Daniel Promislow

Daniel Promislow
University of Washington Seattle | UW · Department of Pathology

About

250
Publications
41,499
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10,959
Citations
Citations since 2017
84 Research Items
4538 Citations
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20172018201920202021202220230200400600800
20172018201920202021202220230200400600800

Publications

Publications (250)
Article
Canine cognitive dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer's disease. Given that physical activity is believed to reduce risk of Alzheimer's 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 hig...
Article
While the lifespan advantage of small body size and mixed breed status has been documented repeatedly, evidence for an effect of genetic diversity across dog breeds is equivocal. We hypothesized that this might be due to a strong right-censoring bias in available breed-specific lifespan estimates where early-dying dogs from birth cohorts that have...
Article
Since interventions such as caloric restriction or fasting robustly promote lipid catabolism and improve aging-related phenotypical markers, we investigated the direct effect of increased lipid catabolism via overexpression of bmm (brummer, FBgn0036449), the major triglyceride hydrolase in Drosophila, on lifespan and physiological fitness. Comprehe...
Article
Full-text available
Along with specialized functions, cells of multicellular organisms also perform essential functions common to most if not all cells. Whether diverse cells do this by using the same set of genes, interacting in a fixed coordinated fashion to execute essential functions, or a subset of genes specific to certain cells, remains a central question in bi...
Article
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Osteoarthritis (OA) is one of the most prevalent age-related chronic conditions that afflict companion dogs, and multiple joint supplements are available to prevent or treat OA, though the efficacy of these treatments is controversial. While the demographic factors that are associated with OA diagnosis are well established, the factors that are ass...
Preprint
Full-text available
Age in dogs is associated with the risk of many diseases, and canine size is a major factor in that risk. However, the size effect is not as simple as the age effect. While small size dogs tend to live longer, some diseases are more prevalent among small dogs. Utilizing owner-reported data on disease history from a substantial number of companion d...
Article
While there has been an abundance of studies on the important relationship between physical activity and age in both dogs and humans, studies on dogs have primarily focused on how a dog’s biological characteristics, such as their weight, affect the age-activity relationship. To date, there is little knowledge about how this relationship may be asso...
Preprint
Full-text available
Canine Cognitive Dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer’s disease. Given that physical activity is believed to reduce risk of Alzheimer’s 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 hig...
Article
A variety of diets have been studied for possible anti-aging effects. In particular, studies of intermittent fasting and time-restricted feeding in laboratory rodents have found evidence of beneficial health outcomes. Companion dogs represent a unique opportunity to study diet in a large mammal that shares human environments. The Dog Aging Project...
Article
Full-text available
In recent years, metabolomics has been used as a powerful tool to better understand the physiology of neurodegenerative diseases and identify potential biomarkers for progression. We used targeted and untargeted aqueous, and lipidomic profiles of the metabolome from human cerebrospinal fluid to build multivariate predictive models distinguishing pa...
Article
The Dog Aging Project is a long-term longitudinal study of ageing in tens of thousands of companion dogs. The domestic dog is among the most variable mammal species in terms of morphology, behaviour, risk of age-related disease and life expectancy. Given that dogs share the human environment and have a sophisticated healthcare system but are much s...
Article
Full-text available
Many biomarkers have been shown to be associated not only with chronological age but also with functional measures of biological age. In human populations, it is difficult to show whether variation in biological age is truly predictive of life expectancy, as such research would require longitudinal studies over many years, or even decades. We follo...
Article
Full-text available
Comparative phylogenetic studies offer a powerful approach to study the evolution of complex traits. While much effort has been devoted to the evolution of the genome and to organismal phenotypes, until now relatively little work has been done on the evolution of the metabolome, despite the fact that it is composed of the basic structural and funct...
Article
Full-text available
Background Differential correlation networks are increasingly used to delineate changes in interactions among biomolecules. They characterize differences between omics networks under two different conditions, and can be used to delineate mechanisms of disease initiation and progression. Results We present a new R package, CorDiffViz, that facilita...
