Biology subjects

Brassington, L.

Publications and source records attributed to Brassington, L..

6 recordsLinked to original sources

bioRxiv2026

Early and current environments exert distinct effects on immune function in the Orang Asli

Humans evolved in environments characterized by subsistence foraging and hunting, high levels of physical activity, and regular and diverse pathogen exposure. Industrialization has rapidly altered these environments, leading to increased metabolic and inflammatory disease risk. These observations have motivated studies of how industrialization shapes immune function, but whether industrialization alters immune biology through developmental embedding of early-life environments or ongoing plastic responses to current conditions remains poorly understood. To address this gap, we worked with the Orang Asli--the Indigenous peoples of Peninsular Malaysia--who currently span a gradient from subsistence horticulture, foraging, and hunting to industrialized, urban environments with substantial inter-individual variation in life course experiences. Leveraging continuous measures of both early-life and current lifestyle, we found that current lifestyle exerts stronger effects on adult immune gene expression than early-life conditions, impacting 1,428 as compared to 223 genes, respectively. Early-life associated genes were enriched for pathways regulating adaptive immunity, particularly T cell development and differentiation, consistent with higher predicted T cell abundance and circulating IL-8 in urban-born individuals. In contrast, current exposure to urban, industrialized conditions was linked to innate immune and inflammatory activation, including dendritic cell abundance, metabolic pathway upregulation, and elevated CRP. Finally, consistent with lower rates of immune disorders in non-industrial settings, current exposure to this lifestyle was associated with up-regulation of genes involved in Th1/Th2 differentiation. Together, these results emphasize that industrialized immune profiles reflect both early-life developmental embedding and ongoing environmental responses, highlighting the importance of considering exposures across the life course. Significance statementHumans evolved in environments with high levels of physical activity, subsistence-based diets, and constant pathogen exposure. Rapid industrialization has dramatically changed these conditions, coinciding with rising rates of non-communicable diseases with inflammatory underpinnings. Our study with the Orang Asli, the Indigenous peoples of Peninsular Malaysia, tests how exposure to industrialization across the life course shapes immune variation. We find that early-life environments leave lasting marks on adaptive immune function particularly T cells, while industrialized adult lifestyle influences innate immune activity and inflammation. These results clarify how different stages of life contribute to immune remodeling and point to a mechanistic link between industrialization and disease risk, highlighting the importance of both early-life and current environments in shaping later life health.

genetics↗

bioRxiv2026

Divergent Biological Consequences of APOE Isoforms Across Industrialized and Non-Industrial Environments

The apolipoprotein {varepsilon}4 (APOE {varepsilon}4) isoform directly alters cholesterol and immune biology and is associated with an increased risk of neurodegenerative and cardiometabolic disease in industrialized settings; nevertheless, APOE {varepsilon}4--which is ancestral in humans--has persisted over evolutionary time. One potential explanation is that the costs and benefits of APOE {varepsilon}4 were significantly different in the environments in which humans evolved compared to those we experience today. In support, previous work has suggested that living in a high pathogen environment, engaging in high levels of physical activity, or eating a low fat diet can dampen the detrimental effects of APOE {varepsilon}4, and has revealed positive effects for fertility. However, direct tests of whether APOE isoforms are associated with different biological outcomes in non-industrial versus industrialized contexts are lacking. Working with the Turkana of Kenya and the Orang Asli of Peninsular Malaysia--two Indigenous groups in which individuals of shared ancestry span a continuum of subsistence, non-industrial to urban, industrialized lifestyles--we investigated how APOE genotypes impact cholesterol, immunological, and reproductive traits and tested for genotype x environment (GxE) interactions. First, we confirmed established genotype effects across lifestyles, showing that more APOE {varepsilon}4 alleles are associated with higher total cholesterol, higher LDL cholesterol, and lower HDL cholesterol. Second, we tested for lifestyle interactions, finding lifestyle-dependent effects of genotype on innate immune biomarkers in the Orang Asli but not Turkana. Finally, we show that more APOE {varepsilon}4 alleles are correlated with an extended reproductive lifespan, however this effect is relatively weak, is not consistent across populations, and does not correspond with a higher reproductive output. Together, our study provides evidence that industrialized environments can modify the biology of APOE {varepsilon}4; however, we find that APOE {varepsilon}4 is not universally beneficial in non-industrial contexts, highlighting the role of local environmental variation in determining its specific costs and benefits.

evolutionary biology↗

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

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↗

bioRxiv2022

Social determinants of health and disease in companion dogs: A cohort study from the Dog Aging Project

Exposure to social environmental adversity is associated with health and survival in many social species, including humans. However, little is known about if and how these health and mortality effects vary across the lifespan, largely due to the difficulty of studying long-lived organisms across much of their lifespan. Here, we leveraged a relatively new and powerful model for human aging, the companion dog, to investigate which components of the social environment are associated with dog health and how these associations vary across the lifespan. We drew on comprehensive survey data collected on 21,410 dogs from the Dog Aging Project and identified five factors that together explained 33.7% of the variation in a dogs social environment. Factors capturing financial and household adversity were associated with poorer health and lower physical mobility in companion dogs, while factors that captured social support, such as living with other dogs, were associated with better health when controlling for dog age and weight. Some of these associations differed across a dogs lifespan, including a stronger relationship between owner age and health in younger (as compared to older) dogs. Taken together, these findings suggest the importance of income, stability, and owner age on owner-reported health outcomes in companion dogs and point to potential behavioral and/or environmental modifiers that can be used to promote healthy aging across species.

evolutionary biology↗