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Cellular senescence is a driver of many age-related pathologies. There is an active search for pharmaceuticals termed senolytics that can mitigate or remove senescent cells in vivo by targeting genes that promote the survival of senescent cells. We utilized single-cell RNA sequencing to identify CRYAB as a robust senescence-induced gene and potential target for senolysis. Using chemical inhibitor screening for CRYAB disruption, we identified 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis, as a potent senolytic. We then validated 25HC as a senolytic in mouse and human cells in culture and in vivo in mouse skeletal muscle. Thus, 25HC represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver.

Presents a checklist designed to help graduate students and postdoctoral fellows critically analyze original research papers. (Author/WRM)

Background Electronic hookah (e-hookah) vaping has increased in popularity among youth, who endorse unsubstantiated claims that flavored aerosol is detoxified as it passes through water. However, e-hookahs deliver nicotine by creating an aerosol of fine and ultrafine particles and other oxidants that may reduce the bioavailability of nitric oxide and impair endothelial function secondary to formation of oxygen-derived free radicals. Methods and Results We examined the acute effects of e-hookah vaping on endothelial function, and the extent to which increased oxidative stress contributes to the vaping-induced vascular impairment. Twenty-six healthy young adult habitual hookah smokers were invited to vape a 30-minute e-hookah session to evaluate the impact on endothelial function measured by brachial artery flow-mediated dilation (FMD). To test for oxidative stress mediation, plasma total antioxidant capacity levels were measured and the effect of e-hookah vaping on FMD was examined before and after intravenous infusion of the antioxidant ascorbic acid (n=11). Plasma nicotine and exhaled carbon monoxide levels were measured before and after the vaping session. Measurements were performed before and after sham-vaping control experiments (n=10). E-hookah vaping, which increased plasma nicotine (+4.93±0.92 ng/mL, P<0.001; mean±SE) with no changes in exhaled carbon monoxide (-0.15±0.17 ppm; P=0.479), increased mean arterial pressure (11±1 mm Hg, P<0.001) and acutely decreased FMD from 5.79±0.58% to 4.39±0.46% (P<0.001). Ascorbic acid infusion, which increased plasma total antioxidant capacity 5-fold, increased FMD at baseline (5.98±0.66% versus 9.46±0.87%, P<0.001), and prevented the acute FMD impairment by e-hookah vaping (9.46±0.87% versus 8.74±0.84%, P=0.002). All parameters were unchanged during sham studies. Conclusions E-hookah vaping has adverse effects on vascular function, likely mediated by oxidative stress, which overtime could a

Inspiratory muscle strength training (IMST) is a form of resistive breathing training traditionally used to strengthen respiratory muscles. In our hands, we have reported significant reductions in blood pressure following six weeks of daily IMST that are driven in part by reductions in systemic vascular resistance. The work set forth in this dissertation addresses outstanding questions resulting from our previous work. Study 1 characterizes the acute cardiovascular and sympathetic response(s) to a single bout of IMST in healthy young adults. We show that IMST acutely increases heart rate with concomitant reductions in sympathetic nervous system outflow. Study 2 assesses the potential for six weeks IMST to alter the cardiovascular response to respiratory muscle fatigue in college-aged adults. The results of this study suggest IMST improves respiratory muscle endurance and as a result, blunts the blood pressure and heart rate responses to respiratory muscle fatigue. Finally, Study 3 documents the effects of six weeks IMST on overnight blood pressure and mediators of systemic vascular resistance in older adults diagnosed with obstructive sleep apnea. In a population that exhibits elevated blood pressure and sympathetic nervous system activity, we show that IMST significantly lowers daytime blood pressure, nighttime systolic blood pressure and resting sympathetic nervous system activity. These studies are the first to characterize the acute cardiovascular effects of IMST and to explore the effects of IMST on mediators of systemic vascular resistance in both healthy and patient populations.

Obesity and the metabolic syndrome are characterized by chronic, low-grade inflammation mainly originating from expanding adipose tissue and resulting in inhibition of insulin signaling and disruption of glycemic control.Transgenic mice expressing human interleukin 37 (IL-37),an anti-inflammatory cytokine of the IL-1 family,are protected against metabolic syndrome when fed a high-fat diet (HFD) containing 45% fat. Here, we examined whether treatment with recombinant IL-37 ameliorates established insulin resistance and obesity-induced inflammation. WT mice were fed a HFD for 22 weeks and then treated daily with IL-37 (1 ug/mouse) during the last 2 weeks. Compared with vehicle only-treated mice, IL-37-treated mice exhibited reduced insulin in the plasma and had significant improvements in glucose tolerance and in insulin content of the islets.The IL-37 treatment also increased the levels of circulating IL-1 receptor antagonist. Cultured adipose tissues revealed that IL-37 treatment significantly decreases spontaneous secretions of IL-1β, tumor necrosis factor α (TNFα), and CXC motif chemokine ligand 1 (CXCL-1). We also fed mice a 60% fat diet with concomitant daily IL-37 for 2 weeks and observed decreased secretion of IL-1β, TNFα, and IL-6 and reduced intracellular levels of IL-1β in the liver and adipose tissue, along with improved plasma glucose clearance. Compared with vehicle treatment, these IL-37-treated mice had no apparent weight gain. In human adipose tissue cultures, the presence of 50 pM IL-37 reduced spontaneous release of TNF and 50% of lipopolysaccharide-induced TNFα. These findings indicate that IL-37's anti-inflammatory effects can ameliorate established metabolic disturbances during obesity.

Evidence suggests different sections of the arteriolar network supplying muscle can respond independently and this may provide a mechanism for the localized distribution of blood flow. This hypothesis was tested in the microcirculation of the cat sartorius muscle by measurement of arteriolar diameter changes during muscle contraction and sympathetic nerve stimulation in each consecutive section of the network. The diameter changes were referenced to the initial distribution of resistance across the network, as determined from arteriolar pressure measurements and morphometric data. This led to an estimate of the change in network resistance. Unlike previous reports, the most distal arterioles dilated little during muscle contraction and our resistance estimate indicates these vessels play an insignificant role in functional hyperemia. The more proximal, third order arterioles dilated proportionately more than other arteriolar orders and made the largest single contribution to resting resistance. Similarly, these vessels were the largest single site of resistance change during sympathetic stimulation. Together, these findings suggest the third order arterioles play a dominant role in regulating flow to the capillaries that each supplies. Antagonism of sympathetic control during muscle contraction has been attributed to direct inhibition of vascular smooth muscle contraction and to inhibition of sympathetic neurotransmission. Evidence to support the latter mechanism comes from the observation that functional dilation is reduced with exogenous norepinephrine as compared to sympathetic stimulation. However, exogenous norepinephrine may bind to both alpha-1 and alpha-2 adrenergic receptors, whereas that released by sympathetic stimulation may bind primarily to alpha-1 receptors. Since this difference could be significant, functional dilation after systemic injection of norepinephrine or phenylephrine, a selective alpha-1 agonist, was compared to that during sympathetic st