Article
Full-text available
Background: The synthetic steroid mifepristone is reported to have anti-obesity and anti-diabetic effects in mammals on normal and high-fat diets (HFD). We previously reported that mifepristone blocks the negative effect on life span caused by mating in female Drosophila melanogaster . Methods: Here we asked if mifepristone could protect virgin fem...
Article
Alzheimer’s disease (AD) is a significant burden for human health that is increasing in prevalence as the global population ages. There is growing recognition that current preclinical models of AD are insufficient to recapitulate key aspects of the disease. Laboratory models for AD include mice, which do not naturally develop AD-like pathology duri...
Article
Quantifying the physiology of aging is essential for improving our understanding of age-related disease and the heterogeneity of healthy aging. Recent studies have shown that in regression models using “-omic” platforms to predict chronological age, residual variation in predicted age is correlated with health outcomes, and suggest that these “omic...
Article
Full-text available
Significance Caloric restriction (CR) increases life and health span, but our understanding of the evolutionary basis of the effect remains unclear. For many years, the disposable soma hypothesis provided the main evolutionary explanation, suggesting animals under restriction divert resources away from reproduction toward somatic maintenance. This...
Article
Full-text available
As the molecular mechanisms of biological aging become better understood, there is growing interest in identifying interventions that target those mechanisms to promote extended health and longevity. The budding yeast Saccharomyces cerevisiae has served as a premier model organism for identifying genetic and molecular factors that modulate cellular...
Article
The University of Washington Nathan Shock Center of Excellence in the Basic Biology of Aging provides leadership and resources to support the geroscience community locally, nationally, and internationally. Services are provided through our Resource Cores and funds are available annually to support pilot projects by external investigators. Aging-rel...
Article
Full-text available
Aging arises from complex interactions among multiple biochemical products. Systems-level analyses of biological networks may provide insights into the causes and consequences of aging that evade single-gene studies. We have previously found that dietary choice is sufficient to modulate aging in the vinegar fly, Drosophila melanogaster . Here we sh...
Article
Full-text available
Background: Interventional clinical trials intended to maintain health in aging dogs are unusual and require particular attention to exclusion criteria. Objectives: To describe reasons for exclusion when a mature adult and senior canine population with normal health status was sought. Animals: Fifty six companion dogs nominated for a randomized con...
Preprint
Full-text available
Quantifying the physiology of aging is essential for improving our understanding of age-related disease and the heterogeneity of healthy aging. Recent studies have shown that in regression models using "-omic" platforms to predict chronological age, residual variation in predicted age is correlated with health outcomes, and suggest that these "omic...
Preprint
Full-text available
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...
Article
Full-text available
Background Heart disease is a frequent cause of hospitalization and mortality for elderly patients. A common feature of both heart disease and aging itself is the involvement of metabolic organ alterations ultimately leading to changes in circulating metabolite levels. However, the specific contribution of aging and ischemic injury to the metabolic...
Preprint
Full-text available
The question of why and how some species or individuals within a population live longer than others is among the most important questions in the biology of aging. A particularly useful model to understand the genetic basis and selective forces acting on the plasticity of lifespan are closely related species or ecologically diverse individuals of th...
Article
Full-text available
Calorie restriction (CR) remains the most robust intervention to extend lifespan and improve healthspan. Though the cerebellum is more commonly associated with motor control, it has strong links with the hypothalamus and is thought to be associated with nutritional regulation and adiposity. Using a global mass spectrometry-based metabolomics approa...
Article
Mating and transfer of male Sex Peptide (SP), or transgenic expression of SP, causes inflammation and decreased life span in female Drosophila. Mifepristone rescues these effects, yielding dramatic increases in life span. Here targeted metabolomics data were integrated with further analysis of extant transcriptomic data. Each of seven genes positiv...
Article
Full-text available
Background The privately owned companion dog is an emerging model in comparative medicine, notably because it shares the human environment including its risk factors, is affected by many analogous age-related diseases, receives comparable medical care, and has excellent veterinary medical data available. Past studies of dog lifespan have used aca...
