Regulatory Mechanisms and Clinical Manifestations of Musculoskeletal Aging

Abstract

Aging is the strongest risk factor for degenerative bone and joint diseases. Clinical therapies for age-related musculoskeletal disorders face significant challenges as their pathogenic mechanisms remain largely unclear. This review article focuses on the recent advances in the understanding of regulatory mechanisms of musculoskeletal aging and their clinical relevance. We begin with the prevalence and socioeconomic impacts of major age-related musculoskeletal disorders such as sarcopenia, osteoporosis, osteoarthritis, and degenerative tendinopathy. The current understanding of responsible biological mechanisms involved in general aging is then summarized. Proposed molecular, cellular, and biomechanical mechanisms relevant to the clinical manifestations of aging in the musculoskeletal system are discussed in detail, with a focus on the disorders affecting muscle, bone, articular cartilage, and tendon. Although musculoskeletal aging processes share many common pathways with the aging of other body systems, unique molecular and cellular mechanisms may be involved in the aging processes of musculoskeletal tissues. Advancements in the understanding of regulatory mechanisms of musculoskeletal aging may promote the development of novel treatments for age-related musculoskeletal disorders. Finally, future research directions for major musculoskeletal tissues including functional interaction between the tissues and their clinical relevance to age-related musculoskeletal disorders are highlighted in the future prospects section.

1. Introduction

Aging is a complex process that is characterized by a progressive loss of physiological function over time. This correlates with an increased susceptibility to many diseases that span all organs systems. In fact, age is considered the greatest risk factor for many neurodegenerative, metabolic, cardiovascular, and musculoskeletal conditions. Understanding the link between aging and disease could have major treatment and socioeconomic impacts as the population is aging at an unprecedented rate. Worldwide, the 65 years and older age group is expected to nearly triple from 617 million in 2015 to 1.57 billion while the 80 years and older age group is expected to more than triple from 126 million to 446 million by 2050.¹ This puts a huge burden on the healthcare economy as utilization and spending increase with patient age.² Identifying possible therapeutic targets that link aging and disease may be able to lengthen the “healthspan” of patients and limit healthcare costs.

The effect of aging in the musculoskeletal system impacts a large proportion of society and is primarily manifested in muscle, bone, cartilage, and tendon. Sarcopenia is a complex condition with age-related loss of muscle mass that results in decreased strength and physical endurance. The estimated direct healthcare costs of sarcopenia was $18.5 billion in 2000 in the United States alone.³ Additionally, low muscle mass and strength makes elderly patients more likely to fall and suffer fractures from low energy mechanisms due to poor bone quality and postural control.⁴ Osteoporosis is highly prevalent in the elderly population as it is estimated that more than 10 million Americans are affected while another 43 million have low bone density.⁵ Roughly one out of two Caucasian women and one in five Caucasian men will have an osteoporosis-related fracture during their life. On an annual basis, this translates into more than two million fractures and 400,000 hospitalizations.⁶ It is estimated that osteoporosis will be responsible for more than $25 billion in annual health care spending by 2025 in the United States.⁶

There is a direct correlation between increasing age and the incidence of osteoarthritis (OA), though the exact pathogenesis is largely unclear. OA is one of the top causes of disability worldwide⁷ and represents nearly $185 billion in total treatment costs and lost wages each year in the United States.⁸ No treatments are currently available to prevent or permanently reverse OA despite multiple basic science and medical innovations, including numerous drug trials.⁹ As such, surgical joint replacement or fusion remains the only option for patients with end-stage OA. Tendons undergo age-associated changes including disorientation of collagen fibers, thinning of fibers, myxoid degeneration and calcification. These changes are clinically evident by the increased prevalence of many tendinopathies with age. Asymptomatic full thickness rotator cuff tears are present in approximately 13% of patients over 50 years and 50% of patients over 80 years.¹⁰ Furthermore, there is an increased incidence of biceps tendinitis and ruptures, lateral epicondylitis, and Achilles tendinitis with age.¹¹

This review will discuss the current understanding of the molecular mechanisms involved in the general aging process and specific mechanisms and clinical manifestations of aging in the musculoskeletal system along with possible therapeutic interventions.

