Joseph W. Kemnitz

Caloric restriction delays disease onset and mortality in rhesus monkeys

Starved to Life? Caloric restriction—reducing the calories ingested by around 30% of that of a normal, fit individual—leads to substantial increases in life span in experimental animals. In an extensive study of caloric restriction in primates, Colman et al. (p. 201) report that rhesus monkeys, which were subjected to caloric restriction as adults and followed for the last 20 years, show decreased mortality and delayed onset of age-related diseases when compared to normally fed control animals. If compliance with such a diet were not so difficult, many humans would be strongly tempted to enjoy the decreased incidence of brain degeneration, cardiovascular disease, diabetes, and cancer apparent in this population of monkeys. Age-associated death and onset of pathologies are delayed by controlled caloric restriction, thus prolonging life span. Caloric restriction (CR), without malnutrition, delays aging and extends life span in diverse species; however, its effect on resistance to illness and mortality in primates has not been clearly established. We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research. In a population of rhesus macaques maintained at the Wisconsin National Primate Research Center, moderate CR lowered the incidence of aging-related deaths. At the time point reported, 50% of control fed animals survived as compared with 80% of the CR animals. Furthermore, CR delayed the onset of age-associated pathologies. Specifically, CR reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy. These data demonstrate that CR slows aging in a primate species.

Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus.

Neurotoxic effects of prenatal administration of dexamethasone were examined in the fetal rhesus monkey brain at 135 and 162 days of gestation (term is 165 days). In an experimental design mimicking human clinical trials, dexamethasone was given intramuscularly to pregnant monkeys on day 132 (single injection with doses of 0.5, 5, or 10 mg/kg maternal body weight) or on days 132 and 133 (multiple injections at 12-h intervals with 0.125 x 4, 1.25 x 4, or 2.5 mg/kg x 4). The fetuses were delivered by caesarean section on day 135 or day 162 and hippocampal slices were prepared for evaluation. Light and electron microscopic observation revealed decreased numbers of pyramidal neurons in the hippocampal CA regions and of granular neurons in the dentate gyrus associated with degeneration of neuronal perikarya and dendrites. Axodendritic synaptic terminals of the mossy fibers in the CA3 hippocampal region showed pronounced degeneration. Degeneration was dose-dependent and multiple injections induced more severe damage than single injections of the same total dose. Even the lowest dose (0.5 mg/kg, which is similar to the dose used in human clinical trials) produced these changes. Degenerative changes induced by dexamethasone treatment (5 mg/kg) on days 132 and 133 were also clearly evident in fetuses studied at 162 days. Therefore, caution is recommended in the use of prenatal corticosteroids in premature deliveries.

Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys

Caloric restriction (CR) without malnutrition increases longevity and delays the onset of age-associated disorders in short-lived species, from unicellular organisms to laboratory mice and rats. The value of CR as a tool to understand human ageing relies on translatability of CR’s effects in primates. Here we show that CR significantly improves age-related and all-cause survival in monkeys on a long-term ~30% restricted diet since young adulthood. These data contrast with observations in the 2012 NIA intramural study report, where a difference in survival was not detected between control-fed and CR monkeys. A comparison of body weight of control animals from both studies with each other, and against data collected in a multi-centred relational database of primate ageing, suggests that the NIA control monkeys were effectively undergoing CR. Our data indicate that the benefits of CR on ageing are conserved in primates.

Energy balance and its components: implications for body weight regulation 1-3

A fundamental principle of nutrition and metabolism is that body weight change is associated with an imbalance between the energy content of food eaten and energy expended by the body to maintain life and to perform physical work. Such an energy balance framework is a potentially powerful tool for investigating the regulation of body weight. However, we need a better understanding of the components of energy balance and their interactions over various time scales to explain the natural history of conditions such as obesity and to estimate the magnitude and potential success of therapeutic interventions. Therefore, the ASN and the International Life Sciences Institute convened a panel composed of members with expertise in weight management, energy metabolism, physical activity, and behavior to review the published scientific literature and to hear presentations from other experts in these fields. The Consensus Panel met 9–12 May 2011 in Chicago, IL, and was charged to provide answers to the following 5 questions: Explain energy balance and imbalance in terms of a biological system in which energy intake and energy expenditure change over time in response to the environment. What are the interactions between the components of energy balance and how are they regulated? What is the veracity of some of the popular beliefs related to energy balance? What limitations do we face in the study of energy balance and its components? What research would better inform our knowledge of energy balance and its components?

