Explorando a Ciência por Trás da Longevidade Canina
Aprenda com o nosso repositório de estudos científicos que fundamentam o avanço da ciência da longevidade. Aqui você encontrará pesquisas detalhadas e as mais recentes descobertas que guiam as nossas práticas e inovações no cuidado e prolongamento da vida saudável dos cães.
Envelhecimento canino
Aging is accompanied by gradual changes in most body systems. Research on the biology of aging focuses on understanding the cellular and molecular processes underlying these changes as well as those accompanying the onset of age-related diseases. As scientists learn more about these processes, experiments can be designed to better understand when and how pathological changes begin, providing important clues toward developing interventions to prevent or treat disease. A great deal has been learned about structural and functional changes that occur in different body systems, and progress is ongoing. Research has expanded our knowledge, too, of the biologic factors associated with extended longevity in humans and animal models. This section of the NIA's narrative discusses some recent advances in the biology of aging, on cloning and transplantation and on lifespan itself. Selected future research directions are described as well, including continuing efforts to find biologic interventions to promote healthy aging, to understand the genetic basis of aging, and to explore the potential of adult stem cells and cell replacement for reducing disease and improving function.
The companion dog is the most phenotypically diverse species on the planet. This enormous variability between breeds extends not only to morphology and behavior but also to longevity and the disorders that affect dogs. There are remarkable overlaps and similarities between the human and canine species. Dogs closely share our human environment, including its many risk factors, and the veterinary infrastructure to manage health in dogs is second only to the medical infrastructure for humans. Distinct breed-based health profiles, along with their well-developed health record system and high overlap with the human environment, make the companion dog an exceptional model to improve understanding of the physiological, social, and economic impacts of the longevity dividend (LD). In this review, we describe what is already known about age-specific patterns of morbidity and mortality in companion dogs, and then explore whether this existing evidence supports the LD. We also discuss some potential limitations to using dogs as models of aging, including the fact that many dogs are euthanized before they have lived out their natural life span. Overall, we conclude that the companion dog offers high potential as a model system that will enable deeper research into the LD than is otherwise possible.
Canine Cognitive Dysfunction (CCD) scores correlate with amyloid beta 42 levels in dog brain tissue
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 during aging, and laboratory Beagle dogs, which do not share the human environment. In contrast, the companion dog shares the human environment and presents a genetically heterogeneous population of animals that might spontaneously develop age-associated AD-like pathology and cognitive dysfunction. Here, we quantitatively measured amyloid beta (Aβ42 or Abeta-42) levels in three areas of the companion dog brain (prefrontal cortex, temporal cortex, hippocampus/entorhinal cortex) and cerebrospinal fluid (CSF) using a newly developed Luminex assay. We found significant positive correlations between Aβ42 and age in all three brain regions. Brain Aβ42 abundance in all three brain regions was also correlated with Canine Cognitive Dysfunction Scale score in a multivariate analysis. This latter effect remained significant when correcting for age, except in the temporal cortex. There was no correlation between Aβ42 in CSF and cognitive scores; however, we found a significant positive correlation between Aβ42 in CSF and body weight, as well as a significant negative correlation between Aβ42 in CSF and age. Our results support the suitability of the companion dog as a model for AD and illustrate the utility of veterinary biobanking to make biospecimens available to researchers for analysis.
Dogs act as companions who provide us with emotional and physical support. Their shorter lifespans compel us to learn about the challenges and gifts of caring for older individuals. Our companion dogs can be exemplars of healthy or unhealthy aging, and sentinels of environmental factors that might increase or decrease our own healthy lifespan. In recent years, the field of aging has emphasized not just lifespan, but healthspan-the period of healthy, active lifespan. This focus on healthy, active aging is reflected in the World Health Organization's current focus on healthy aging for the next decade and the 2016 Healthy Aging in Action initiative in the US. This paper explores the current research into aging in both people and companion dogs, and in particular, how the relationship between older adults and dogs impacts healthy, active aging for both parties. The human-dog relationship faces many challenges as dogs, and people, age. We discuss potential solutions to these challenges, including suggestions for ways to continue contact with dogs if dog ownership is no longer possible for an older person. Future research directions are outlined in order to encourage the building of a stronger evidence base for the role of dogs in the lives of older adults.