2. Biological Mechanisms of General Aging

Aging is a multifactorial process that results from both genetic and environmental factors. Recent advances in the understanding of the molecular mechanisms of general aging are summarized below with 10 subheadings, which are primarily based on the “Hallmarks of Aging” as proposed by López-Otín et. al. in their landmark review article.¹²

2.1. Genomic alterations

A long-purposed theory of aging centers on the accumulation of genetic damage (DNA crosslinking, point mutations, translocations, etc.) over time from both exogenous (e.g. radiation, smoking) and endogenous (e.g. reactive oxygen species, DNA replication errors) sources which alters gene expression and intracellular signaling.^{13, 14} These genetic errors accumulate despite organisms’ complex DNA repair machinery. This theory of aging is supported by progeroid syndromes such as Werner’s syndrome in which defects in DNA repair machinery lead to accelerated aging.¹⁵ Ultimately, these genetic changes can limit stem cell renewal, trigger pathologic inflammatory processes or even cellular senescence, apoptosis, or unregulated expansion.¹³

2.2. Telomere shortening

Telomeres, highly specialized repetitive nucleotide sequences, protect the ends of chromosomes from deterioration. In humans, telomere length is reduced with age in many tissue/cell populations such as liver, kidney, spleen, peripheral blood cells, dermal fibroblast, and mucosal keratinocytes and has been linked to stem cell exhaustion.^{16, 17} Telomerase, a reverse transcriptase, attempts to counteract this shortening by adding new DNA onto the telomeres and is highly expressed in cells with unlimited proliferative potential.¹⁸ Telomerase deficiency in humans has been linked to the early onset of multiple clinical syndromes including pulmonary fibrosis, dyskeratosis congenital, and aplastic anemia¹⁹. Conversely, mice expressing elevated amounts of telomerase have an extended maximum lifespan compared to wild-type littermates.²⁰

2.3. Altered epigenetic modifications

Epigenetics is the alteration of gene expression without modification to the underlying genetic code; these changes include DNA methylation, histone modifications, and non-coding RNA (ncRNA). Age-related epigenetic modifications occur due to ROS, nutrient dysregulation, chronic inflammation, and telomere shortening.²¹ DNA methylation occurs so predictably with age that it can accurately predict a patient’s age and is thus known as the “epigenetic clock.”²² Other epigenetic alterations, to include histone modification and ncRNA, have been shown to affect the lifespan of several model organisms.^{23, 24} The role of epigenetics in aging and osteoarthritis has recently been reviewed.^{25, 26} Epigenetics is a growing field secondary to the potential reversibility, and therefore treatability, of the aging-related changes.

2.4. Loss of proteostasis

Cell function depends on protein homeostasis, proper protein folding and degradation of misfolded/non-functional proteins. Protein chaperons play a role in folding while proteolytic systems help degrade proteins. These processes may be disrupted with aging, leading to the accumulation of damaged, aggregated, and/or dysfunctional proteins.²⁷ This accumulation has been linked to age-associated disorders such as cataracts, Alzheimer’s disease, and Parkinson’s disease.²⁸

Autophagy, a mechanism used to remove misfolded or aggregated proteins and eliminate intracellular pathogens, is a highly regulated cytoprotective process that plays an important role in cell growth, development and homeostasis.²⁹ The expression of specific proteins required for autophagy induction is reduced in aged tissues and age-related diseases, including OA.^30–32 Moreover, mitochondrial dysfunction, which contributes to cellular aging, occurs in part because of the inability of cells to remove their damaged mitochondria.³³

2.5. Deregulated nutrient sensing

Caloric restriction is one of the most well studied mechanisms of increased lifespan. Limiting caloric intake has been shown to increase the lifespan of multiple species, including humans.^34–37 The responsible molecular signaling pathways remain unclear; however, evidence suggests that the Insulin/Insulin-like growth factor-1 (IGF-1) pathway and its downstream effector, mTor, are involved via nutrient “sensing” molecules. Genetic mutations of this pathway and its downstream effects have been linked to longevity.^{38, 39} Sirtuins, an NAD-dependent family of proteins, play a crucial role in nutrient “sensing” and are linked to increased longevity with caloric restriction in multiple model organisms ranging from yeast to mammals.⁴⁰ Additionally, pharmacologically targeting sirtuins with activating molecules has shown promise for increasing disease resistance and longevity⁴¹. Caloric restriction may also extend lifespan by preventing the age-associated decline in autophagy.⁴²

2.6. Mitochondrial dysfunction and reactive oxygen species

Reactive oxygen species (ROS) are a group of diverse reactive chemical species involving oxygen which have both physiologic and pathologic roles. Most are generated in mitochondria during the process of oxidative phosphorylation but exogenous sources such as pollutants and radiation also produce ROS.⁴³ Physiologically, ROS play a major role in cellular signaling and infection prevention. However, they also have many deleterious effects on cell metabolism and are linked to the development of several age-related diseases including Alzheimer’s, obesity, and diabetes.^{44, 45} The accumulation of ROS over time is thought to result from mitochondrial dysfunction and a reduction in ROS scavenging mechanisms such as superoxide dismutases, a class of enzymes that act as endogenous antioxidants.⁴⁶

2.7. Cellular senescence

Cellular senescence results when cells no longer progress through the cell cycle. Hayflick first described cellular senescence in cultured fibroblast in the 1960s⁴⁷. Cellular senescence is known to increase with aging⁴⁸ and can result from multiple mechanisms including telomere shorting⁴⁹ and the accumulation of genomic damage⁵⁰. It is unknown if cellular senescence is protective by preventing replication of damaged cells or pathologic.

