Repetitive element transcript accumulation is associated with inflammaging in humans.

Chronic, low-grade inflammation increases with aging, contributing to functional declines and diseases that reduce healthspan. Growing evidence suggests that transcripts from repetitive elements (RE) in the genome contribute to this "inflammaging" by stimulating innate immune activation, but evidence of RE-associated inflammation with aging in humans is limited. Here, we present transcriptomic and clinical data showing that RE transcript levels are positively related to gene expression of innate immune sensors, and to serum interleukin 6 (a marker of systemic inflammation), in a large group of middle-aged and older adults. We also: (1) use transcriptomics and whole-genome bisulfite (methylation) sequencing to show that many RE may be hypomethylated with aging, and that aerobic exercise, a healthspan-extending intervention, reduces RE transcript levels and increases RE methylation in older adults; and (2) extend our findings in a secondary dataset demonstrating age-related changes in RE chromatin accessibility. Collectively, our data support the idea that age-related RE transcript accumulation may play a role in inflammaging in humans, and that RE dysregulation with aging may be due in part to upstream epigenetic changes.

Novel whole blood transcriptome signatures of changes in maximal aerobic capacity in response to endurance exercise training in healthy women.

Maximal aerobic exercise capacity [maximal oxygen consumption (V̇o2max)] is one of the strongest predictors of morbidity and mortality. Aerobic exercise training can increase V̇o2max, but inter-individual variability is marked and unexplained physiologically. The mechanisms underlying this variability have major clinical implications for extending human healthspan. Here, we report a novel transcriptome signature related to ΔV̇o2max with exercise training detected in whole blood RNA. We used RNA-Seq to characterize transcriptomic signatures of ΔV̇o2max in healthy women who completed a 16-wk randomized controlled trial comparing supervised, higher versus lower aerobic exercise training volume and intensity (4 training groups, fully crossed). We found significant baseline gene expression differences in subjects who responded to aerobic exercise training with robust versus little/no ΔV̇o2max, and differentially expressed genes/transcripts were mostly related to inflammatory signaling and mitochondrial function/protein translation. Baseline gene expression signatures associated with robust versus little/no ΔV̇o2max were also modulated by exercise training in a dose-dependent manner, and they predicted ΔV̇o2max in this and a separate dataset. Collectively, our data demonstrate the potential utility of using whole blood transcriptomics to study the biology of inter-individual variability in responsiveness to the same exercise training stimulus.

The reverse transcriptase inhibitor 3TC protects against age-related cognitive dysfunction.

Aging is the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease. Major hallmarks of brain aging include neuroinflammation/immune activation and reduced neuronal health/function. These processes contribute to cognitive dysfunction (a key risk factor for Alzheimer's disease), but their upstream causes are incompletely understood. Age-related increases in transposable element (TE) transcripts might contribute to reduced cognitive function with brain aging, as the reverse transcriptase inhibitor 3TC reduces inflammation in peripheral tissues and TE transcripts have been linked with tau pathology in Alzheimer's disease. However, the effects of 3TC on cognitive function with aging have not been investigated. Here, in support of a role for TE transcripts in brain aging/cognitive decline, we show that 3TC: (a) improves cognitive function and reduces neuroinflammation in old wild-type mice; (b) preserves neuronal health with aging in mice and Caenorhabditis elegans; and (c) enhances cognitive function in a mouse model of tauopathy. We also provide insight on potential underlying mechanisms, as well as evidence of translational relevance for these observations by showing that TE transcripts accumulate with brain aging in humans, and that these age-related increases intersect with those observed in Alzheimer's disease. Collectively, our results suggest that TE transcript accumulation during aging may contribute to cognitive decline and neurodegeneration, and that targeting these events with reverse transcriptase inhibitors like 3TC could be a viable therapeutic strategy.

Daily blueberry consumption for 12 weeks improves endothelial function in postmenopausal women with above-normal blood pressure through reductions in oxidative stress: a randomized controlled trial.

Estrogen-deficient postmenopausal women have oxidative stress-mediated suppression of endothelial function that is exacerbated by high blood pressure. Previous research suggests blueberries may improve endothelial function through reductions in oxidative stress, while also exerting other cardiovascular benefits. The objective of this study was to examine the efficacy of blueberries to improve endothelial function and blood pressure in postmenopausal women with above-normal blood pressure, and to identify potential mechanisms for improvements in endothelial function. A randomized, double-blind, placebo-controlled, parallel-arm clinical trial was performed, where postmenopausal women aged 45-65 years with elevated blood pressure or stage 1-hypertension (total n = 43, endothelial function n = 32) consumed 22 g day-1 of freeze-dried highbush blueberry powder or placebo powder for 12 weeks. Endothelial function was assessed at baseline and 12 weeks through ultrasound measurement of brachial artery flow-mediated dilation (FMD) normalized to shear rate area under the curve (FMD/SRAUC) before and after intravenous infusion of a supraphysiologic dose of ascorbic acid to evaluate whether FMD improvements were mediated by reduced oxidative stress. Hemodynamics, arterial stiffness, cardiometabolic blood biomarkers, and plasma (poly)phenol metabolites were assessed at baseline and 4, 8, and 12 weeks, and venous endothelial cell protein expression was assessed at baseline and 12 weeks. Absolute FMD/SRAUC was 96% higher following blueberry consumption compared to baseline (p < 0.05) but unchanged in the placebo group (p > 0.05), and changes from baseline to 12 weeks were greater in the blueberry group than placebo (+1.09 × 10-4 ± 4.12 × 10-5vs. +3.82 × 10-6 ± 1.59 × 10-5, p < 0.03, respectively). The FMD/SRAUC response to ascorbic acid infusion was lower (p < 0.05) at 12 weeks compared to baseline in the blueberry group with no change in the placebo group (p > 0.05). The sum of plasma (poly)phenol metabolites increased at 4, 8, and 12 weeks in the blueberry group compared to baseline, and were higher than the placebo group (all p < 0.05). Increases in several plasma flavonoid and microbial metabolites were also noted. No major differences were found for blood pressure, arterial stiffness, blood biomarkers, or endothelial cell protein expression following blueberry consumption. These findings suggest daily consumption of freeze-dried blueberry powder for 12 weeks improves endothelial function through reduced oxidative stress in postmenopausal women with above-normal blood pressure. The clinical trial registry number is NCT03370991 (https://clinicaltrials.gov).

