Inhibition of the protein kinase mechanistic target of rapamycin (mTOR) with the Food and Drug Administration (FDA)-approved therapeutic rapamycin promotes health and longevity in diverse model organisms. More recently, specific inhibition of mTORC1 to treat aging-related conditions has become the goal of basic and translational scientists, clinicians and biotechnology companies. Here, we review the effects of rapamycin on the longevity and survival of both wild-type mice and mouse models of human diseases. We discuss recent clinical trials that have explored whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging. Finally, we discuss how new molecules may provide routes to the safer and more selective inhibition of mTOR complex 1 (mTORC1) in the decade ahead. We conclude by discussing what work remains to be done and the questions that will need to be addressed to make mTOR inhibitors part of the standard of care for diseases of aging. 

/pdf/targeting-the-biology-of-aging-with-mtor-inhibitors-mlurlz4b.pdf

Targeting the biology of aging with mTOR inhibitors

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.

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

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 has been collecting data on thousands of companion dogs of all different ages, sizes, and breeds since 2019. We leveraged this diverse cross-sectional dataset to investigate associations between feeding frequency and cognitive function (n = 10,474) as well as nine broad categories of health conditions (n = 24,238). Controlling for sex, age, breed, and other potential confounders, we found that dogs fed once daily rather than more frequently had lower mean scores on a cognitive dysfunction scale, and lower odds of having gastrointestinal, dental, orthopedic, kidney/urinary, and liver/pancreas disorders. Therefore, we find that once-daily feeding is associated with better health in multiple domains. Future research with longitudinal data can provide stronger evidence for a possible causal effect of feeding frequency on health in companion dogs. 

Once-daily feeding is associated with better health in companion dogs: results from the Dog Aging Project

Although cancer is widely regarded as a major contributor to canine morbidity and mortality, its frequency in companion dogs has only infrequently been characterized. We analyzed cross-sectional data from the baseline survey of owners of 27,541 living companion dogs enrolled in the Dog Aging Project as of December 31 2020 to estimate the lifetime prevalence of malignant and benign tumors and several potentially-associated characteristics. Survey questions elicited information on history of "cancer or tumors" including organ site and histologic type. Owners reported 819 malignant tumors (56% sited in the skin, muscle, or other soft tissue) and 404 benign tumors (69% sited in the skin, muscle, or other soft tissue). The lifetime prevalence of malignant tumors (29.7/1000 dogs) was approximately double the lifetime prevalence of benign tumors (14.7/1000 dogs). Lifetime prevalence of both malignant and benign tumors increased with dog age at survey completion. There were no statistically discernable differences in age-adjusted lifetime prevalence of malignant (prevalence ratio (PR) = 0.93 [95% confidence interval (CI) 0.82, 1.07] or benign tumors (PR=1.10, 95% CI 0.91, 1.34) in mixed vs. purebred dogs. The lifetime prevalence of malignant tumors increased with increasing dog size class; compared to toy and small dogs, the age-adjusted PRs (95% CIs) for medium, standard, large, and giant dogs were 1.65 (1.28, 2.11), 2.92 (2.35, 3.64), 3.67 (2.92, 4.62) and 2.99 (1.23, 4.02), respectively. Similar though less pronounced patterns in relation to dog size class were observed for benign tumors. Ongoing prospective data collection will permit future studies on risk factors for canine tumor incidence.

Lifetime prevalence of malignant and benign tumors in companion dogs: cross-sectional analysis of Dog Aging Project (DAP) baseline survey.

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 dogs, we investigate how body size, as measured by weight, associates with the prevalence of a reported condition and its pattern across age for various disease categories. We found significant positive associations between weight and prevalence of skin, bone/orthopedic, gastrointestinal, ear/nose/throat, cancer/tumor, brain/neurologic, endocrine, and infectious diseases. Similarly, weight was negatively associated with the prevalence of eye, cardiac, liver/pancreas, and respiratory disease categories. Kidney/urinary disease prevalence did not vary by weight. We also found that the association between age and disease prevalence varied by dog size for many conditions including eye, cardiac, orthopedic, ear/nose/throat, and cancer. Controlling for sex, purebred/mixed breed, and geographic region made little difference in all disease categories we studied. Our results align with the reduced lifespan in larger dogs for most of the disease categories but suggest potential avenues for further examination.

Dog size and patterns of disease history across the canine age spectrum: Results from the Dog Aging Project

An open science study of ageing in companion dogs

/pdf/author-correction-an-open-science-study-of-ageing-in-2jfywbqb.pdf

Author Correction: An open science study of ageing in companion dogs

/pdf/author-correction-evaluation-of-cognitive-function-in-the-cfb85mzb.pdf

Author Correction: Evaluation of cognitive function in the Dog Aging Project: associations with baseline canine characteristics

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An open science study of ageing in companion dogs

Author Correction: An open science study of ageing in companion dogs

Author Correction: Evaluation of cognitive function in the Dog Aging Project: associations with baseline canine characteristics