Mindspan: lessons from rat models of neurocognitive aging

Research on the biology of aging seeks to enhance understanding of basic mechanisms and thus support improvements in outcomes throughout the lifespan, including longevity itself, susceptibility to disease, and life-long adaptive capacities. The focus of this review is the use of rats as an animal model of cognitive change during aging, and specifically lessons learned from aging rats in behavioral studies of cognitive processes mediated by specialized neural circuitry. An advantage of this approach is the ability to compare brain aging across species where functional homology exists for specific neural systems; in this article we focus on behavioral assessments that target the functions of the medial temporal lobe and prefrontal cortex. We also take a critical look at studies using calorie restriction (CR) as a well-defined experimental approach to manipulating biological aging. We conclude that the effects of CR on cognitive aging in rats are less well established than commonly assumed, with much less supportive evidence relative to its benefits on longevity and susceptibility to disease, and that more research in this area is necessary.     

Neuroendocrine and immune characteristics of aging in avian species

Avian species show a remarkable diversity in lifespan. The differing lifespan patterns are found across a number of birds, in spite of higher body temperature and apparent increased metabolic rate. These characteristics make study of age-related changes of great interest, especially for understanding the biology of aging associated with surprisingly long lifespan in some birds. Our studies have focused on a short-lived avian model, the Japanese quail in order to describe reproductive aging and the neuroendocrine characteristics leading to reproductive senescence. Biomarkers of aging used in mammalian species include telomere length, oxidative damage, and selected metabolic indicators. These markers provide confirming evidence that the long-lived birds appear to age more slowly. A corollary area of interest is that of immune function and aging. Immune responses have been studied in selected wild birds and there has been a range of studies that have considered the effects of stress in wild and domestic species. Our laboratory studies have specifically tested response to immune challenge relative to aging in the quail model and these studies indicate that there is an age-related change in the qualitative aspects of the response. However, there are also intriguing differences in the ability of the aging quail to respond that differ from mammalian data. Finally, another approach to understanding aging is to attempt to develop or test strategies that may extend lifespan and presumably health. One area of great interest has been to consider the effect of calorie restriction, which is a treatment shown to extend lifespan in a variety of species. This approach is routinely used in domestic poultry as a means for extending reproductive function and enhancing health. Our data indicate that moderate calorie restriction has beneficial effects, and that physiological and endocrine responses reflect these benefits.     

Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms

Although all cells in the body require energy to survive and function properly, excessive calorie intake over long time periods can compromise cell function and promote disorders such as cardiovascular disease, type-2 diabetes and cancers. Accordingly, dietary restriction (DR; either caloric restriction or intermittent fasting, with maintained vitamin and mineral intake) can extend lifespan and can increase disease resistance. Recent studies have shown that DR can have profound effects on brain function and vulnerability to injury and disease. DR can protect neurons against degeneration in animal models of Alzheimer's, Parkinson's and Huntington's diseases and stroke. Moreover, DR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which may increase the ability of the brain to resist aging and restore function following injury. Interestingly, increasing the time interval between meals can have beneficial effects on the brain and overall health of mice that are independent of cumulative calorie intake. The beneficial effects of DR, particularly those of intermittent fasting, appear to be the result of a cellular stress response that stimulates the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors such as brain-derived neurotrophic factor (BDNF), protein chaperones such as heat-shock proteins, and mitochondrial uncoupling proteins. Some beneficial effects of DR can be achieved by administering hormones that suppress appetite (leptin and ciliary neurotrophic factor) or by supplementing the diet with 2-deoxy-d-glucose, which may act as a calorie restriction mimetic. The profound influences of the quantity and timing of food intake on neuronal function and vulnerability to disease have revealed novel molecular and cellular mechanisms whereby diet affects the nervous system, and are leading to novel preventative and therapeutic approaches for neurodegenerative disorders.     

