INK4a-positive senescent cells with ganciclovir mitigated age-associated IVDD, reduced matrix degradation, and preserved disc proteoglycan content[1]. Available studies suggest that reducing the burden of senescent disc cells may help delay age-related disc degeneration. However, most of the available evidence remains experimental, and further studies are needed to clarify the safety, delivery routes, and long-term effects of senolytic interventions in IVDD. Representative pharmacological strategies targeting IVDD and aging are summarized in Table 1.

Table 1 Representative intervention strategies targeting intervertebral disc degeneration and aging.

Classification	Medicine	Effect	Signal pathway	Evidence type	Ref.
Anti-oxidative stress and mitochondrial protection	Curcumin	Anti-inflammatory; reduces oxidative damage; mitochondrial protection	MAPK	Cell; animal	[49-51]
	Resveratrol	Modulates mitochondrial function, ROS generation, and cellular energy metabolism; prevents loss of ΔΨm; preserves intracellular ATP; reduces OS-induced apoptosis; promotes matrix biosynthesis	PI3K/Akt	Cell	[52-55]
	Naringin	Anti-apoptotic; mitochondrial protection	PI3K/Akt	Cell	[57,58]
	Epigallocatechin-3-gallate	Protects ΔΨm; promote cell survival		Cell	[59]
	Kinsenoside	Inhibits NP cell senescence and mitochondrial dysfunction; enhances antioxidant capacity	AKT-ERK1/2-Nrf2	Cell; animal	[60]
	Apigenin	Protects NP cells from senescence		Cell	[61]
	HSP70	Alleviates oxidative stress-induced senescence in NP cells	JNK/c-Jun	Cell	[63]
	PGA-Mn-TP04	Restores mitochondrial function by modulating mitochondrial dynamics; improves NP cell survival; preserves disc height and NP hydration		Cell; animal	[64]
	Honokiol	Suppresses apoptosis-related proteins, oxidative stress markers, inflammatory mediators, and ECM-degrading enzymes; promotes ECM anabolic protein expression	NF-κB/JNK	Cell	[65]
Redox modulators and mitochondria-targeted antioxidants	PQQ, fullerene, fullerol	Reduce ROS-related damage; protect disc cells from oxidative injury; fullerol promotes matrix synthesis		Cell; animal	[67-72]
	Glutathione	Reduce ROS		Cell	[69]
	Estrogen	Alleviates IVDD partly by modulating antioxidant enzymes and autophagy-related pathways		Animal	[73,74]
	MitoQ	Regulate mitochondrial dynamics	Nrf2	Cell; Animal	[75]
	MitoTEMPO	Mitigates mitochondrial ROS accumulation, inflammatory activation, and mitochondrial dysfunction		Cell	[26]
	SkQ1	Anti-apoptotic; restores ΔΨm and reduces ROS levels		Cell	[77]
	XJB-5-131	Restore disc structure		Animal	[78]
Mitophagy regulation	Urolithin A	Promote mitophagy	AMPK	Cell; animal	[83]
Anti-inflammatory therapy	Higenamine	Inhibition of NF-κB pathway activation and aging of NP cells	NF-κB	Cell	[94]
	Omentin-1	Alleviate NP cell senescence, reduce G1 phase cell cycle arrest, and enhance ECM synthesis		Cell	[95]
	Dehydrocostus lactone	Reduce inflammation and ECM degradation	NF-κB; MAPK; STING-TBK1/NF-κB	Cell; animal	[96]
Senolytic therapy	O-vanillin	Reduces senescent cell burden and improves matrix synthesis		Human disc cells/tissues	[101]
	Dasatinib + quercetin	Remove senescent cells		Animal	[99,100]

PQQ: Pyrroloquinoline quinone; IVDD: Intervertebral disc degeneration; NP: Nucleus pulposus; ECM: Extracellular matrix; ROS: Reactive oxygen species; OS: Oxidative stress; ATP: Adenosine triphosphate; ΔΨm: Mitochondrial membrane potential.

Clinical translation and therapeutic challenges

Despite the large number of candidate compounds identified in preclinical studies, the clinical translation of IVDD therapies remains limited. Most candidate disease-modifying interventions, including natural polyphenols, mitochondria-targeted antioxidants, and autophagy-regulating agents, have been evaluated predominantly in in vitro and animal models, with relatively few advancing to clinical trials specifically for IVDD. Current evidence remains weighted toward preclinical research, while high-quality clinical data are still scarce[104-108].

Clinical and epidemiological studies support a strong association between IVDD and aging[109]. Moreover, aging-related hallmarks, including OS, cellular senescence, and ECM degradation, have been identified in human disc tissues and patient-derived samples[110]. However, these observations remain largely correlative and have not yet led to clinically established disease-modifying therapies. A major translational barrier lies in the unique characteristics of the intervertebral disc. As a largely avascular tissue, it depends on passive diffusion through the CEP for nutrient and molecular transport, which limits drug penetration and retention[111]. In addition, the harsh intradiscal microenvironment, characterized by hypoxia, acidity, mechanical loading, and OS, may further compromise therapeutic stability, bioavailability, and durability in vivo[112-114].

Local delivery strategies, particularly intradiscal injection, have been explored to overcome these limitations. Early clinical studies of platelet-rich plasma (PRP) and mesenchymal stem cells-based therapies have reported potential benefits in pain relief and functional improvement; however, interpretation remains constrained by small sample sizes, heterogeneous study designs, variable product preparation protocols, and inconsistent structural outcome measures[105-108]. Emerging delivery systems, such as biomaterials, nanoparticles, and hydrogels, have shown promise in improving local retention and controlled release in preclinical models, but most remain at an early translational stage[115]. Overall, a substantial gap persists between experimental efficacy and clinical applicability. Future efforts should focus on optimized delivery strategies, better-defined therapeutic windows, standardized efficacy endpoints, and stronger clinical validation.

CONCLUSION

IVDD and aging are common degenerative conditions in clinical practice. Although their clinical manifestations differ, they share substantial mechanistic overlap. In this review, these shared alterations are discussed within the aging-hallmarks framework, which helps distinguish primary damage-associated drivers such as genomic instability and telomere attrition from downstream but self-reinforcing processes such as mitochondrial dysfunction, cellular senescence, and chronic inflammation. This framework clarifies why IVDD should not be viewed as the product of a single pathway, but rather as the outcome of interacting hallmarks that progressively destabilize disc homeostasis. At the therapeutic level, currently available pharmacological studies suggest convergence on a limited set of antioxidant, anti-inflammatory, and mitochondria-protective pathways. However, the evidence base remains predominantly preclinical, and direct comparison across compounds is limited by heterogeneous models and endpoints. Future work should therefore focus on mechanistic stratification, standardized efficacy evaluation, biomarker development, and eventual clinical translation, so that multi-target interventions can be moved from descriptive promise toward evidence-based precision treatment for IVDD and related age-associated degeneration.