diet compared to controls led to a severe increase in OA symptoms. Doses of free cholesterol as recommended clinically resulted in overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. Hypertrophic and degradative markers were upregulated in chondrocytes, resulting in increased breakdown of the cartilage matrix. The authors reported that the severity of these diet-induced OA symptoms was reduced by the application of atorvastatin and a mitochondrial-targeting antioxidant, thus implicating that hypercholesterolemia promotes OA progression by mitochondrial dysfunction in chondrocytes, which was in part a result of increasing ROS production and apoptosis. In a post-hoc analysis of the SEKOIA trial, the impact of statin use on radiological progression in patients with radiological and symptomatic knee OA was investigated. Results demonstrated that the use of statins was related to radiological deterioration over the course of 3 years irrespective of other potentially related factors, such as obesity or T2DM hypertension, disease duration, symptom intensity and radiological severity 42. Another trial investigated the association between statin therapy initiation and incidence of hand OA, but no association was observed in this study 43. A pooled analysis based on time-to-event analysis of four population-based large cohorts demonstrated that statin use is not associated with reduced risk of consultation or surgery for OA of the hip or knee . It appears that repurposing some drugs such as metformin might identify valuable candidates for the treatment of OA in the context of metabolic syndrome. However, clinical studies assessing the effect of other compounds, such as statins, on knee OA progression have shown conflicting results. In line with this, more data and a priori clinical studies are necessary to correlate unambiguously the increase of metabolic syndrome in modern times with OA. Age is a key risk factor for the development of OA, and age-related changes within the joint might represent targets for therapy. Aging and OA are closely related but still occur independently of one another. Some hallmarks of aging can influence the development of OA, such as genomic instability, telomere attrition, epigenetic alterations, loss of proteolytic homeostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication 137, 138. So far, no human clinical trials have been designed to specifically target aging-related processes, but pre-clinical studies targeting some of the age-related factors generated promising data which may lead to novel therapeutic strategies. In the meantime, there are several “senolytics” known, which have the potential to qualify as therapeutic agents to treat OA. Cell cycle inhibitors Cellular senescence leads to the senescence-associated secretory phenotype (SASP), which is characterized by cell-cycle arrest, enhanced production of pro-inflammatory cytokines and other factors 138, and increased expression of the cell cycle inhibitor p16 Ink4a 139. Baker et al. addressed the physiological relevance and effects of naturally occurring senescent cells. The authors injected a transgene, INK-ATTAC, which was previously established in their lab, into p16 Ink4a-expressing cells of wild-type mice to induce apoptosis 140. Their study did not address OA specifically, but they convincingly demonstrated that p16 Ink4a-positive cells accumulate during adulthood and have a detrimental effect on lifespan and encourage age-dependent alterations in various organs. Removing these cells could offer an attractive approach to healthy lifespan extension in joint tissues, which overexpress this cell cycle inhibitor. A direct connection to OA was tested by using the p16-3MR transgenic mouse, which harbors a Introducing OA in this mouse strain after anterior cruciate ligament transection (ACLT) allowed the selective following and removal of senescent cells. I.a. injection of a senolytic molecule,