br Senolytics Pre clinical Studies Demonstrating Phenotype A

Senolytics: Pre-clinical Studies Demonstrating Phenotype Alleviation In mice, senolytics alleviate a range of conditions that have been associated with effects of senescent cells. So far, these include effects on cardiac, vascular, metabolic, neurological, radiation-induced, chemotherapy-induced, renal, and pulmonary function as well as mobility and frailty in several animal models (Zhu et al., 2015b; Xu et al., 2015a; Roos et al., 2016; Schafer et al., 2017; Chang et al., 2016; Baar et al., 2017 #4270). The first demonstration that clearing senescent cells has any effects on phenotypes in naturally-aged animals, as opposed to the progeroid INK-ATTAC;BubR1H/H mice from which p16 senescent cells had been reduced by AP20187 (Baker et al., 2011), was reported in 24month old mice treated with D+Q (Zhu et al., 2015b). In these mice, cardiac ejection fraction and fractional shortening, measured by echocardiography, were improved within 4days after a single course of D+Q, which was sufficient to clear senescent cells from multiple tissues in the same animals. In these old mice, D+Q also enhanced aortic vascular reactivity, with modest improvement in endothelium-dependent relaxation elicited by 5-alpha reductase inhibitors and substantially-improved vascular smooth muscle cell relaxation in response to nitroprusside. This alleviation of vascular hypo-reactivity in old mice was confirmed in old mice as well as hypercholesterolemic high fat-fed ApoE mice that develop an atherosclerosis-like state in another study (Roos et al., 2016). Genetic removal of senescent cells in INK-ATTAC mice paralleled the effects of D+Q. Furthermore, vascular calcification was reduced in these mice. Importantly, there are no current treatments available for the many atherosclerotic or elderly subjects with hypo-reactivity and calcification of major blood vessels. These vascular changes are associated with and may contribute to systolic hypertension (and therefore stroke risk), atrial fibrillation, and congestive heart failure in elderly or atherosclerotic humans (Chaikriangkrai et al., 2017; Lanzer et al., 2014). Perhaps senolytics will become the first effective treatment for this common condition. Subsequent to the studies showing that decreasing senescent cell abundance improves cardiac function and alleviation of vascular hypo-reactivity, reducing macrophages with senescent-like properties by genetic targeting of p16 cells or administering N was suggested to be an approach for stabilizing plaques, at least in the atherosclerosis-like state in LDL-R−/− mice fed a high fat diet (Childs et al., 2016). This adds another option for slowing plaque development or stabilizing plaques to the treatments that are already available for this indication, such as statins. This study confirmed an earlier one demonstrating that suppressing activated macrophages stabilizes atherosclerotic plaques in CD11b diphtheria toxin receptor transgenic mice (Stoneman et al., 2007). Thus, senolytics may have multiple applications in cardiovascular disease. Intermittent administration of D+Q alleviated frailty, neurological dysfunction, osteoporosis, and vertebral disk degeneration related to loss of glycosaminoglycans in Ercc mice, which have an accelerated aging-like state (Zhu et al., 2015b). Furthermore, in mice with impaired mobility due to radiation of one of their legs 3months previously, treadmill endurance improved within 4days after completing a single course of D+Q. This improvement persisted for at least 7months. D+Q has an elimination half-life of a few hours. These outcomes following intermittent or single courses of agents with short elimination half-lives are consistent with the long-lasting type of effect expected from reducing senescent cell abundance, as opposed to what would be expected if D+Q had to be continuously present to suppress or activate cellular processes by occupying a receptor or acting on an enzyme. Thus, intermittent rather than continuous treatment with senolytics may be effective in alleviating senescence-related diseases or disorders, allowing these agents to be administered during periods of good health and potentially decreasing risk of side-effects.