Case report: Severe asymptomatic hypertriglyceridemia associated with long-term low-dose rapamycin administration in a healthy middle-aged Labrador retriever

Rapamycin is an mTOR inhibitor that has been shown to extend the lifespan of laboratory model organisms. In humans, rapamycin is used at higher doses as an immunosuppressive medication to prevent organ rejection. Numerous adverse effects are seen with rapamycin treatment in humans, with one of the most common being dysregulation of lipid metabolism. In humans, this often manifests as mild to moderate serum lipid elevations, with a small subset developing extreme triglyceride elevations. This case report describes an eight-year-old, castrated male, clinically healthy Labrador retriever who developed severe hypertriglyceridemia associated with low-dose rapamycin administration over a six-month period. During this time, the dog was asymptomatic and displayed no other clinical abnormalities, aside from a progressive lipemia. Within 15 days of discontinuing rapamycin treatment, and with no targeted lipemic intervention, the dog’s lipemia and hypertriglyceridemia completely resolved

Demographic factors associated with joint supplement use in dogs from the Dog Aging Project

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 associated with joint supplement use are not as well studied. Using data collected from the Dog Aging Project, we analyzed owner survey responses regarding joint supplement administration and OA diagnosis for 26,951 adult dogs. In this cross-sectional analysis, logistic regression models and odds-ratios (OR) were employed to determine demographic factors of dogs and their owners that were associated with joint supplement administration. Forty percent of adult dogs in our population were given some type of joint supplement. Perhaps not surprisingly, dogs of older age, larger size, and those that were ever overweight were more likely to receive a joint supplement. Younger owner age, urban living, owner education, and feeding commercial dry food were associated with a reduced likelihood of administration of joint supplements to dogs. Interestingly, mixed breed dogs were also less likely to be administered a joint supplement (OR: 0.73). Dogs with a clinical diagnosis of OA were more likely to receive a joint supplement than those without a reported OA diagnosis (OR: 3.82). Neutered dogs were more likely to have a diagnosis of OA, even after controlling for other demographic factors, yet their prevalence of joint supplement administration was the same as intact dogs. Overall, joint supplement use appears to be high in our large population of dogs in the United States. Prospective studies are needed to determine if joint supplements are more commonly administered as a preventative for OA or after an OA clinical diagnosis

Lifespan of companion dogs seen in three independent primary care veterinary clinics in the United States

Abstract 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 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. Results As previously reported, body size was negatively correlated with lifespan. Gonadectomy was associated with a longer lifespan, with the effect being stronger in females than in males. This lifespan advantage was conserved in gonadectomized female dogs that lived to at least ages 5 and 8 years. We did not find significant differences in lifespan between purebred and mixed breed dogs; however, breeds with larger effective population sizes and/or lower inbreeding coefficients had median survival times 3–6 months longer than breeds with smaller effective population sizes or higher inbreeding coefficients, indicating that these measures of genetic diversity may be affecting breed lifespans. We also found that dog breeds belonging to the “Mountain” ancestral group had median survival times that were 3.5–4.6 years shorter than other purebred dog groups, which remained significant even when correcting for body size. Conclusions Our findings show that it is possible to obtain and analyze data from independent veterinary clinics in the US, an approach that could be useful for studies of comparative epidemiology under the One Health and One Welfare paradigms. We also show that the lifespan effects of gonadectomy are not identical between the sexes and should be investigated separately by sex in future analyses. More research is needed to further clarify the influence of age at gonadectomy, as well as the factors leading to the observed differences in lifespan in the “Mountain” ancestral group and in dog breeds of varying inbreeding coefficients and effective population sizes

Relationships among urinary protein‐to‐creatinine ratio, urine specific gravity, and bacteriuria in canine urine samples