Caloric restriction: beneficial effects on brain aging and Alzheimer’s disease

Dietary interventions such as caloric restriction (CR) extend lifespan and health span. Recent data from animal and human studies indicate that CR slows down the aging process, benefits general health, and improves memory performance. Caloric restriction also retards and slows down the progression of different age-related diseases, such as Alzheimer’s disease. However, the specific molecular basis of these effects remains unclear. A better understanding of the pathways underlying these effects could pave the way to novel preventive or therapeutic strategies. In this review, we will discuss the mechanisms and effects of CR on aging and Alzheimer’s disease. A potential alternative to CR as a lifestyle modification is the use of CR mimetics. These compounds mimic the biochemical and functional effects of CR without the need to reduce energy intake. We discuss the effect of two of the most investigated mimetics, resveratrol and rapamycin, on aging and their potential as Alzheimer’s disease therapeutics. However, additional research will be needed to determine the safety, efficacy, and usability of CR and its mimetics before a general recommendation can be proposed to implement them.     

Calorie restriction mimetics: an emerging research field

When considering all possible aging interventions evaluated to date, it is clear that calorie restriction (CR) remains the most robust. Studies in numerous species have demonstrated that reduction of calories 30-50% below ad libitum levels of a nutritious diet can increase lifespan, reduce the incidence and delay the onset of age-related diseases, improve stress resistance, and decelerate functional decline. A current major focus of this research area is whether this nutritional intervention is relevant to human aging. Evidence emerging from studies in rhesus monkeys suggests that their response to CR parallels that observed in rodents. To assess CR effects in humans, clinical trials have been initiated. However, even if results from these studies could eventually substantiate CR as an effective pro-longevity strategy for humans, the utility of this intervention would be hampered because of the degree and length of restriction required. As an alternative strategy, new research has focused on the development of 'CR mimetics'. The objective of this strategy is to identify compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. For example, drugs that inhibit glycolysis (2-deoxyglucose), enhance insulin action (metformin), or affect stress signaling pathways (resveratrol), are being assessed as CR mimetics (CRM). Promising results have emerged from initial studies regarding physiological responses which resemble those observed in CR (e.g. reduced body temperature and plasma insulin) as well as protection against neurotoxicity (e.g. enhanced dopamine action and up-regulated neurotrophic factors). Ultimately, lifespan analyses in addition to expanded toxicity studies must be accomplished to fully assess the potential of any CRM. Nonetheless, this strategy clearly offers a very promising and expanding research endeavor.     

Caloric restriction: powerful protection for the aging heart and vasculature

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Research has shown that the majority of the cardiometabolic alterations associated with an increased risk of CVD (e.g., insulin resistance/type 2 diabetes, abdominal obesity, dyslipidemia, hypertension, and inflammation) can be prevented, and even reversed, with the implementation of healthier diets and regular exercise. Data from animal and human studies indicate that more drastic interventions, i.e., calorie restriction with adequate nutrition (CR), may have additional beneficial effects on several metabolic and molecular factors that are modulating cardiovascular aging itself (e.g., cardiac and arterial stiffness and heart rate variability). The purpose of this article is to review the current knowledge on the effects of CR on the aging of the cardiovascular system and CVD risk in rodents, monkeys, and humans. Taken together, research shows that CR has numerous beneficial effects on the aging cardiovascular system, some of which are likely related to reductions in inflammation and oxidative stress. In the vasculature, CR appears to protect against endothelial dysfunction and arterial stiffness and attenuates atherogenesis by improving several cardiometabolic risk factors. In the heart, CR attenuates age-related changes in the myocardium (i.e., CR protects against fibrosis, reduces cardiomyocyte apoptosis, prevents myosin isoform shifts, etc.) and preserves or improves left ventricular diastolic function. These effects, in combination with other benefits of CR, such as protection against obesity, diabetes, hypertension, and cancer, suggest that CR may have a major beneficial effect on health span, life span, and quality of life in humans.     

