Near-infrared spectroscopy detects age-related differences in skeletal muscle oxidative function: promising implications for geroscience

Age is the greatest risk factor for chronic disease and is associated with a marked decline in functional capacity and quality of life. A key factor contributing to loss of function in older adults is the decline in skeletal muscle function. While the exact mechanism(s) remains incompletely understood, age-related mitochondrial dysfunction is thought to play a major role. To explore this question further, we studied 15 independently living seniors (age: 72 ± 5 years; m/f: 4/11; BMI: 27.6 ± 5.9) and 17 young volunteers (age: 25 ± 4 years; m/f: 8/9; BMI: 24.0 ± 3.3). Skeletal muscle oxidative function was measured in forearm muscle from the recovery kinetics of muscle oxygen consumption using near-infrared spectroscopy (NIRS). Muscle oxygen consumption was calculated as the slope of change in hemoglobin saturation during a series of rapid, supra-systolic arterial cuff occlusions following a brief bout of exercise. Aging was associated with a significant prolongation of the time constant of oxidative recovery following exercise (51.8 ± 5.4 sec vs. 37.1 ± 2.1 sec, P = 0.04, old vs. young, respectively). This finding suggests an overall reduction in mitochondrial function with age in nonlocomotor skeletal muscle. That these data were obtained using NIRS holds great promise in gerontology for quantitative assessment of skeletal muscle oxidative function at the bed side or clinic

Behavioral changes in FPR2/ALX and Chemr23 receptor knockout mice are exacerbated by prenatal alcohol exposure

IntroductionPrenatal alcohol exposure (PAE) causes neuroinflammation that may contribute to the pathophysiology underlying Fetal Alcohol Spectrum Disorder. Supplementation with omega-3 polyunsaturated fatty acids (PUFAs) has shown success in mitigating effects of PAE in animal models, however, the underlying mechanisms are unknown. Some PUFA metabolites, specialized pro-resolving mediators (SPMs), play a role in the resolution phase of inflammation, and receptors for these are in the brain.MethodsTo test the hypothesis that the SPM receptors FPR2 and ChemR23 play a role in PAE-induced behavioral deficits, we exposed pregnant wild-type (WT) and knockout (KO) mice to alcohol in late gestation and behaviorally tested male and female offspring as adolescents and young adults.ResultsMaternal and fetal outcomes were not different among genotypes, however, growth and behavioral phenotypes in the offspring did differ and the effects of PAE were unique to each line. In the absence of PAE, ChemR23 KO animals showed decreased anxiety-like behavior on the elevated plus maze and FPR2 KO had poor grip strength and low activity compared to age-matched WT mice. WT mice showed improved performance on fear conditioning between adolescence and young adulthood, this was not seen in either KO.DiscussionThis PAE model has subtle effects on WT behavior with lower activity levels in young adults, decreased grip strength in males between test ages, and decreased response to the fear cue indicating an effect of alcohol exposure on learning. The PAE-mediated decreased response to the fear cue was also seen in ChemR23 KO but not FPR2 KO mice, and PAE worsened performance of adolescent FPR2 KO mice on grip strength and activity. Collectively, these findings provide mechanistic insight into how PUFAs could act to attenuate cognitive impairments caused by PAE

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Projecting the Suicide Burden of Climate Change in the United States

Abstract We quantify and monetize changes in suicide incidence across the conterminous United States (U.S.) in response to increasing levels of warming. We develop an integrated health impact assessment model using binned and linear specifications of temperature‐suicide relationship estimates from Mullins and White (2019), in combination with monthly age‐ and sex‐specific baseline suicide incidence rates, projections of six climate models, and population projections at the conterminous U.S. county scale. We evaluate the difference in the annual number of suicides in the U.S. corresponding to 1–6°C of warming compared to 1986–2005 average temperatures (mean U.S. temperatures) and compute 2015 population attributable fractions (PAFs). We use the U.S. Environmental Protection Agency’s Value of a Statistical Life to estimate the economic value of avoiding these mortality impacts. Assuming the 2015 population size, warming of 1–6°C could result in an annual increase of 283–1,660 additional suicide cases, corresponding to a PAF of 0.7%–4.1%. The annual economic value of avoiding these impacts is $2 billion–$3 billion (2015 U.S. dollars, 3% discount rate, and 2015 income level). Estimates based on linear temperature‐suicide relationship specifications are 7% larger than those based on binned temperature specifications. Accounting for displacement decreases estimates by 17%, while accounting for precipitation decreases estimates by 7%. Population growth between 2015 and the future warming degree arrival year increases estimates by 15%–38%. Further research is needed to quantify and monetize other climate‐related mental health outcomes (e.g., anxiety and depression) and to characterize these risks in socially vulnerable populations

Electrophysiological responsiveness to isoproterenol in rat hippocampal slices correlates with changes in [beta]-adrenergic receptor density induced by chronic morphine treatment

