Kelli L. Vaughan

Pharmacological Inhibition of PI3K Reduces Adiposity and Metabolic Syndrome in Obese Mice and Rhesus Monkeys

Genetic inhibition of PI3K signaling increases energy expenditure, protects from obesity and metabolic syndrome, and extends longevity. Here, we show that two pharmacological inhibitors of PI3K, CNIO-PI3Ki and GDC-0941, decrease the adiposity of obese mice without affecting their lean mass. Long-term treatment of obese mice with low doses of CNIO-PI3Ki reduces body weight until reaching a balance that is stable for months as long as the treatment continues. CNIO-PI3Ki treatment also ameliorates liver steatosis and decreases glucose serum levels. The above observations have been recapitulated in independent laboratories and using different oral formulations of CNIO-PI3Ki. Finally, daily oral treatment of obese rhesus monkeys for 3 months with low doses of CNIO-PI3Ki decreased their adiposity and lowered their serum glucose levels, in the absence of detectable toxicities. Therefore, pharmacological inhibition of PI3K is an effective and safe anti-obesity intervention that could reverse the negative effects of metabolic syndrome in humans.

An overview of nonhuman primates in aging research

&NA; A graying human population and the rising costs of healthcare have fueled the growing need for a sophisticated translational model of aging. Nonhuman primates (NHPs) experience aging processes similar to humans and, as a result, provide an excellent opportunity to study a closely related species. Rhesus monkeys share > 92% homology and are the most commonly studied NHP. However, their substantial size, long lifespan, and the associated expense are prohibitive factors. Marmosets are rapidly becoming the preferred NHP for biomedical testing due to their small size, low zoonotic risk, reproductive efficiency, and relatively low‐cost. Both species experience age‐related pathology similar to humans, such as cancer, diabetes, arthritis, cardiovascular disease, and neurological decline. As a result, their use in aging research is paving the way to improved human health through a better understanding of the mechanisms of aging. HighlightsNHPs have aging characteristics and pathogeneses that closely resemble humans.Rhesus monkeys provide a robust model for translational aging research.The marmosets comparatively shorter lifespan is advantageous for aging studies.NHP studies are a crucial component in the progression of bench to bedside research.

Caloric Restriction Study Design Limitations in Rodent and Nonhuman Primate Studies

For a century, we have known that caloric restriction influences aging in many species. However, only recently it was firmly established that the effect is not entirely dependent on the calories provided. Instead, rodent and nonhuman primate models have shown that the rate of aging depends on other variables, including the macronutrient composition of the diet, the amount of time spent in the restricted state, age of onset, the gender and genetic background, and the particular feeding protocol for the control group. The field is further complicated when attempts are made to compare studies across different laboratories, which seemingly contradict each other. Here, we argue that some of the contradictory findings are most likely due to methodological differences. This review focuses on the four methodological differences identified in a recent comparative report from the National Institute on Aging and University of Wisconsin nonhuman primate studies, namely feeding regimen, diet composition, age of onset, and genetics. These factors, that may be influencing the effects of a calorie restriction intervention, are highlighted in the rodent model to draw parallels and elucidate findings reported in a higher species, nonhuman primates.

Obesity and Aging in Humans and Nonhuman Primates: A Mini-Review.

The prevalence of obesity in the US is increasing exponentially across gender, age and ethnic groups. Obesity and a long-term hypercaloric diet result in what appears to be accelerated aging, often leading to a multi-systemic deterioration known as the metabolic syndrome. Due to their physiological similarity to humans as well as comparable rates of spontaneous obesity and diabetes mellitus, nonhuman primates provide a useful translational model for the human condition. They allow for an in vivo study of disease progression, interaction of comorbidities, and novel interventions. However, defining obesity in aged humans and nonhuman primates is difficult as the physiological changes that occur with aging are not accounted for using our current systems (BMI - body mass index and BCS - body condition score). Nonetheless, nonhuman primate studies have greatly contributed to our understanding of obesity and metabolic dysfunction and should continue to play a large role in translational research. Here, methods for defining obesity and metabolic syndrome in humans and nonhuman primates are described along with the prevalence and effects of these conditions.

Comparison of anesthesia protocols for intravenous glucose tolerance testing in rhesus monkeys.

Drugs commonly used to sedate non‐human primates for physiological sample collection can affect the metabolic system and alter rates of glucose metabolism. This study was designed to compare the physiological and metabolic effects of ketamine/diazepam, telazol, and ketamine/dexmedetomidine.

Natural infection of human adenovirus 36 in rhesus monkeys is associated with a reduction in fasting glucose 36.

