Citations

Abstract Aging and obesity increase multimorbidity and disability risk, and determining interventions for reversing healthspan decline is a critical public health priority. Exercise and time restricted feeding (TRF) benefit multiple health parameters when initiated in early-life, but their efficacy and safety when initiated at older ages are uncertain. Here, we tested the effects of exercise versus TRF in diet-induced obese, aged mice from 20 to 24 months of age. We characterized healthspan across key domains: body composition, physical, metabolic, and cardiovascular function, activity of daily living (ADL) behavior, and pathology. We demonstrate that both exercise and TRF improved aspects of body composition. Exercise uniquely benefited physical function, and TRF uniquely benefited metabolism, ADL behavior, and circulating indicators of liver pathology. No adverse outcomes were observed in exercised mice, but in contrast, lean mass and cardiovascular maladaptations were observed following TRF. Through a composite index of benefits and risks, we conclude the net healthspan benefits afforded by exercise are more favorable than those of TRF. Extrapolating to obese older adults, exercise is a safe and effective option for healthspan improvement, but additional comprehensive studies are warranted before recommending TRF.

AbstractAging and obesity increase multimorbidity and disability risk, and determining interventions for reversing healthspan decline is a critical public health priority. Exercise and time‐restricted feeding (TRF) benefit multiple health parameters when initiated in early life, but their efficacy and safety when initiated at older ages are uncertain. Here, we tested the effects of exercise versus TRF in diet‐induced obese, aged mice from 20 to 24 months of age. We characterized healthspan across key domains: body composition, physical, metabolic, and cardiovascular function, activity of daily living (ADL) behavior, and pathology. We demonstrate that both exercise and TRF improved aspects of body composition. Exercise uniquely benefited physical function, and TRF uniquely benefited metabolism, ADL behavior, and circulating indicators of liver pathology. No adverse outcomes were observed in exercised mice, but in contrast, lean mass and cardiovascular maladaptations were observed following TRF. Through a composite index of benefits and risks, we conclude the net healthspan benefits afforded by exercise are more favorable than those of TRF. Extrapolating to obese older adults, exercise is a safe and effective option for healthspan improvement, but additional comprehensive studies are warranted before recommending TRF.

Abstract Adipose tissue inflammation and dysfunction are associated with obesity‐related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug‐inducible “suicide” genes driven by the p16 Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra‐abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity‐related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity‐related metabolic dysfunction and its complications.

The balance between local asymmetric dimethylarginine (ADMA) levels and dimethylarginine dimethylaminohydrolase 1 (DDAH1) activity is a major determinant of local nitric oxide synthase activity. Previous studies suggested that increased plasma ADMA levels are strongly associated with the aortic valve stenosis, causal or mechanistic links have yet to be elucidated. Thus, the aim of this study was to investigate whether reduction or overexpression of DDAH1 protects aortic valve dysfunction in mice. To experimentally alter DDAH1 levels, we used low density lipoprotein receptor deficient, apolipoprotein B100-only (LA) mice that were either DDAH1 wild-type (D +/+ or D 0/0 ), heterozygous (D +/- ), or transgenic/overexpressing (D Tg/0 ) littermates. All mice were fed a western diet for 6 months. Reducing DDAH1 increased plasma ADMA levels (LA-D +/+ =0.89 ± 0.02 μmol/L, LA-D +/- =1.1 ± 0.02 μmol/L, p< 0.05) and blood pressure (LA-D +/+ = 125 ± 4 mmHg, LA-D +/- = 141 ± 3 mmHg, p< 0.05) following 6 months of western diet feeding. Critically, aortic valve function was significantly worse in DDAH1-deficient mice (LA-D +/+ 2.20±0.09 m/sec versus LA-D +/- =2.41±0.11 m/sec, p< 0.05) and was associated with higher levels of valve cusp calcification (Alizarin Red, LA-D +/+ = 10 ± 3% versus LA-D +/- = 20 ± 4%). Reciprocally, overexpression of DDAH1 in hypercholesterolemic littermates reduced ADMA levels (LA-D 0/0 = 1.4 ± 0.2 μmol/L, LA-D Tg/0 = 0.7 ± 0.1μmol/L, p< 0.05) and systolic blood pressure (LA-D 0/0 = 136 ± 6 mmHg, LA-D Tg/0 = 124 ± 4 mmHg, p< 0.05). Interestingly, aortic valve function was not improved by overexpression of DDAH1 (LA-D 0/0 = 2.36 ± 0.06 m/sec versus LA-D Tg/0 mice (2.43 ± 0.21 m/sec), nor was valvular calcification. These results suggest that while endogenous levels of DDAH1 expression protect against increases in circulating ADMA, blood pressure, valvular calcification, and valvular dysfunction. Interestingly, overexpression of DDAH1 does not appear to confer additional protection against progression of valvular stenosis. Collectively, our data suggest effective therapeutic harnessing of the DDAH1/ADMA/NOS axis will require targeting of downstream effector molecules—such as oxidation state of soluble guanylate cyclase—known to be pathologically altered and rate limiting in a variety of cardiovascular diseases.