Article
Full-text available
Background: Genetic association studies that seek to explain the inheritance of complex traits typically fail to explain a majority of the heritability of the trait under study. Thus, we are left with a gap in the map from genotype to phenotype. Several approaches have been used to fill this gap, including those that attempt to map endophenotype s...
Poster
Full-text available
Mitochondrial diseases are frequently characterized by mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like symptoms. Leading causes of mitochondrial diseases are mutations affecting the assembly of complex-I, reducing its ability to couple electron transfer to proton pumping, ATP production, and efficient energy production....
Article
A novel coronavirus, SARS-CoV-2, emerged in December 2019, leading within a few months to a global pandemic. COVID-19, the disease caused by this highly contagious virus, can have serious health consequences, though risks of complications are highly age-dependent. Rates of hospitalization and death are less than 0.1% in children, but increase to 10...
Article
Full-text available
Calorie restriction (CR) has a positive impact on health and lifespan. Previous work however does not reveal the whole underlying mechanism of behavioral phenotypes under CR. We propose a new approach based on phase space reconstruction (PSR) to analyze the behavioral responses of mice to graded CR. This involved reconstructing high-dimensional att...
Article
Full-text available
Inbreeding poses a real or potential threat to nearly every species of conservation concern. Inbreeding leads to loss of diversity at the individual level, which can cause inbreeding depression, and at the population level, which can hinder ability to respond to a changing environment. In closed populations such as endangered species and ex situ br...
Article
Full-text available
A major obstacle for preclinical testing of Alzheimer’s disease (AD) therapies is the availability of translationally relevant AD models. Critical for the validation of such models is the application of the same approaches and techniques used for the neuropathological characterization of AD. Deposition of amyloid-β 42 (Aβ42) plaques and neurofibril...
Poster
Mutations in the ND2 gene (mitochondrially encoded NADH dehydrogenase 2) have been linked to a reduction in efficient energy production, shortened lifespan, progressive neurodegeneration, and mitochondrial diseases such as Leigh’s syndrome. The ND2 gene codes for the production of NADH, a crucial portion of the electron transport chain in cellular...
Article
Full-text available
Significance Mutations accumulate throughout life in every cell of the body. A long-standing question is to what extent these mutations contribute to aging. Age is the single greatest risk factor for cancer, a disease driven by random mutagenesis and selection for malignant phenotypes. We wondered whether cancer cells, being the most heavily mutage...
Article
Full-text available
The angiotensin-converting enzyme (ACE) is a peptidase that is involved in the synthesis of Angiotensin II, the bioactive component of the renin-angiotensin system. A growing body of literature argues for a beneficial impact of ACE inhibitors (ACEi) on age-associated metabolic disorders, mediated by cellular changes in reactive oxygen species (ROS)...
Preprint
The angiotensin-converting enzyme (ACE) is a peptidase that is involved in the synthesis of Angiotensin II, the bioactive component of the renin-angiotensin system. A growing body of literature argues for a beneficial impact of ACE inhibitors (ACEi) on age-associated metabolic disorders, mediated by cellular changes in reactive oxygen species (ROS)...
Preprint
The angiotensin-converting enzyme (ACE) is a peptidase that is involved in the synthesis of Angiotensin II, the bioactive component of the renin-angiotensin system. A growing body of literature argues for a beneficial impact of ACE inhibitors (ACEi) on age-associated metabolic disorders, mediated by cellular changes in reactive oxygen species (ROS)...
Article
Full-text available
A hallmark of aging is a decline in metabolic homeostasis, which is attenuated by dietary restriction (DR). However, the interaction of aging and DR with the metabolome is not well understood. We report that DR is a stronger modulator of the rat metabolome than age in plasma and tissues. A comparative metabolomic screen in rodents and humans identi...
Article
Full-text available
Significance In eukaryotes, about one-third of all proteins are folded in the endoplasmic reticulum (ER). When protein folding demand exceeds capacity of the ER, the unfolded protein response (UPR) is activated to counteract ER stress. However, the mechanisms of adaptation to ER stress are not restricted to the UPR. Here, we report that gain of chr...