Dietary restriction and aging in rhesus monkeys: the University of Wisconsin study.

Dietary restriction (DR) retards aging and extends the maximum lifespan of laboratory mice and rats. To determine whether DR has similar actions in a primate species, we initiated a study in 1989 to investigate the effects of a 30% DR in 30 adult male rhesus monkeys. In 1994, an additional 30 females and 16 males were added to the study. Although the animals are still middle-aged, a few differences have developed between the control and DR animals suggesting that DR may induce physiologic changes in the rhesus monkey similar to those observed in rodents. Fasting basal insulin and glucose concentrations are lower in DR compared to control animals while insulin sensitivity is higher in the restricted animals. DR has also altered circulating LDL in a manner that may inhibit atherogenesis. These results suggest that DR may be slowing some age-related physiologic changes. In addition to measures of glucose and lipid metabolism, the animals are evaluated annually for body composition, energy expenditure, physical activity, hematologic indices, and blood or urinary hormone concentrations. In the next few years, the first animals will reach the average lifespan ( approximately 26 years) of captive rhesus monkeys and it will become possible to determine if DR retards the aging process and extends the lifespan in a primate species.

Insights into the Development of Polycystic Ovary Syndrome (PCOS) from Studies of Prenatally Androgenized Female Rhesus Monkeys

The developmental pathophysiology of polycystic ovary syndrome (PCOS) is unknown. However, prenatally androgenized female rhesus monkeys exhibit ovarian and endocrinological features that mimic those found in women with PCOS. Thus, prenatal androgen excess may provide an etiology for hyperandrogenism and anovulation in adulthood.

Pioglitazone Increases Insulin Sensitivity, Reduces Blood Glucose, Insulin, and Lipid Levels, and Lowers Blood Pressure, in Obese, Insulin-Resistant Rhesus Monkeys

The antidiabetic effects of pioglitazone hydrochloride were evaluated in 6 spontaneously obese, insulin-resistant rhesus monkeys. The animals were studied during six successive 2-wk treatment phases separated by 2-wk rest periods: two placebo phases; 0.3, 1.0, and 3.0 mg · kg−1 · day−1 pioglitazone hydrochloride phases; and a final placebo phase. During the second week of each treatment phase, serum insulin (immunoreactive insulin [IRI]), plasma glucose, and serum triglyceride (TG) levels were measured after an overnight fast and after a standardized meal. Blood pressure was measured and glucose tolerance tests (modified minimal model protocol) were performed a few days after the meal tests. Pioglitazone hydrochloride significantly improved fasting and postprandial levels of IRI, plasma glucose, and TG in a dose-related manner (P < 0.05). Fasting values during treatment with 3.0 mg · kg−1 · day−1 were reduced by 64% for IRI, 19% for plasma glucose, and 44% for TG compared with the placebo phase before treatment. Efficacy of pioglitazone hydrochloride was more marked for those animals with fasting hyperglycemia. Insulin sensitivity was increased by pioglitazone hydrochloride (P = 0.05), whereas glucose effectiveness and glucose disappearance rate were not detectably affected. Systolic and mean arterial blood pressures were significantly decreased by pioglitazone hydrochloride (P < 0.05). No toxic side effects of pioglitazone hydrochloride treatment were noted.