Across mammals, increased body size is positively associated with lifespan. However, within species, this relationship is inverted. This is well illustrated in dogs (Canis familiaris), where larger dogs exhibit accelerated life trajectories: growing faster and dying younger than smaller dogs. Similarly, some age-associated traits (e.g., growth rate and physiological pace of aging) exhibit accelerated trajectories in larger breeds. Yet, it is unknown whether cognitive performance also demonstrates an accelerated life course trajectory in larger dogs. Here, we measured cognitive development and aging in a cross-sectional study of over 4000 dogs from 66 breeds using nine memory and decision-making tasks performed by citizen scientists as part of the Dognition project. Specifically, we tested whether cognitive traits follow a compressed (accelerated) trajectory in larger dogs, or the same trajectory for all breeds, which would result in limited cognitive decline in larger breeds. We found that all breeds, regardless of size or lifespan, tended to follow the same quadratic trajectory of cognitive aging-with a period of cognitive development in early life and decline in later life. Taken together, our results suggest that cognitive performance follows similar age-related trajectories across dog breeds, despite remarkable variation in developmental rates and lifespan.
Lifespan of companion dogs seen in three independent primary care veterinary clinics in the United States
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 academic, corporate or insurance data. While independent primary care data exist for the UK, none have as of yet been published for the US. This study analyzed data from three independent primary care US veterinary hospitals and identified factors that influence lifespan and mortality in a cohort of n = 20,970 privately owned dogs using Kaplan-Meier survival estimators and Cox Proportional Hazards modelling, including body size as a covariate.
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 breeding programs, some degree of inbreeding is inevitable. It is therefore vital to understand how different patterns of breeding and inbreeding can affect fitness in real animals. Domestic dogs provide an excellent model, showing dramatic variation in degree of inbreeding and in lifespan, an important aspect of fitness that is known to be impacted by inbreeding in other species. There is a strong negative correlation between body size and lifespan in dogs, but it is unknown whether the higher rate of aging in large dogs is due to body size per se or some other factor associated with large size. We used dense genome-wide SNP array data to calculate average inbreeding for over 100 dog breeds based on autozygous segment length and found that large breeds tend to have higher coefficients of inbreeding than small breeds. We then used data from the Veterinary medical Database and other published sources to estimate life expectancies for pure and mixed breed dogs. When controlling for size, variation in inbreeding was not associated with life expectancy across breeds. When comparing mixed versus purebred dogs, however, mixed breed dogs lived about 1.2 years longer on average than size-matched purebred dogs. Furthermore, individual pedigree coefficients of inbreeding and lifespans for over 9000 golden retrievers showed that inbreeding does negatively impact lifespan at the individual level. Registration data from the American Kennel Club suggest that the molecular inbreeding patterns observed in purebred dogs result from specific breeding practices and/or founder effects and not the current population size. Our results suggest that recent inbreeding, as reflected in variation within a breed, is more likely to affect fitness than historic inbreeding, as reflected in variation among breeds. Our results also indicate that occasional outcrosses, as in mixed breed dogs, can have a substantial positive effect on fitness.
Humans, as well as their closest ancestors, the higher African primates, exhibit female-biased survival and multiple sex differences in causes of death. However, the effects of sex on aging and longevity in an excellent model of human health, the companion dog, have not been well explored. Using two large independent databases on companion dog longevity and causes of death, we performed the most extensive analysis of sex differences in dog aging to date. Unlike the findings in humans, we observed only a small effect of sex on canine longevity. When broken down by neutering status, we discovered a small male advantage in survival among intact dogs but a clear female survival advantage among neutered dogs. Overall, the effect of neutering on life span was greater than the effect of sex. However, we found few sex differences in causes of death in either intact or neutered dogs. The results of this study suggest limited sex effects on either longevity or causes of death in the companion dog. Our analysis suggests that the majority of apparent sex differences in the wider canine populations may be due to the effects of neutering.
Dog Aging Project
Big data from small animals: integrating multi-level environmental data into the Dog Aging Project
Environmental exposures can have large impacts on health outcomes. While many resources have been dedicated to understanding how humans are influenced by the environment, few efforts have been made to study the role of built and natural environmental features on animal health. The Dog Aging Project (DAP) is a longitudinal community science study of aging in companion dogs. Using a combination of owner-reported surveys and secondary sources linked through geocoded coordinates, DAP has captured home, yard and neighbourhood variables for over 40,000 dogs. The DAP environmental data set spans four domains: the physical and built environment; chemical environment and exposures; diet and exercise; and social environment and interactions. By combining biometric data, measures of cognitive function and behaviour, and medical records, DAP is attempting to use a big-data approach to transform the understanding of how the surrounding world affects the health of companion dogs. In this paper, the authors describe the data infrastructure developed to integrate and analyse multi-level environmental data that can be used to improve the understanding of canine co-morbidity and aging.
