An open science study of ageing in companion dogs

Creevy, Kate E.; Akey, Joshua M.; Kaeberlein, Matt; Promislow, Daniel E. L.; Barnett, Brian B.; Benton, Brooke; Borenstein, Elhanan; Castelhano, Marta G.; Chou, Lucy; Collins, Devin; Coleman, Amanda E.; Crowder, Kyle; Dunbar, Matthew D.; Evans, Jeremy; Fajt, Virginia R.; Fitzpatrick, Annette L.; Jeffery, Unity; Jonlin, Erica C.; Karlsson, Elinor K.; Kerr, Kathleen F.; Lee, Hannah; Levine, Jonathan M.; Ma, Jing; McClelland, Robyn L.; McNulty, Kellyn E.; Morrill, Kathleen M.; Nam, Yunbi; Ruple, Audrey; Schwartz, Stephen M.; Shrager, Sandi; Snyder‐Mackler, Noah; Thistlethwaite, William; Tinkle, Amanda K.; Tolbert, M. Katherine; Urfer, Silvan R.; Wilfond, Benjamin S.

doi:10.1038/s41586-021-04282-9

Cited by 70 publications

(62 citation statements)

References 21 publications

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“…For example, administration of metformin, which interacts with mitochondrial complex I (and is a non-specific AMPK activator (Pernicova and Korbonits, 2014)), produces trending male-specific longevity bias as seen in the Intervention Testing Program (ITP, https://phenome.jax.org/projects/ITP1). This approach is now expanded for other models, including dogs, which represent an exciting model for aging (Bray et al, 2021; Creevy et al, 2022). However, the molecular mechanisms behind these longevity differences are largely unknown (Austad, 2011; Austad and Fischer, 2016), and could provide exciting opportunities for manipulating health and disease.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, pharmacological longevity interventions, such as via metformin administration (a non-specific AMPK activator (Pernicova and Korbonits, 2014)), produces trending male-specific longevity effects (https://phenome.jax.org/projects/ITP1). Exploring sex differences in longevity is feasible in other vertebrate models, including dogs (Bray et al, 2021; Creevy et al, 2022), and could be further examined in human clinical trials (Barzilai, 2017; Kulkarni et al, 2020). Thus, better understanding the molecular mechanisms behind sex-specific longevity differences could provide unique opportunities for manipulating health and disease.…”

Section: Discussionmentioning

confidence: 99%

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Sex-specific regulation of metabolic health and vertebrate lifespan by AMP biosynthesis

Astre

Atlan

Goshtchevsky

et al. 2022

Preprint

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The loss of energy homeostasis seen during aging, is causally linked to multiple age-related pathologies. The AMP-activated protein kinase (AMPK) directly senses cellular energy levels, which are reflected in the ratio between AMP:ATP. However, the genetic regulation of vertebrate aging by the AMPK pathway remains poorly understood. Here, we manipulate ATP production by mutating APRT, a key enzyme in AMP biosynthesis, and extend vertebrate lifespan in a male-specific manner. Using a multi-omics approach, we demonstrate that the APRT mutation restores metabolic plasticity, and identify a distinct transcriptional signature linking mitochondria with the sex-related differences in longevity. Accordingly, APRT mutant cells display a reduction in mitochondrial functions and ATP levels, and an increase in AMPK activity, resembling a persistent state of energy starvation. In-vivo, a fasting-like response was observed exclusively in male mutants, including resistance to a high-fat diet. Finally, intermittent fasting eliminated the longevity benefits mediated by the APRT mutation in males. Together, these data identify AMP biosynthesis as a sex-specific mediator of vertebrate longevity and metabolic health.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sex-specific regulation of metabolic health and vertebrate lifespan by AMP biosynthesis

Astre

Atlan

Goshtchevsky

et al. 2022

Preprint

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“…All dogs were members of the Dog Aging Project (DAP), a nationwide research study of companion dogs that aims to better understand the biological and environmental factors that impact health span and lifespan (Creevy et al, 2022; Kaeberlein et al, 2016). While the DAP is an ongoing longitudinal study, the data in the current study were cross-sectional, drawing on initial responses from owners whose dogs are enrolled in the first cohort.…”

Section: Methodsmentioning

confidence: 99%

“…Companion dogs have been proposed as a model for aging research with high translational potential (Creevy, Akey, Kaeberlein, & Promislow, 2022; Kaeberlein, Creevy, & Promislow, 2016). Unlike laboratory populations, companion dogs are genetically heterogeneous, and share many important features with humans, including the same living environments, disease risks and burdens, patterns of actuarial aging, and access to a sophisticated health care system (Hoffman, Creevy, Franks, O’Neill, & Promislow, 2018).…”

Section: Introductionmentioning

confidence: 99%

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

Bray

Raichlen

Forsyth

et al. 2022

Preprint

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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 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 Alzheimer’s 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.

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“…A large number of case-derived tissue samples are necessary to create various types of disease model organoids and use them for research with reasonable reliability. With the recent increase in the number of companion animals who receive life-long veterinary care, reports on animal diseases which have similarities to those seen in humans have been growing ( 16 , 127 ). Therefore, strategic collaboration with veterinary medicine would accelerate accumulation of disease samples which are common between humans and animals, helping to develop a solid base, or so called disease organoid biobanks, for translational research.…”

Section: Roles Of Farm and Companion Animal Organoids In One Health I...mentioning

confidence: 99%

Farm and Companion Animal Organoid Models in Translational Research: A Powerful Tool to Bridge the Gap Between Mice and Humans

Kawasaki

Goyama

Tachibana

et al. 2022

Front. Med. Technol.

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Animal organoid models derived from farm and companion animals have great potential to contribute to human health as a One Health initiative, which recognize a close inter-relationship among humans, animals and their shared environment and adopt multi-and trans-disciplinary approaches to optimize health outcomes. With recent advances in organoid technology, studies on farm and companion animal organoids have gained more attention in various fields including veterinary medicine, translational medicine and biomedical research. Not only is this because three-dimensional organoids possess unique characteristics from traditional two-dimensional cell cultures including their self-organizing and self-renewing properties and high structural and functional similarities to the originating tissue, but also because relative to conventional genetically modified or artificially induced murine models, companion animal organoids can provide an excellent model for spontaneously occurring diseases which resemble human diseases. These features of companion animal organoids offer a paradigm-shifting approach in biomedical research and improve translatability of in vitro studies to subsequent in vivo studies with spontaneously diseased animals while reducing the use of conventional animal models prior to human clinical trials. Farm animal organoids also could play an important role in investigations of the pathophysiology of zoonotic and reproductive diseases by contributing to public health and improving agricultural production. Here, we discuss a brief history of organoids and the most recent updates on farm and companion animal organoids, followed by discussion on their potential in public health, food security, and comparative medicine as One Health initiatives. We highlight recent evolution in the culturing of organoids and their integration with organ-on-a-chip systems to overcome current limitations in in vitro studies. We envision multidisciplinary work integrating organoid culture and organ-on-a-chip technology can contribute to improving both human and animal health.

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An open science study of ageing in companion dogs

Cited by 70 publications

References 21 publications

Sex-specific regulation of metabolic health and vertebrate lifespan by AMP biosynthesis

Sex-specific regulation of metabolic health and vertebrate lifespan by AMP biosynthesis

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

Farm and Companion Animal Organoid Models in Translational Research: A Powerful Tool to Bridge the Gap Between Mice and Humans

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