Biology subjects

Avery, A.

Publications and source records attributed to Avery, A..

8 recordsLinked to original sources

bioRxiv2024

Mapping the canine microbiome: Insights from the Dog Aging Project

Companion dogs (Canis lupus familiaris) offer a unique model for studying the gut microbiome and its relation to aging due to their cohabitation with humans, sharing similar environments, diets, and healthcare practices. Here, we present the Dog Aging Project (DAP) Precision cohort, the largest population-wide study of the canine gut microbiome to date. This cohort encompasses over 900 dogs of diverse breeds, environments, and demographics living across the United States. Coupling fecal shotgun metagenomic sequencing with comprehensive phenotypic and environmental surveys and clinical lab tests, we explore the intricate relationships between microbiome composition, aging, and key factors such as diet, health, and living conditions. Our analyses identify various factors associated with microbiome composition. In addition, we find a gradual shift in microbiome composition with age, which allows us to develop a novel metagenomics-based "clock" to predict biological aging based on microbial signatures. Overall, these findings provide an unprecedented and detailed understanding of the role the gut microbiome plays in our four-legged companions, offering both potential applications in veterinary medicine and an exciting model for aging research.

microbiology↗

bioRxiv2024

Aberrant iron deposition in the multiple sclerosis spinal cord relates to neurodegeneration

BackgroundIron accumulates in microglia-macrophages at the edge of multiple sclerosis (MS) lesions in the brain. Iron-rimmed brain lesions strongly predict disability accumulation, supporting iron metabolism is crucial in MS pathology. Little is known about iron distribution in the spinal cord. MethodsAutopsy cervical, thoracic and lumbar spinal cord samples from 9 controls and 46 MS donors of whom a subset (n=36) had mesiofrontal motor cortical tissue available for study, were labelled and systematically assessed for iron (DAB-enhanced Turnbull), myelin (PLP), axons (Palmgren silver), microglia-macrophages (TMEM119, Iba1, CD68), astroglia (GFAP), oligodendroglia (OLIG2), acute axonal injury (B-APP, SMI-32, NPY-1R) and oxidative stress (E06). MS lesional and non-lesional areas were considered. Total non-haem iron was quantified by inductively coupled plasma optical emission spectroscopy (ICP-OES). ResultsIn controls, iron predominantly localised to oligodendrocytes with total non-haem iron relating to total myelin fraction, which markedly differed in MS where iron accumulated in microglia-macrophages, subpial astrocytes, and axons in non-lesional areas. Iron laden microglia-macrophages were over-represented relative to total microglial-macrophages and displayed dysmorphic features. Iron-positive axons showed a disto-proximal gradient (highest at lumbar level) with a predilection for the corticospinal tracts. The extent of iron axon positivity related to smaller spinal cord area, lower total axonal counts, and greater oxidative stress. Iron positivity in each cellular compartment (i.e. subpial astrocytes, microglia-macrophage and axons) related to one-another and total non-haem iron correlated with axonal counts in MS. No iron-rimmed lesions were detected in the spinal cord unlike in cortical grey and subcortical white matter of the same cases where 22% and 80% of iron-rimmed lesions, respectively, were seen. ConclusionsDespite the conspicuous absence of iron-rimmed lesions in the MS spinal cord, we demonstrate widespread aberrant iron distribution in the MS spinal cord that relates to oxidative stress and neurodegeneration independent of demyelination. The distal cord predominant and corticospinal tract specific accumulation of iron in axons mirrors the pattern of length-dependent motoric disability commonly encountered in progressive MS. These findings implicate aberrant iron accumulation as a novel, clinically relevant, feature of MS spinal cord pathology.

neuroscience↗

bioRxiv2024

Protein catabolites as blood-based biomarkers of aging physiology: Findings from the Dog Aging Project