Development of calorie restriction mimetics as therapeutics for obesity, diabetes, inflammatory and neurodegenerative diseases

Calorie restriction (CR) is the most robust intervention that decreases morbidity and mortality, and thereby increases the lifespan of many organisms. Although the signaling pathways involved in the beneficial effects of CR are not yet fully understood. Several candidate pathways and key molecules have been identified. The effects of CR are highly conserved from lower organisms such as yeast to higher mammals such as rodents and monkeys. Recent studies have also demonstrated beneficial effects of CR in humans, although we need much longer studies to evaluate whether CR also increases the lifespan of humans. In reality, it is difficult for us to conduct CR interventions in humans because the subjects must be kept in a state of hunger and the duration of this state needed to achieve a clinically meaningful effect is still unknown. Thus, research in this field is focusing on the development of molecules that mimic the beneficial effects of CR without reducing food intake. Some of these candidate molecules include plant-derived functional chemicals (phyto-chemicals), synthetic small molecules, and endocrine molecules such as adipokines. Several studies have already shown that this research field may yield novel drugs for the treatment of age-related diseases such as diabetes. In this article, we describe the target pathways, candidate molecules, and strategies to develop CR mimetics.     

Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans

Reduced function mutations in the insulin/IGF-I signaling pathway increase maximal lifespan and health span in many species. Calorie restriction (CR) decreases serum IGF-1 concentration by ~40%, protects against cancer and slows aging in rodents. However, the long-term effects of CR with adequate nutrition on circulating IGF-1 levels in humans are unknown. Here we report data from two long-term CR studies (1 and 6 years) showing that severe CR without malnutrition did not change IGF-1 and IGF-1 : IGFBP-3 ratio levels in humans. In contrast, total and free IGF-1 concentrations were significantly lower in moderately protein-restricted individuals. Reducing protein intake from an average of 1.67 g kg(-1) of body weight per day to 0.95 g kg(-1) of body weight per day for 3 weeks in six volunteers practicing CR resulted in a reduction in serum IGF-1 from 194 ng mL(-1) to 152 ng mL(-1). These findings demonstrate that, unlike in rodents, long-term severe CR does not reduce serum IGF-1 concentration and IGF-1 : IGFBP-3 ratio in humans. In addition, our data provide evidence that protein intake is a key determinant of circulating IGF-1 levels in humans, and suggest that reduced protein intake may become an important component of anticancer and anti-aging dietary interventions.     

Dietary calorie restriction,DNA-repair and brain aging

It is now well established, in many species, that dietary calorie restriction confers beneficial effects like slowing down many age dependent processes and extending the lifespan. There are indications that this phenomenon may be applicable even in non-human primates and humans. However the precise mechanism through which these effects are achieved is not known. Since decreasing DNA repair has been correlated with increasing age, information available on the effect of dietary calorie restriction on DNA repair potential in different species, including humans, is reviewed with special emphasis on brain in view of its uniqueness and the age related appearance of several neurodegenerative disorders. There is considerable evidence to indicate that calorie restriction reduces the rate of, among other things, the age dependent decrease in DNA repair potential thus leading to a better maintenance of genomic integrity. In brain also dietary calorie restriction is found to improve the activities of some enzymes supposedly involved in DNA repair. It is suggested that one of the lifespan extending mechanisms of calorie restriction may be to channel the limited energy resource available to maintain a process like DNA repair rather than towards reproductive and anabolic activities.     

Beneficial Effects of Caloric Restriction on Chronic Kidney Disease in Rodent Models: A Meta-Analysis and Systematic Review

Background

Numerous studies have demonstrated the life-extending effect of caloric restriction. It is generally accepted that caloric restriction has health benefits, such as prolonging lifespan and delaying the onset and progression of CKD in various species, especially in rodent models. Although many studies have tested the efficacy of caloric restriction, no complete quantitative analysis of the potential beneficial effects of reducing caloric intake on the development and progression of CKD has been published.