In humans, natural Ad36 infection is crosssectionally and temporally associated with adiposity and better glycemic control. 1–3 In vitro studies indicate that the early gene 4, open reading frame 1 (E4orf1) gene of Ad36 is necessary and sufficient to improve cellular glucose disposal. 4,5 Consequentially, E4orf1 protein offers an excellent template to develop antidiabetic drugs. 4 Considering the human relevance of a rhesus monkey model for preclinical drug development, we determined the associations of natural Ad36 infection with changes in glycemic control in rhesus monkeys. For this study, serum samples were obtained from 20 male rhesus monkeys (Macaca mulatta; 7–13 years of age) enrolled in an ongoing study described earlier. 6

α-Motor neurons are spared from aging while their synaptic inputs degenerate in monkeys and mice

Motor function deteriorates with advancing age, increasing the risk of adverse health outcomes. While it is well established that skeletal muscles and neuromuscular junctions (NMJs) degenerate with increasing age, the effect of aging on α‐motor neurons and their innervating synaptic inputs remains largely unknown. In this study, we examined the soma of α‐motor neurons and innervating synaptic inputs in the spinal cord of aged rhesus monkeys and mice, two species with vastly different lifespans. We found that, in both species, α‐motor neurons retain their soma size despite an accumulation of large amounts of cellular waste or lipofuscin. Interestingly, the lipofuscin profile varied considerably, indicating that α‐motor neurons age at different rates. Although the rate of aging varies, α‐motor neurons do not atrophy in old age. In fact, there is no difference in the number of motor axons populating ventral roots in old mice compared to adult mice. Moreover, the transcripts and proteins associated with α‐motor neurons do not decrease in the spinal cord of old mice. However, in aged rhesus monkeys and mice, there were fewer cholinergic and glutamatergic synaptic inputs directly abutting α‐motor neurons, evidence that aging causes α‐motor neurons to shed synaptic inputs. Thus, the loss of synaptic inputs may contribute to age‐related dysfunction of α‐motor neurons. These findings broaden our understanding of the degeneration of the somatic motor system that precipitates motor dysfunction with advancing age.

Breaking the Ceiling of Human Maximal Life span

While average human life expectancy has increased dramatically in the last century, the maximum life span has only modestly increased. These observations prompted the notion that human life span might have reached its maximal natural limit of ~115 years. To evaluate this hypothesis, we conducted a systematic analysis of all-cause human mortality throughout the 20th century. Our analyses revealed that, once cause of death is accounted for, there is a proportional increase in both median age of death and maximum life span. To examine whether pathway targeted aging interventions affected both median and maximum life span, we analyzed hundreds of interventions performed in multiple organisms (yeast, worms, flies, and rodents). Three criteria: median, maximum, and last survivor life spans were all significantly extended, and to a similar extent. Altogether, these findings suggest that targeting the biological/genetic causes of aging can allow breaking the currently observed ceiling of human maximal life span.

Contents Vol. 62, 2016

Clinical Section D. Aarsland, Stockholm J. Attems, Newcastle upon Tyne M. Burtscher, Innsbruck G. Del Giudice, Siena V.C. Emery, Guildford J.D. Erusalimsky, Cardiff L. Fontana, St. Louis, Mo. J.J. Goronzy, Stanford, Calif. U. Granacher, Potsdam K. Hauer, Heidelberg F. Kronenberg, Innsbruck T.F. Lue, San Francisco, Calif. A.B. Maier, Parkville, Vic. J. Olshansky, Chicago, Ill. A. Stuck, Bern T.M. Stulnig, Vienna J. Tao, Guangzhou D.C. Willcox, Ginowan D. Ziegler, Düsseldorf

Natural infection of human adenovirus 36 in rhesus monkeys is associated with a reduction in fasting glucose 恒河猴自然感染人36型腺病毒与空腹血糖下降有关

In humans, natural Ad36 infection is crosssectionally and temporally associated with adiposity and better glycemic control. 1–3 In vitro studies indicate that the early gene 4, open reading frame 1 (E4orf1) gene of Ad36 is necessary and sufficient to improve cellular glucose disposal. 4,5 Consequentially, E4orf1 protein offers an excellent template to develop antidiabetic drugs. 4 Considering the human relevance of a rhesus monkey model for preclinical drug development, we determined the associations of natural Ad36 infection with changes in glycemic control in rhesus monkeys. For this study, serum samples were obtained from 20 male rhesus monkeys (Macaca mulatta; 7–13 years of age) enrolled in an ongoing study described earlier. 6