Journal of Aging Research demonstrated by a meta-analysis of 32 controlled trials [40]. Furthermore, physical activity seems to have preventive eﬀects on OA. A consensus stating that performing struc- tured strengthening exercises has a favorable eﬀect on pain and functioning in sedentary patients with knee OA has been formulated by several organisations, for example, by the MOVE consensus [41]. In ﬁrst line, physical activity in OA patients encounters clinical or subclinical muscle atro- phy which has implications on joint stability [42], but also stimulates weight reduction [43]. 8. The Role of Immunosenescence in OA In the last decade, inﬂammation in OA has attracted increas- ing interest. A growing arsenal of anti-inﬂammatory com- pounds now is available which successfully works in inﬂam- matory arthritis. On the search for disease modifying osteo- arthritis drugs (DMOADs), some of those compounds have also been successfully applied to OA, at least in case reports or case series [44]. Inﬂammation in OA is often encountered clinically by swelling of the joint, redness and night pain. This “disease activation” in OA typically occurs in episodes, either resolving spontaneously, or sometimes by the intra- articular injection of steroids [45]. The eﬃcacy of steroids in activated OA is well documented and safe, if applied under sterile conditions and in right intervals. Synovial inﬁltration by inﬂammatory cells such as macrophages, mast cells or lymphocytes occurs in around 50% of the patients [6]. In MRI studies, synovitis shown with or without contrast agent correlates with pain and also radiological progression of OA. The inﬂammatory status of the joint is also reﬂected by increased pro-inﬂammatory cytokine levels such as TNF-alpha or IL-1 [46]. This is likely a result of the inﬂammatory cell inﬁltration in the joint and mast cell activation. Interestingly, recent ﬁndings indi- cate that mast cells, but also subchondral osteoblasts express mechanoreceptors which change their expression pattern upon mechanical stimulation, for example, by the expres- sion of IL-8 [35]. But also synovial ﬁbroblasts and even chondrocytes produce more proinﬂammatory cytokines and participate in inﬂammation. In animal models, it has been shown that exercise leads to an increased expression of interleukin-10 in the joint [47]. IL-10 is a strong anti-inﬂammatory mediator and therefore likely implicated in the resolution of mechanically induced inﬂammation or irritation (Figure 3). Immunosenescence is characterized by a reduced capac- ity of immune cells to encounter antigens and resolution of inﬂammation. Recent data showed that physical activity indeed counter- acts immunoscenesence [48]. Although the exact mechanism is still unclear, exercise impacts multiple aspects of the immune response including T-cell phenotype, T-cell pro- liferation, and as for IL-10, cytokine expression [49]. 9. Cell Renewal and Stem Cell Capacity in OA Cartilage has a low regeneration capacity due to lack of viable progenitor cells. Mesenchymal stem cells are postulated to Inﬂammatory Anti-inﬂammatory OA IL-1 IL-6 TNF IL-10 Physical activity 5 Figure 3: Cytokine expression at rest and during physical activity. OA: osteoarthritis, IL: interleukin, TNF: tumor necrosis factor. be involved in connective tissue homeostasis and repair. The failure of repair mechanisms in connective tissues in OA is compelling. Indeed, reduced numbers of multipotent mesen- chymal progenitor CD105+/CD166+ cells have been detect- ed in the elderly. Furthermore, a lower number and lower chondrogenic and osteogenic diﬀerentiation capacity in pro- genitors cells from aged individuals have been demonstrated [50, 51]. Multipotent stem cells were also isolated from human cruciate ligaments suggesting their regenerative capa- city also occurring in ligament structures [52]. Increased numbers of MCS are seen in the synovial ﬂuid of patients with OA indicating a biological response [53]. These obser- vations open the way for new therapeutic options notably in the elderly by applying those cells in the joints. Current studies investigate the possibility to obtain autologous MSC from synovial tissue in OA patients [54]. On the other hand, MSC can be obtained from other tissue, for example, adipose tissue. Notwithstanding, controlled clinical trials showing a clear eﬃcacy of MSC treatment in OA, are still lacking. 10. Conclusion Aging alters the human musculoskeletal system on a molecu- lar and functional levels. Cellular renewal, matrix modiﬁca- tion, and immunosenescence aﬀect the regeneration capacity of connective tissue in general, but notably of bone and cartilage. This explains the important role of aging in the development and progression of OA. On the other side, several features observed during aging such as muscle atro- phy, BMD, and inﬂammation are potentially reversible and should be counteracted, regardless of age. References [1] J. W. Bijlsma, F. Berenbaum, and F. P. Lafeber, “Osteoarthritis: an update with relevance for clinical practice,” The Lancet, vol. 377, no. 9783, pp. 2115–2126, 2011. [2] T. Aigner, J. Rose, J. Martin, and J. Buckwalter, “Aging theories of primary osteoarthritis: from epidemiology to molecular