The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys

BackgroundActivation of the peroxisome proliferator-activated receptor gamma (PPAR-γ) has been proposed as a possible neuroprotective strategy to slow down the progression of early Parkinsons disease (PD). Here we report preclinical data on the use of the PPAR-γ agonist pioglitazone (Actos®; Takeda Pharmaceuticals Ltd.) in a paradigm resembling early PD in nonhuman primates.MethodsRhesus monkeys that were trained to perform a battery of behavioral tests received a single intracarotid arterial injection of 20 ml of saline containing 3 mg of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Twenty-four hours later the monkeys were assessed using a clinical rating scale, matched accordingly to disability, randomly assigned to one of three groups [placebo (n = 5), 2.5 (n = 6) or 5 (n = 5) mg/kg of pioglitazone] and their treatments started. Three months after daily oral dosing, the animals were necropsied.ResultsWe observed significant improvements in clinical rating score (P = 0.02) in the animals treated with 5 mg/kg compared to placebo. Behavioral recovery was associated with preservation of nigrostriatal dopaminergic markers, observed as higher tyrosine hydroxylase (TH) putaminal optical density (P = 0.011), higher stereological cell counts of TH-ir (P = 0.02) and vesicular monoamine transporter-2 (VMAT-2)-ir nigral neurons (P = 0.006). Stereological cell counts of Nissl stained nigral neurons confirmed neuroprotection (P = 0.017). Pioglitazone-treated monkeys also showed a dose-dependent modulation of CD68-ir inflammatory cells, that was significantly decreased for 5 mg/kg treated animals compared to placebo (P = 0.018). A separate experiment to assess CSF penetration of pioglitazone revealed that 5 mg/kg p.o. induced consistently higher levels than 2.5 mg/kg and 7.5 mg/kg. p.o.ConclusionsOur results indicate that oral administration of pioglitazone is neuroprotective when administered early after inducing a parkinsonian syndrome in rhesus monkeys and supports the concept that PPAR-γ is a viable target against neurodegeneration.

Caloric restriction improves health and survival of rhesus monkeys

Caloric restriction (CR) without malnutrition extends lifespan and delays the onset of age-related disorders in most species but its impact in nonhuman primates has been controversial. In the late 1980s two parallel studies were initiated to determine the effect of CR in rhesus monkeys. The University of Wisconsin study reported a significant positive impact of CR on survival, but the National Institute on Aging study detected no significant survival effect. Here we present a direct comparison of longitudinal data from both studies including survival, bodyweight, food intake, fasting glucose levels and age-related morbidity. We describe differences in study design that could contribute to differences in outcomes, and we report species specificity in the impact of CR in terms of optimal onset and diet. Taken together these data confirm that health benefits of CR are conserved in monkeys and suggest that CR mechanisms are likely translatable to human health.

Lateral Hypothalamic Lesions and Norepinephrine Turnover in Rats

Animals with lateral hypothalamic lesions lost significantly more weight in the 18 h following this lesion than did sham-operated animals or rats with cerebral cortical lesions deprived of food for the same time period. In the acutely fasted sham-operated animals the turnover of norepinephrine in interscapular brown adipose tissue, heart, and pancreas was slowed but in fasted rats with lateral hypothalamic lesions norepinephrine turnover rates were three- to ninefold faster in all three organs. Exposure to the cold (4 degrees C) significantly increased norepinephrine turnover in the interscapular brown adipose tissue, heart, and pancreas of fasted sham-operated rats, but did not further increase the rate of turnover in lateral hypothalamic-lesioned rats. Rats with lesions in the cerebral cortex responded in a fashion similar to that of the sham-operated animals. Gastric erosions and microhemorrhagic gastric mucosa were observed in five of six acutely fasted rats with lateral hypothalamic lesions whereas all sham-operated rats had a normal appearance of the stomach lining. Animals with lateral hypothalamic lesions made 3 wk earlier also showed an increased rate of norepinephrine turnover in the interscapular brown adipose tissue, heart, and pancreas following an 18 h fast. Rats with bilateral lesions in the paraventricular region of the hypothalamus, however, responded similarly to sham-operated animals with a reduction in the turnover in norepinephrine with fasting and an increase in norepinephrine turnover rate after cold exposure even with fasting. These data suggest that lateral hypothalamic lesions produce an acute increase in turnover of norepinephrine, and that this increased turnover persists for up to 3 wk.