Age-related Shift Research Articles

Age-related shift in the hippocampal synaptic plasticity is dependent on p75 neurotrophin receptor

Age-related shift in the hippocampal synaptic plasticity is dependent on p75 neurotrophin receptor

Age-related changes in late synaptic inputs to corticospinal neurons and their functional significance: A paired-pulse TMS study

BackgroundRecent work suggests that the function of intracortical interneurons activated by transcranial magnetic stimulation (TMS) is modified in older adults, with the circuits generating short-interval intracortical facilitation (SICF) at longer intervals appearing to be particularly affected. ObjectiveTo use SICF to quantify age-related changes in the excitability and recruitment of late synaptic inputs to corticospinal neurons, and investigate if changes within these circuits contribute to altered motor performance in older adults. MethodsSICF was recorded with 3 different conditioning intensities in 23 young (23.0 ± 4.2 years) and 21 older (67.1 ± 1.1 years) adults. These measures were performed with conventional (posterior-anterior, PA) and reverse (anterior-posterior, AP) current directions using interstimulus intervals targeting late synaptic inputs to corticospinal neurons (3.5–5.3 ms). ResultsPeak SICF recorded with a PA current (SICFPA) was reduced in older adults (P < 0.0001), and occurred at a longer latency (P < 0.05). Furthermore, there was reduced recruitment of SICFPA in older adults (P < 0.0001), but this did not interact with the age-related shift in SICFPA (P = 0.2). In addition, reduced performance on the Purdue pegboard was predicted by increased SICFPA (P < 0.04) occurring at longer latencies (P < 0.04) in old but not young adults. For SICF recorded with an AP current (SICFAP), facilitation was again reduced at longer latencies in older adults (P < 0.0001), but recruitment was not different between groups (P = 0.7) and was unrelated to motor function. ConclusionThese results suggest that there are age-related changes in late synaptic inputs to corticospinal neurons and that these changes influence fine motor performance.

Age-related differences in brain activations during spatial memory formation in a well-learned virtual Morris water maze (vMWM) task

The current study applied a rodent-based virtual Morris water maze (vMWM) protocol to an investigation of differences in search performance and brain activations between young and older male human adults. All participants completed in-lab practice and testing before performing the task in the fMRI scanner. Behavioral performance during fMRI scanning – measured in terms of corrected cumulative proximity (CCProx) to the goal – showed that a subgroup of older good performers attained comparable levels of search accuracy to the young while another subgroup of older poor performers exhibited consistently lower levels of search accuracy than both older good performers and the young. With regard to brain activations, young adults exhibited greater activations in the cerebellum and cuneus than all older adults, as well as older poor performers. Older good performers exhibited higher activation than older poor performers in the orbitofrontal cortex (BA 10/11), as well as in the cuneus and cerebellum. Brain-behavior correlations further showed that activations in regions involved in visuomotor control (cerebellum, lingual gyrus) and egocentric spatial processing (premotor cortex, precuneus) correlated positively with search accuracy (i.e., closer proximity to goal) in all participants. Notably, activations in the anterior hippocampus correlated positively with search accuracy (CCProx inversed) in the young but not in the old. Taken together, these findings implicated the orbitofrontal cortex and the cerebellum as playing crucial roles in executive and visuospatial processing in older adults, supporting the proposal of an age-related compensatory shift in spatial memory functions away from the hippocampus toward the prefrontal cortex.

Expansion of Luminal Progenitor Cells in the Aging Mouse and Human Prostate

SUMMARYAging is associated with loss of tissue mass and a decline in adult stem cell function in many tissues. In contrast, aging in the prostate is associated with growth-related diseases including benign prostatic hyperplasia (BPH). Surprisingly, the effects of aging on prostate epithelial cells have not been established. Here we find that organoid-forming progenitor activity of mouse prostate basal and luminal cells is maintained with age. This is caused by an age-related expansion of progenitor-like luminal cells that share features with human prostate luminal progenitor cells. The increase in luminal progenitor cells may contribute to greater risk for growth-related disease in the aging prostate. Importantly, we demonstrate expansion of human luminal progenitor cells in BPH. In summary, we define a Trop2+ luminal progenitor subset and identify an age-related shift in the luminal compartment of the mouse and human prostate epithelium.

Longitudinal comparative transcriptomics reveals unique mechanisms underlying extended healthspan in bats.

