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1.
J Alzheimers Dis ; 68(1): 115-126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30689563

RESUMO

The degeneration in the locus coeruleus associated with Alzheimer's disease suggests an involvement of the noradrenergic system in the disease pathogenesis. The role of depleted norepinephrine was tested in adult and aged rhesus macaques to develop a potential model for testing Alzheimer's disease interventions. Monkeys were injected with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or vehicle at 0, 3, and 6 months; brains were harvested at 9 months. Reduced norepinephrine in the locus coeruleus was accompanied by decreased dopamine ß-hydroxylase staining and increased amyloid-ß load in the aged group, and the proportion of potentially toxic amyloid-ß42 peptide was increased. Immunohistochemistry revealed no effects on microglia or astrocytes. DSP4 treatment altered amyloid processing, but these changes were not associated with the induction of chronic neuroinflammation. These findings suggest norepinephrine deregulation is an essential component of a nonhuman primate model of Alzheimer's disease, but further refinement is necessary.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Benzilaminas/farmacologia , Locus Cerúleo/metabolismo , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Feminino , Locus Cerúleo/efeitos dos fármacos , Macaca mulatta , Norepinefrina/antagonistas & inibidores , Fragmentos de Peptídeos/antagonistas & inibidores , Distribuição Aleatória
2.
Cell Metab ; 20(1): 183-90, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24882067

RESUMO

Central arterial wall stiffening, driven by a chronic inflammatory milieu, accompanies arterial diseases, the leading cause of cardiovascular (CV) morbidity and mortality in Western society. An increase in central arterial wall stiffening, measured as an increase in aortic pulse wave velocity (PWV), is a major risk factor for clinical CV disease events. However, no specific therapies to reduce PWV are presently available. In rhesus monkeys, a 2 year diet high in fat and sucrose (HFS) increases not only body weight and cholesterol, but also induces prominent central arterial wall stiffening and increases PWV and inflammation. The observed loss of endothelial cell integrity, lipid and macrophage infiltration, and calcification of the arterial wall were driven by genomic and proteomic signatures of oxidative stress and inflammation. Resveratrol prevented the HFS-induced arterial wall inflammation and the accompanying increase in PWV. Dietary resveratrol may hold promise as a therapy to ameliorate increases in PWV.


Assuntos
Aorta/efeitos dos fármacos , Dieta Hiperlipídica , Estilbenos/farmacologia , Sacarose/farmacologia , Aldeídos/metabolismo , Animais , Aorta/enzimologia , Aorta/metabolismo , Caspase 3/metabolismo , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Humanos , Inflamação , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Primatas , Análise de Onda de Pulso , Resveratrol , Transcrição Gênica/efeitos dos fármacos
3.
Cell Metab ; 18(4): 533-45, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-24093677

RESUMO

Obesity is associated with a chronic, low-grade, systemic inflammation that may contribute to the development of insulin resistance and type 2 diabetes. Resveratrol, a natural compound with anti-inflammatory properties, is shown to improve glucose tolerance and insulin sensitivity in obese mice and humans. Here, we tested the effect of a 2-year resveratrol administration on proinflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Resveratrol supplementation (80 and 480 mg/day for the first and second year, respectively) decreased adipocyte size, increased sirtuin 1 expression, decreased NF-κB activation, and improved insulin sensitivity in visceral, but not subcutaneous, WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS ± resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/farmacologia , Dieta Hiperlipídica , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Carboidratos , Linhagem Celular , Inflamação/metabolismo , Insulina/sangue , Insulina/metabolismo , Macaca mulatta/metabolismo , Masculino , Camundongos , NF-kappa B/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Resveratrol , Sirtuína 1/metabolismo , Transcriptoma , Vísceras/metabolismo , Vísceras/patologia
4.
Nature ; 489(7415): 318-21, 2012 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-22932268

RESUMO

Calorie restriction (CR), a reduction of 10­40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7­14 years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate.