Article
Objective To describe a large population of dogs with a diagnosis of hyperadrenocorticism at the time of death in North American veterinary teaching hospitals, and to identify comorbid conditions associated with hyperadrenocorticism. Materials and Methods Retrospective cohort study of 1519 dogs with hyperadrenocorticism from a population of 70,574...
Poster
Full-text available
Introduction The Shar-Pei is a breed of dog whose levels of hyaluronic acid (HA) are roughly 5-10 times higher than in other dogs, which is due to overexpression of HAS2 and causes the breed’s characteristic wrinkly skin phenotype. High molecular weight HA is known to be tumor protective in other species both in vitro and in vivo. The best-studied...
Poster
Full-text available
Introduction Dog health and welfare are increasingly important to owners. Dogs are also becoming an exciting epidemiological model of human disease and mortality because they share the human environment and receive comparable medical care. Availability of large electronic medical record (EMR) databases on dogs supports modelling both patterns of i...
Poster
Full-text available
Alzheimer’s Disease (AD) is one of the leading causes of death in the United States. Studies suggest that the root cause of AD is due to two proteins, Aβ1-42 and tau, which accumulate and aggregate into amyloid plaques and neurofibrillary tangles, respectively. Current studies on the heritability and genetic foundation for AD are not well resolved....
Poster
Full-text available
The purebred domestic dog is an interesting model in population genetics due to the availability of both pedigree and phenotype data. While a number of statistical genetics studies in dogs using pedigree data exist, such studies are generally based on data that only covers a relatively low number of generations, even though systematic breeding star...
Article
Full-text available
Calorie restriction (CR) remains the most robust intervention to extend life span and improve health span. Using a global mass spectrometry–based metabolomics approach, we identified metabolites that were significantly differentially expressed in the plasma of C57BL/6 mice, fed graded levels of calorie restriction (10% CR, 20% CR, 30% CR, and 40% C...
Article
Full-text available
Among mammal species, almost all life-history traits are strongly size dependent. This size dependence even occurs at a molecular level. For example, both telomere length and telomerase expression show a size-dependent threshold. With some exceptions, species smaller than approximately 2 kg express telomerase, while species larger than that do not....
Article
Full-text available
Around the world, human populations have experienced large increases in average lifespan over the last 150 years, and while individuals are living longer, they are spending more years of life with multiple chronic morbidities. Researchers have used numerous laboratory animal models to understand the biological and environmental factors that influen...
Article
Significance: Reductionist studies have contributed greatly to our understanding of the basic biology of aging in recent years but we still do not understand fundamental mechanisms for many identified drugs and pathways. Use of systems approaches will help us move forward in our understanding of aging. Recent Advances: Recent work described here h...
Article
Full-text available
Individuals choose their mates so as to maximize reproductive success, and one important component of this choice is assessment of traits reflecting mate quality. Little is known about why specific traits are used for mate quality assessment nor about how they reflect it. We have previously shown that global manipulation of insulin signaling, a nut...
Data
Model for tissue insulin signaling effects on female attractiveness. Schematic representation of the effects observed in this study of tissue-specific insulin signaling on female attractiveness (solid blue lines) and on tissue dilp2 or dilp6 mRNA (dashed blue lines). Black suppression arrow is based on Bai et al. (2012). We have not detected any ef...
Data
IS manipulations in oenocytes do not affect attractiveness. For any duration of UAS transgene activation tested (6, 9, and 12 days of exposure to the activating temperature, 29°C) there was no effect on female attractiveness of IS manipulations in oenocytes when using PromE800-Gal4,TubP-Gal80ts as a driver. (EPS)
Data
Systemic insulin signaling manipulations do not affect attractiveness. (A) Treatments known to affect systemic insulin signaling (Park et al. 2014) have no affect attractiveness, including manipulating insulin signaling (gsDilp2>InR, gsDilp2>Pten) or neuron firing activity (Dilp2R>TrpA1, Dilp2R>Kir2.1,Tub-Gal80ts) of brain insulin producing cells (...
Data
CHC changes with ovarian ablation and with germline IS manipulations. (A) Ovarian ablation with ovoD1 either abolished or reversed individual CHC changes caused by global IS manipulations (compare to Fig 5B–these are part of the same experiment). All saturated CHC responses flipped for both IS manipulations (Binomial test for 7 out of 7, p = 0.0078...