Social determinants of health and disease in companion dogs: a cohort study from the Dog Aging Project
Exposure to social environmental adversity is associated with health and survival across many social species, including humans. However, little is known about how these health and mortality effects vary across the lifespan and may be differentially impacted by various components of the environment. Here, we leveraged a relatively new and powerful model for human aging, the companion dog, to investigate which components of the social environment are associated with dog health and how these associations vary across the lifespan. We drew on comprehensive survey data collected on 21,410 dogs from the Dog Aging Project and identified five factors that together explained 33.7% of the variation in a dog's social environment. Factors capturing financial and household adversity were associated with poorer health and lower physical mobility in companion dogs, while factors that captured social support, such as living with other dogs, were associated with better health when controlling for dog age and weight. Notably, the effects of each environmental component were not equal: the effect of social support was 5× stronger than financial factors. The strength of these associations depended on the age of the dog, including a stronger relationship between the owner's age and the dog's health in younger as compared to older dogs. Taken together, these findings suggest the importance of income, stability and owner's age on owner-reported health outcomes in companion dogs and point to potential behavioral and/or environmental modifiers that can be used to promote healthy aging across species.
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 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.
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 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.
Associations between Neighborhood Disadvantage and Dog Walking among Participants in the Dog Aging Project
Although neighborhood socioeconomic disadvantage is negatively related to overall physical activity, prior studies reveal a complex relationship between disadvantage and particular walking behaviors. While disadvantage is associated with reduced recreational walking through a hypothesized "fear-of-crime" mechanism, the built environment in disadvantaged neighborhoods may encourage utilitarian walking. To date, no study has assessed how disadvantage relates to dog walking, a distinct walking behavior that is neither strictly recreational nor utilitarian but represents a key mechanism through which pet ownership may affect human health. We employ a large (n = 19,732) dataset from the Dog Aging Project to understand how neighborhood disadvantage is associated with dog walking when controlling for individual-, household-, and environmental-level factors. We find that dog owners in more disadvantaged neighborhoods report less on-leash walking activity compared to owners in advantaged neighborhoods and discuss the possibility of a fear-of-crime mechanism underlying this association. These findings improve our understanding of the relationship between neighborhood disadvantage and physical function and highlight the need for public health interventions that encourage dog ownership to consider neighborhood disadvantage.
Evaluation of cognitive function in the Dog Aging Project: associations with baseline canine characteristics
Canine cognitive dysfunction (CCD) is a neurodegenerative disease in aging dogs. It has been described previously in relatively small cohorts of dogs using multiple different rating scales. This study aimed to use a minimally modified CCD rating scale developed by previous researchers to describe the prevalence of CCD more thoroughly in a large, nationwide cohort of companion dogs participating in the Dog Aging Project (DAP) (n = 15,019). Associations between various canine characteristics, predicted lifespan quartiles, and CCD were examined using univariable and multivariable logistic regression models and receiver operating curve (ROC) analysis. When controlling for all other characteristics, the odds of CCD increased 52% with each additional year of age. Among dogs of the same age, health status, breed type, and sterilization status, odds of CCD were 6.47 times higher in dogs who were not active compared to those who were very active. When controlling for age, breed type, activity level, and other comorbidities, dogs with a history of neurological, eye, or ear disorders had higher odds of CCD. Lifespan quartile analysis showed excellent discriminating ability between CCD positive and negative dogs. Weight-based lifespan quartile estimation could therefore serve as a tool to inform CCD screening by veterinarians.
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 associated with contextual- and owner-level characteristics. We leveraged a large and novel data set from the Dog Aging Project (DAP) to investigate the extent to which the age-activity relationship is associated with certain dog and owner characteristics, namely dog size, owner age, and the environment in which they live. Dogs are a unique model for aging research as they are exposed to similar social and environmental elements as humans but have a shorter life span, allowing researchers to observe their entire life course. We find that older dogs are less active than younger dogs; rural dogs are more active than suburban and urban dogs, especially at younger ages; and larger dogs are more active than smaller dogs. These findings are generally consistent with previous studies. However, a surprising finding is that older owners have more active dogs than younger owners. As one of the first studies to utilize the large survey data from the DAP, this study lays the foundation for future investigations to further understand and identify the biological, social, and environmental causes, as well as consequences, of aging.
