胰岛素抵抗和认知功能障碍

近年来阿尔茨海默病(AD)已被学术界称为"3型糖尿病",这是由于AD具有和糖尿病相似的发病机制,即大脑胰岛素缺乏和胰岛素抵抗.糖尿病通过"肝-脑轴"将外周胰岛素抵抗向中枢"传递",从而促进认知功能障碍的发生,是AD重要的危险因素,而这种"传递"作用甚至可能在糖尿病前期--葡萄糖调节受损状态就已经存在.在认知功能障碍的防...     

Adult neurogenesis in the hippocampus of long-lived mice during aging

Ames dwarf mice live considerably longer than normal animals, exhibit apparently normal cognitive functions, and maintain them into advanced age. Neurogenesis occurs throughout adult life span in the dentate gyrus of mammalian hippocampus and has been suggested to play an important role in cognitive function. We now report that the total number of bromodeoxyuridine (BrdU)-labeled cells in this brain region in aged Ames dwarf mice was not different from that in aged normal mice, whereas the fraction of newly generated neurons was significantly increased by monitoring BrdU labeling and cell marker expression. Evidence of activation of anti-apoptosis signal transduction cascade was also found in the hippocampus of aged dwarf mice. Together with previous findings, the results may suggest that an increase in hippocampal insulin-like growth factor-I protein expression and subsequent activation of antiapoptotic signaling might contribute to survival of newly born neurons and subsequently to the delay of cognitive loss during aging in these long-lived dwarf mice.     

Profiling psychomotor and cognitive aging in four-way cross mice

In part due to their genetic uniformity and stable characteristics, inbred rodents or their F1 progeny are frequently used to study brain aging. However, it is recognized that focus on a single genotype could lead to generalizations about brain aging that might not apply to the species as a whole, or to the human population. As a potential alternative to uniform genotypes, genetically heterogeneous (HET) mice, produced by a four-way cross, were tested in the current study to determine if they exhibit age-related declines in cognitive and psychomotor function similar to other rodent models of brain aging. Young (4 months) and older (23 months) CB6F1 × C3D2F1 mice were administered a variety of tests for cognitive, psychomotor, and sensory/reflexive capacities. Spontaneous locomotion, rearing, and ability to turn in an alley all decreased with age, as did behavioral measures sensitive to muscle strength, balance, and motor coordination. Although no effect of age was found for either startle response amplitude or reaction time to shock stimuli, the old mice reacted with less force to low intensity auditory stimuli. When tested on a spatial swim maze task, the old mice learned less efficiently, exhibited poorer retention after a 66-h delay, and demonstrated greater difficulty learning a new spatial location. In addition, the older mice were less able to learn the platform location when it was identified by a local visual cue. Because there was a significant correlation between spatial and cued discrimination performance in the old mice, it is possible that age-related spatial maze learning deficits could involve visual or motor impairments. Variation among individuals increased with age for most tests of psychomotor function, as well as for spatial swim performance, suggesting that four-way cross mice may be appropriate models of individualized brain aging. However, the analysis of spatial maze learning deficits in older CB6F1 × C3D2F1 mice may have limited applicability in the study of brain aging, because of a confounding with visually cued performance deficits.     

Insulin resistance and beta-cell dysfunction in aging: the importance of dietary carbohydrate