Our understanding of age-related physiology and metabolism has grown through the study of systems biology, including transcriptomics, single-cell analysis, proteomics and metabolomics. Studies in lab organisms in controlled environments, while powerful and complex, fall short of capturing the breadth of genetic and environmental variation in nature. Thus, there is now a major effort in geroscience to identify aging biomarkers and to develop aging interventions that might be applied across the diversity of humans and other free-living species. To meet this challenge, the Dog Aging Project (DAP) is designed to identify cross-sectional and longitudinal patterns of aging in complex systems, and how these are shaped by the diversity of genetic and environmental variation among companion dogs. Here we surveyed the plasma metabolome from the first year of sampling of the Precision Cohort of the DAP. By incorporating extensive metadata and whole genome sequencing information, we were able to overcome the limitations inherent in breed-based estimates of genetic and physiological effects, and to probe the physiological and dietary basis of the age-related metabolome. We identified a significant effect of age on approximately 40% of measured metabolites. Among other insights, we discovered a potentially novel biomarker of age in the post-translationally modified amino acids (ptmAAs). The ptmAAs, which can only be generated by protein hydrolysis, covaried both with age and with other biomarkers of amino acid metabolism, and in a way that was robust to diet. Clinical measures of kidney function mediated about half of the higher ptmAA levels in older dogs. This work identifies ptmAAs as robust indicators of age in dogs, and points to kidney function as a physiological mediator of age-associated variation in the plasma metabolome.

systems biology↗

bioRxiv2024

DNA methylation of transposons pattern aging differences across a diverse cohort of dogs from the Dog Aging Project

Within a species, larger individuals often have shorter lives and higher rates of age-related disease. Despite this well-known link, we still know little about underlying age-related epigenetic differences, which could help us better understand inter-individual variation in aging and the etiology, onset, and progression of age-associated disease. Dogs exhibit this negative correlation between size, health, and longevity and thus represent an excellent system in which to test the underlying mechanisms. Here, we quantified genome-wide DNA methylation in a cohort of 864 dogs in the Dog Aging Project. Age strongly patterned the dog epigenome, with the majority (66% of age-associated loci) of regions associating age-related loss of methylation. These age effects were non-randomly distributed in the genome and differed depending on genomic context. We found the LINE1 (long interspersed elements) class of TEs (transposable elements) were the most frequently hypomethylated with age (FDR < 0.05, 40% of all LINE1 regions). This LINE1 pattern differed in magnitude across breeds of different sizes- the largest dogs lost 0.26% more LINE1 methylation per year than the smallest dogs. This suggests that epigenetic regulation of TEs, particularly LINE1s, may contribute to accelerated age and disease phenotypes within a species. Since our study focused on the methylome of immune cells, we looked at LINE1 methylation changes in golden retrievers, a breed highly susceptible to hematopoietic cancers, and found they have accelerated age-related LINE1 hypomethylation compared to other breeds. We also found many of the LINE1s hypomethylated with age are located on the X chromosome and are, when considering X chromosome inactivation, counter-intuitively more methylated in males. These results have revealed the demethylation of LINE1 transposons as a potential driver of intra-species, demographic-dependent aging variation.

genomics↗

bioRxiv2024

Aging at scale: Younger dogs and larger breeds from the Dog Aging Project show accelerated epigenetic aging.

Dogs exhibit striking within-species variability in lifespan, with smaller breeds often living more than twice as long as larger breeds. This longevity discrepancy also extends to health and aging-larger dogs show higher rates of age-related diseases. Despite this well-established phenomenon, we still know little about the biomarkers and molecular mechanisms that might underlie breed differences in aging and survival. To address this gap, we generated an epigenetic clock using DNA methylation from over 3 million CpG sites in a deeply phenotyped cohort of 864 companion dogs from the Dog Aging Project, including some dogs sampled annually for 2-3 years. We found that the largest breed size tends to have epigenomes that are, on average, 0.37 years older per chronological year compared to the smallest breed size. We also found that higher residual epigenetic age was significantly associated with increased mortality risk, with dogs experiencing a 34% higher risk of death for each year increase in residual epigenetic age. These findings not only broaden our understanding of how aging manifests within a diverse species but also highlight the significant role that demographic factors play in modulating the biological mechanisms underlying aging. Additionally, they highlight the utility of DNA methylation as both a biomarker for healthspan-extending interventions, a mortality predictor, and a mechanism for understanding inter-individual variation in aging in dogs.

genomics↗

bioRxiv2024

Molecular consequences of SCA5 mutations in the spectrin-repeat domains of beta-III-spectrin