The effects of chronic morphine treatment and morphine withdrawal on [beta]-adrenergic receptor density and electrophysiological responsiveness in rat hippocampus were examined. Chronic treatment of rats with morphine for 14 days resulted in a 19% increase in the number of [beta]-adrenergic receptors in hippocampus, as measured by the binding of the specific antagonist [3H]dihydroalprenolol (DHA). In comparison, the number of specific binding sites for [3H]DHA was decreased 27% in hippocampus in morphine-withdrawn animals, compared to saline-treated controls. These alterations in [beta]-adrenergic receptor density were not accompanied by a significant change in the dissociation constant (Kd) for [3H]DHA or in the inhibitory constants (Ki) for the displacement of the [3H]-antagonist by either norepinephrine or isoproterenol. Electrophysiological experiments in the in vitro hippocampal slice preparation revealed that responses to threshold as well as maximal concentrations of isoproterenol were significantly enhanced in morphine-dependent animals, compared to controls, whereas electrophysiological responsiveness to maximal concentrations of isoproterenol was decreased in slices from morphine-withdrawn rats. The results of this study indicate that [beta]-adrenergic receptors in hippocampus are up-regulated during the development of morphine dependence and down-regulated during opiate withdrawal. These changes in hippocampal [beta]-adrenergic receptor density are likely to be of functional relevance since they are manifested in a corresponding increase and decrease, respectively, in electrophysiological responsiveness to an exogenously administered [beta]-adrenergic receptor agonist.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27963/1/0000394.pd

Near-infrared spectroscopy detects age-related differences in skeletal muscle oxidative function: promising implications for geroscience

Age is the greatest risk factor for chronic disease and is associated with a marked decline in functional capacity and quality of life. A key factor contributing to loss of function in older adults is the decline in skeletal muscle function. While the exact mechanism(s) remains incompletely understood, age-related mitochondrial dysfunction is thought to play a major role. To explore this question further, we studied 15 independently living seniors (age: 72 ± 5 years; m/f: 4/11; BMI: 27.6 ± 5.9) and 17 young volunteers (age: 25 ± 4 years; m/f: 8/9; BMI: 24.0 ± 3.3). Skeletal muscle oxidative function was measured in forearm muscle from the recovery kinetics of muscle oxygen consumption using near-infrared spectroscopy (NIRS). Muscle oxygen consumption was calculated as the slope of change in hemoglobin saturation during a series of rapid, supra-systolic arterial cuff occlusions following a brief bout of exercise. Aging was associated with a significant prolongation of the time constant of oxidative recovery following exercise (51.8 ± 5.4 sec vs. 37.1 ± 2.1 sec, P = 0.04, old vs. young, respectively). This finding suggests an overall reduction in mitochondrial function with age in nonlocomotor skeletal muscle. That these data were obtained using NIRS holds great promise in gerontology for quantitative assessment of skeletal muscle oxidative function at the bed side or clinic

Dual Wavelength Diffuse Correlation Spectroscopy: A Novel Tool for Identifying Determinants of Oxygen Consumption

Near-infrared diffuse correlation spectroscopy (DCS) is a novel method for measuring microvascular skeletal muscle blood flow. Our lab recently found excellent agreement between single wavelength DCS and Doppler ultrasound of the brachial artery during rhythmic handgrip exercise. PURPOSE: Here, we report new data utilizing a dual wavelength DCS system (785nm and 852nm), which extends our prior work by combining novel microvascular perfusion assessment with real-time quantification of tissue oxygenation. METHODS: We enrolled eight individuals (male/female: 3/5, mean: age 48±22 (range: 22-76 years), height 170±8cm, and weight 75±12kg). Subjects were instrumented with the DCS probe placed over the belly of the flexor digitorum profundus. Duplex ultrasound of the brachial artery was performed concurrently to provide and additional measure of skeletal muscle blood flow. Each subject performed two bouts of rhythmic hand grip exercise at 20% of their maximum voluntary contraction (MVC). Resting baseline data were acquired prior to each bout of exercise, and each period of data collection were separated by a minimum of 10 minutes of rest. The data derived from both rest and exercise periods were averaged. RESULTS: As reported previously using our single wavelength DCS device, blood flow index (BFI, the primary output from DCS) increased significantly (119+37%) with exercise. We also observed a 1.9+1.1% change in oxyhemoglobin and 21.8+10.0% change in deoxyhemoglobin resulting in a -5.9±2.6% change in tissue saturation with exercise. Using these data, relative muscle oxygen consumption (rmVO2) was calculated and found to increase by 160.2+55.4%. The novelty of this new approach is best illustrated by a case-comparison between two subjects, who performed nearly equivalent absolute (11 vs 10 kg) and relative work (20%), and yet achieved strikingly different levels of oxygen utilization during exercise (ΔrmO2 = 307% vs. 214%, Case A vs. Case B respectively). This disparity appears to be attributable to muscle oxygen extraction as both brachial artery blood flow and microvascular perfusion (by DCS) were similar in both subjects. By contrast, Case A exhibited a much greater change in StO2 (-17.8%) compared to Case B, whose StO2 more closely mirrored the group average (-6.8%). To aid in the interpretation of these results, we evaluated skeletal muscle oxidative capacity in both subjects using an established NIRS-based cuff occlusion protocol (Rosenberry et al. 2018. JoVE). Remarkably, these additional data corroborated our hypothesis; Case A exhibited a much faster muscle oxygen consumption recovery time (34 seconds) whereas Case B’s recovery time was 93 seconds. CONCLUSION: Taken together, these data establish strong proof-of-concept that dual wavelength DCS can provide valuable mechanistic insight into the determinants of oxygen consumption