Aging is associated with a progressive decrease in glucose tolerance. This decrease is associated with insulin resistance and beta-cell dysfunction. This study was performed to evaluate the possible role of dietary factors in the glucose intolerance of aging. Two groups of men were studied: one young (Y; n = 8; age range, 18-36 yr) and one elderly (E; n = 10; age range, 65-82 yr). Frequently sampled iv glucose tolerance tests were performed in random order: 1) during ad libitum home dietary conditions; 2) after a 3- to 5-day regimen of very high (85%) carbohydrate intake; and 3) after a 3- to 5-day regimen of low (30%) carbohydrate intake (Y only). From the frequently sampled iv glucose tolerance test data, we calculated the glucose disappearance rate (Kg) and metabolic parameters according to the minimal model method, including the insulin sensitivity index (S1) and the first and second phase beta-cell responsivity to glucose (phi 1 and phi 2). The elderly men, while eating an ad libitum diet, were less tolerant to glucose than the young [mean Kg: E = 1.5 +/- 0.2% (+/- SE) min-1; Y = 2.3 +/- 0.3% min-1; P less than 0.025], had relative insulin resistance (mean Si: Y = 6.1 +/- 1.1; E = 2.4 +/- 0.7 min-1 10(-4)/(microU/mL) [0.85 +/- 0.15 vs. 0.33 +/- 0.10 min-1 10(-4)/(pmol/L)]; P less than 0.01), and lesser second phase beta-cell responsiveness to glucose (mean phi 2: Y = 18.5 +/- 3.6; E = 8.7 +/- 2.7 (microU/mL).min-2/(mg/dL) [2390 +/- 465 vs. 1120 +/- 349 (pmol/L).min-2/(mmol/L)]; P less than 0.05). A maximum improvement in Kg and S1 occurred at 41% carbohydrate feeding in the young men, whereas in the elderly men there was a significant increase in both of these parameters while eating the very high (85%) carbohydrate diet. Thus, the difference in glucose tolerance between groups was corrected by the very high carbohydrate diet (mean Kg: Y = 2.2 +/- 0.2%; E = 2.0 +/- 0.3%/min; P greater than 0.05), as was the age-related difference in insulin sensitivity (mean S1: Y = 5.6 +/- 1.2; E = 4.4 +/- 1.3 min-1 10(-4)/(microU/mL) [0.78 +/- 0.17 vs. 0.61 +/- 0.18 min-1 10(-4)/(pmol/L)]; P greater than 0.5).(ABSTRACT TRUNCATED AT 400 WORDS)     

Insulin resistance possible risk factor for cognitive impairment in fibromialgic patients

To evaluate glucose metabolism and/or insulin resistance (IR) in 96 patients with Fibromyalgia (FM), associated or not to cognitive impairment. We investigated glucose metabolism in 96 FM patients. Enrolled patients were divided into two groups: 48 patients with memory deficit (group A) and 48 without memory deficit (control group). We evaluated glucose and insulin levels after a 2 h-Oral-Glucose-Tolerance-Test (2 h-OGTT) and insulin resistance (IR) by the homeostasis model assessment formula (HOMA). Body Mass Index (BMI), waist-to-hip-ratio (WHR), anxiety level, fasting plasma insulin and Non-Steroidal Anti-Inflammatory agents use were higher in patients with FM with memory impairment; while age, sex, waist circumference, education level, fasting plasma glucose, glycate hemoglobin, triglycerides, blood lipid profile, C- Reactivity-Protein (CRP), blood pressure and smoking habits were similar in both groups. Following OGTT the prevalence of glucose metabolism abnormalities was significantly higher in group A. IR was present in 79 % patients, of whom 23 % had also impaired glucose tolerance, 4 % newly diagnosed diabetes mellitus and 52 % IR only. Obesity and overweight prevailed in group A. IR, but not BMI or WHR was associated to an increased risk of memory impairment (OR?=?2,6; 95 % CI: 1,22–3,7). The results of this study suggest that IR may represent a risk factor for memory impairment in fibromialgic patients.     