Senescence-associated secretory phenotype (SASP) refers to senescent cells that accumulate and secrete inflammatory chemical mediators including cytokines and matrix degrading proteases. SASP cells have been implicated in the aging process and documented in multiple cell types,^{51, 52} including chondrocytes.⁵³ The removal of senescent cells in transgenic mice is associated with an increased lifespan and reduced morbidity, highlighting their role in aging.⁵⁴

2.8. Stem cell exhaustion

Stem cells are the pluripotent cells of the body and represent the major repository of regenerative potential within organ systems. Stem cell reserves decrease with age across multiple tissues including skin, immune, hematopoietic, musculoskeletal, and nervous systems.⁵⁵ Within the hematopoietic system, aged stem cells have lower rates of replication and there is an increase in anemia and myeloid cancers with age.^{56, 57} Similar to cellular senescence, stem cell exhaustion appears to be the result of the accumulation of multiple aging mechanisms including genomic instability, loss of proteostasis, telomere attrition, and mitochondrial dysfunction.

2.9. Inflammation and altered intercellular communication

The major change in intercellular communication with aging is associated with inflammation. Levels of inflammatory mediators typically increase with age even in the absence of acute infection or other physiologic stress.⁵⁸ While levels are still in the sub-acute range, this chronic pro-inflammatory state underlies many aging-related conditions⁵⁹ and has been termed “inflammaging.”⁶⁰ Proposed causes include the accumulation of tissue damage, an inability of the immune system to clear pathogens, and the proinflammatory phenotype of SASPs cells, as discussed previously. In addition, a reduction in nutrient “sensing” sirtuins may impact aging through altered intracellular communication and increased inflammation.⁶¹

2.10. Abnormal crosslinking

Crosslinking refers to the accumulation of abnormal bonds between molecules, especially biomacromolecules such as collagens as well nucleic acids and sugars. It is one of the deleterious effects of ROS in aging.^{62, 63} The addition of sugar molecules to proteins and nucleic acids, a process known as non-enzymatic glycosylation, leads to the production of advanced glycosylation end products (AGEs) which can promote crosslinking. AGEs have been implicated in tissue and organ system dysfunction in aging and diabetes.⁶⁴ Age-related manifestations of crosslinking are the loss of skin elasticity, stiffening of blood vessels, changes in the lens of the eye, and delayed wound healing.^{65, 66}

The possible mechanisms of general aging which impacts all organ systems are summarized in Table 1. Some of these mechanisms also play a role in the aging of the musculoskeletal system.

Table 1.

Possible mechanisms of general aging

Risk Factors	Possible mechanisms	References
Genomic alterations	Genetic errors accumulate over time which ultimately leads to cellular apoptosis/senescence, limited stem cell renewal, and altered cytokine secretion.	12–15
Telomere shortening	Progressive telomere shortening occurs with cellular division which leads to decreased cellular proliferation, function, and possibly lifespan.	16–20
Altered epigenetic modification	Epigenetic modifications alter gene expression and cellular function in an age-dependent manner and alter cellular function over time.	21–26
Loss of proteostasis	Protein misfolding and decreased activity of proteolytic and autophagy systems leads to an accumulation of dysfunctional proteins altering cellular metabolism.	27–33
Deregulated nutrient sensing	Caloric restriction increases lifespan via activation of nutrient “sensing” molecules like sirtuins and modify the Insulin/IGF-1/mTor signaling pathway.	34–42
Mitochondrial dysfunction and ROS	Mitochondrial dysfunction increases reactive oxygen species that damage nucleic acids and oxidize fatty acids/proteins leading to genetic alterations and cellular dysfunction.	43–46
Cellular senescence	Aged cells no longer replicate and adopt a “senesence-associated secretory phenotype” that promotes inflammation and aging.	47–54
Stem cell exhaustion	Stem cell levels decrease with age, reducing the repair and regenerative capacity of tissues over the lifespan.	55–57
Inflammation and altered intercellular communication	Changes in cellular communication and inflammatory mediators lead to tissue dysfunction via multiple pathways including DNA damage, ROS, protein dysfunction, and altered autophagy.	58–61
Abnormal crosslinking	Abnormal intra- and inter-molecular bonding leads to altered transcription, translation and tissue properties.	62–66

3. Mechanisms and Manifestations of Musculoskeletal Aging

In the musculoskeletal system, the primary tissues affected with age are muscle, bone, cartilage and tendon. Age-related changes and disorders in the musculoskeletal system, which represent some of the most disabling diseases, are summarized in Figure 1.