Rapamicina
A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs
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 study, 24 middle-aged healthy dogs received either placebo or a non-immunosuppressive dose of rapamycin for 10 weeks. All dogs received clinical and hematological exams before, during, and after the trial and echocardiography before and after the trial. Our results showed no clinical side effects in the rapamycin-treated group compared to dogs receiving the placebo. Echocardiography suggested improvement in both diastolic and systolic age-related measures of heart function (E/A ratio, fractional shortening, and ejection fraction) in the rapamycin-treated dogs. Hematological values remained within the normal range for all parameters studied; however, the mean corpuscular volume (MCV) was decreased in rapamycin-treated dogs. Based on these results, we will test rapamycin on a larger dog cohort for a longer period of time in order to validate its effects on cardiac function and to determine whether it can significantly improve healthspan and reduce mortality in companion dogs.
A masked, placebo-controlled, randomized clinical trial evaluating safety and the effect on cardiac function of low-dose rapamycin in 17 healthy client-owned dogs
Geroscience studies of low-dose rapamycin in laboratory species have identified numerous benefits, including reversing age-related cardiac dysfunction. Cardiovascular benefits have been observed in dogs with 10 weeks of treatment, raising questions about possible benefits and adverse effects of long-term use of low-dose rapamycin. The objectives of this study were to assess the impact of 6 months of low-dose rapamycin on echocardiographic indices of cardiac function in healthy dogs and to document the occurrence of adverse events.
Investigation of the effects of mTOR inhibitors rapamycin and everolimus in combination with carboplatin on canine malignant melanoma cells
Malignant melanoma in dogs is considered to be largely resistant to conventional chemotherapy, although responses to carboplatin have been documented. Invasion and early metastasis are common features of certain melanoma subtypes that contribute to tumour progression despite aggressive local and systemic therapy. Upregulation of the PI3K/AKT/mTOR pathway has been observed in canine malignant melanoma and may represent a potential target for therapy. Rapamycin (sirolimus) and everolimus are commercially available small molecule inhibitors that target mTOR and therefore may have anticancer activity in canine melanoma. It was hypothesized that there is synergism between rapamycin or everolimus and platinum chemotherapy, and that combination drug treatment would inhibit target/downstream proteins involved in cell viability/proliferation and increase cell death in canine melanoma cells. It was further hypothesized that rapamycin or everolimus would impact metabolism by reducing glycolysis in these cells. Four canine melanoma cell lines were treated in vitro with rapamycin and everolimus as sole treatment or combined with carboplatin. Cell viability, apoptosis, target modulation, and glycolytic metabolism were evaluated by crystal violet colourimetric assay, Annexin V/PI flow cytometry, western blotting, and Seahorse bioanalyzer, respectively.
Rapamycin (sirolimus) is a macrolide immunosuppressant that inhibits the mechanistic target of rapamycin (mTOR) protein kinase and extends lifespan in model organisms including mice. Although rapamycin is an FDA-approved drug for select indications, a diverse set of negative side effects may preclude its wide-scale deployment as an antiaging therapy. mTOR forms two different protein complexes, mTORC1 and mTORC2; the former is acutely sensitive to rapamycin whereas the latter is only chronically sensitive to rapamycin in vivo. Over the past decade, it has become clear that although genetic and pharmacological inhibition of mTORC1 extends lifespan and delays aging, inhibition of mTORC2 has negative effects on mammalian health and longevity and is responsible for many of the negative side effects of rapamycin. In this review, we discuss recent advances in understanding the molecular and physiological effects of rapamycin treatment, and we discuss how the use of alternative rapamycin treatment regimens or rapamycin analogs has the potential to mitigate the deleterious side effects of rapamycin treatment by more specifically targeting mTORC1. Although the side effects of rapamycin are still of significant concern, rapid progress is being made in realizing the revolutionary potential of rapamycin-based therapies for the treatment of diseases of aging.
In 2009, rapamycin was reported to increase the lifespan of mice when implemented later in life. This observation resulted in a sea-change in how researchers viewed aging. This was the first evidence that a pharmacological agent could have an impact on aging when administered later in life, i.e., an intervention that did not have to be implemented early in life before the negative impact of aging. Over the past decade, there has been an explosion in the number of reports studying the effect of rapamycin on various diseases, physiological functions, and biochemical processes in mice. In this review, we focus on those areas in which there is strong evidence for rapamycin’s effect on aging and age-related diseases in mice, e.g., lifespan, cardiac disease/function, central nervous system, immune system, and cell senescence. We conclude that it is time that pre-clinical studies be focused on taking rapamycin to the clinic, e.g., as a potential treatment for Alzheimer’s disease.