Bats are the longest-lived mammals, given their body size. However, the underlying molecular mechanisms of their extended healthspans are poorly understood. To address this question we carried out an eight-year longitudinal study of ageing in long-lived bats (Myotis myotis). We deep-sequenced ~1.7 trillion base pairs of RNA from 150 blood samples collected from known aged bats to ascertain the age-related transcriptomic shifts and potential microRNA-directed regulation that occurred. We also compared ageing transcriptomic profiles between bats and other mammals by analysis of 298 longitudinal RNA sequencing datasets. Bats did not show the same transcriptomic changes with age as commonly observed in humans and other mammals, but rather exhibited a unique, age-related gene expression pattern associated with DNA repair, autophagy, immunity and tumour suppression that may drive their extended healthspans. We show that bats have naturally evolved transcriptomic signatures that are known to extend lifespan in model organisms, and identify novel genes not yet implicated in healthy ageing. We further show that bats' longevity profiles are partially regulated by microRNA, thus providing novel regulatory targets and pathways for future ageing intervention studies. These results further disentangle the ageing process by highlighting which ageing pathways contribute most to healthy ageing in mammals.

Integrating across memory episodes: Developmental trends.

Memory enables us to use information from our past experiences to guide new behaviours, calling for the need to integrate or form inference across multiple distinct episodic experiences. Here, we compared children (aged 9–10 years), adolescents (aged 12–13 years), and young adults (aged 19–25 years) on their ability to form integration across overlapping associations in memory. Participants first encoded a set of overlapping, direct AB- and BC-associations (object-face and face-object pairs) as well as non-overlapping, unique DE-associations. They were then tested on these associations and inferential AC-associations. The experiment consisted of four such encoding/retrieval cycles, each consisting of different stimuli set. For accuracy on both unique and inferential associations, young adults were found to outperform teenagers, who in turn outperformed children. However, children were particularly slower than teenagers and young adults in making judgements during inferential than during unique associations. This suggests that children may rely more on making inferences during retrieval, by first retrieving the direct associations, followed by making the inferential judgement. Furthermore, young adults showed a higher correlation between accuracy in direct (AB, BC) and inferential AC-associations than children. This suggests that, young adults relied closely on AB- and BC-associations for making AC decisions, potentially by forming integrated ABC-triplets during encoding or retrieval. Taken together, our findings suggest that there may be an age-related shift in how information is integrated across experienced episodes, namely from relying on making inferences at retrieval during middle childhood to forming integrated representations at different memory processing stages in adulthood.

'Pressure fatigue': the influence of sap pressure cycles on cavitation vulnerability in Acer negundo.

Vulnerability-to-cavitation curves (VCs) can vary within a tree crown in relation to position or branch age. We tested the hypothesis that VC variation can arise from differential susceptibility to the number of diurnal sap pressure cycles experienced. We designed a method to distinguish between effects of cycling vs exposure time to negative pressure, and tested the influence of sap pressure cycles on cavitation vulnerability between upper and lower branches in Acer negundo L. trees using static and flow centrifuge, and air-injection methods. Branches from the upper crown had greater hydraulic conductivity and were more resistant to cavitation than branches from the lower crown. Upper branches also showed little change after exposure to 10 or 20 pressure cycles between -0.5 MPa and -2.0 MPa. Lower branches, however, showed a marked increase in vulnerability to cavitation after pressure-cycling. This result suggests that 'cavitation fatigue' can occur without the actual induction (and reversal) of cavitation as documented previously, but simply from the cycling of pressures in the sub-cavitation range. This 'pressure fatigue' may explain age-related shifts in VCs that could eventually induce dieback in suppressed branches or trees. Pressure fatigue may help explain developmental variation in hydraulic capacity of branches within individuals.

Age Related Decline in Cortical Multifocal Flash VEP: Latency Increases Shown to Be Predominately Magnocellular.