Figure 1:

Age-associated conditions of the musculoskeletal system. Sarcopenia is a decrease in muscle mass and function with age. Tendons undergo degenerative changes with age and contribute to increased rotator cuff tears, biceps tendinitis and Achilles tendinitis. The vertebral column undergoes multiple age-related changes that contribute to increased disc herniations, spinal stenosis, foraminal stenosis, instability and deformity. Age-dependent changes in bone metabolism and structure lead to osteoporosis and increased risk of fragility fractures, specifically vertebral compression fractures, hip fractures, and distal radius fractures. Alterations in subchondral bone and overlying cartilage with age increase the risk for osteoarthritis.

3.1. Muscle

Sarcopenia is the loss of muscle mass, strength, and function with age due to changes in muscle fiber type/size, alterations of the motor nerve unit and fatty infiltration of muscle. Longitudinal studies have shown a 1–1.5% reduction in muscle strength per year in elderly patients⁶⁷ with a 30–50% accumulated decrease in muscle mass by age 80.⁶⁸ This results in increased frailty, fall risk, and loss of independence. The molecular and cellular mechanisms underlying these changes may include loss of repair mechanisms, accumulated damage, and altered signaling.

Failure of regeneration and repair of accumulated damage is a recognized cause for decreased muscle function. Satellite cells, the regenerative cells of skeletal muscle, are reduced in number, proliferative capacity, and differentiation ability with age.^{69, 70} Furthermore, satellite cell signaling in response to growth factors, such as fibroblast growth factor, is blunted with age which appears to be driven by epigenetic changes.^{71, 72} Additional epigenetic changes in muscle include several ncRNA that play roles in muscle aging via alterations of SIRT1, telomerase, and IGF-1/TGF-β anabolic pathways.⁷³ Reduction in autophagy, an important cell maintenance function, has also been demonstrated in aged muscle fibers. The function of autophagy is important for muscle health and is a proposed mechanism for the beneficial effects of physical exercise in elderly patients.⁷⁴

Accumulation of damage to the muscle cell machinery for contraction and energy production also results in decreased function. Post-translational changes accumulate on myosin which limit coupling with actin resulting in decreased force generation with age.⁷⁵ Muscle mitochondria, the power plant of the cell, also accumulate damage with age, resulting in decreased ATP production and increased ROS.⁷⁶

Muscle mass loss with age appears to be partly driven by a reduction in muscle fiber number. Aged humans lose approximately 50% of their muscle fibers⁷⁷ which is primarily mediated by apoptosis.⁷⁸ This apoptosis may be induced by ROS damage to mitochondrial DNA and primarily affects the large type II fast fibers. It is often accompanied by infiltration of fibrous or fatty tissue. Additional proposed mechanisms of muscle mass loss are the denervation of motor neurons and loss of trophic support.⁷⁹ Sixty-year-old patients have 25–50% less motor neurons than 20-year-old patients,⁸⁰ and these changes may be governed by neural redox signaling.⁸¹

Signaling pathways, particularly protein kinase B (PKB, also known as AKT) and mechanistic target of rapamycin (mTOR), are important mediators of overall lifespan and muscle function. AKT phosphorylation is decreased with age⁸² and the contraction induced activation of AKT/mTOR is blunted in mice with increasing age.⁸³ These changes may decrease protein synthesis, disrupt the repair and regenerative balance of muscle, and decrease overall muscle size and strength.

Myostatin is a negative regulator of muscle mass that was first described in 1997.⁸⁴ Myostatin knockout mice have a 2–3 times increase in body weight from muscle hypertrophy and hyperplasia. Agents and antibodies targeting myostatin and its downstream receptor, activin, are showing promise for sarcopenia treatment.⁸⁵ Interestingly, one aspect of myostatin intra-cellular signaling is via the Akt/mTor pathway, an important mediator of aging.⁸⁶

The role of caloric restriction in aging muscle is not well defined. Reduction in the Insulin/IGF-1 signaling pathway seen in caloric restriction is associated with preserved muscle mass as aged non-human primates increased muscle mass by 30% with caloric restriction.⁸⁷ It has been shown that caloric restriction results in less mitochondrial dysfunction, less ROS generation, and decreased activation of apoptotic pathways in muscle.⁸⁸ There is also a reduction in the inflammatory cascade in muscle from aged rats with caloric restriction.⁸⁹ Conversely, muscle specific overexpression of IGF-1 in transgenic mice prevents age-associated muscle atrophy.⁹⁰ As such, more mechanistic, dose-dependent, and longitudinal studies are needed to further characterize the exact role of caloric restriction and Insulin/IGF-1 signaling in muscle aging.