Methods

All studies regarding the relationship between caloric restriction and chronic kidney diseases were searched in electronic databases, including PubMed/MEDLINE, EMBASE, Science Citation Index (SCI), OVID evidence-based medicine, Chinese Bio-medical Literature and Chinese science and technology periodicals (CNKI, VIP, and Wan Fang). The pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated by using fixed- or random-effects models.

Results

The data from 27 of all the studies mentioned above was used in the Meta analysis. Through the meta-analysis, we found that the parameter of blood urea nitrogen, serum creatinine and urinary protein levels of the AL group was significant higher than that of the CR group, which are 4.11 mg/dl, 0.08mg/dl and 33.20mg/kg/24h, respectively. The incidence of the nephropathy in the caloric restriction (CR) group was significantly lower than that in the ad libitum—fed (AL) group. We further introduced the subgroup analysis and found that the effect of caloric restriction on the occurrence of kidney disease was only significant with prolonged intervention; the beneficial effects of CR on the 60%-caloric-restriction group were greater than on the less-than-60%-caloric-restriction group, and caloric restriction did not show obvious protective effects in genetically modified strains. Moreover, survival rate of the caloric restriction group is much higher than that of the ad libitum—fed (AL) group.

Conclusions

Our findings demonstrate for the first time that compared with the AL group, the caloric restriction indeed decreased urea nitrogen, creatinine, urine protein, incidence of kidney diseases and increased the survival rate on 700~800 days.     

Lifelong calorie restriction affects indicators of colonic health in aging C57Bl/6J mice

Diminished colonic health is associated with various age-related pathologies. Calorie restriction (CR) is an effective strategy to increase healthy lifespan, although underlying mechanisms are not fully elucidated. Here, we report the effects of lifelong CR on indicators of colonic health in aging C57Bl/6J mice. Compared to an ad libitum control and moderate-fat diet, 30% energy reduction was associated with attenuated immune- and inflammation-related gene expression in the colon. Furthermore, expression of genes involved in lipid metabolism was higher upon CR, which may point towards efficient regulation of energy metabolism. The relative abundance of bacteria considered beneficial to colonic health, such as Bifidobacterium and Lactobacillus, increased in the mice exposed to CR for 28 months as compared to the other diet groups. We found lower plasma levels of interleukin-6 and lower levels of various metabolites, among which are bile acids, in the colonic luminal content of CR-exposed mice as compared to the other diet groups. Switching from CR to an ad libitum moderate-fat diet at old age (24 months) revealed remarkable phenotypic plasticity in terms of gene expression, microbiota composition and metabolite levels, although expression of a subset of genes remained CR-associated. This study demonstrated in a comprehensive way that CR affects indicators of colonic health in aging mice. Our findings provide unique leads for further studies that need to address optimal and feasible strategies for prolonged energy deprivation, which may contribute to healthy aging.     

Endothelial nitric oxide synthase,vascular integrity and human exceptional longevity

Aging is the sum of the deleterious changes that occur as time goes by. It is the main risk factor for the development of cardiovascular disease, and aging of the vasculature is the event that most often impacts on the health of elderly people. The “free-radical theory of aging” was proposed to explain aging as a consequence of the accumulation of reactive oxygen species (ROS). However, recent findings contradict this theory, and it now seems that mechanisms mediating longevity act through induction of oxidative stress. In fact, calorie restriction ? a powerful way of delaying aging ? increases ROS accumulation due to stimulation of the basal metabolic rate; moreover, reports show that antioxidant therapy is detrimental to healthy aging. We also now know that genetic manipulation of the insulin-like-growth-factor-1/insulin signal (IIS) has a profound impact on the rate of aging and that the IIS is modulated by calorie restriction and physical exercise. The IIS regulates activation of nitric oxide synthase (eNOS), the activity of which is essential to improving lifespan through calorie restriction, as demonstrated by experiments on eNOS knockout mice. Indeed, eNOS has a key role in maintaining vascular integrity during aging by activating vasorelaxation and allowing migration and angiogenesis. In this review, we will overview current literature on these topics and we will try to convince the reader of the importance of vascular integrity and nitric oxide production in determining healthy aging.     

