Molecular mechanisms of biological aging in intervertebral discs

Abstract

Advanced age is the greatest risk factor for the majority of human ailments, including spine-related chronic disability and back pain, which stem from age-associated intervertebral disc degeneration (IDD). Given the rapid global rise in the aging population, understanding the biology of intervertebral disc aging in order to develop effective therapeutic interventions to combat the adverse effects of aging on disc health is now imperative. Fortunately, recent advances in aging research have begun to shed light on the basic biological process of aging. Here we review some of these insights and organize the complex process of disc aging into three different phases to guide research efforts to understand the biology of disc aging. The objective of this review is to provide an overview of the current knowledge and the recent progress made to elucidate specific molecular mechanisms underlying disc aging. In particular, studies over the last few years have uncovered cellular senescence and genomic instability as important drivers of disc aging. Supporting evidence comes from DNA repair-deficient animal models that show increased disc cellular senescence and accelerated disc aging. Additionally, stress-induced senescent cells have now been well documented to secrete catabolic factors, which can negatively impact the physiology of neighboring cells and ECM. These along with other molecular drivers of aging are reviewed in depth to shed crucial insights into the underlying mechanisms of age-related disc degeneration. We also highlight molecular targets for novel therapies and emerging candidate therapeutics that may mitigate age-associated IDD.

TRPC6 in simulated microgravity of intervertebral disc cells

“…Apart from analyzing cell proliferation and cell cycle progression, we also measured changes in cellular senescence (as assessed by SA-β galactosidase staining), a hallmark of IVD degeneration [43,44]. TRPC channel inhibition and simulated microgravity both increased cellular senescence in IVD cells.…”

The role of transient receptor potential channels in joint diseases

“…Interleukin-1 beta (IL-1β) and tumour necrosis factor alpha (TNF-α) contribute to disease progression and pain, by acting directly not only as nociceptive triggers, but also by inducing generation of other potentially nociceptive molecules, including nitric oxide and prostaglandin E (Liu et al, 2016;. IL-1β and TNF-α are secreted by cells of the immune system, such as macrophages, and by a variety of other cells types, including chondrocytes, annulus fibrosus (AF) and nucleus pulposus (NP) cells, regulating host responses to stress, inflammation, infection or trauma (Berenbaum, 2013;Johnson et al, 2015;Oda et al, 2004;Vo et al, 2016). IL-1β and TNF-α are known to activate nuclear factor κB (NF-κB), c-Jun N-terminal protein kinase (JNK) and/ or p38 mitogen-activated protein kinase (MAPK) (Hoyland et al, 2008;McNulty et al, 2009;Vo et al, 2013;Wang et al, 2015;Wilusz et al, 2008).…”

Nicotinamide Phosphoribosyltransferase Inhibitor APO866 Prevents IL-1β-Induced Human Nucleus Pulposus Cell Degeneration via Autophagy

“…IDD is associated with the proteolytic degradation of ECM, leading to large structural changes [10]. The low cellularity of the discs limits repair processes, making them susceptible to injury and age-associated accumulation of tissue damage [12]. ECM metabolic disorders disrupt the boundary between the outer annulus fibrosus and inner NP, which impairs the mechanical function of the discs [13,14].…”