Exogenous Hsp70 delays senescence and improves cognitive function in aging mice

Molecular chaperone Heat Shock Protein 70 (Hsp70) plays an important protective role in various neurodegenerative disorders often associated with aging, but its activity and availability in neuronal tissue decrease with age. Here we explored the effects of intranasal administration of exogenous recombinant human Hsp70 (eHsp70) on lifespan and neurological parameters in middle-aged and old mice. Long-term administration of eHsp70 significantly enhanced the lifespan of animals of different age groups. Behavioral assessment after 5 and 9 mo of chronic eHsp70 administration demonstrated improved learning and memory in old mice. Likewise, the investigation of locomotor and exploratory activities after eHsp70 treatment demonstrated a significant therapeutic effect of this chaperone. Measurements of synaptophysin show that eHsp70 treatment in old mice resulted in larger synaptophysin-immunopositive areas and higher neuron density compared with control animals. Furthermore, eHsp70 treatment decreased accumulation of lipofuscin, an aging-related marker, in the brain and enhanced proteasome activity. The potential of eHsp70 intranasal treatment to protect synaptic machinery in old animals offers a unique pharmacological approach for various neurodegenerative disorders associated with human aging.Heat shock proteins (HSPs) serve to maintain intracellular protein homeostasis and have been shown to prevent protein damage during aging in different animal models (1). HSPs are required for longevity (2, 3), and a number of studies suggest that longer-lived species have higher constitutive expression of HSPs (4–7). Consistent with this finding, overexpression of HSP genes increased longevity in Drosophila, Caenorhabditis elegans, and vertebrates (1, 8, 9). Hsp70 is the major cytoprotective molecular chaperone with many different functions in the cell (10–12). Observations suggest that genetic variants of the Hsp70 family contribute to longevity in a wide range of organisms (9, 13, 14). Its defensive role in multiple neurodegenerative disorders (15, 16) can be explained by the multifaceted action of this protein. Indeed, the induction of Hsp70 has been shown to diminish oxidative stress damage (17, 18), suppress apoptosis (19), support proteasomal and lysosomal functioning (20), suppress toxic protein aggregation such as Aβ (21), inhibit proinflammatory signaling (22), and increase survival of endogenous neural progenitor cells (21). Notwithstanding Hsp70’s importance, its chaperone activity, as well as the rate of its synthesis and induction in response to stimuli, decreases in neurons with age (3, 6, 21, 22), suggesting that a pharmacological approach aiming to recover this chaperone in the aging brain may counter neurodegeneration.To our knowledge, the effect of exogenous HSPs on longevity has not yet been investigated. We previously showed that intranasally injected Hsp70 rapidly entered the brain of wild-type mice and was transported within neurons (23, 24). Furthermore, chronic Hsp70 treatment ameliorated multiple behavioral and molecular disturbances in two models of Alzheimer’s disease (AD)-type neurodegeneration (23). In this study, we explored the geroprotection potential of recombinant exogenous Hsp70 (eHsp70) in healthy mice. For all of the described experiments, we used highly pure LPS-free human eHsp70 (25), which rules out a possibility of confounding inflammatory responses associated with contaminated Hsp70. Our results demonstrate that long-term intranasal administration of human eHsp70 improves longevity and ameliorates aging-related behavioral deficits and molecular alterations to synaptic structure in the brains of aging mice.     

Insulin resistance in skeletal muscles of caveolin-3-null mice

Type 2 diabetes is preceded by the development of insulin resistance, in which the action of insulin is impaired, largely in skeletal muscles. Caveolin-3 (Cav3) is a muscle-specific subtype of caveolin, an example of a scaffolding protein found within membranes. Cav is also known as growth signal inhibitor, although it was recently demonstrated that the genetic disruption of Cav3 did not augment growth in mice. We found, however, that the lack of Cav3 led to the development of insulin resistance, as exemplified by decreased glucose uptake in skeletal muscles, impaired glucose tolerance test performance, and increases in serum lipids. Such impairments were markedly augmented in the presence of streptozotocin, a pancreatic beta cell toxin, suggesting that the mice were susceptible to severe diabetes in the presence of an additional risk factor. Insulin-stimulated activation of insulin receptors and downstream molecules, such as IRS-1 and Akt, was attenuated in the skeletal muscles of Cav3 null mice, but not in the liver, without affecting protein expression or subcellular localization. Genetic transfer of Cav3 by needle injection restored insulin signaling in skeletal muscles. Our findings suggest that Cav3 is an enhancer of insulin signaling in skeletal muscles but does not act as a scaffolding molecule for insulin receptors.     

Stress resistance in long-lived mouse models

Cellular stress resistance has been observed in a variety of long-lived mouse systems. The Ames and Snell dwarf mice show altered hormonal profiles (low levels of growth hormone/IGF-1 and of other hormones). These altered hormonal profiles lead to physiological changes in cells, leading to increased resistance to multiple forms of stress including UV light, oxidative stress, heat, and the heavy metal cadmium. The cells also show resistance to carcinogen and senescence-like growth arrest induced by ambient oxygen. Thus, cellular stress resistance may confer resistance to various diseases associated with stress insults. Stress resistance has also been observed in various long-lived mice (hemizygous knockout of igf-1r, a mutation in p66(shc), and klotho overexpression) and in vitro CR (Carolie Restriction) system. Many of the long-lived mouse systems show reduction or inhibition of the insulin/IGF-1-FOXO pathway, thus suggesting that there may be an overlapping mechanism for increased life span. The insulin/IGF-1-FOXO pathway interlocks to several signal transduction pathways through AKT, FOXO, JNK, and other components. Taken together, stress resistance may be an essential function in cells that leads to increased longevity. I will summarize molecular basis of stress resistance and further discuss stress resistance in other systems.     

