Spermidine-triggered autophagy ameliorates memory during aging

The aging process drives the progressive deterioration of an organism and is thus subject to a complex interplay of regulatory and executing mechanisms. Our understanding of this process eventually aims at the delay and/or prevention of age-related pathologies, among them the age-dependent decrease in cognitive performance (e.g., learning and memory). Using the fruit fly Drosophila melanogaster, which combines a generally high mechanistic conservation with an efficient experimental access regarding aging and memory studies, we have recently unveiled a protective function of polyamines (including spermidine) against age-induced memory impairment (AMI). The flies’ age-dependent decline of aversive olfactory memory, an established model for AMI, can be rescued by both pharmacological treatment with spermidine and genetic modulation that increases endogenous polyamine levels. Notably, we find that this effect strictly depends on autophagy, which is remarkable in light of the fact that autophagy is considered a key regulator of aging in other contexts. Given that polyamines in general and spermidine in particular are endogenous metabolites, our findings place them as candidate target substances for AMI treatment.     

Peptides and aging: Their role in anorexia and memory

The rapid aging of the world's population has led to a need to increase our understanding of the pathophysiology of the factors leading to frailty and cognitive decline. Peptides have been shown to be involved in the pathophysiology of frailty and cognitive decline. Weight loss is a major component of frailty. In this review, we demonstrate a central role for both peripheral peptides (e.g., cholecystokinin and ghrelin) and neuropeptides (e.g., dynorphin and alpha-MSH) in the pathophysiology of the anorexia of aging. Similarly, peripheral peptides (e.g., ghrelin, glucagon-like peptide 1, and cholecystokinin) are modulators of memory. A number of centrally acting neuropeptides have also been shown to modulate cognitive processes. Amyloid-beta peptide in physiological levels is a memory enhancer, while in high (pathological) levels, it plays a key role in the development of Alzheimer's disease.     

Neurocognitive systems related to real-world prospective memory

Background

Prospective memory (PM) denotes the ability to remember to perform actions in the future. It has been argued that standard laboratory paradigms fail to capture core aspects of PM.

Methodology/Principal Findings

We combined functional MRI, virtual reality, eye-tracking and verbal reports to explore the dynamic allocation of neurocognitive processes during a naturalistic PM task where individuals performed errands in a realistic model of their residential town. Based on eye movement data and verbal reports, we modeled PM as an iterative loop of five sustained and transient phases: intention maintenance before target detection (TD), TD, intention maintenance after TD, action, and switching, the latter representing the activation of a new intention in mind. The fMRI analyses revealed continuous engagement of a top-down fronto-parietal network throughout the entire task, likely subserving goal maintenance in mind. In addition, a shift was observed from a perceptual (occipital) system while searching for places to go, to a mnemonic (temporo-parietal, fronto-hippocampal) system for remembering what actions to perform after TD. Updating of the top-down fronto-parietal network occurred at both TD and switching, the latter likely also being characterized by frontopolar activity.

Conclusion/Significance

Taken together, these findings show how brain systems complementary interact during real-world PM, and support a more complete model of PM that can be applied to naturalistic PM tasks and that we named PROspective MEmory DYnamic (PROMEDY) model because of its dynamics on both multi-phase iteration and the interactions of distinct neurocognitive networks.     

Commentary: Spermidine-triggered autophagy ameliorates memory during aging

The aging process drives the progressive deterioration of an organism and is thus subject to a complex interplay of regulatory and executing mechanisms. Our understanding of this process eventually aims at the delay and/or prevention of age-related pathologies, among them the age-dependent decrease in cognitive performance (e.g., learning and memory). Using the fruit fly Drosophila melanogaster, which combines a generally high mechanistic conservation with an efficient experimental access regarding aging and memory studies, we have recently unveiled a protective function of polyamines (including spermidine) against age-induced memory impairment (AMI). The flies’ age-dependent decline of aversive olfactory memory, an established model for AMI, can be rescued by both pharmacological treatment with spermidine and genetic modulation that increases endogenous polyamine levels. Notably, we find that this effect strictly depends on autophagy, which is remarkable in light of the fact that autophagy is considered a key regulator of aging in other contexts. Given that polyamines in general and spermidine in particular are endogenous metabolites, our findings place them as candidate target substances for AMI treatment.     

