Table 4 Sirtuins and cellular senescence in IVDD

Stich et al. (2020)

An experimental study

Gene expression profiling and in vitro experiments

To assess whether cells from degraded AF are capable of initiating gene expression in extracellular matrix (ECM) molecular regeneration patterns

Mildly degraded natural AF tissue exhibited higher gene expression of common cartilage ECM genes. RTD-PCR analysis of BMP2 and TGFβ1-stimulated cells from mildly and severely degraded AF tissues showed increased expression of cartilage-related genes.TNFα stimulation increased the expression of MMP1, 3, and 13

Gene expression in natural AF tissues is different considering the grade of degeneration of the IVD

Li et al. (2019a)

An experimental study

In vitro study

This study aimed to investigate the specific role of Wnt/β-catenin signaling in compression-induced apoptosis, autophagy, and senescence in rat nucleus pulposus (NP) cells

compression elicited a time-dependent activation of Wnt/β-catenin signaling. The IWP-2 treatment decreased cell survival rate, which corresponded to downregulation of autophagy as well as increases in apoptosis and senescence. LiCl treatment enabled more efficient of cell survival accompanied by increased autophagy and downregulated apoptosis and senescence; however, in contrast to LiCl, overexpression of β-catenin aggravated compression-induced NP cells death

Moderate activation of Wnt/β-catenin signaling allows NP cells to survive more efficiently by down-regulating apoptosis, senescence, and up-regulating autophagy, whereas over-activation of Wnt/β-catenin signaling produces the opposite effect

Novais et al. (2019)

An experimental study

Experimental in vivo and in vitro study

Exploring the functional role of p16Ink4a in disc degeneration and aging

The cKO mice maintained expression of NP-cell phenotypic markers CA3, Krt19 and GLUT-1. Moreover, in cKO discs, levels of p19Arf and RB were higher without alterations in Ki67, γH2AX, CDK4 and Lipofuscin deposition. Interestingly, the cKO discs showed lower levels of SASP markers, IL-1β, IL-6, MCP1 and TGF-β1

p16Ink4a is dispensable for induction and maintenance of senescence, conditional loss of p16Ink4a reduces apoptosis, limits the SASP phenotype and alters matrix homeostasis of disc cells

Che et al. (2019)

An experimental study

A micro- and nano-level structural analysis of degenerative discs of rat tails

The aimed to assess the micro-nano structural characteristics of the degenerative disc to provide more specific biomechanical information than the Pfirrmann score

IVDD was observed microscopically at an earlier Pfirrmann grade (Pfirrmann II). As the Pfirrmann grade increased to III-V. In addition, the total GAG content of the nucleus pulposus decreased from an average of 640.33 μg GAG/ng DNA at the Pfirrmann grade I to 271.33 μg GAG/ng DNA at the Pfirrmann grade V. In the early stages of clinical degeneration of the discs (Pfirrmann grades II and III), compared with the inner layers, the mechanical properties of the outer annulus fibrosus underwent a significantly changed

The Pfirrmann grading system combined with intervertebral disc micro-nano structural changes more comprehensively reflected the extent of disc degeneration. These data may help improve our understanding of the pathogenesis and process of clinical disc degeneration

Wang et al. (2020a)

An experimental study

In vitro study using human IVD nucleus pulposus (NP) cells

The aimed to investigate the role of SIRT1 in IVDD by assessing the effects of SIRT1 overexpression on high-magnitude compression-induced senescence in NP cells

SIRT1-overexpression attenuated senescence and mitochondrial injury in NP cells subjected to high-magnitude compression. However, depletion of PINK1, a key mitophagic regulator, impaired mitophagy and blocked the protective role of SIRT1 against compression induced senescence in NP cells

SIRT1 plays a protective role in alleviating NP cell senescence and mitochondrial dysfunction under high-magnitude compression, the mechanism of which is associated with the regulation of PINK1-dependent mitophagy

Zhuo et al. (2021)

An experimental study

Experimental in vivo and in vitro study

The aim of this study was to investigate the biological role of SIRT1 in apoptosis and autophagy in rat NPCs under high-pressure stress and to determine whether the interaction between LC3B and Fas is involved in this process

High-magnitude compression aggravated cellular apoptosis and attenuated the expression levels of SIRT1 and microtubule-associated protein-1 light chain-3B (LC3B) in rat NPCs in a three-dimensional (3D) cell culture model and an in vivo rat tail compression model, whereas SIRT1 overexpression in NPCs partially reversed these indicators. Moreover, SIRT1 overexpression increased the formation of the LC3B/Fas complex, alleviated activation of the NF-κB pathway, and reduced NPC apoptosis. Finally, downregulation of LC3B partially activated the NF-κB pathway and aggravated NPC apoptosis

Upregulation of SIRT1 increased the formation of the LC3B/Fas complex, which inhibited NPC apoptosis by suppressing the NF-κB pathway under high compressive stress

Hao et al. (2022)

An experimental study

Experimental in vivo and in vitro study

The aim of this study was to investigate the potential role and pathophysiologic mechanisms of p300 in IDD

p300 increases FOXO3 expression by binding to the Sirt1 promoter, which contributes to the inactivation of the Wnt/β-catenin pathway. p300 slows the progression of IDD by disrupting the FOXO3/ Sirt1 axis of the Wnt/β-catenin pathway to slow down the progression of IDD. p300 is also known to be associated with the FOXO3/β-catenin pathway

p300 can inhibit IDD through a FOXO3-dependent mechanism

Wang et al. (2018a)

An experimental study

Experimental in vivo and in vitro study

The aim of this study was to explore the expression of SIRT3 in IVDD in vivo and in vitro and the role of SIRT3 in senescence, apoptosis and mitochondrial homeostasis under oxidative stress

The expression of SIRT3 decreased with IVDD, and SIRT3 knockdown reduced the tolerance of NPCs to oxidative stress. Honokiol (10 μM) improved the viability of NPCs under oxidative stress and promoted their properties of anti-oxidation, mitochondrial dynamics and mitophagy in a SIRT3-dependent manner. Furthermore, honokiol activated SIRT3 through the AMPK-PGC-1α signaling pathway

SIRT3 is involved in IVDD and showed the potential of the SIRT3 agonist honokiol for the treatment of IVDD

Lin et al. (2021a)

An experimental study

Experimental in vivo and in vitro study

The aim of this study was to investigate the effects and mechanisms of SIRT3 on NPC aging in vitro and in vivo

SIRT3 expression is reduced in degenerated NP tissues but increased in H2 O2 -induced NPC. Moreover, SIRT3 upregulation decreased oxidative stress, delayed senescence, and degeneration of NPC. In addition, activation of the AMPK/PGC-1α pathway can partially mitigate the NPC oxidative stress, senescence, and degeneration caused by SIRT3 knockdown. The study in vivo revealed that local SIRT3 overexpression can significantly reduce oxidative stress and ECM degradation of NPC, delay NPC senescence, thereby mitigating IVDD

SIRT3 mediated by the AMPK/PGC-1α pathway mitigates IVDD by delaying oxidative stress-induced NPC senescence