Effect of Aging on Tendon Biology, Biomechanics and Implications for Treatment Approaches

Abstract

Tendon aging is associated with an increasing prevalence of tendon injuries and/or chronic tendon diseases, such as tendinopathy, which affects approximately 25% of the adult population. Aged tendons are often characterized by a reduction in the number and functionality of tendon stem/progenitor cells (TSPCs), fragmented or disorganized collagen bundles, and an increased deposition of glycosaminoglycans (GAGs), leading to pain, inflammation, and impaired mobility. Although the exact pathology is unknown, overuse and microtrauma from aging are thought to be major causative factors. Due to the hypovascular and hypocellular nature of the tendon microenvironment, healing of aged tendons and related injuries is difficult using current pain/inflammation and surgical management techniques. Therefore, there is a need for novel therapies, specifically cellular therapy such as cell rejuvenation, due to the decreased regenerative capacity during aging. To augment the therapeutic strategies for treating tendon-aging-associated diseases and injuries, a comprehensive understanding of tendon aging pathology is needed. This review summarizes age-related tendon changes, including cell behaviors, extracellular matrix (ECM) composition, biomechanical properties and healing capacity. Additionally, the impact of conventional treatments (diet, exercise, and surgery) is discussed, and recent advanced strategies (cell rejuvenation) are highlighted to address aged tendon healing. This review underscores the molecular and cellular linkages between aged tendon biomechanical properties and the healing response, and provides an overview of current and novel strategies for treating aged tendons. Understanding the underlying rationale for future basic and translational studies of tendon aging is crucial to the development of advanced therapeutics for tendon regeneration.

Keywords: biomechanical properties; extracellular matrix; tendinopathy; tendon aging and degeneration; tendon healing; tendon stem/progenitor cells; treatment and therapy.

Figure 1

Tendon ECM compositional and structural changes under healthy and aged states. Upper right: [50,51,52] Left: [3,40,53,54] Right: [3,55,56,57]. (A) Cellular and extracellular components in healthy tendons. Collagen-secreting tenocytes and their progenitor cells, TSPCs, are located between collagen fibers and crucial for maintaining their anisotropic arrangement and tensile strength [58,59]. Collagen fibers are organized in a parallel and homogenous manner [52,58] and interspersed within other ECM components [52,58]. Matrix metalloproteinase (MMPs) and tissue inhibitor of metalloproteinase (TIMPs) coordinate with PGs to modulate collagen fibrillogenesis, cell/growth factor interactions, matrix assembly and fibril sliding during musculoskeletal movement [49,60,61]. Adapted from [50,52]. (B) Age-related changes in tendon cellular and ECM components. TSPC or tenocyte dysfunctionality [47,62] as well as an increased MMP/TIMP ratio [3] contribute to collagen fragmentation and results in a disorganized ECM [53,63]. In addition to intramolecular bonding (in yellow) between the collagen triple helix, intermolecular bonding or advanced glycation end product (AGE) related crosslinks (in green) increase during aging [56]. AGE formation can be further accelerated by hyperglycemia (in brown) and increased levels of reactive oxygen species (ROS) (in purple) (induced by cell senescence) [64,65]. Alterations of PGs and GPs in aging tendons are inconclusive [3,51,53,66,67]. Adapted from [52,57].

Figure 2

Tendon healing in healthy and aged conditions. (A) Schematic diagram illustrating the three general phases of tendon healing. Adapted from [145]. (B) Table comparing the tendon healing stages in healthy [126,156,157,158] and aged conditions [3,15,55,77,148,149,150,151,152,154,155].