Self-selected fluid volume and flavor strength does not alter fluid intake, body mass loss, or physiological strain during moderate-intensity exercise in the heat.

INTRODUCTION: The purpose of this study was to determine the effects of ad libitum flavor and fluid intake on changes in body mass (BM) and physiological strain during moderate intensity exercise in the heat. METHODS: Ten subjects (24±3yrs, 7M/3F) performed 60 min of treadmill walking at 1.3 m/s and 7% grade in an environmental chamber set to 33 °C and 10% relative humidity while carrying a 22.7 kg pack on two different occasions. Subjects consumed either plain water or water plus flavor (Infuze), ad libitum, at each visit. Pre and post exercise, fluid consumption (change in fluid reservoir weight) and BM (nude) were measured. During exercise, heart rate (HR), systolic blood pressure (SBP), rate of perceived exertion (RPE), oxygen consumption (VO2), respiratory exchange ratio (RER), core temperature (TC), and physiological strain index (PSI) were recorded every 15 min during exercise. RESULTS: No significant differences were observed for fluid consumption between fluid conditions (512 ± 97.2 mL water vs. 414.3 ± 62.5 mL Infuze). Despite a significant decrease from baseline, there were no significant differences in overall change of BM (Δ -1.18 vs. -0.64 Kg) or percent body weight loss for water and Infuze conditions, respectively (1.58 ± 0.6 and 0.79 ± 0.2%). Furthermore, there were no significant differences in HR (144 ± 6 vs. 143 ± 8 bpm), SBP (157 ± 5 vs. 155 ± 5 mmHg), RPE, VO2 (27.4 ± 0.9 vs. 28.1 ± 1.2 ml/Kg/min), RER, TC (38.1 ± 0.1 vs. 37.0 ± 0.1 °C), and peak PSI (5.4 ± 0.4 vs. 5.7 ± 0.8) between conditions. CONCLUSIONS: Offering individuals the choice to actively manipulate flavor strength did not significantly influence ad libitum fluid consumption, fluid loss, or physiological strain during 60 min of moderate intensity exercise in the heat.

The use of progenitor cell/biodegradable MMP2-PLGA polymer constructs to enhance cellular integration and retinal repopulation.

The inability of the adult mammalian retina to regenerate can be partly attributed to the expression of injury-induced inhibitory extracellular matrix (ECM) and cell adhesion molecules. In particular, photoreceptor degeneration stimulates deposition of the inhibitory ECM proteins neurocan and CD44 at the outer limits of the dystrophic retina, where they act as a barrier against cellular migration and axonal extension. We have previously shown that degradation of these molecules, via induction of MMP2, promotes host-donor integration and retinal repopulation following transplantation. Here we present a biodegradable/biocompatible polymer scaffold that has the ability to deliver MMP2, in conjunction with retinal progenitor cells, directly to the site of retinal injury in an attempt to enhance cellular integration and promote retinal repopulation. Pre-activated MMP2, loaded into a PLGA polymer, maintained its activity throughout polymer fabrication and hydrolysis. Following delivery, significant degradation of CD44 and neurocan from the outer limits of the dystrophic retina, without further disruption of retinal architecture, was observed. As a result, the number of retinal progenitor cells that migrated beyond the glial barrier into the degenerating host increased significantly. These cells took up residence in the retinal outer nuclear layer, adopted appropriate photoreceptor morphology and expressed the mature photoreceptor markers recoverin and rhodopsin. Thus, we have created a cell delivery platform that upon transplantation provides controlled release of active-MMP2 directly to the site of retinal injury, stimulating inhibitory ECM barrier removal and enhancement of stem cell integration and retinal repopulation.

Electrospinning of collagen nanofiber scaffolds from benign solvents.

Nanofiber scaffolds of collagen have been fabricated via electrospinning using benign solvent systems as a replacement for 1,1,1,3,3,3 hexafluoro-2-propanol. Simple binary mixtures of phosphate-buffered saline and ethanol have been found to be highly effective for electrospinning. FTIR spectra suggest that the triple helical structure of collagen was conserved after dissolution and electrospinning. Crosslinking of the electrospun collagen scaffolds was achieved with standard methods.