ABSTRACT Recent studies have demonstrated an effect of neurotrophins, particularly brain‐derived neurotrophic factor (BDNF), on airway contractility [ via increased airway smooth muscle (ASM) intracellular calcium [Ca 2+ ] i ] and remodeling (ASM proliferation and extracellular matrix formation) in the context of airway disease. In the present study, we examined the role of BDNF in allergen‐induced airway inflammation using 2 transgenic models: 1 ) tropomyosin‐related kinase B (TrkB) conditional knockin (TrkBKI) mice allowing for inducible, reversible disruption of BDNF receptor kinase activity by administration of 1NMPP1, a PP1 derivative, and 2) smooth muscle‐specific BDNF knockout (BDNF fl/fl /SMMHCll Cre/0 ) mice. Adult mice were intranasally challenged with PBS or mixed allergen ( Altemaria alternata, Aspergillus fumigatus , house dust mite, and ovalbumin) for 4 wk. Our data show that administration of 1NMPP1 in TrkBKI mice during the 4‐wk allergen challenge blunted airway hyper‐responsiveness (AHR) and reduced fibronectin mRNA expression in ASM layers but did not reduce inflammation per se . Smooth muscle‐specific deletion of BDNF reduced AHR and blunted airway fibrosis but did not significantly alter airway inflammation. Together, our novel data indicate that TrkB signaling is a key modulator of AHR and that smooth muscle‐derived BDNF mediates these effects during allergic airway inflammation.—Britt, R. D., Jr., Thompson, M. A., Wicher, S. A., Manlove, L. J., Roesler, A., Fang, Y.‐H., Roos, C., Smith, L., Miller, J. D., Pabelick, C. M., Prakash, Y. S. Smooth muscle brain‐derived neurotrophic factor contributes to airway hyperreactivity in a mouse model of allergic asthma. FASEB J. 33, 3024–3034 (2019). www.fasebj.org

An open-circuit (OpCirc) acetylene uptake cardiac output (Q˙t) method was modified for use during exercise. Two computational techniques were used. OpCirc1 was based on the integrated uptake vs. end-tidal change in acetylene, and OpCirc2 was based on an iterative finite difference modeling method. Six subjects [28–44 yr, peak oxygen consumption (V˙o2) = 120% predicted] performed cycle ergometry exercise to compareQ˙t using OpCirc and direct Fick methods. An incremental protocol was repeated twice, separated by a 10-min rest, and subsequently subjects exercised at 85–90% of their peak work rate. Coefficient of variation of the OpCirc methods and Fick were highest at rest (OpCirc1, 7%, OpCirc2, 12%, Fick, 10%) but were lower at moderate to high exercise intensities (OpCirc1, 3%, OpCirc2, 3%, Fick, 5%). OpCirc1 and OpCirc2 Q˙t correlated highly with Fick Q˙t( R2= 0.90 and 0.89, respectively). There were minimal differences between OpCirc1 and OpCirc2 compared with Fick up to moderate-intensity exercise (<70% peakV˙o2); however, both techniques tended to underestimate Fick at >70% peakV˙o2. These differences became significant for OpCirc1 only. Part of the differences between Fick and OpCirc methods at the higher exercise intensities are likely related to inhomogeneities in ventilation and perfusion matching ( R2= 0.36 for Fick − OpCirc1 vs. alveolar-to-arterial oxygen tension difference). In conclusion, both OpCirc methods provided reproducible, reliable measurements ofQ˙t during mild to moderate exercise. However, only OpCirc2 appeared to approximate FickQ˙t at the higher work intensities.

This study evaluated the hypothesis that active muscle blood flow is lower during exercise at a given submaximal power output after aerobic conditioning as a result of unchanged cardiac output and blunted splanchnic vasoconstriction. Eight untrained subjects (4 men, 4 women, 23–31 yr) performed high-intensity aerobic training for 9–12 wk. Leg blood flow (femoral vein thermodilution), splanchnic blood flow (indocyanine green clearance), cardiac output (acetylene rebreathing), whole body O2 uptake (V˙o 2), and arterial-venous blood gases were measured before and after training at identical submaximal power outputs (70 and 140 W; upright 2-leg cycling). Training increased ( P < 0.05) peak V˙o 2(12–36%) but did not significantly change submaximalV˙o 2 or cardiac output. Leg blood flow during both submaximal power outputs averaged 18% lower after training ( P = 0.001; n = 7), but these reductions were not correlated with changes in splanchnic vasoconstriction. Submaximal leg V˙o 2 was also lower after training. These findings support the hypothesis that aerobic training reduces active muscle blood flow at a given submaximal power output. However, changes in leg and splanchnic blood flow resulting from high-intensity training may not be causally linked.

Our understanding of the fundamental biology and identification of efficacious therapeutic targets in aortic valve stenosis has lagged far behind the fields of atherosclerosis and heart failure. In this review, we highlight the most clinically relevant problems facing men and women with fibrocalcific aortic valve stenosis, discuss the fundamental biology underlying valve calcification and fibrosis, and identify key molecular points of intersection with sex hormone signaling.