Gliflozina
Using mouse models and high-throughput proteomics, we conducted an in-depth analysis of the proteome changes induced in response to seven interventions known to increase mouse lifespan. This included two genetic mutations, a growth hormone receptor knockout (GHRKO mice) and a mutation in the Pit-1 locus (Snell dwarf mice), four drug treatments (rapamycin, acarbose, canagliflozin, and 17α-estradiol), and caloric restriction. Each of the interventions studied induced variable changes in the concentrations of proteins across liver, kidney, and gastrocnemius muscle tissue samples, with the strongest responses in the liver and limited concordance in protein responses across tissues. To the extent that these interventions promote longevity through common biological mechanisms, we anticipated that proteins associated with longevity could be identified by characterizing shared responses across all or multiple interventions. Many of the proteome alterations induced by each intervention were distinct, potentially implicating a variety of biological pathways as being related to lifespan extension. While we found no protein that was affected similarly by every intervention, we identified a set of proteins that responded to multiple interventions. These proteins were functionally diverse but tended to be involved in peroxisomal oxidation and metabolism of fatty acids. These results provide candidate proteins and biological mechanisms related to enhancing longevity that can inform research on therapeutic approaches to promote healthy aging.
It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium–glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.
SGLT2 inhibitors are widely prescribed drugs for type 2 diabetes and heart failure. It seems that their beneficial health effects are multifaceted and not only limited to the amelioration of glycemic profile. It is suggested that SGLT2 inhibitors-induced glycosuria causes a metabolic shift that mimics the fasting response. It is also known that calorie restriction leads to enhanced longevity in mice. Thus, we hypothesized that long-term treatment of mice with SGLT2 inhibitors might extend their life span. To this end male C57BL6 mice at the age of 4 months were put on a normal chow diet or on a diet supplemented with 200 mg/kg canagliflozin. The canagliflozin-treated mice showed lower body weight gain over time and increased life span. The median survival of control mice was 107.5 weeks, while that of the canagliflozin-treated group was 112.5 weeks (p=0.011). No difference was seen in the presence or severity of cataracts. This study showed for the first time an enhanced median survival of canagliflozin-treated male mice with a homogeneous genetic background (C57BL6). Further analyses are in progress to elucidate the metabolic adaptations and mechanisms underlying this effect.
Canagliflozin retards age-related lesions in heart, kidney, liver, and adrenal gland in genetically heterogenous male mice
Canagliflozin (Cana), a clinically important anti-diabetes drug, leads to a 14% increase in median lifespan and a 9% increase in the 90th percentile age when given to genetically heterogeneous male mice from 7 months of age, but does not increase lifespan in female mice. A histopathological study was conducted on 22-month-old mice to see if Cana retarded diverse forms of age-dependent pathology. This agent was found to diminish incidence or severity, in male mice only, of cardiomyopathy, glomerulonephropathy, arteriosclerosis, hepatic microvesicular cytoplasmic vacuolation (lipidosis), and adrenal cortical neoplasms. Protection against atrophy of the exocrine pancreas was seen in both males and females. Thus, the extension of lifespan in Cana-treated male mice, which is likely to reflect host- or tumor-mediated delay in lethal neoplasms, is accompanied by parallel retardation of lesions, in multiple tissues, that seldom if ever lead to death in these mice. Canagliflozin thus can be considered a drug that acts to slow the aging process and should be evaluated for potential protective effects against many other late-life conditions.
Canagliflozin (Cana) is an FDA-approved diabetes drug that protects against cardiovascular and kidney diseases. It also inhibits the sodium glucose transporter 2 by blocking renal reuptake and intestinal absorption of glucose. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing Cana at 180 ppm at 7 months of age until their death. Cana extended median survival of male mice by 14%. Cana also increased by 9% the age for 90th percentile survival, with parallel effects seen at each of 3 test sites. Neither the distribution of inferred cause of death nor incidental pathology findings at end-of-life necropsies were altered by Cana. Moreover, although no life span benefits were seen in female mice, Cana led to lower fasting glucose and improved glucose tolerance in both sexes, diminishing fat mass in females only. Therefore, the life span benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in male mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e., slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.