INTRODUCTION

Degenerative changes in the intervertebral disc (IVD) cause the loss of normal spine structure and function.1 IVD degeneration is not typically aging. It is possible that injuries can influence the long-term course of spine degeneration. However, spine degeneration is a biomechanically related continuum of molecular, biochemical, cellular, and anatomic alterations evolving over time, metabolic injury.2 Human beings are living longer lives and expect to enjoy pain-free mobile lifestyles. Degenerative diseases of the joints and the spine are largely associated with aging, obesity, poor diets, and occupational factors. Although our ancestors have been around for about 6 million years, modern humans (Homo sapiens) only evolved about 200,000 years ago. Early humans did not live long enough to suffer from age-related musculoskeletal conditions, and degenerative diseases of the joints and the spine are thought to have been extremely rare in early humans, but this is probably because of an underrepresentation of older adults in the skeletal records of the ancient civilizations. Longer life expectancy and the strains, sprains, and overuse of the back over many decades result in a gradual IVD degeneration in the spine.3 According to the World Health Organization, low back pain (LBP) is a leading cause of disability across the world.a LBP occurs in similar proportions in all cultures, interferes with quality of life and work performance, and is currently the most common reason for medical consultations globally. Although LBP has many causes, IVD degeneration has been shown to be an important underlying cause.4 Despite the growing prevalence and burden of LBP, IVD, and spine degeneration, there are no effective cures. Degenerative changes in the spine are associated with biomechanical and metabolic alterations and it has been proposed that the degeneration is an adaptation, rather than a disease. 2 It has also been proposed that in the absence of a cure for LBP, IVD, and spine degeneration, the only way to reduce the global burden of these conditions is developing earlier diagnostics, improving management regimes, and conceiving realistic long-term strategies for prevention. Diagnosis of all degenerative joint and spine conditions begins with radiography. However, MRI is increasingly used to image discs, nerves, and the spinal canal space. Computed tomography may be used to resolve inconsistencies between the MRI and the patient’s symptoms.
Disc studies, also known as discograms, may be ordered to determine if a patient’s pain is being caused by a damaged spinal disc. Treatment depends on the type and severity of the patient’s condition. In most cases, nonsurgical treatment
is all that is required. These treatments may include exercise to increase flexibility and muscle strength, braces, or medication. Pain medication and steroids may be administered via epidural injection. In extreme cases surgery may be required    due to external insults, such as mechanical or   due to a specific injury but rather it is related to   for herniated discs or spinal stenosis, particularly where there is radicular pain. The treatment applied is often for radiculopathy, that is, sciatica, or other nerve issues that cause loss of function, rather than for the LBP itself. In addition to age, gender, lifestyle, and genetic predisposition, other inciting risk factors for disc degeneration may include previous spine injuries or even osteoporosis (Fig. 1). This article focuses on IVD degeneration and how cell and gene therapy may be used for spine regeneration. THE HALLMARKS OF SPINE DEGENERATION All human diseases are characterized by “hallmarks,” which summarize the key biological alterations that occur in a particular disease. For example, cancer comprises 6 biological capabilities that are gradually acquired during the multistep development of human tumors.5,6 In the case of spine degeneration, there are many similarities
with the hallmarks of aging.7 The hallmarks of aging include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Many of the hallmarks of aging are also seen in IVD degeneration and in articular cartilage in degenerative joint diseases such as osteoarthritis (OA).

CELLULAR SENESCENCE

Senescence of the cells in the specialized tissues of the IVD is a normal part of aging8; however, cellular senescence has been shown to be accelerated in degeneration9 with a range of causes proposed.10 There is a gradual decline in cell number
in the IVD with aging through increased apoptosis, and secondary necrosis reduces the cellularity of the tissue and its ability to repair and regenerate. However, there are reports that there is also increased cellularity in some areas
of degenerate discs, with clusters of chondrocyte-like cells forming by cell proliferation in degenerating areas.11 Interestingly, regional chondrocyte hypocellularity and cloning is also seen in degenerating articular cartilage,12,13 reminding us of the many similarities between IVD and cartilage, especially with regard to extracellular matrix (ECM) composition. Changes in cellularity are important because they alter the nutritional status and metabolic substrate requirements of the disc and impact on the

concentration gradients of nutrients, metabolites, and waste products.11 The normally avascular disc in the healthy adult can become increasingly vascularized and innervated with degeneration and disease. This may lead to an increased supply of oxygen and nutrients to the disc, altering the metabolism of the disc and the phenotype of its resident cells. Furthermore, vascularization and innervation can also introduce other cell types, including inflammatory cells, and a range of bioactive molecules such as proinflammatory cytokines and growth factors. The increased production and secretion of proinflammatory cytokines, particularly tumor necrosis factor a and interleukin 1 b, drives autophagic changes as well as cell death.14 The relationship between autophagy, apoptosis,15,16 cell senescence,17,18 and mitochondrial dysfunction has not been extensively explored in the aging and degenerating disc, and it has been suggested that all these mechanisms are implicated in spine degeneration. Senescent cells cannot divide and they promote the development of a senescence-associated secretory phenotype (SASP). Research at the intersection between the fields of oncology and immunology has demonstrated that the acquisition of SASP can turn senescent stromal fibroblasts into proinflammatory cells that have the ability to promote tumor progression.19 So what is the relevance of this phenomenon to degenerative diseases of the joints and the spine? SASP defines the ability of senescent cells to express and secrete a variety of extracellular modulators that includes cytokines, chemokines, proteases, growth factors, and bioactive lipids. The SASP secretome can mediate chronic inflammation and stimulate the growth and survival of aggressive and persistent cells with inflammatory potential.20 SASP may reduce the disc’s ability to generate new cells to replace cells lost to necrosis or apoptosis and may seriously compromise the most promising and evidence-based strategies for spine regeneration, including approaches that might use stem cells and gene therapy. Therefore, all future therapeutic and regenerative strategies must first attenuate and eliminate SASP and promote a microenvironment that is more conducive to supporting endogenous or stem cell–facilitated tissue repair and regeneration.21,22

MOLECULAR ALTERATIONS IN DISC DEGENERATION

The precise sequence of molecular events involved in the degeneration of the IVD is not clear. However, it is generally accepted that disc degeneration begins at the molecular level early in life, long before the appearance of any radiographic changes or pain symptoms. The degeneration involves a cascade of changes at the cellular and molecular level that results in degradation of the disc ECM, leading to biomechanical failure of this unique and complex structure.23 IVD degeneration
is thought to occur where there is a loss of homeostatic balance with a predominantly catabolic metabolic profile.24 Once again, similar molecular mechanisms occur in joint degeneration in OA, starting with a long-lasting and asymptomatic “molecular phase,” which is followed many years later by loss of articular cartilage, evident