3.2. Bone

Age-dependent changes in bone may result in Paget’s disease of bone⁹¹, osteoporosis, and increased fracture risk. Osteoporosis, the most common bone disease in humans, is characterized by low bone mass and disruption of bone architecture with subsequent compromised bone strength and an increased risk of fracture. The prevalence of osteoporosis increases with age. Bone mass peaks in early adulthood and then declines with age due to an imbalance in bone formation and resorption.⁹²

The most common osteoporotic fragility fractures are hip, vertebral compression, and distal radius fractures. Elderly patients with hip fractures consistently have decreased activities of daily living⁹³ and a 30 percent mortality rate at 1 year following fracture.⁹⁴ Osteoporotic vertebral compression fractures are the most common fragility fracture with a prevalence of 5–10% in patients aged 50–60 years and greater than 40% in patients over 80 years.⁹⁵ This results in over 70,000 hospitalizations⁹⁶ and $13.8 billion in annual healthcare costs.⁹⁷ Even in the absence of fracture, other age related degenerative changes of the spine lead to significant morbidity due to radiculopathy, central stenosis, spondylolisthesis, and degenerative scoliosis.⁹⁸

Multiple mechanisms drive age related changes to bone. Osteoblasts are the bone-forming cells derived from undifferentiated mesenchymal stem cells (MSCs). Osteoblasts proliferation, maturation, and subsequent bone matrix mineralization are decreased with increased ROS, accumulation of DNA damage, and reduced autophagy activity.^99–101 MSCs also undergo several age-related changes which limit their differentiation and regenerative capacity. First, MSCs proliferate at slower rates,¹⁰² have reduced autophagy,¹⁰³ and preferentially differentiate to adipocytes versus osteoblasts with aging¹⁰⁴ leading to increased adiposity of bone marrow. This change in cell differentiation along with delayed periosteal reaction and prolonged endochondral calcification results in delayed bone healing of fractures from aged mice.¹⁰⁵ Second, MSC telomeres play an important role in bone aging. Transgenic mice with reduced telomerase function have reduced bone mass secondary to uncoupling of osteoblast and osteoclast function.^{106, 107} Conversely, MSC telomerase activation maintains differentiation in vitro and increases bone mass in vivo.^{108, 109} Third, cellular responses of MSCs to anabolic signaling pathways decreases with age. For example, Wnt10b deficiency results in age-dependent loss of bone mass and progressive reduction of mesenchymal progenitor cells.¹¹⁰ Wnt-β-catenin signaling via mechanoreceptors is also involved in MSC differentiation to osteoblasts.¹¹¹ Furthermore, MSC response to anabolic transforming growth factor beta (TGF-beta)/bone morphogenetic protein (BMP) signaling decreases with aging.^{112, 113} Together, these changes highlight the importance of MSC role in maintaining aging bone health.

Pharmacological interventions based on aging mechanisms that have shown promise include inhibitors of wnt antagonist,¹¹⁴ suppression of peroxisome proliferator-activated receptor gamma,¹¹⁵ anti-oxidant treatment,¹¹⁶ and recent evidence suggesting that SIRT1 activation via both pharmacological and caloric restriction can increase bone mass.¹¹⁷

Additional factors leading to changes in bone density are dysregulation of hormones (e.g. estrogen and parathyroid hormone) on osteoblasts, osteoclasts, and osteocyte activities, alterations in cellular response to hormones, and vitamin D metabolism.^{118, 119} These changes may increase intra-cortical porosity through remodeling and coalescence of existing cortical canals.⁹² Additionally, osteocyte signaling in response to mechanical load is reduced and the osteoprotective effect of the muscle factor β-aminoisobutyric acid (BAIBA) is lost with age. Theses alterations may further contribute to the progression of osteoporosis and to the attenuated effect of exercise on bone with aging.^{120, 121}

Epigenetic modification has multiple roles in bone aging. First, DNA methylation controls Receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) expression.¹²² Second, transgenic mice with SIRT1 knockout have a reduction in bone mass similar to aged animals.¹²³ Third, non-coding RNA (ncRNA) have been shown to regulate osteoblast cell function and bone density in vivo.^124–126 Finally, rapamycin inhibition of mTOR, which is known to have lifespan prolonging effects, reduces osteoclastic activity and bone loss in mice.¹²⁷

3.3. Articular Cartilage

The incidence of osteoarthritis (OA) increases with age. Articular cartilage is avascular and has limited capacity for repair. Chondrocytes reside within the cartilage to secrete and maintain the extracellular matrix (ECM). With aging, the number of chondrocytes decrease with an overall decrease in ECM synthesis.¹²⁸ Like aging in other tissues, SASP cells have been found in cartilage. SASP chondrocytes increase expression of inflammatory mediators and matrix degrading proteases, similar to the periarticular environment in OA.¹²⁹ This increase in basal inflammation may explain why surgical models of OA show more rapid progression in aged mice as compared to young mice.¹³⁰ Chondrocyte senescence has also been associated with telomere shortening.¹³¹

