Genetic Pathways of Aging and Their Relevance in the Dog as a Natural Model of Human Aging

Sándor, Sára; Kubinyi, Enikő

doi:10.3389/fgene.2019.00948

Cited by 36 publications

(32 citation statements)

References 531 publications

(583 reference statements)

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“…The unique establishment of dogs as close human companions and the high level of sequence identity between the two species has resulted in the recognition of dogs as natural models of human ageing and disease (Sandor & Kubinyi, 2019). This, in part, can be attributed to breeding programs and implementation of veterinary medicine, resulting in aging canine populations, and with this, diseases that are prevalent in aging human populations such as chronic pain, inflammation, and neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological and genetic characterisation of the canine P2X4 receptor

Sophocleous

Berg

Finol‐Urdaneta

et al. 2020

British J Pharmacology

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Background and Purpose: P2X4 receptors are emerging therapeutic targets for treating chronic pain and cardiovascular disease. Dogs are well-recognised natural models of human disease, but information regarding P2X4 receptors in dogs is lacking. To aid the development and validation of P2X4 receptor ligands, we have characterised and compared canine and human P2X4 receptors.Experimental Approach: Genomic DNA was extracted from whole blood samples from 101 randomly selected dogs and sequenced across the P2RX4 gene to identify potential missense variants. Recombinant canine and human P2X4 receptors tagged with Emerald GFP were expressed in 1321N1 and HEK293 cells and analysed by immunoblotting and confocal microscopy. In these cells, receptor pharmacology was characterised using nucleotide-induced Fura-2 AM measurements of intracellular Ca 2 + and known P2X4 receptor antagonists. P2X4 receptor-mediated inward currents in HEK293 cells were assessed by automated patch clamp. Key Results:No P2RX4 missense variants were identified in any canine samples.Canine and human P2X4 receptors were localised primarily to lysosomal compartments. ATP was the primary agonist of canine P2X4 receptors with near identical efficacy and potency at human receptors. 2 0 (3 0 )-O-(4-benzoylbenzoyl)-ATP, but not ADP, was a partial agonist with reduced potency for canine P2X4 receptors compared to the human orthologues. Five antagonists inhibited canine P2X4 receptors, with 1-(2,6-dibromo-4-isopropyl-phenyl)-3-(3-pyridyl)urea displaying reduced sensitivity and potency at canine P2X4 receptors.Conclusion and Implications: P2X4 receptors are highly conserved across dog pedigrees and display expression patterns and pharmacological profiles similar to human receptors, supporting validation and use of therapeutic agents for P2X4 receptorrelated disease onset and management in dogs and humans.Abbreviations: 5-BDBD, 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one; BX430, 1-(2,6-dibromo-4-isopropyl-phenyl)-3-(3-pyridyl)urea; BzATP, 2 0 (3 0 )-O-(4-benzoylbenzoyl)-ATP; ECS, extracellular Ca 2+ solution; EmGFP, Emerald GFP; SR, seal resistance; TNP-ATP, 2 0 ,3 0 -O-(2,4,6-trinitrophenyl)-ATP.

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Section: Discussionmentioning

confidence: 99%

Pharmacological and genetic characterisation of the canine P2X4 receptor

Sophocleous

Berg

Finol‐Urdaneta

et al. 2020

British J Pharmacology

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“…In this study we included an additional 157 genes that were related to autophagy and other pathways, which also may affect aging (adding up to 1,145 genes in total) and identified their canine homologs (in total, 1,062 homologs were found). Although the related genetic pathways were already associated with aging, only limited information is currently available regarding the contribution of individual genes to aging either in humans or in dogs (Sándor and Kubinyi, 2019).…”

Section: Candidate Gene Setmentioning

confidence: 99%

“…For many reasons, the companion dog is an especially promising model organism for translational approaches in aging research (Gilmore and Greer, 2015;Kaeberlein et al, 2016;Sándor and Kubinyi, 2019). Firstly, dogs have a much shorter life expectancy than humans -10-13 years on average in dogs (Adams et al, 2010;Leroy et al, 2015;Inoue et al, 2018) vs. 72 years in humans (2016 estimation; World Health Organization [WHO], 2018) -making aging-related longitudinal studies much shorter in time.…”

