Biology subjects

Promislow, D. E.

Publications and source records attributed to Promislow, D. E..

8 recordsLinked to original sources

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

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↗

bioRxiv2023

Cell age drives asynchronous transcriptome aging

Organs age at different rates within a single individual. Such asynchrony in aging has been widely observed at multiple levels, from functional hallmarks, such as anatomical structures and physiological processes, to molecular endophenotypes, such as the transcriptome and metabolome. However, we lack a conceptual framework to understand why some components age faster than others. Just as demographic models explain why aging evolves, here we test the hypothesis that demographic differences among cell types, determined by cell-specific differences in turnover rate, can explain why the transcriptome shows signs of aging in some cell types but not others. Through analysis of mouse single-cell transcriptome data across diverse organs and ages, we find that cellular age explains a large proportion of the variation in the age-related increase in transcriptome variance. We further show that long-lived cells are characterized by relatively high expression of genes associated with proteostasis, and that the transcriptome of long-lived cells shows greater evolutionary constraint than short-lived cells. In contrast, in short-lived cell types the transcriptome is enriched for genes associated with DNA repair. Based on these observations, we develop a novel heuristic model that explains how and why aging rates differ among cell types.

systems biology↗

bioRxiv2023

Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites and pathways that regulate lifespan

Altered mitochondrial function is tightly linked to lifespan regulation, but underlying mechanisms remain unclear. Here, we report the chronological and replicative lifespan variation across 168 yeast knock-out strains, each lacking a single nuclear-coded mitochondrial gene, including 144 genes with human homologs, many associated with diseases. We dissected the signatures of observed lifespan differences by analyzing profiles of each strains proteome, lipidome, and metabolome under fermentative and respiratory culture conditions, which correspond to the metabolic states of replicative and chronologically aging cells, respectively. Examination of the relationships among extended longevity phenotypes, protein, and metabolite levels revealed that although many of these nuclear-encoded mitochondrial genes carry out different functions, their inhibition attenuates a common mechanism that controls cytosolic ribosomal protein abundance, actin dynamics, and proteasome function to regulate lifespan. The principles of lifespan control learned through this work may be applicable to the regulation of lifespan in more complex organisms, since many aspects of mitochondrial function are highly conserved among eukaryotes.

genetics↗

bioRxiv2022

Associations between physical activity and cognitive dysfunction in older companion dogs: Results from the Dog Aging Project

Canine Cognitive Dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimers disease. Given that physical activity is believed to reduce risk of Alzheimers disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6-18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity--with several important covariates--as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate = -0.10, 95% CI: -0.11 to - 0.08, p < 0.001), extent of symptom worsening over a 6-month interval (estimate = -0.07, 95% CI: -0.09 to -0.05, p <0.001), and whether a dog reached a clinical level of CCD (odds ratio = 0.53, 95% CI: 0.45 to 0.63, p <0.001). Physical activity was robustly associated with better cognitive outcomes in dogs. Our findings illustrate the value of companion dogs as a model for investigating relationships between physical activity and cognitive aging, including aspects of dementia that may have translational potential for Alzheimers disease. While the current study represents an important first step in identifying a relationship between physical activity and cognitive function, it cannot determine causality. Future studies are needed to rule out reverse causation by following the same dogs prospectively over time, and to evaluate causality by administering physical-activity interventions.

animal behavior and cognition↗

bioRxiv2021

Serotonin signaling modulates aging-associated metabolic network integrity in response to nutrient choice

Aging arises from complex interactions among multiple biochemical and metabolic products. Systems-level analyses of biological networks may provide insights into the causes and consequences of aging that evade single-gene or single-pathway studies. We have shown that dietary choice per se is sufficient to modulate aging and metabolic health in the vinegar fly, Drosophila melanogaster. In other words, how each meal is presented, or the way in which it is eaten, is influential, independent of the amount or type of nutrients that are consumed. For example, when major macronutrients were presented separately, male flies exhibited a rapid and significant increase in mortality rate and a reduced overall lifespan relative to those fed a single medium containing both sugar and yeast. These effects are mediated by specific components of serotonin signaling, as a mutation in serotonin receptor 2A (5-HT2A) eliminated the effects of dietary choice. Here we show that dietary choice influenced several measures of metabolic network integrity, including connectivity, average shortest distance, community structure, and robustness, with the effects of the latter two restricted to tissues in the head. These changes in network structure were associated with organism resilience and increased susceptibility to genetic perturbation, as measured by starvation survival. Our data suggest that the behavioral or perceptual consequences of exposure to individual macronutrients, involving serotonin signaling through 5-HT2A, qualitatively change the state of metabolic networks throughout the organism from one that is highly connected and robust to one that is fragmented, fragile, and vulnerable to perturbations.

genetics↗

bioRxiv2021

Pharmacokinetics of long-term low-dose oral rapamycin in four healthy middle-aged companion dogs

ObjectiveTo determine the blood concentration and pharmacokinetic parameters of rapamycin in companion dogs following long-term, low-dose oral administration of rapamycin. AnimalsFour healthy, middle-aged, medium-to-large breed privately owned dogs participated. ProceduresAll dogs had been receiving oral rapamycin at a dose of 0.025 mg/kg on Monday, Wednesday, and Friday mornings for at least one month. An initial blood sample was collected prior to morning rapamycin administration, and samples were collected at 1, 2, 6, and 24 hours after rapamycin was given. Blood samples were transferred to blood spot collection cards, air-dried and stored at -80{degrees}C. Rapamycin concentrations were determined via HPLC/MS. All blood collections occurred on Wednesdays, so that the previous dose of rapamycin had taken place 48 hours prior to blood collection. ResultsFor all dogs, rapamycin Tmax was 2 hours. Median Cmax was 1.47 ng/ml (0.912 - 2.13), and the median AUC0-last was 15.7 ng*hr/mL (1.30 - 36.3). Due to sample size and timing, the only estimates related to elimination rate reported are for mean residence time with a median of 4.70 hrs (0.90 - 7.30). Conclusions and Clinical RelevanceA 0.025 mg/kg oral dose of rapamycin, administered three times a week, resulted in concentrations of rapamycin in the blood capable of being measured in ng/ml.

pharmacology and toxicology↗

bioRxiv2020

Serotonin 2A receptor signaling coordinates central metabolic processes to modulate aging in response to nutrient choice

It has been recognized for nearly a century that diet modulates aging. Despite early experiments suggesting that reduced caloric intake augmented lifespan, accumulating evidence indicates that other characteristics of the diet may be equally or more influential in modulating aging. We demonstrate that behavior, metabolism, and lifespan in Drosophila are affected by whether flies are provided a choice of different nutrients or a single, complete medium, largely independent of the amount of nutrients that are consumed. Meal choice elicits a rapid metabolic reprogramming that indicates a potentiation of TCA cycle and amino acid metabolism, which requires serotonin 2A receptor. Knockdown of glutamate dehydrogenase, a key TCA pathway component, abrogates the effect of dietary choice on lifespan. Our results reveal a mechanism of aging that applies in natural conditions, including our own, in which organisms continuously perceive and evaluate nutrient availability to promote fitness and well-being.

genetics↗