The accumulation of ROS has been shown to affect chondrocyte apoptosis, senescence, ECM synthesis, and signaling through nitric oxide (NO).¹³² NO alters singling through tyrosine activated receptors in chondrocytes from both aged mice and mice with OA.¹³³ Additional chondrocyte changes with age include decreased mechanical stimulation and blunted responsiveness to growth factors.¹³⁴ These changes tip the anabolic/catabolic ratio in favor of catabolic breakdown and lower the threshold for developing OA.^{135, 136}

The ECM of articular cartilage undergoes age-associated changes. Articular cartilage ECM is primarily composed of water, type II collagen, and proteoglycans. Overtime, there is a reduction in the water content, increased stiffness, and loss of tensile strength leading to increased brittleness and risk of failure. Many of these changes are attributed to passive glycation and crosslinking of the ECM, primarily from AGEs.¹³⁷ Changes to the ECM alter the hydrostatic biomechanics of cartilage leading to a reduction in the capacity for deformation, which increases the risk of injury. With aging, there is also increased collagenase-mediated breakdown of type II collagen, an increased ratio of keratan sulfate to chondroitin sulfate, and smaller disorganized aggrecan molecules.¹³⁸ Many of these changes have been found to be under epigenetic control via DNA methylation of matrix metalloproteinases promoters¹³⁹ and ncRNA regulation of anabolic signaling.¹⁴⁰

NFAT1, a member of the nuclear factor of activated T-cells (NFAT) family of transcription factors, has recently been discovered as a regulator of joint homeostasis by controlling expression of multiple anabolic and catabolic genes.¹⁴¹ NFAT1 knockout mice display down-regulation of anabolic genes and up-regulation of catabolic genes at the initiation stage, leading to cartilage breakdown.¹⁴² Furthermore, NFAT1 is highly expressed in young adult articular cartilage but declines with age in correlation with cartilage degeneration, as compared to SOX9 which is primarily expressed in developing cartilage.^143–145 This spontaneous decrease in NFAT1 expression with age is regulated primarily by epigenetic histone modifications.¹⁴⁵ Further understanding of the connection between epigenetics, cartilage aging, and OA is important for the development of therapeutic strategies and has recently been reviewed in depth.^{26, 143}

The advancement of mechanistic studies on OA pathogenesis has substantially improved our understanding of the link between biological changes and clinical manifestations of articular cartilage aging and OA. For example, increased expression of catabolic genes encoding proinflammatory cytokines and matrix metalloproteinases (MMPs) in articular cartilage is linked to degeneration and loss of cartilage, causing joint stiffness. Synovial inflammation and subchondral bone marrow edema with increased pressure in the bone marrow cavity may irritate the nerves in the synovium and periarticular bone, respectively, causing joint pain.

3.4. Tendon

Tendons are highly organized structures that transmit muscle forces to bone to produce movement. They are comprised primarily of type I collagen organized into fibrils. Tenocytes are the specialized fibroblast-like cells of tendons that maintain tendon structure, synthesize the ECM, and assist in tissue repair. Many tendinopathies increase with age. The structural changes associated with these degenerative changes have been extensively studied; however, the molecular mechanisms have not been well defined.

Changes in tendon structure with age include decreased fiber size with reduced collagen density and disorganization of the collagen fibrils. Other documented changes in tendon with age include decreased water content, decreased proteoglycans, increased calcification and lipid accumulation and an increase in crosslinking.¹⁴⁶ Together these changes contribute to increased stiffness and decreased tensile strength, ultimately lowering the fatigue failure threshold.^147–149 Inflammation and the expression of matrix metalloproteinases (MMPs) in tendons increases with age, which may contribute to these observed structural changes and clinical manifestations.^{150 151} Treatment with MMP inhibitors has been shown to prevent reduction in tendon strength in vitro.¹⁵²

Age associated changes have been documented in 2 cell populations within tendons, tenocytes and the recently described tendon stem/progenitor cells (TSC). Tenocytes decrease in number and their morphology changes to a thinner and spindle shape with increased nuclear to cytoplasm ratio with age. Tenocytes in aged animals have decreased proliferation rates and increased cellular senescence.⁶¹ Recent evidence also suggests that aging tenocytes also have a pro-inflammatory senescent phenotype, similar to previously described SASP cells.¹⁵³ TSCs are a distinct population of progenitor cells within tendons that contribute to healing and regeneration.¹⁵⁴ Application of TSC sheets in a rat model of Achilles injury improved biomechanical and histological appearance of the tendons as compared to controls.¹⁵⁵ There is a documented 70% reduction in TSCs with age from poor self-renewal and limited differentiation capacity causing stem cell exhaustion.¹⁵⁶ This contributes to weaker tendon healing at the tendon-bone junction. Aged TSC also have decreased protein synthesis, less growth, and less regenerative potential with higher cellular senescence.^{156, 157} New evidence also demonstrates a role for epigenetic modification in tendon aging. Modulation of TSC senescence is regulated by the ncRNA, miR-135a, while TSC differentiation is regulated via microRNA-217.^{158, 159} Along the “altered inter-cellular communication” aging pathway, recent evidence in TSC have shown that increased signaling via ephrin receptors may have anti-aging properties by promoting cell-cell communication.¹⁶⁰