As the visual system ages, flicker sensitivity decreases and the latencies of cortical visual evoked potentials (VEP) increase. However, the extent to which these effects reflect age-related changes in the magnocellular (M) and or parvocellular (P) pathways remain unclear. Here, we investigated the relation between flicker fusion frequencies and VEP non-linearities induced by rapid stimulation, as a function of age over 6 decades. The approach, using Wiener kernel analysis of multifocal flash (mf)VEP, allows the extraction of signatures of both M and P processing and hence establishing a neural basis of the known decline in flicker fusion threshold. We predicted that, in a sample of 86 participants, age would be associated with a latency increase in early mfVEP response components and that flicker fusion thresholds, for both low and high contrast stimuli, would relate to the temporal efficiency of the M-generated VEP component amplitudes. As expected, flicker fusion frequency reduced with age, while latencies of early second order peaks of the mfVEP increased with age, but M temporal efficiency (amplitude ratio of first to second order peaks) was not strongly age-related. The steepest increases in latency were associated with the M dominated K2.1 (second order first slice) N70 components recorded at low and high contrast (6.7 and 5.9 ms/decade, respectively). Interestingly, significant age-related latency shifts were not observed in the first order responses. Significant decreases in amplitude were found in multiple first and second order components up to 30 years of age, after which they remained relatively constant. Thus, aging and decline in visual function appears to be most closely related to the response latencies of non-linearities generated by the M pathway.

Increased use of stepping strategy in response to medio-lateral perturbations in the elderly relates to altered reactive tibialis anterior activity

BackgroundThe influence of aging on reactive control of balance during walking has been mainly investigated in the sagittal plane, whereas balance control in response to frontal plane perturbations is largely unexplored in the elderly. This is remarkable, given that walking mainly requires active control in the frontal plane. An extensive gait perturbation protocol was used to test whether reactive control of walking balance changes with aging and whether these changes are more pronounced in the frontal than in the sagittal plane. Research questionDo alterations in reactive muscle activity cause an age-related shift in stepping strategy in response to perturbations in the frontal and sagittal planes during walking? MethodA treadmill-based perturbation protocol imposed frontal and sagittal plane perturbations of different magnitudes during different phases of the gait cycle. Motion capture and electromyography measured the response to the different perturbations in a group of eighteen young and ten older adults. ResultsOnly for a small subset of the perturbations, reactive muscle activity and kinematic strategies differed between young and older subjects. When perturbation magnitude increased, the older adults relied more on a stepping strategy for inward directed frontal plane perturbations and for sagittal plane perturbation just before heelstrike. Tibialis anterior activity increased less in the older compared to the young subjects. Using simulations, we related tibialis anterior activity to backward and outward movement of the center of pressure in the stance foot and confirmed its contribution to the ankle strategy. We concluded that deficient tibialis anterior activity predisposes elderly to use stepping rather than lateral ankle strategies to control balance. SignificanceRehabilitation targets for fall prevention in elderly need to also focus on ankle muscle reactivity.

Advanced Aging Enhances the Positivity Effect in Memory: Due to Cognitive Control or Age-Related Decline in Emotional Processing?

Older adults typically remember more positive than negative information compared to their younger counterparts; a phenomenon referred to as the ‘positivity effect.’ According to the socioemotional selectivity theory (SST), the positivity effect derives from the age-related motivational shift towards attaining emotionally meaningful goals which become more important as the perception of future time becomes more limited. Cognitive control mechanisms are critical in achieving such goals and therefore SST predicts that the positivity effect is associated with preserved cognitive control mechanisms in older adults. In contrast, the aging-brain model suggests that the positivity effect is driven by an age-related decline in the amygdala which is responsible for emotional processing and emotional learning. The aim of the current research was to address whether the age-related positivity effect is associated with cognitive control or impaired emotional processing associated with aging. We included older old adults, younger old adults and younger adults and tested their memory for emotional stimuli, cognitive control and amygdala-dependent fear conditioned responses. Consistent with prior research, older adults, relative to younger adults, demonstrate better memory for positive over negative images. We further found that within a group of older adults, the positivity effect increases as a function of age, such that older old adults demonstrated a greater positivity effect compared to younger older adults. Furthermore, the positivity effect in older old adults was associated with preserved cognitive control, supporting the prediction of SST. Contrary to the prediction of the aging-brain model, participants across all groups demonstrated similar enhanced skin conductance responses to fear conditioned stimuli – responses known to rely on the amygdala. Our results support SST and suggest that the positivity effect in older adults is achieved by the preserved cognitive control mechanisms and is not a reflection of the impaired emotional function associated with age.

Clarifying the neurobehavioral sequelae of moderate drinking lifestyles and acute alcohol effects with aging.

