DISCUSSION
myocardial infarction, osteoarthritis, inflammation, mitochondrial dysfunction, anemia, proteotoxic stress, gout
MYOCARDIAL INFARCTION, OSTEOARTHRITIS, INFLAMMATION, ANEMIA, DISORDERS, LUNG CANCERS, SECONDARY, EVENTS, GOUT, MITOCHONDRIAL DYSFUNCTION, PATHOGENESIS
CANTOS has previously demonstrated that IL‐1b inhibition with canakinumab, compared with placebo, lowers the inflammatory biomarkers CRP and IL6 by 35 to 45 percent and significantly reduces rates of several clinical disorders associated with aging, including cardiovascular events, lung cancers, gout, anemia, and large joint osteoarthritis (Ferrucci & Fabbri, Although the underlying pathogenesis of frailty remains poorly defined, inflammation has been identified as a key contributor across diverse observational studies (Fulop et al., What are the implications of our study? It is possible that frailty may develop secondary to upstream hallmarks of aging phenomena that may contribute to inflammation, but which are not fully controlled by anti‐inflammatory interventions such as canakinumab. As such, future work should consider other hallmarks of aging, such as mitochondrial dysfunction, proteotoxic stress, senescence, and stem cell exhaustion that may be associated with frailty in those who also have inflammation, when considering therapeutics that target those mechanisms (Kulkarni et al., While prior evidence from randomized treatment trials of anti‐inflammatory agents to reduce frailty is scant, observational studies have been inconsistent. In an observational study that examined the role of aspirin and NSAIDs on risk of frailty in 12,101 men, regular aspirin use over an average of 11 years was associated with a significant reduction in frailty (Orkaby et al., We elected not to include CRP or IL‐6 in the frailty index for this study, as canakinumab is well‐known to lower these inflammatory biomarkers (Ridker et al., It is notable that risk of a major adverse cardiovascular events was highest in those who entered the trial with a frailty index >0.2, consistent with the prior literature that has highlighted the increased risk of cardiovascular events among those who are frail (Damluji et al., There are considerable strengths to our study, including its large sample size, prospective follow‐up, use of well‐validated frailty measures, and most important, random allocation to anti‐inflammatory therapy or placebo. Nonetheless, limitations of our study merit consideration. Although CANTOS participants had all survived myocardial infarction prior to trial initiation, participants were still healthier than the general older adult population. This is reflected in the maximal FI value in CANTOS of 0.46, which is lower than maximal FI values of 0.7 in US Medicare populations (Kim et al., 