Changes in vascularity are a documented cause of aging- or injury-mediated tendon degeneration. The supraspinatus¹⁶¹ and Achilles tendons¹⁶² have a hypovascular region that correlates with the location of common tears. Immobilization appears to reduce blood flow to tendons secondary to under stimulation.¹⁶³ Histopathology of tendon tears shows blood vessel narrowing that is more significant in older patients,¹⁶⁴ possibly from crosslinking within the vessel walls.

Similar to other parts of the musculoskeletal systems, exercise and mechanical stimulation has beneficial effects on tendon. In tendon, moderate exercise and mechanical loading negates some of the “stem cell exhaustion” associated with aging. TSC show increased expression of stem cell markers and proliferation with mechanical loading and AGEs are reduced in aged Achilles tendons after training.¹⁶⁵

These discussed structural and molecular changes cumulatively result in clinical diseases such as tendinopathy in the biceps, rotator cuff, and Achilles tendons which can lead to overt tears that may require surgical intervention. Better understanding of the biomechanical aspects of tendon aging will hopefully lead to improved patient quality of life and function.

4. Future Prospects

Mechanisms of aging and degenerative musculoskeletal conditions are closely linked. Understanding the molecular and cellular mechanisms of musculoskeletal aging will promote the development of targeted treatments for age-related disorders of musculoskeletal tissues (Figure 2). Indeed, certain areas have already shown promise. However, there remains a disconnect between the described mechanisms of aging and current treatment modalities of age associated musculoskeletal disorders. The gaps between basic science results and clinical treatments of diseases in muscle, bone, articular cartilage, and tendon are highlighted below.

Figure 2:

Proposed mechanisms of musculoskeletal aging. Chronic inflammation and catabolic pathway activation, cumulative cellular damage, decreased repair/regeneration, telomere shortening, epigenetic modifications and increased reactive oxygen species (ROS) are common pathways amongst many tissues of the musculoskeletal system. Age-associated fiber loss is unique to muscle aging, while crosslinking affects primarily tendons and cartilage.

4.1. Muscle

Despite the substantial clinical impact of sarcopenia, treatment options are lacking secondary to poor understanding of the involved molecular mechanisms. Resistance exercise along with supplementation of vitamin D and protein is the current treatment of choice.^{166, 167} Currently there are no FDA approved pharmacologic treatments for sarcopenia. Growth hormone/IGF1 and anabolic steroids have been tried with moderate success and several medications are currently being tested including ghrelin agonist, β-adrenergic agonist/antagonist, fast skeletal muscle troponin activators, biologic anti-inflammatories (infliximab, tocilizumab) and angiotension converting enzyme inhibitors. The major gap in sarcopenia treatment is an unclear understanding of the interplay between the aging mechanisms and a disconnect between the pathogenesis and treatment options. Furthermore, treatments need to be able to impact multiple mechanisms, as aging and sarcopenia are multifactorial conditions. Finally, animal models that more accurately simulate human sarcopenia will provide more robust preclinical studies.¹⁶⁸

4.2. Bone

Osteoporosis is an increasing worldwide concern secondary to the increased aging population. Current treatment involves weight-bearing exercise, vitamin D and calcium supplementation with the addition of a pharmacological agent. Current pharmacological treatment of osteoporosis primarily targets reducing osteoclast bone resorption.¹⁶⁹ The most popular and successful drug class is the bisphosphonates, but increasing concerns are being raised about “adynamic” bone and atypical femur fractures after long-term use. Additional anti-resorptive medications include hormone-based therapies and denusomab, a RANK-L decoy receptor. Currently the only anabolic agent available is teriparatide, a parathyroid analogue that targets osteoblasts and bone formation. Several new drugs are being developed including cathepsin K inhibitors, src kinase inhibitors, calcilytics, and inhibitors of Wnt antagonist.¹⁶⁹

Patients with osteoporosis are often not diagnosed until they sustain a fragility fracture, or on screening at age 65, at which time bone density may be severely decreased. Gaps within osteoporosis research and treatment include delayed diagnosis, limited medications focusing on prevention, and a lack of treatments targeting the multifactorial nature of osteoporosis. Continued studies to highlight the changes in bone biology and mechanical response with age will help provide new treatment options and provide opportunities to develop earlier diagnosis and preventative measures.