Epidemiological estimates indicate not only an increase in the proportion of older adults, but also an increase in those who continue moderate alcohol consumption. Substantial literatures have attempted to characterize health benefits/risks of moderate drinking lifestyles. Not uncommonly, reports address outcomes in a single outcome, such as cardiovascular function or cognitive decline, rather than providing a broader overview of systems. In this narrative review, retaining focus on neurobiological considerations, we summarize key findings regarding moderate drinking and three health domains, cardiovascular health, Type 2 diabetes (T2D), and cognition. Interestingly, few investigators have studied bouts of low/moderate doses of alcohol consumption, a pattern consistent with moderate drinking lifestyles. Here, we address both moderate drinking as a lifestyle and as an acute event. Review of health-related correlates illustrates continuing inconsistencies. Although substantive reductions in risk for cardiovascular and T2D events are reported, robust conclusions remain elusive. Similarly, whereas moderate drinking is often associated with enhanced cognition and lower dementia risk, few benefits are noted in rates of decline or alterations in brain structure. The effect of sex/gender varies across health domains and by consumption levels. For example, women appear to differentially benefit from alcohol use in terms of T2D, but experience greater risk when considering aspects of cardiovascular function. Finally, we observe that socially relevant alcohol doses do not consistently impair performance in older adults. Rather, older drinkers demonstrate divergent, but not necessarily detrimental, patterns in neural activation and some behavioral measures relative to younger drinkers. Taken together, the epidemiological and laboratory studies reinforce the need for greater attention to key individual differences and for the conduct of systematic studies sensitive to age-related shifts in neurobiological systems.

Age-related variability in decision-making: Insights from neurochemistry.

Despite dopamine's significant role in models of value-based decision-making and findings demonstrating loss of dopamine function in aging, evidence of systematic changes in decision-making over the life span remains elusive. Previous studies attempting to resolve the neural basis of age-related alteration in decision-making have typically focused on physical age, which can be a poor proxy for age-related effects on neural systems. There is growing appreciation that aging has heterogeneous effects on distinct components of the dopamine system within subject in addition to substantial variability between subjects. We propose that some of the conflicting findings in age-related effects on decision-making may be reconciled if we can observe the underlying dopamine components within individuals. This can be achieved by incorporating in vivo imaging techniques including positron emission tomography (PET) and neuromelanin-sensitive MR. Further, we discuss how affective factors may contribute to individual differences in decision-making performance among older adults. Specifically, we propose that age-related shifts in affective attention ("positivity effect") can, in some cases, counteract the impact of altered dopamine function on specific decision-making processes, contributing to variability in findings. In an effort to provide clarity to the field and advance productive hypothesis testing, we propose ways in which in vivo dopamine imaging can be leveraged to disambiguate dopaminergic influences on decision-making, and suggest strategies for assessing individual differences in the contribution of affective attentional focus.

Depressive symptoms and time perspective in older adults: associations beyond personality and negative life events

Objectives: To examine the extent to which time perspective, an individual’s habitual way of relating to the past, the present, and the future time frames, accounts for variations in self-reported depressive symptoms among older adults.Method: Four hundred two participants (60–90 years) completed the Center for Epidemiological Studies Depression scale (CES-D) and the Swedish Zimbardo Time perspective Inventory (S-ZTPI). The influence of personality as reflected by the Temperament and Character Inventory (TCI) and self-reported negative life events (NLEs) were controlled for in hierarchic regression analyses.Results: The six S-ZTPI dimensions accounted for 24.5% of the variance in CES-D scores beyond age and gender. Half of the variance remained when the TCI factors and NLEs were controlled for. Past Negative, Future Negative, and Past Positive (inverse association) were the significant unique predictors. Significant age interactions were observed for two S-ZTPI dimensions, with a diminished association to depressive symptoms for Future Negative and a magnified association for Present Fatalistic with higher age.Conclusions: The results demonstrate a substantial relation between facets of time perspective and depressive symptoms in old age. They also indicate an age-related shift in the relative importance from concerns about of the future (Future Negative) to the present (Present Fatalistic) with increased age. In young old-age, when the future is more ‘open’, future worries (Future Negative) may be a more frequent source of distress. In late senescence, perceived threats to autonomy (e.g. physical health problems and cognitive deficits), as reflected by higher scores on Present Fatalistic, may instead have more bearing on mood state.