Insulin resistance,diabetes and cognitive function: Consequences for preventative strategies

Cognitive decline and dementia both place a heavy burden on patients and their relatives, and any means of preventing such age-related changes are worthy of consideration. Those who have the metabolic syndrome with or without diabetes suffer more often from dysexecutive problems and slower psychomotor speed than do other patients. In epidemiological studies, diabetes has appeared to be a risk factor for all types of dementia, including vascular dementia, although the role of the metabolic syndrome in the risk of Alzheimer's disease is still a matter of debate. The possible mechanisms of cognitive alterations are multiple, and may differ according to age group and duration of diabetes or the metabolic syndrome. Drug interventional trials addressing the prevention of cognitive decline through action on the metabolic syndrome are disappointing-albeit scarce at this time. Lifestyle interventions in middle-aged or younger-elderly subjects should also be implemented in the general population.     

Protein nonenzymatic modifications and proteasome activity in skeletal muscle from the short-lived rat and long-lived pigeon

What are the mechanisms determining the rate of animal aging? Of the two major classes of endothermic animals, bird species are strikingly long-lived compared to similar size mammalian counterparts. Since oxidative stress is causally related to the basic aging process, markers of different kinds of oxidative damage to proteins (glutamic semialdehyde, aminoadipic semialdehyde, N(epsilon)-(carboxyethyl)lysine; N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(malondialdehyde)lysine and dinitrophenylhydrazyne-reactive protein carbonyls, peptidase activities of the proteasome, and amino acid and membrane fatty acyl composition were identified and measured in skeletal muscle from the short-lived rat (maximum life span, 4 years) and compared with the long-lived pigeon (maximum life span, 35 years). Skeletal muscle from pigeon showed significantly higher levels of glutamic semialdehyde, protein carbonyls (by western blot), N(epsilon)-(carboxyethyl)lysine and N(epsilon)-(carboxymethyl)lysine. No differences were observed for aminoadipic semialdehyde, whereas the lipoxidation marker N(epsilon)-(malondialdehyde)lysine displayed a significant low steady-state level, probably related with their significantly lower membrane unsaturation. The amino acid compositional analysis revealed that arginine, serine, threonine and methionine showed significantly lower levels in pigeon. Finally, pigeon samples showed also significantly lower levels of the peptidase activities of the proteasome. These results reinforces the role of structural components such as membrane unsaturation and protein composition in determining the longer maximum life span showed by birds compared with mammals of similar body size.     

Insulin exposure and unifying aging

BACKGROUND: Absence of a widely agreed upon central paradigm for mammalian aging. OBJECTIVE: Detailed elaboration of a proposed mammalian aging paradigm. METHODS: Elaboration of a new theoretical model. RESULTS: Hormonal imbalance-growth factor exposure theory (HI-GFE theory) can account for two major aging phenomena: (1) decline in mammalian 'reserve capacity' and consequent rise of diseases of maintenance, and (2) rise then peaking of most age-associated proliferative diseases. Reserve capacity decline via gradual decline in mitochondrial maximal energy production (state 3) accounts for the gradual redirection of declined maximal energy production toward survival functions like ion pumping to the relative detriment of RNA and protein synthesis as seen in lesser synthetic rates and slower turnover with consequent gradual cellular impairment. Developmental program triggered, and over-ample nutritionally driven, growth factor exposure in youth to middle age encourages promotional events that lead to proliferative diseases that rise coincident to rapidly declining reserve capacity and cumulative increased mutational status of age. CONCLUSIONS: Declining mitochondrial state 3 aging energy production status is easily and safely reversible with probable consequences of greatly postponing the decline in overall 'reserve capacity' which may also improve insulin: growth hormone balance and result in lower overall growth factor exposure and consequent longer healthy life of a potentially greater magnitude increase in life spans than that seen in calorie-restricted animals.     