4.3. Articular cartilage

OA is the most common form of joint disease and the major cause of chronic disability in middle-aged and older populations.^{170, 171} Cartilage degradation is a major hallmark of OA, though multiple joint tissues may be involved in the progression of OA. Many risk factors, such as aging, obesity, joint trauma, abnormal mechanical loading, genetic predisposition and sex hormone alterations, have been proposed to increase the susceptibility to OA.^172–174 However, the precise mechanisms underlying OA pathogenesis remain unclear. Current pharmacologic management of OA pain with analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) may relieve pain temporarily but does not cure the disease. Development of disease-modifying OA drugs (DMOADs) has been aimed to halt or reverse progression of articular cartilage damage. Many candidate DMOADs have been tested, but none have been approved by food and drug regulatory agencies in the United States or other countries.^{175, 176} The lack of effective non-surgical OA therapy currently drives about a million Americans to joint replacement surgery annually,¹⁷⁷ which is not an ideal treatment modality for younger individuals who desire to preserve their natural joints. Therefore, a better understanding of OA pathogenesis is paramount to development of effective non-surgical OA therapy.

Our recent studies indicate that NFAT1 overexpression in cultivated articular chondrocytes from aged mice can significantly reverse the imbalanced chondrocyte anabolic/catabolic activities and is under epigenetic control.¹⁴⁵ This novel finding needs to be further confirmed in preclinical and clinical studies. Epigenetic modifications with histone deacetylase inhibitors, ncRNAs, and NAD-dependent deacetylase sirtuin-1(SIRT1) activators have been shown to improve chondrocyte function and protect against age-associated OA.^{178, 179} Targeting these reversible aging mechanisms in cartilage could be an additional pathway to developing treatments for cartilage aging and OA.

4.4. Tendon

Anti-inflammatories, corticosteroid injections and physical therapy remain the mainstay of treatment for tendinopathy, but refractory cases may require surgical debridement.¹⁸⁰ Physical therapy modalities include stretching/strengthening, therapeutic ultrasound, iontophoresis, low level laser treatment, and phonophoresis. Additional treatment options that have been utilized include extracorporeal shock wave therapy, nitric oxide treatments via glyceryl trinitrate patches, hyperthermia, and sclerotherapy. Growth factor therapy, especially in the form of platelet rich plasma (PRP) injections, has recently gained significant attention and has shown some positive results, but more stringent studies are needed to determine efficacy, timing and dosing.¹⁸¹

The current repertoire of treatment options does not include any medications targeting mechanisms of tendinopathy or tendon degeneration and represents a major gap between the current treatment options and mechanistic basic science studies. Translational studies of aging mechanisms may highlight new target options, particularly with the discovery TSCs. Continued efforts to develop preclinical models for aging and tendinopathy will also greatly improve our understanding of these conditions and promote development of new treatment modalities.

4.5. Crosstalk and interaction of musculoskeletal tissues

Musculoskeletal tissues are closely associated in both anatomy and function, but the mechanisms that coordinate their functional interactions are not well defined. Recent studies have shed some light on the crosstalk between tissues/cells. For example, crosstalk between MLO-Y4 osteocytes and C2C12 muscle cells is found to be mediated by the Wnt/β-catenin pathway,¹⁸² while muscle-derived myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218.¹⁸³ Additionally, epigenetic mechanisms regulate the aging and healing process of the tendon-bone junction.¹⁵⁶ Articular cartilage trophic support is provided by the surround synovial fluid and underlying subchondral bone. Subchondral bone support of cartilage decreases with age, which consequently compromises the metabolism and mechanical properties of articular cartilage.¹³⁰ Furthermore, age-related comorbidities, such as chronic obstructive pulmonary disease or congestive heart failure, can limit mobility resulting in decreased bone density and muscle mass thus propagating changes already occurring in the musculoskeletal system.

5. Conclusions

Aging has a profound effect on all systems in the body, including the musculoskeletal system. This review summarizes the current understanding of molecular, cellular, and biomechanical mechanisms relevant to the clinical manifestations of musculoskeletal aging, with a focus on the disorders affecting muscle, bone, articular cartilage, and tendon. Interplay between the organs/tissues may magnify the clinical manifestations of age. Signaling crosstalk and functional interaction between the musculoskeletal tissues may further increase the risk of falls and fractures, coupled with a reduced healing capacity, contributing to significant morbidity and mortality in elderly patients. Improved understanding of the responsible mechanisms underlying age-related musculoskeletal disorders will promote the development of better treatment modalities and achieve more active, pain free, and healthy aging.