Background Proteinuria is a marker of chronic kidney disease in dogs and a risk factor for increased morbidity and death. Predictive models using the results of readily available screening tests could foster early recognition. Objective To determine whether urine specific gravity (USG) and semiquantitative category of dipstick protein can be used to predict urinary protein‐to‐creatinine ratio (UP : C) and to examine the effect of urine culture results on UP : C in dogs. Animals Three hundred ninety‐four dogs (482 visits) presented to a university Community Practice Clinic or Veterinary Teaching Hospital between January 2011 and November 2015. Methods Retrospective study. Medical records were searched to identify dogs for which urinalysis, UP : C measurement, and urine culture testing were performed during a single hospital visit. Urine specific gravity, UP : C, dipstick protein concentration, and findings of urine sediment analysis and urine culture were recorded. Regression or Spearman correlation analysis was used to test for relationships between UP : C and USG within dipstick categories and between UP : C and bacterial colony‐forming units per milliliter, respectively. Cohen's kappa test was used to evaluate agreement between urine culture and UP : C testing. Results There were significant (P < .05) weak negative correlations (R2 range, 0.14‐0.37) between UP : C and USG for all nonnegative urine protein dipstick categories. The presence of a positive urine culture did not agree with the presence of abnormal UP : C (κ = −0.06). Conclusions and Clinical Importance Within dipstick protein categories, UP : C cannot be accurately predicted from USG. Repeating UP : C measurement after resolution of urinary tract infection is advisable

Reproductive Capability Is Associated with Lifespan and Cause of Death in Companion Dogs

<div><p>Reproduction is a risky affair; a lifespan cost of maintaining reproductive capability, and of reproduction itself, has been demonstrated in a wide range of animal species. However, little is understood about the mechanisms underlying this relationship. Most cost-of-reproduction studies simply ask how reproduction influences age at death, but are blind to the subjects' actual causes of death. Lifespan is a composite variable of myriad causes of death and it has not been clear whether the consequences of reproduction or of reproductive capability influence all causes of death equally. To address this gap in understanding, we compared causes of death among over 40,000 sterilized and reproductively intact domestic dogs, <i>Canis lupus familiaris</i>. We found that sterilization was strongly associated with an increase in lifespan, and while it decreased risk of death from some causes, such as infectious disease, it actually increased risk of death from others, such as cancer. These findings suggest that to understand how reproduction affects lifespan, a shift in research focus is needed. Beyond the impact of reproduction on <i>when</i> individuals die, we must investigate its impact on <i>why</i> individuals die, and subsequently must identify the mechanisms by which these causes of death are influenced by the physiology associated with reproductive capability. Such an approach may also clarify the effects of reproduction on lifespan in people.</p></div

Effect of sterilization on longevity and diagnoses.

<p>(A) Kaplan-Meier plots of longevity for males (left) and females (right). Blue lines indicate sterilized dogs and red lines indicate intact dogs. (B) Common log-odds ratios with 95% confidence intervals (CI) for pathophysiological processes (PP). Height of each bar indicates the relative frequency of each PP among all deaths. (C) Effects of sterilization on specific neoplastic diagnoses, showing common log odds ratios and 95% CI. Height of each bar indicates fraction of individuals with this diagnosis at the time of death. Transitional CC – transitional cell carcinoma; Squamous CC – squamous cell carcinoma. All cancers significant at <i>P</i><0.01 except prostate cancer, squamous cell carcinoma and melanoma (<i>P</i>>0.05). (D) As in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061082#pone-0061082-g001" target="_blank">Figure 1C</a>, but for specific infectious disease diagnoses. All infectious diseases significant at <i>P</i><0.01 except blastomycosis (<i>P</i>>0.4).</p

Risk of death by pathophysiologic process (PP) for sterilized dogs.

<p>Odds ratios for each of the eight PP are shown. Data for sterilized males (top) and sterilized females (bottom) are shown separately, and intact dogs of the same sex served as the reference population for each group.</p

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

Introduction: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.Methods:Seventeen client-owned dogs aged 6–10 years, weighing 18–36 kg, and without significant systemic disease were included in a prospective, randomized, placebo-controlled, masked clinical trial. Low-dose rapamycin (0.025 mg/kg) or placebo was administered three times per week for 6 months. Baseline, 6-month, and 12-month evaluation included physical examination, cardiology examination, and clinicopathology. Three-month evaluation included physical examination and clinicopathology. Owners completed online questionnaires every 2 weeks.Results:There were no statistically significant differences in echocardiographic parameters between rapamycin and placebo groups at 6 or 12 months. No clinically significant adverse events occurred. In 26.8% of the bi-weekly surveys owners whose dogs received rapamycin reported perceived positive changes in behavior or health, compared to 8.1% in the placebo group (p = 0.04).Discussion:While no clinically significant change in cardiac function was observed in dogs treated with low-dose rapamycin, the drug was well-tolerated with no significant adverse events