Strategy for identifying biomarkers of aging in long-lived species

If effective anti-aging interventions are to be identified for human application, then the development of reliable and valid biomarkers of aging are essential for this progress. Despite the apparent demand for such gerotechnology, biomarker research has become a controversial pursuit. Much of the controversy has emerged from a lack of consensus on terminology and standards for evaluating the reliability and validity of candidate biomarkers. The initiation of longitudinal studies of aging in long-lived non-human primates has provided an opportunity for establishing the reliability and validity of biomarkers of aging potentially suitable for human studies. From the primate study initiated in 1987 at the National Institute on Aging (NIA), the following criteria for defining a biomarker of aging have been offered: (1) significant cross-sectional correlation with age; (2) significant longitudinal change in the same direction as the cross-sectional correlation; (3) significant stability of individual differences over time. These criteria relate to both reliability and validity. However, the process of validating a candidate biomarker requires a greater standard of proof. Ideally, the rate of change in a biomarker of aging should be predictive of lifespan. In short-lived species, such as rodents, populations differing in lifespan can be identified, such as different strains of rodents or groups on different diets, such as those subjected to calorie restriction (CR), which live markedly longer. However, in the NIA primate study, the objective is to demonstrate that CR retards the rate of aging and increases lifespan. In the absence of lifespan data associated with CR in primates, validation of biomarkers of aging must rely on other strategies of proof. With this challenge, we have offered the following strategy: If a candidate biomarker is a valid measure of the rate of aging, then the rate of age-related change in the biomarker should be proportional to differences in lifespan among related species. Thus, for example, the rate of change in a candidate biomarker of aging in chimpanzees should be twice that of humans (60 vs 120 years maximum lifespan); in rhesus monkeys three times that of humans (40 vs 120 years maximum lifespan). The realization of this strategy will be aided by developing a primate aging database, a project that was recently launched in cooperation with the NIA, the National Center for Research Resources, and the University of Wisconsin Regional Primate Research Center.     

Insulin signaling cascade in the hearts of long-lived growth hormone receptor knockout mice: effects of calorie restriction

Calorie restriction (CR) improves insulin sensitivity and increases life span in normal but not in long-lived growth hormone-resistant knockout (GHRKO) mice. In this study, we examined interactive effects of GH resistance and long-term CR on cardiac insulin action. GHRKO mice exhibited marked increases in the insulin-induced phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), Akt, and ERK1/2 along with elevated insulin-stimulated IRS-1-associated regulatory subunit of phosphatidylinositol 3-kinase in the heart. These changes were associated with elevated protein levels of IR, IRS-1, and Akt and with a down-regulation of cardiac glucose transporter 4 (GLUT4). In normal mice, CR induced an important increase in the phosphorylation of cardiac Akt without elevation of Akt protein, reaching activation levels similar to those seen in GHRKO mice. This change may be cardioprotective and thus contribute to increased longevity in response to CR. Interestingly, the insulin signaling cascade in the heart of GHRKO mice was unaffected by CR.     

Testing hypotheses of aging in long-lived mice of the genus Peromyscus: association between longevity and mitochondrial stress resistance, ROS detoxification pathways, and DNA repair efficiency

In the present review we discuss the potential use of two long-lived mice of the genus Peromyscus—the white-footed mouse (P. leucopus) and the deer mouse (P. maniculatus) maximum lifespan potential ～8 years for both—to test predictions of theories about aging from the oxidative stress theory, mitochondrial theory and inflammatory theory. Previous studies have shown that P. leucopus cells exhibit superior antioxidant defense mechanisms and lower cellular production of reactive oxygen species (ROS) than do cells of the house mouse, Mus musculus (maximum lifespan ～3.5 years). We present new data showing that mitochondria in P. leucopus cells produce substantially less ROS than mitochondria in M. musculus cells, and that P. leucopus mitochondria exhibit superior stress resistance to those of M. musculus. We also provide evidence that components of the DNA repair system (e.g., pathways involved in repair of DNA damage induced by γ-irradiation) are likely to be more efficient in P. leucopus than in M. musculus. We propose that mitochondrial stress resistance, ROS detoxification pathways and more efficient DNA repair contribute to the previously documented resistance of P. leucopus cells toward oxidative stress-induced apoptosis. The link between these three pathways and species longevity is discussed.     

Decline in oxygen consumption correlates with lifespan in long-lived and short-lived mutants of Caenorhabditis elegans

In humans, the basal energy metabolism is thought to decline linearly with age. On the other hand, in the nematode Caenorhabditis elegans, two research groups reported independently that it declined exponentially. In this study, furthermore, we used various lifespan-mutant strains to determine whether the previous conclusion is more likely to be true. We can indirectly estimate the metabolic energy by conveniently measuring the oxygen consumption rates of C. elegans using an optical apparatus. From the profile of respiratory rates as a function of age, we can quantitatively isolate the physiological decline rate, λ, that exponentially represents the decay rate of respiratory activity with age. In addition, quantitative analysis indicates that the respiratory activity of worms has a finite value in advanced age. We also show that the maximum and mean lifespans strongly correlate with the reciprocal of the λ. These findings offer crucial biochemical evidence for a molecular mechanism at work in biological aging. Consequently, we here propose a mechanism based on a chemical reaction and offer a definition of the physiological decline rate and the finiteness of respiratory activity in advanced age.