Jonathan G. Crowston

Conclusions: Previous evidence showed that transient receptor potential vanilloid 4 (TRPV4) inhibition was protective of retinal ganglion cell (RGC) loss after chronic intraocular pressure (IOP) elevation in young animals. However, the role of TRPV4 in mechanosensing IOP changes in the aging eye is not well understood. Objective: This study compared the recovery of retinal function and structure after acute IOP elevation in 3- and 12-month-old mouse eyes with and without TRPV4 inhibition. Methods: We examined retinal TRPV4 expression in 2-month-old rodent eyes using immunohistochemistry and transcript analysis of isolated macroglia and RGCs. To modulate TRPV4, mice were treated daily with either vehicle or a TRPV4 antagonist (HC-067047 10 mg/kg) delivered intraperitoneally for 7 days before and 7 days after IOP elevation (50 mmHg for 30 minutes). Retinal function and structure were assessed using dark-adapted full-field electroretinography and optical coherence tomography, respectively. Results: We showed that Müller cells strongly expressed TRPV4. Seven days after IOP elevation, RGC functional recovery was significantly poorer in older mice treated with TRPV4 antagonist compared with age-matched vehicle controls (-54 ± 7% vs. -24 ± 10%, p=0.046) and their younger TRPV4 antagonist-treated counterparts (-5 ± 5%, p<0.001). Conclusions: This study showed that there was an age-related deficit in RGC functional recovery from IOP elevation with TRPV4 inhibition.

The purpose of this study was to investigate the hypothesis that muscle-related factors influence glaucoma risk, we examined the association of grip strength (GS), thigh muscle volume (TMV), and walking pace (WP) with glaucoma and its related traits. We included UK Biobank participants with data on IOP (N = 114,284), optical coherence tomography (OCT) macular inner retinal layer thickness measures (N = 44,141) and glaucoma status (N = 105,556; 2006-2010). Linear regression was used to evaluate multivariable-adjusted associations of GS, TMV, and WP with IOP and macular inner retinal OCT parameters, and logistic regression was used to evaluate associations with glaucoma status. We additionally examined gene-GS interactions with each outcome using a polygenic risk score (PRS) that combined the effects of 2673 genetic variants associated with glaucoma. After adjustment for key anthropometric, lifestyle, and medical covariables, we found each additional standard deviation (SD) increase in GS (8.6 kg in men and 6.1 kg in women) was associated with thicker macular retinal nerve fiber layer (mRNFL) by 0.08 µm (P = 0.013) and 0.07 µm (P = 0.010) in men and women, respectively; thicker macular ganglion cell-inner plexiform layer (mGCIPL) by 0.12 µm (P = 0.003) and 0.17 µm (P < 0.001); higher IOP by 0.15 millimeters of mercury (mm Hg; P < 0.001) and 0.16 mm Hg (P < 0.001) and lower odds of glaucoma (odds ratio [OR] = 0.83, P < 0.001) in men only. The association with glaucoma was replicated in the independent EPIC-Norfolk cohort. Faster WP and greater TMV were also associated with lower odds of glaucoma in men only (P = 0.004 and P = 0.017, respectively). Stronger GS-IOP associations were observed in participants with a higher level of genetic risk for glaucoma (Pinteraction < 0.001). In this cross-sectional and gene-environment interaction study, factors relating to muscle strength, mass, and function were consistently associated with higher IOP, thicker inner retinal OCT measures in both sexes, and lower odds of glaucoma in men.

To gain insight into the root causes of metabolic dysfunction, it is essential to understand how tissues communicate and coordinate their metabolic functions. Here, we sought to address this in the context of cold exposure, a well-studied metabolic perturbation. We performed proteomics across six metabolic tissues and plasma, quantifying 11,394 proteins. Beginning our investigation in brown adipose tissue (BAT), we identified a mechanism to explain enhanced glucose utilization in cold-adapted BAT. This was characterized by select remodeling of upper glycolysis and pentose cycling to increase oxygen consumption, likely by increasing uncoupling protein 1 activity through the production of reactive oxygen species. Cold-induced remodeling of the plasma proteome appeared to underpin the ability of BAT to modify its fuel preference, stimulating lipolysis in white adipose tissue and glucose production in the liver. These findings emphasize the importance of considering metabolic adaptations in the context of the whole body and suggest overlap between the mechanisms of cold adaptation and obesity.

Sarcopenia is the age-related degeneration of skeletal muscle, resulting in loss of skeletal muscle tone, mass, and quality. Skeletal muscle is a source of systemic metabolites and macromolecules important for neuronal health, function, and healthy neuronal aging. Age-related loss of skeletal muscle might result in decreased metabolite and macromolecule availability, resulting in reduced neuronal function or increased susceptibility to unhealthy aging and neurodegenerative diseases. We aimed to identify muscle metabolite candidates that regulate healthy aging. C57BL/6J mice were aged to young adult (4 months) and old age (25 months) and skeletal muscle was collected. Age-related muscle loss was confirmed by reduced muscle mass, muscle fiber degeneration, reduced myosin intensity, in addition to a metabolic shift and increased DNA damage in skeletal muscle. Using a low molecular weight enriched metabolomics protocol, we assessed the metabolic profile of skeletal muscle from young adult and old age mice and identified 20 metabolites that were significantly changed in aged muscle. These metabolite candidates were tested in C. elegans assays of lifespan, healthspan, muscle, and mitochondrial morphology under normal and stressed conditions. We identified four metabolite candidates (beta-alanine, 4-guanidinobutanoic acid, 4-hydroxyproline, pantothenic acid) that, when supplemented in C. elegans provided robust gero- and mitochondrial protection. These candidates also affected life-, and health- span in C. elegans models of amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD). Our findings support that aging muscle can be used to identify novel metabolite modulators of lifespan and health and may show promise for future treatments of neurodegenerative and neuromuscular disorders.

Objective: This study evaluates if characteristics (eg, location, size, volume) of clusters of defects on an initial visual field (VF) test were predictive of a repeatable defect in the subsequent two tests. Methods: Retrospective cohort study of 197 eyes of 103 patients with healthy, suspect or early glaucoma. Using the initial VF pattern deviation probability grid, we defined the number of clusters (≥1 location of p<5%) and associated size (number of adjoining defect locations) and volume (sum of corresponding total deviation values) for each cluster stratified by the four probability levels (ie, p<5%; p<2%; p<1% and p<0.5%). Results: Of 4424 locations with a defect of p<5%, only 1189 (26.9%) were repeatable. The size [area under the receiver operating characteristic curve (AUC) 0.80, CI 0.76 to 0.85)] and volume (AUC 0.80, CI 0.76 to 0.85) of clusters were predictive of a repeatable defect within the cluster. The optimal thresholds for predicting a repeatable location within each cluster at 95% specificity based on initial cluster size were >6 locations at p<5%, >4 locations at p<2%, >3 locations at p<1% and >2 locations at p<0.5%. Defining cluster defects by involvement of central or peripheral rim locations improved the predictive value compared with the entire 24-2 grid. Conclusions: The location, size and volume of clusters of defects on an initial VF test may be predictive of subsequent repeatability. This may help distinguish eyes with a higher risk of repeatable defects.

An Open-label Phase I Study to Evaluate the Safety, Tolerability and Biodegradation Period of PolyActiva PA5108 Ocular Implant When Administered Intracamerally to the Anterior Chamber of the Eye