成功的前瞻记忆编码与提取的神经机制研究

前瞻记忆是指对将来行为和事件的记忆,而相继记忆效应（Dm效应）是指根据记忆提取阶段的成绩,分析与之对应的编码阶段的项目和忘的项目之间的神经活动的差异.本研究采用任务转化范式,借助ERP仪器,使用汉字材料,探讨了前瞻记忆的Dm效应.研究发现,100～200ms（P150）,250～280ms（fbN2）,400～700ms（LPC）随后前瞻记忆击中的ERPs比随后前瞻记忆忘的ERPs更正.其中,早期的相继记忆效应（P150更正）可能反映了前瞻记忆将来意向的加工或者准备意的加工;而后两个时段与以往的研究结果一致,fbN2可能与汉语材料的加工有关,LPC则反映了记忆的精确编码.总之,本研究从ERP的角度提供了前瞻记忆编码与以往情景记忆编码有相同之处（LPC更正）,又存在一些差异（P150更正）的证据,但这种差异需要进一步的研究来论证.     

Neural basis for successful encoding and retrieval of prospective memory

Prospective memory (PM) refers to memory for future intentions. Difference due to memory (Dm effect) is the difference in neural activity related to stimuli that were subsequently remembered or forgotten. Using event-related potentials (ERPs), the present study investigated the Dm effect for PM using a subsequent task-switching paradigm. The results showed that a Dm effect of ERP P150 was more positive-going for later PM hit trials than for later PM forgotten trials during 100–200 ms. This Dm effect may reflect the process for the production of future intention or the process for attention. Consistent with previously reported Dm effects of other types of memory, we found that the fbN2 (250–280 ms) and late positivity component (400–700 ms) were stronger in later PM hit trials than in forgotten trials. The fbN2 was evoked by Chinese characters. The late positivity component was related to the precise encoding process. In conclusion, because of the early P150, PM encoding appears to be somewhat different from previously identified Dm effects. However, further research is needed. Our findings reveal that Dm effects of PM share similar characteristics with known Dm effects of other types of episodic memory after the very early stage of neural processing.     

Mechanisms underlying the link between cannabis use and prospective memory

While the effects of cannabis use on retrospective memory have been extensively examined, only a limited number of studies have focused on the links between cannabis use and prospective memory. We conducted two studies to examine the links between cannabis use and both time-based and event-based prospective memory as well as potential mechanisms underlying these links. For the first study, 805 students completed an online survey designed to assess cannabis consumption, problems with cannabis use indicative of a disorder, and frequency of experiencing prospective memory failures. The results showed small to moderate sized correlations between cannabis consumption, problems with cannabis use, and prospective memory. However, a series of mediation analyses revealed that correlations between problems with cannabis use and prospective memory were driven by self-reported problems with retrospective memory. For the second study, 48 non-users (who had never used cannabis), 48 experimenters (who had used cannabis five or fewer times in their lives), and 48 chronic users (who had used cannabis at least three times a week for one year) were administered three objective prospective memory tests and three self-report measures of prospective memory. The results revealed no objective deficits in prospective memory associated with chronic cannabis use. In contrast, chronic cannabis users reported experiencing more internally-cued prospective memory failures. Subsequent analyses revealed that this effect was driven by self-reported problems with retrospective memory as well as by use of alcohol and other drugs. Although our samples were not fully characterized with respect to variables such as neurological disorders and family history of substance use disorders, leaving open the possibility that these variables may play a role in the detected relationships, the present findings indicate that cannabis use has a modest effect on self-reported problems with prospective memory, with a primary problem with retrospective memory appearing to underlie this relationship.     

Electrophysiological correlates of strategic monitoring in event-based and time-based prospective memory

Prospective memory (PM) is the ability to remember to accomplish an action when a particular event occurs (i.e., event-based PM), or at a specific time (i.e., time-based PM) while performing an ongoing activity. Strategic Monitoring is one of the basic cognitive functions supporting PM tasks, and involves two mechanisms: a retrieval mode, which consists of maintaining active the intention in memory; and target checking, engaged for verifying the presence of the PM cue in the environment. The present study is aimed at providing the first evidence of event-related potentials (ERPs) associated with time-based PM, and at examining differences and commonalities in the ERPs related to Strategic Monitoring mechanisms between event- and time-based PM tasks.The addition of an event-based or a time-based PM task to an ongoing activity led to a similar sustained positive modulation of the ERPs in the ongoing trials, mainly expressed over prefrontal and frontal regions. This modulation might index the retrieval mode mechanism, similarly engaged in the two PM tasks. On the other hand, two further ERP modulations were shown specifically in an event-based PM task. An increased positivity was shown at 400-600 ms post-stimulus over occipital and parietal regions, and might be related to target checking. Moreover, an early modulation at 130-180 ms post-stimulus seems to reflect the recruitment of attentional resources for being ready to respond to the event-based PM cue. This latter modulation suggests the existence of a third mechanism specific for the event-based PM; that is, the "readiness mode".     