Impact of 6‐month Caloric Restriction on Autonomic Nervous System Activity in Healthy,Overweight, Individuals

Caloric restriction (CR) increases maximum lifespan but the mechanisms are unclear. Dominance of the sympathetic nervous system (SNS) over the parasympathetic nervous system (PNS) has been shown to be a strong risk factor for cardiovascular disease. Obesity and aging are associated with increased SNS activity, and weight loss and/or exercise seem to have positive effects on this balance. We therefore evaluated the effect of different approaches of CR on autonomic function in 28 overweight individuals participating in the Comprehensive Assessment of Long‐term Effects of Reducing Intake of Energy (CALERIE) trial. Participants were randomized to either control, CR: 25% decrease in energy intake, CREX: 12.5% CR + 12.5% increase in energy expenditure, or LCD: low‐calorie diet until 15% weight reduction followed by weight maintenance. Autonomic function was assessed by spectral analysis of heart‐rate variability (HRV) while fasting and after a meal. Measurements were performed at baseline and 6 months. HR and SNS index decreased and PNS index increased in all intervention groups but reached significance only in CREX. HR and SNS index increased and PNS index decreased in response to the meal in all intervention groups. The results therefore suggest that weight loss improved SNS/PNS balance especially when CR is combined with exercise.     

Sirtuin regulation in calorie restriction

The beneficial effects of calorie restriction diet in extending lifespan and preventing diseases have long been recognized. Recent genetic and molecular studies in model organisms began to uncover the molecular regulation of calorie restriction response, with the gene SIR2 playing an essential role. This article summarizes the latest development on how mammalian SIR2 homologs coordinately regulate the calorie restriction response.     

Calorie restriction attenuates hypertrophy-induced redox imbalance and mitochondrial ATP-sensitive K+ channel repression

Oxidative stress has been implicated in the pathogenesis of cardiac hypertrophy and associated heart failure. Cardiac tissue grows in response to pressure or volume overload, leading to wall thickening or chamber enlargement. If sustained, this condition will lead to a dysfunctional cardiac tissue and oxidative stress. Calorie restriction (CR) is a powerful intervention to improve health and delay aging. Here, we investigated whether calorie restriction in mice prevented isoproterenol-induced cardiac hypertrophy in vivo by avoiding reactive oxygen species (ROS) production and maintaining antioxidant enzymatic activity. Additionally, we investigated the involvement of mitochondrial ATP-sensitive K⁺ channels (mitoKATP) in cardiac hypertrophy. CR was induced by 40% reduction in daily calorie ingestion. After 3 weeks on CR or ad libitum (Control) feeding, Swiss mice were treated intraperitoneally with isoproterenol (30 mg/kg per day) for 8 days to induce hypertrophy. Isoproterenol-treated mice had elevated heart weight/tibia length ratios and cardiac protein levels. These gross hypertrophic markers were significantly reduced in CR mice. Cardiac tissue from isoproterenol-treated CR mice also produced less H₂O₂ and had lower protein sulfydryl oxidation. Additionally, calorie restriction blocked hypertrophic-induced antioxidant enzyme (catalase, superoxide dismutase and glutathione peroxidase) activity repression during cardiac hypertrophy. MitoKATP opening was repressed in isolated mitochondria from hypertrophic hearts, in a manner sensitive to calorie restriction. Finally, mitoKATP inhibition significantly blocked the protective effects of calorie restriction. Altogether, our results suggest that CR improves intracellular redox balance during cardiac hypertrophy and prevents this process in a mechanism involving mitoKATP activation.     

