Journal of Aging Research In a recent meta-analysis, Pietrosimone et al. [13] showed that patients with knee OA have a deﬁcit in the activation of the quadriceps muscles. Additionally, there is evidence that weak knee extensor increases the risk to develop sympto- matic knee OA [14, 15]. The muscles surrounding the knee joint are important for the stability. Muscle weakness can therefore impair the neuromuscular protection of the joint leading to microtraumas and possibly joint damage [16]. Hence, muscular dysfunction might not only be a consequence of the disease but could also play a role in the development of OA [14, 16]. 3. Biomechanical Changes in the Elderly Walking speed is relatively consistent between age 20 and 70 and declines after age 70 [17, 18]. Older people often walk with a reduced step length which is a possible adaptation to lower muscle strength and fear of tripping and falling [19, 20]. In this study it has been shown that patients with knee OA produce lower knee extension forces than age- matched controls. These force levels were comparable to those of an on average 20 years older age group. In contrast to the knee OA patients that also showed joint laxity, the healthy elderly could maintain normal joint biomechanics during walking by increasing the muscle activity. Additionally, aging aﬀects the joint proprioception. In older subjects the joint position sense was worse than in young ones. It was also seen that knee OA patients have an even worse joint position sense than healthy elderly of a similar age. This could indicate that the age-related decline in proprioception increases the risk of OA due to reduced joint stability and increased joint stress [21]. While some age-related changes in the gait pattern like a reduced walking speed could be beneﬁcial in reducing the risk or progression of OA [10], other changes, like muscle weakness or reduced proprioception, could increase the risk of OA, especially in the presence of additional factors such as joint laxity or pain. Obesity has a negative impact on biomechanics, at least in weight bearing joints [22] and has been demonstrated as a risk factor for OA in large studies [23]. Interestingly, the negative eﬀect of obesity on cartilage decay is reversible. A recent study postulated an improved cartilage quality in the medial compartment in patients with knee OA after weight loss [24]. In the elderly, obesity in combination with sar- copenia is frequently encountered, a combination which has further negative inﬂuence on OA [25]. Whether obesity causes sarcopenia in the elderly, or obesity is a consequen- ce of reduced physical activity, remains a chicken-egg ques- tion. 4. Cartilage Decay with Age Progressive loss of articular cartilage is considered as the hallmark of OA. Cartilage consists of chondrocytes that are embedded in a specialized extracellular matrix (ECM), which is composed of water, collagen II, and proteoglycans. Chondrocytes are quiescent nondividing cells responsible for the maintenance of cartilage homeostasis through a balanced 3 production of catabolic and anabolic factors. During aging, senescence is induced either by progressive telomere short- ening due to repeated cell division or environmental stress factors, such as oxidative damage, chronic inﬂammation or ultraviolet radiation [26]. Indeed, in vitro proliferation of chondrocytes from young donors diﬀers dramatically from aged and OA donors, due to a complete lack of cell division in the latter [27]. However, as chondrocyte proliferation is scarcely observed in normal or osteoarthritic cartilage, telomere shortening is not regarded as the most likely mech- anism for senescence [28]. Accumulation of oxidative dam- age is considered as a major player in the induction of sen- escence in chondrocytes. Decreased expression of oxygen radical scavengers, such as superoxide dismutase, has been demonstrated in OA cartilage [29]. There is ample evidence that age-dependent alterations in chondrocyte metabolism or signal transduction associates with progression of OA [30, 31]. These epigenetic-induced changes in chondrocytes skew the balance that dictates cartilage homeostasis and induces alterations of the ECM and cartilage integrity that promote development of OA. Loss of biomechanical function of carti- lage during aging has been associated with a decrease in gly- cosaminoglycan content [32], which is normally deposited by chondrocytes. Besides direct modulation of the ECM by chondrocytes, age-related changes in ECM components has been proposed to mediate cartilage decay. Age-dependent accumulation and consequent cross-linking of advanced glycation end products (AGE) in collagen has been shown to increase cartilage stiﬀness, which makes it brittle and impairs its load-absorbing function [3]. Moreover, chondrocytes express the receptor for AGE (RAGE) and engagement of the receptor induces the production of cartilage-degrading enzymes [33]. Together, age-related changes in chondrocytes and components of ECM crucially impair the function of cartilage and its capacity to cope with mechanical or environ- mental stress factors, which is likely to predispose to OA development (Table 1). 5. Subchondral Bone Adaption in Aging and the Role of Bone Mass in OA The microarchitecture of the skeleton, notably the subchon- dral bone, constantly adapts to mechanical loading. Mechan- otransduction processes lead to bone modeling and remodel- ing. Impaired joint loading patterns trigger high subchondral bone density, probably in order to avoid (micro) fractures and to ensure minimal joint function. Subchondral density can be accurately assessed by computed tomography osteo- absorptiometry (CT-OAM) [34]. Figure 2 shows a tibial plateau of a geriatric patient suﬀering from end stage knee OA who underwent joint replacement. Complete cartilage loss is seen on the medial side. Below, CT-OAM was performed. Highest subchondral bone mineral density (BMD) indicated in red is observed in the region of maximal cartilage damage. On a molecular level, mech- anosensors on osteoblasts have been discovered which induce interleukin-6 and -8 expression within subchondral bone aﬀected by OA upon cyclic mechanical stimulation [35]. This