Assuntos
Envelhecimento/fisiologia , Restrição Calórica , Saúde , Longevidade/fisiologia , National Institute on Aging (U.S.) , Idade de Início , Animais , Glicemia/análise , Doenças Cardiovasculares/sangue , Colesterol/sangue , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Macaca mulatta , Masculino , Modelos Animais , Doenças dos Macacos/sangue , Neoplasias/sangue , Taxa de Sobrevida , Triglicerídeos/sangue , Incerteza , Estados Unidos
5.
Neurobiol Aging ; 26(7): 1117-27, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15748792

RESUMO

Human studies have documented age-related declines in caloric intake that are pronounced at advanced ages. We examined caloric intake from a longitudinal study of aging in 60 male and 60 female rhesus monkeys (Macaca mulatta) collected for up to 10 years. Monkeys were provided a standardized, nutritionally fortified diet during two daily meals, and intake was measured quarterly. About half of the monkeys were on a regimen of caloric restriction (CR) representing about a 30% reduction in caloric intake compared to controls (CON) of comparable age and body weight. CR was applied to determine if this nutritional intervention retards the rate of aging in monkeys similar to observations in other mammalian studies. Following reproductive maturity at 6 years of age, there was a consistent age-related decline in caloric intake in these monkeys. Although males had higher intake than females, and CON had higher intake compared to CR, the sex and diet differences converged at older ages (>20 years); thus, older CR monkeys were no longer consuming 30% less than the CON. When adjusted for body weight, an age-related decline in caloric intake was still evident; however, females had higher intake compared to males while CR monkeys still consumed less food, and again differences converged at older ages. Motivation for food was assessed in 65 of the monkeys following at least 8 years in their respective diet groups. Using an apparatus attached to the home cage, following an overnight fast, monkeys were trained to reach out of their cage to retrieve a biscuit of their diet by pushing open a clear plastic door on the apparatus. The door was then locked, and thus the biscuit was irretrievable. The time spent trying to retrieve the biscuit was recorded as a measure of motivation for food. We observed an age-related decline in this measure, but found no consistent differences in retrieval time between CR and CON groups of comparable age and time on diet. The results demonstrate an age-related decline in food intake and motivation for food in rhesus monkeys paralleling findings in humans; however, we found no evidence that monkeys on a long-term CR regimen were more motivated for food compared to CON. Examining the relationship of selected blood proteins to food intake following 7-11 years on the study, we found a negative correlation between globulin and intake among males and females after accounting for differences in age. In addition, a positive correlation was observed between leptin and intake in males.


Assuntos
Envelhecimento/fisiologia , Ingestão de Energia/fisiologia , Comportamento Alimentar/fisiologia , Motivação , Fatores Etários , Albuminas/metabolismo , Animais , Comportamento Animal , Peso Corporal/fisiologia , Restrição Calórica/métodos , Feminino , Globulinas/metabolismo , Leptina/sangue , Estudos Longitudinais , Macaca mulatta , Masculino , Tempo de Reação , Fatores Sexuais
6.
Proc Natl Acad Sci U S A ; 101(52): 18171-6, 2004 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-15604149

RESUMO

We report that a low-calorie diet can lessen the severity of neurochemical deficits and motor dysfunction in a primate model of Parkinson's disease. Adult male rhesus monkeys were maintained for 6 months on a reduced-calorie diet [30% caloric restriction (CR)] or an ad libitum control diet after which they were subjected to treatment with a neurotoxin to produce a hemiparkinson condition. After neurotoxin treatment, CR monkeys exhibited significantly higher levels of locomotor activity compared with control monkeys as well as higher levels of dopamine (DA) and DA metabolites in the striatal region. Increased survival of DA neurons in the substantia nigra and improved manual dexterity were noted but did not reach statistical significance. Levels of glial cell line-derived neurotrophic factor, which is known to promote the survival of DA neurons, were increased significantly in the caudate nucleus of CR monkeys, suggesting a role for glial cell line-derived neurotrophic factor in the anti-Parkinson's disease effect of the low-calorie diet.


Assuntos
Comportamento Animal , Restrição Calórica , Fatores de Crescimento Neural/biossíntese , Neuroquímica/métodos , Doença de Parkinson/patologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Encéfalo/anatomia & histologia , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Corpo Estriado/patologia , Modelos Animais de Doenças , Dopamina/farmacologia , Ensaio de Imunoadsorção Enzimática , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Haplorrinos , Macaca mulatta , Masculino , Neuroglia/metabolismo , Neurotoxinas/metabolismo , Neurotrofina 3/metabolismo , Tomografia por Emissão de Pósitrons , Substância Negra/patologia , Fatores de Tempo
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