Mild mitochondrial uncoupling and calorie restriction increase fasting eNOS, akt and mitochondrial biogenesis

Enhanced mitochondrial biogenesis promoted by eNOS activation is believed to play a central role in the beneficial effects of calorie restriction (CR). Since treatment of mice with dinitrophenol (DNP) promotes health and lifespan benefits similar to those observed in CR, we hypothesized that it could also impact biogenesis. We found that DNP and CR increase citrate synthase activity, PGC-1α, cytochrome c oxidase and mitofusin-2 expression, as well as fasting plasma levels of NO^• products. In addition, eNOS and Akt phosphorylation in skeletal muscle and visceral adipose tissue was activated in fasting CR and DNP animals. Overall, our results indicate that systemic mild uncoupling activates eNOS and Akt-dependent pathways leading to mitochondrial biogenesis.     

Yeast as a model to understand the interaction between genotype and the response to calorie restriction

Calorie restriction is reported to enhance survival and delay the onset of age-related decline in many different species. Several proteins have been proposed to play a role in mediating the response to calorie restriction, including the target of rapamycin kinase, sirtuins, and AMP kinase. An enhanced mechanistic understanding of calorie restriction has popularized the concept of "calorie restriction mimetics", drugs that mimic the beneficial effects of caloire restriction without requiring a reduction in nutrient intake. In theory, such drugs should delay the onset and progression of multiple age-related diseases, similar to calorie restriction in mammals. Despite the potential benefits of such calorie restriction mimetics, however, relatively little is known about the interaction between genetic variation and individual response to calorie restriction. Limited evidence from model systems indicates that genotype plays a large role in determining both the magnitude and direction of effect that calorie restriction has on longevity. Here we present an overview of these data from the perspective of using yeast as a model to study aging and describe an approach we are taking to further characterize the molecular mechanisms underlying genotype-dependent responses to calorie restriction.     

热量限制延长寿命的分子机制

很多研究均发现,热量限制在很多物种中都有延长寿命的作用.这些报道认为,寿命的延长可 能与氧化应激和炎症过程有关.值得注意的是,热量限制调节氧化应激与脂质代谢调控、抑 制细胞凋亡、DNA保护等分子过程有密切关系.最近,有研究者表明,热量限制调控氧化应激和炎症过程是通过胰岛素/胰岛素样生长因子信号通路起作用的.热量限制在所有的动物模型实验中都显示延长寿命,然而,在人类中应用热量限制,可能还存在很多对人体健康问题值得关注.本文就热量限制如何调控寿命的机制的研究进展作一综述.     

Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction

Reduced dietary methionine intake (0.17% methionine, MR) and calorie restriction (CR) prolong lifespan in male Fischer 344 rats. Although the mechanisms are unclear, both regimens feature lower body weight and reductions in adiposity. Reduced fat deposition in CR is linked to preservation of insulin responsiveness in older animals. These studies examine the relationship between insulin responsiveness and visceral fat in MR and test whether, despite lower food intake observed in MR animals, decreased visceral fat accretion and preservation of insulin sensitivity is not secondary to CR. Accordingly, rats pair fed (pf) control diet (0.86% methinone, CF) to match the food intake of MR for 80 weeks exhibit insulin, glucose, and leptin levels similar to control-fed animals and comparable amounts of visceral fat. Conversely, MR rats show significantly reduced visceral fat compared to CF and PF with concomitant decreases in basal insulin, glucose, and leptin, and increased adiponectin and triiodothyronine. Daily energy expenditure in MR animals significantly exceeds that of both PF and CF. In a separate cohort, insulin responses of older MR animals as measured by oral glucose challenge are similar to young animals. Longitudinal assessments of MR and CF through 112 weeks of age reveal that MR prevents age-associated increases in serum lipids. By 16 weeks, MR animals show a 40% reduction in insulin-like growth factor-1 (IGF-1) that is sustained throughout life; CF IGF-1 levels decline much later, beginning at 112 weeks. Collectively, the results indicate that MR reduces visceral fat and preserves insulin activity in aging rats independent of energy restriction.