Red and processed meat and colorectal cancer incidence: meta-analysis of prospective studies

Background

The evidence that red and processed meat influences colorectal carcinogenesis was judged convincing in the 2007 World Cancer Research Fund/American Institute of Cancer Research report. Since then, ten prospective studies have published new results. Here we update the evidence from prospective studies and explore whether there is a non-linear association of red and processed meats with colorectal cancer risk.

Methods and Findings

Relevant prospective studies were identified in PubMed until March 2011. For each study, relative risks and 95% confidence intervals (CI) were extracted and pooled with a random-effects model, weighting for the inverse of the variance, in highest versus lowest intake comparison, and dose-response meta-analyses. Red and processed meats intake was associated with increased colorectal cancer risk. The summary relative risk (RR) of colorectal cancer for the highest versus the lowest intake was 1.22 (95% CI  = 1.11−1.34) and the RR for every 100 g/day increase was 1.14 (95% CI  = 1.04−1.24). Non-linear dose-response meta-analyses revealed that colorectal cancer risk increases approximately linearly with increasing intake of red and processed meats up to approximately 140 g/day, where the curve approaches its plateau. The associations were similar for colon and rectal cancer risk. When analyzed separately, colorectal cancer risk was related to intake of fresh red meat (RR _{for 100 g/day increase}  = 1.17, 95% CI  = 1.05−1.31) and processed meat (RR _{for 50 g/day increase}  = 1.18, 95% CI  = 1.10−1.28). Similar results were observed for colon cancer, but for rectal cancer, no significant associations were observed.

Conclusions

High intake of red and processed meat is associated with significant increased risk of colorectal, colon and rectal cancers. The overall evidence of prospective studies supports limiting red and processed meat consumption as one of the dietary recommendations for the prevention of colorectal cancer.     

Caenorhabditis elegans as a model system to study aging of learning and memory

The nematode Caenorhabditis elegans is an excellent model organism to study biological processes relevant to a wide variety of human and rodent disease systems. Previous studies have suggested that mutants of the insulin/insulin-like growth factor-1 pathway show life extension and increased stress resistance in various species, including C. elegans, the fruit fly, and the mouse. It has recently been shown that the life-extending mutants, including the age-1 phosphatidylinositol- 3 OH kinase mutants and the daf-2 insulin-like receptor mutants, display improvement in a type of associative learning behavior called thermotaxis learning behavior. The age-1 mutant shows a dramatic threefold extension of the health-span that ensures thermotaxis learning behavior, suggesting strong neuroprotective actions during aging. The age-1 and daf-2 mutants show resistance to multiple forms of stress and upregulates the genes involved in reactive oxygen species scavenging, heat shock, and P450 drug-detoxification. The life-extending mutants may confer resistance to various stress and diseases in neurons. Therefore, C. elegans provides an emerging system for the prevention of age-related deficits in the nervous system and in learning behaviors. This article discusses the aging of learning and memory and the neuroprotection effects of life-extending mutants on learning behaviors.     

Effects of green tea and physical exercise on memory impairments associated with aging

We investigated the effects of physical exercise and green tea supplementation (associated or not) on biochemical and behavioral parameters in the time course of normal aging. Male Wistar rats aged 9 months were divided into groups: control, physical exercise (treadmill running), and supplemented with green tea while either performing physical exercise or not. A young control group was also studied. Physical exercise and green tea supplementation lasted 3 months. Afterwards, behavioral and biochemical tests were performed. Biochemical measurements revealed differences in antioxidant and oxidant responses in hippocampus, prefrontal cortex and striatum. Behavioral testing showed age-related memory impairments reversed by physical exercise. The association of green tea supplementation and physical exercise did not provide aged rats with additional improvements in memory or brain oxidative markers. Green tea per se significantly decreased reactive oxygen species levels and improved antioxidant defenses although it did not reverse memory deficits associated with normal aging.     

