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.

Keywords: Apoptosis; Autophagy; Intervertebral disc degeneration; Oxidative stress; SIRTs.

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

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

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

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