Data
CHC abundances upon manipulation of insulin signaling in various tissues. (XLS)
Data
Fecundity does not predict attractiveness. (A) Despite having the same (positive) effect on attractiveness (Fig 2B), the two opposing IS manipulations in early follicle cells had opposing effects on fecundity. (B) Upregulation of IS in oenocytes (using PromE800-Gal4, tubP-Gal80ts as a driver) decreased fecundity and IS downregulation had no effect,...
Data
CHC changes with oenocyte IS manipulations, and with ovarian ablation in Yolk>Pten females. (A) Saturated CHCs increased consistently in Yolk>Pten, the pattern reversed by ovarian ablation (Binomial test p = 0.0078). (B) IS manipulations in oenocytes changed CHC relative amounts independent of saturation class: although 20/28 total CHCs changed in...
Data
Contrasting influence of tissue-specific IS on attractiveness is reflected in female CHC profiles. Principal component analysis of relative CHC abundances depicts desaturation changes (PC2) when insulin signaling is manipulated in the fat body and globally: proportion of saturated CHCs increase when insulin signaling is downregulated in the fat bod...
Article
Full-text available
Calorie restriction (CR) may extend longevity by modulating the mechanisms involved in aging. Different hypotheses have been proposed for its main mode of action. We quantified hepatic transcripts of male C57BL/6 mice exposed to graded levels of CR (0% to 40% CR) for three months, and evaluated the responses relative to these various hypotheses. Of...
Article
Age is the single greatest risk factor for a wide range of diseases, and as themean age of human populations grows steadily older, the impact of this risk factor grows as well. Laboratory studies on the basic biology of ageing have shed light on numerous genetic pathways that have strong effects on lifespan. However, we still do not know the degree...
Article
A hallmark of aging is a decline in metabolic homeostasis, and these adverse changes can be attenuated by dietary restriction (DR). However, the impact of aging, DR and their interaction on the metabolome, is not clear. Fischer 344 x Brown Norway F1 rats were provided ad libitum (AL) or DR (60% AL) access to food from 3 to 6 months of age (YAL and...
Conference Paper
The privately owned domestic dog is an emerging model in the field of geroscience, notably because it shares the human environment including its risk factors, is affected by many of the same age-related diseases, receives comparable medical care, and has excellent veterinary medical data available. The concept that a shared environment with similar...
Data
Table S1 Significantly differentiated metabolites based on Benjamini‐Hochberg adjusted P‐Value ≤ 0.05. 10, 20, 30 and 40CR compared to 12AL control group. Colour indicates pathway metabolite is primarily involved in. Table S2 Differentiated metabolites up and downregulated for each CR group relative to the 12AL control (p ≤ 0.05). Table S3 Correl...
Article
Full-text available
Calorie restriction (CR) leads to a remarkable decrease in adipose tissue mass and increases longevity in many taxa. Since the discovery of leptin, the secretory abilities of adipose tissue have gained prominence in the responses to CR. We quantified transcripts of epididymal white adipose tissue of male C57BL/6 mice exposed to graded levels of CR...
Article
Costs of reproduction are thought to result from natural selection optimizing organismal fitness within putative physiological constraints. Phenotypic and population genetic studies of reproductive costs are plentiful across taxa, but an understanding of their mechanistic basis would provide important insight into the diversity in life-history trai...
Article
Full-text available
Age is the single greatest risk factor for most causes of morbidity and mortality in humans and their companion animals. As opposed to other model organisms used to study aging, dogs share the human environment, are subject to similar risk factors, receive comparable medical care, and develop many of the same age-related diseases humans do. In this...
Article
Full-text available
Under calorie restriction (CR) animals need to lower energy demands. Whether this involves a reduction in cellular metabolism is an issue of contention. We exposed C57BL/6 mice to graded CR for 3 months, measured BMR and dissected out 20 body compartments. From a separate age-matched group (n=57), we built 7 predictive models for BMR. Unadjusted BM...