杭白菊总黄酮对衰老小鼠学习记忆的影响

目的：探讨杭白菊总黄酮（TFCM）对衰老小鼠学习记忆能力及胆碱能系统的影响。方法：采用皮下注射D-半乳糖的方法制备衰老小鼠模型。ICR小鼠随机分为5组（n=10）：正常对照组,模型组,低、中、高剂量TFCM处理组。TFCM处理组于造模后第2周开始每天给予TFCM（50、100或150mg／kg）灌胃。用Morris水迷宫法检测小鼠学习记忆能力,用比色法测定血清和大脑组织中丙二醛（MDA）含量,以及超氧化物歧化酶（SOD）和乙酰胆碱酯酶（Ach E）活性。结果：与正常对照组相比,模型组学习记忆能力减退,MDA含量和Ach E活性增加,SOD活性降低。与模型组相比,中高浓度TFCM处理组（100、150mg／kg）小鼠学习记忆能力明显改善,MDA含量和Ach E活性明显降低,SOD活性增高。结论：TFEM能显著改善D-半乳糖衰老小鼠学习记忆能力,其机制可能与TFCM的抗氧化特性以及提高中枢胆碱能系统功能有关。     

Role of connectivity in immune and neural network models: memory development and aging.

In this paper we analyzed how connectivity (defined as number of connections between network elements) can affect the memory capacity of a network-based model of the Immune System (IS) and of a model of the Nervous System (NS) synaptic plasticity (BCM model). The key point is the concept of competition between the characteristic variables that represent the response of such systems to environmental stimuli: the clonal concentrations for the IS, and the neuron responses for the BCM model. The memory states of both systems are characterized by a high selectivity to specific input patterns, reflecting a similar behaviour of their development rules. This selectivity property of memory states can be controlled by changing the degree of the internal connectivity in each system. We can explain the changes occurring in IS memory states during lifespan as due to a reshaping of its internal connectivity. This assumption is in agreement with experimental observations, reporting an increase of IS memory cells during lifespan. The change of connectivity in the BCM model leads to the introduction of quasilocal variables governing the plasticity of groups of synaptic junctions. This could be interpreted as the result of a refinement of neuron internal mechanisms during development, or it could be seen as a different learning rule deriving from the original BCM theory. We argue that connectivity seems to play an important role in a large class of biological systems controlled by competition mechanisms. Moreover, changes in connectivity may lead to changes in memory properties during development and aging.     

慢性精神分裂症患者前瞻性记忆障碍的康复训练

目的探讨慢性精神分裂症患者前瞻性记忆障碍实施康复训练的效果。方法选取我院2014年1月~2016年3月收治的60例慢性精神分裂症前瞻性记忆障碍患者,采用随机数字表法将患者分为对照组和观察组,对照组患者实施常规康复训练,观察组患者实施综合康复训练,观察两组患者实施康复训练6周和12周后记忆障碍的恢复情况。结果经过康复训练,观察组患者在康复训练6周和12周后记忆功能均较康复训练前的瞬时、短时、长时记忆有明显好转(P0.05),对照组患者在康复训练6周和12周后记忆功能与康复训练前比较无明显差异性(P0.05),两组患者康复训练后同时期记忆功能比较差异有统计学意义(P0.05)。两组患者入院时和出院时的焦虑情况比较,观察组患者明显优于对照组,差异有统计学意义(P0.05);出院时SCL-90症状自评量表评分,观察组各项指标均低于住院时(P0.05),而对照组各项指标与住院时比较无明显改变(P0.05),两组指标比较,观察组明显低于对照组,差异具有统计学意义(P0.05)。结论在慢性精神分裂症患者前瞻性记忆障碍的治疗中采取康复训练,能使患者的记忆功能显著提高,缓解了患者的临床症状,促进了患者康复。     

Role of the apolipoprotein E and catechol-O-methyltransferase genes in prospective and retrospective memory traits

Human memory is a complex neurocognitive process. By combining psychological and molecular genetics expertise, we examined the APOE ε4 allele, a known risk factor for Alzheimer's disease, and the COMT Val 158 polymorphism, previously implicated in schizophrenia, for association with lowered memory functioning in healthy adults. To assess memory type we used a range of memory tests of both retrospective and prospective memory. Genotypes were determined using RFLP analysis and compared with mean memory scores using univariate ANOVAs. Despite a modest sample size (n=197), our study found a significant effect of the APOE ε4 polymorphism in prospective memory. Supporting our hypothesis, a significant difference was demonstrated between genotype groups for means of the Comprehensive Assessment of Prospective Memory total score (p=0.036; ε4 alleles=1.99; all other alleles=1.86). In addition, we demonstrate a significant interactive effect between the APOE ε4 and COMT polymorphisms in semantic memory. This is the first study to investigate both APOE and COMT genotypes in relation to memory in non-pathological adults and provides important information regarding the effect of genetic determinants on human memory.