Biology subjects

Harrison, B. R.

Publications and source records attributed to Harrison, B. R..

9 recordsLinked to original sources

bioRxiv2026

Blood biomarkers and breed genetics of aging in pet dogs

Pet dogs share human-like environments while aging on a compressed timescale, making them a powerful translational model for aging research. Using genomic and phenotypic data from 7,627 dogs in the Dog Aging Project, including 976 profiled for 159 blood metabolites and clinical analytes, we generated the first GWAS catalog in dogs. Blood traits map to orthologous loci in dogs and humans, indicating deeply conserved pathways. Breed ancestry explains substantial variance in blood traits, and selection on visible characteristics such as fur type has pleiotropic metabolic effects. Leveraging mosaic ancestry in mixed-breed dogs and longitudinal mortality data, we identify blood traits elevated in short-lived breeds that predict individual mortality risk -- including globulin and potassium -- and protective traits enriched in long-lived breeds, such as ethanolamine. Although some aging-associated traits relate to growth hormone pathways, many do not, indicating that aging in dogs is multifactorial. These findings establish dogs as a translational system for identifying genetic determinants and biomarkers of aging relevant to extending healthy lifespans.

genetics↗

bioRxiv2025

Rapamycin Differentially Impacts Germline Stem Cell Quiescence Across Diverse Genetic Backgrounds of Drosophila Melanogaster

In response to ionizing radiation, stem cells enter a state of temporary quiescence, safeguarding the stem cell pool for tissue regeneration. Quiescence requires the inhibition of mTORC1, a kinase complex that promotes growth and suppresses autophagy, and cell cycle re-entry requires the reactivation of mTORC1. The pharmacological inhibition of mTORC1 in quiescent stem cells by rapamycin prevents cell cycle re-entry and subsequent tissue regeneration. It is well established that pharmacological responses can vary across genetic backgrounds, however, the extent to which genetic variation can impact the quiescence response to rapamycin is unclear. Here, we tested the sensitivity of stem cell quiescence to rapamycin in different genetic backgrounds within the Drosophila Genetic Reference Panel. These analyses revealed substantial variation across different genetic backgrounds, indicating that genetic variation can modulate drug-induced effects on stem cell dynamics. Our analyses suggest that mitophagy, rather than DNA damage response, is associated with the persistence of quiescence and delayed tissue regeneration by rapamycin. This work underscores the critical role of genetic background in determining drug efficacy, highlighting important implications for the therapeutic application of rapamycin.

developmental biology↗

bioRxiv2025

Dogs and humans share biomarkers of mortality

There is growing interest in the use of molecular features as predictors of age, age-related disease risk and age-related mortality. A major shortcoming of this field, however, is the lack of suitable translational research models to identify and understand the underlying mechanisms of these predictive biomarkers in human populations. In particular, we lack a system which, like humans, is genetically variable, lives in diverse environments, and experiences aging-related chronic conditions treated in the context of a sophisticated health care system. Here, we present results from our analysis of data from the Dog Aging Project, a long-term longitudinal study of aging in more than 50,000 companion dogs. In particular, using longitudinal survival models, we present the striking finding of a strong, highly significant positive correlation between the effect of individual metabolites on all-cause mortality in humans, and the association of those same metabolites on all-cause mortality in dogs. We also find that across these independent human studies, the biomarkers identified are also highly correlated, strongly suggesting a general signature of mortality within the plasma metabolome across humans, and now in dogs as well. Given the many similarities between dogs and humans with respect to genetics, environment, disease, and disease treatment, and the fact that dogs are so much shorter lived than humans, we argue that dogs represent an extremely valuable translational model in our ongoing effort to understand the underlying molecular causes and consequences of age-related morbidity and mortality in humans.

systems 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

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

Tissue-specific metabolomic signatures for a doublesex model of reduced sexual dimorphism

Sex has a major effect on the metabolome. However, we do not yet understand the degree to which these quantitative sex differences in metabolism are associated with anatomical dimorphism and modulated by sex-specific tissues. In the fruit fly, Drosophila melanogaster, knocking out the doublesex (dsx) gene gives rise to adults with intermediate sex characteristics. Here we sought to determine the degree to which this key node in sexual development leads to sex differences in the fly metabolome. We measured 91 metabolites across head, thorax and abdomen in Drosophila, comparing the differences between distinctly sex-dimorphic flies with those of reduced sexual dimorphism: dsx null flies. Notably, in the reduced dimorphism flies, we observed a sex difference in only 1 of 91 metabolites, kynurenate, whereas 51% of metabolites (46/91) were significantly different between wildtype XX and XY flies in at least one tissue, suggesting that dsx plays a major role in sex differences in fly metabolism. Kynurenate was consistently higher in XX flies in both the presence and absence of functioning dsx. We observed tissue-specific consequences of knocking out dsx. Metabolites affected by sex were significantly enriched in branched chain amino acid metabolism and the mTOR pathway. This highlights the importance of considering variation in genes that cause anatomical sexual dimorphism when analyzing sex differences in metabolic profiles and interpreting their biological significance.

systems biology↗

bioRxiv2024

Selection for early reproduction leads to accelerated aging and extensive metabolic remodeling in Drosophila melanogaster populations

Experimental evolution studies that feature selection on life-history characters are a proven approach for studying the evolution of aging and variation in rates of senescence. Recently, the incorporation of genomic and transcriptomic approaches into this framework has led to the identification of hundreds of genes associated with different aging patterns. However, our understanding of the specific molecular mechanisms underlying these aging patterns remains limited. Here, we incorporated extensive metabolomic profiling into this framework to generate mechanistic insights into aging patterns in Drosophila melanogaster. Specifically, we characterized metabolomic change over adult lifespan in populations of D. melanogaster where selection for early reproduction has led to an accelerated aging phenotype relative to their controls. Using these data we: i) evaluated evolutionary repeatability across the metabolome; ii) assessed the value of the metabolome as a predictor of "biological age" in this system; and iii) identified specific metabolites associated with accelerated aging. Generally, our findings suggest that selection for early reproduction resulted in highly repeatable alterations to the metabolome and the metabolome itself is a reliable predictor of "biological age". Specifically, we find clusters of metabolites that are associated with the different rates of senescence observed between our accelerated aging population and their controls, adding new insights into the metabolites that may be driving the accelerated aging phenotype. SignificanceWhile experimental evolution studies featuring Drosophila melanogaster have generated significant insights into the forces that shape aging and life history patterns, more recent efforts incorporating genomic and transcriptomic data have had comparatively little success identifying the molecular mechanisms underlying these patterns. Here we work to incorporate molecular phenotyping into this general framework as a way forward. Specifically, we characterize how the metabolome changes with age in populations of D. melanogaster where hundreds of generations of selection for early reproduction have led to enrichment for an accelerated aging phenotype. By comparing to control populations, we show that the metabolome does appear to capture true signals of "biological age" and provides a new avenue for understanding the factors that underlie complex trait variation in real populations.

evolutionary biology↗