Spinocerebellar ataxia type 5 (SCA5) mutations in the protein {beta}-III-spectrin cluster to the N-terminal actin-binding domain (ABD) and the central spectrin-repeat domains (SRDs). We previously reported that a common molecular consequence of ABD-localized SCA5 mutations is increased actin binding. However, little is known about the molecular consequences of the SRD-localized mutations. It is known that the SRDs of {beta}-spectrin proteins interact with -spectrin to form an /{beta}-spectrin dimer. In addition, it is known that SRDs neighbouring the {beta}-spectrin ABD enhance actin binding. Here, we tested the impact of the SRD-localized R480W and the E532_M544del mutations on the binding of {beta}-III-spectrin to -II-spectrin and actin. Using multiple experimental approaches, we show that both the R480W and E532_M544del mutants can bind -II-spectrin. However, E532_M544del causes partial uncoupling of complementary SRDs in the /{beta}-spectrin dimer. Further, the R480W mutant forms large intracellular inclusions when co-expressed with -II-spectrin in cells, supporting that R480W mutation grossly disrupts the -II/{beta}-III-spectrin physical complex. Moreover, actin-binding assays show that E532_M544del, but not R480W, increases {beta}-III-spectrin actin binding. Altogether, these data support that SRD-localized mutations alter key interactions of {beta}-III-spectrin with -II-spectrin and actin.

biochemistry↗

bioRxiv2023

Variability in donor lung culture and relative humidity impact the stability of 2009 pandemic H1N1 influenza virus on nonporous surfaces

Respiratory viruses can transmit by multiple modes, including contaminated surfaces, commonly referred to as fomites. Efficient fomite transmission requires that a virus remain infectious on a given surface material over a wide range of environmental conditions, including different relative humidities. Prior work examining the stability of influenza viruses on surfaces has relied upon virus grown in media or eggs, which does not mimic the composition of virus-containing droplets expelled from the human respiratory tract. In this study, we examined the stability of the 2009 pandemic H1N1 (H1N1pdm09) virus on a variety of nonporous surface materials at four different humidity conditions. Importantly, we used virus grown in primary human bronchial epithelial (HBE) cultures from different donors to recapitulate the physiological microenvironment of expelled viruses. We observed rapid inactivation of H1N1pdm09 on copper under all experimental conditions. In contrast to copper, viruses were stable on polystyrene plastic, stainless steel, aluminum, and glass, at multiple relative humidity conditions, but greater decay on ABS plastic was observed at short time points. However, the half-lives of viruses at 23% relative humidity were similar among non-copper surfaces and ranged from 4.5 to 5.9 hours. Assessment of H1N1pdm09 longevity on nonporous surfaces revealed that virus persistence was governed more by differences among HBE culture donors than by surface material. Our findings highlight the potential role of an individuals respiratory fluid on viral persistence and could help explain heterogeneity in transmission dynamics. IMPORTANCESeasonal epidemics and sporadic pandemics of influenza cause a large public health burden. Although influenza viruses disseminate through the environment in respiratory secretions expelled from infected individuals, they can also be transmitted by contaminated surfaces where virus-laden expulsions can deposit. Understanding virus stability on surfaces within the indoor environment is critical to assessing influenza transmission risk. We found that influenza virus stability is affected by the host respiratory secretion in which the virus is expelled, the surface material on which the droplet lands, and the ambient relative humidity of the environment. Influenza viruses can remain infectious on many common surfaces for prolonged periods, with half-lives of 4.5-5.9 hours. These data imply that influenza viruses are highly persistent in indoor environments in biologically-relevant matrices. Decontamination and engineering controls should be used to mitigate influenza virus transmission.

microbiology↗

bioRxiv2020

Pre-existing immunity provides a barrier to airborne transmission of influenza viruses

Human-to-human transmission of influenza viruses is a serious public health threat, yet the precise role of immunity from previous infections on the susceptibility to airborne viruses is still unknown. Using human seasonal influenza viruses in a ferret model, we examined the roles of exposure duration and heterosubtypic immunity on influenza transmission. We found that airborne transmission of seasonal influenza strains is abrogated in recipient animals with pre-existing non-neutralizing immunity, indicating that transmissibility of a given influenza virus strain should be examined in the context of ferrets that are not immunologically naive.

microbiology↗