Section: Introductionmentioning

confidence: 99%

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A Preliminary Study to Investigate the Genetic Background of Longevity Based on Whole-Genome Sequence Data of Two Methuselah Dogs

et al. 2020

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Aging is the largest risk factor in many diseases and mortality alike. As the elderly population is expected to increase at an accelerating rate in the future, these phenomena will pose a growing socioeconomic burden on societies. To successfully cope with this challenge, a deeper understanding of aging is crucial. In many aspects, the companion dog is an increasingly popular model organism to study aging, with the promise of producing results that are more applicable to humans than the findings that come from the studies of classical model organisms. In this preliminary study we used the whole-genome sequence of two extremely old dogs-age: 22 and 27 years (or 90-135% more, than the average lifespan of dogs)-in order to make the first steps to understand the genetic background of extreme longevity in dogs. We identified more than ∼80 1000 novel SNPs in the two dogs (7500 of which overlapped between them) when compared to three publicly available canine SNP databases, which included SNP information from850 dogs. Most novel mutations (∼52000 SNPs) were identified at non-coding regions, while 4.6% of the remaining SNPs (n∼1600) were at exons, including 670 missense variants-76 of which overlapped between the two animalsacross 472 genes. Based on their gene ontologies, these genes were related-among others-to gene transcription/translation and its regulation, to immune response and the nervous system in general. We also detected 12 loss-of-function mutations, although their actual effect is unclear. Several genetic pathways were also identified, which pathways may be tempting candidates to be investigated in large sample sizes in order to confirm their relevance in extreme longevity in dogs (and possibly, in humans). We hypothesize a possible link between extreme longevity and the regulation of gene transcription/translation, which hypothesis should be further investigated in the future. This phenomenon could define an interesting direction for future research aiming to better understand longevity. The presented preliminary results highlight the utility of the companion dog in the study of the genetic background of longevity and aging.

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“…It has been demonstrated that hydrocephalus in humans presents with progressive cognitive decline and ultimately dementia [18]. As dogs appear to be an ideal model of hydrocephalus [1,19,20] and of aging-related disorders [12,[21][22][23][24][25][26][27], it is reasonable to predict that ventriculomegaly present in dogs would result in cognitive or neurological decline over time as well.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal Volumetric Assessment of Ventricular Enlargement in Pet Dogs Trained for Functional Magnetic Resonance Imaging (fMRI) Studies

Gunde

Czeibert

Gábor

et al. 2020

Veterinary Sciences

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Background: Recent studies suggest that clinically sound ventriculomegaly in dogs could be a preliminary form of the clinically significant hydrocephalus. We evaluated changes of ventricular volumes in awake functional magnetic resonance imaging (fMRI) trained dogs with indirectly assessed cognitive abilities over time (thus avoiding the use of anaesthetics, which can alter the pressure). Our research question was whether ventricular enlargement developing over time would have any detrimental effect on staying still while being scanned; which can be extrapolated to the ability to pay attention and to exert inhibition. Methods: Seven healthy dogs, 2–8 years old at the baseline scan and 4 years older at rescan, participated in a rigorous and gradual training for staying motionless (<2 mm) in the magnetic resonance (MR) scanner without any sedation during 6 minute-long structural MR sequences. On T1 structural images, volumetric analyses of the lateral ventricles were completed by software guided semi-automated tissue-type segmentations performed with FMRIB Software Library (FSL, Analysis Group, Oxford, UK). Results and conclusion: We report significant enlargement for both ventricles (left: 47.46 %, right: 46.07 %) over time while dogs retained high levels of attention and inhibition. The results suggest that even considerable ventricular enlargement arising during normal aging does not necessarily reflect observable pathological changes in behavior.

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Genetic Pathways of Aging and Their Relevance in the Dog as a Natural Model of Human Aging

Cited by 36 publications

References 531 publications

Pharmacological and genetic characterisation of the canine P2X4 receptor

Pharmacological and genetic characterisation of the canine P2X4 receptor

A Preliminary Study to Investigate the Genetic Background of Longevity Based on Whole-Genome Sequence Data of Two Methuselah Dogs

Longitudinal Volumetric Assessment of Ventricular Enlargement in Pet Dogs Trained for Functional Magnetic Resonance Imaging (fMRI) Studies

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