Who Is the Better Eyewitness? Sometimes Adults but at Other Times Children

Suggestibility is regarded as a major issue when children testify in court. Many legal professionals and memory researchers view children as inferior witnesses. Although differences in suggestibility exist between children and adults, they are much more complex than is usually assumed. We show that under certain conditions, adults are more susceptible than children to suggestion and false memories. We provide evidence that age-related shifts in suggestibility and false memory appear contingent on how quickly and automatically children and adults make associations when experiencing events. Specifically, when confronted with suggestive information about a related but nonexperienced detail, adults more frequently automatically generate links between items experienced and those already in memory, making them more susceptible to suggestion than children.

The development of children's preferences for equality and equity across 13 individualistic and collectivist cultures

A concern for fairness is a fundamental and universal element of morality. To examine the extent to which cultural norms are integrated into fairness cognitions and influence social preferences regarding equality and equity, a large sample of children (N 2,163) aged 4-11 were tested in 13 diverse countries. Children participated in three versions of a third-party, contextualized distributive justice game between two hypothetical recipients differing in terms of wealth, merit, and empathy. Social decision-making in these games revealed universal age-related shifts from equality-based to equity-based distribution motivations across cultures. However, differences in levels of individualism and collectivism between the 13 countries predicted the age and extent to which children favor equity in each condition. Children from the most individualistic cultures endorsed equitable distributions to a greater degree than children from more collectivist cultures when recipients differed in regards to wealth and merit. However, in an empathy context where recipients differed in injury, children from the most collectivist cultures exhibited greater preferences to distribute resource equitably compared to children from more individualistic cultures. Children from the more individualistic cultures also favored equitable distributions at an earlier age than children from more collectivist cultures overall. These results demonstrate aspects of both cross-cultural similarity and divergence in the development of fairness preferences.

Older adults use a prefrontal regulatory mechanism to reduce negative memory vividness of a highly emotional real-world event.

Previous research has revealed an age-related shift in how individuals recall events from their personal past, with older adults reporting events that are more positive than young adults. We recently showed that age-by-valence interactions may be partially driven by a prefrontally mediated control mechanism recruited by older adults during retrieval of negative laboratory events to reduce phenomenological richness. Specifically, age was associated with greater increases in prefrontal recruitment during retrieval of negative relative to positive events, with this recruitment linked to decreases in hippocampal activity and subjective vividness ratings. In the current study, we examined whether older adults may rely on a similar mechanism during retrieval of a complex, highly emotional real-world event. Participants (n=58, age: 18-87 years) were presented with images related to the 2013 Boston Marathon Bombings and were asked to retrieve a memory associated with each image. Images cued participants with either negative (associated with fear, destruction, and sadness) or positive (images of hope, resilience, support) features. This study replicated previous episodic memory tasks: age was associated with more negative hippocampal connectivity with dorsomedial prefrontal regions during retrieval of memories triggered by negative relative to positive cues. Such findings suggest that older adults may be recruiting a similar regulatory mechanism during retrieval of both negative laboratory stimuli and highly negative events from their past. These findings are discussed in relation to previous work showing that young and older adults interact differently with the negative details related to a highly negative event.

Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors

Synaptic dysfunction plays a central role in Alzheimer’s disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene—ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related conditions. We report, for the first time, a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca2+ influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A2AR blockade. This A2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.

Age-related changes in neural mechanisms of prospective memory.

The capability to remember and execute intentions in the future - termed prospective memory (PM) - may be of special significance for older adults to enable successful completion of important activities of daily living. Despite the importance of this cognitive function, mixed findings have been obtained regarding age-related decline in PM, and, currently, there is limited understanding of potential contributing mechanisms. In the current study, older (N=41) and younger adults (N=47) underwent task-functional MRI during performance of PM conditions that encouraged either spontaneous retrieval (Focal) or sustained attentional monitoring (Non-focal) to detect PM targets. Older adults exhibited a reduction in PM-related sustained activity within the anterior prefrontal cortex (aPFC) and associated dorsal frontoparietal cognitive control network, due to an increase in non-specific sustained activation in (no-PM) control blocks (i.e., an age-related compensatory shift). Transient PM-trial specific activity was observed in both age groups within a ventral parietal memory network that included the precuneus. However, within a left posterior inferior parietal node of this network, transient PM-related activity was selectively reduced in older adults during the non-focal condition. These age differences in sustained and transient brain activity statistically mediated age-related declines in PM performance, and were potentially linked via age-related changes in functional connectivity between the aPFC and precuneus. Together, they support an account consistent with the Dual Mechanisms of Control framework, in which age-related PM declines are due to neural mechanisms that support proactive cognitive control processes, such as sustained attentional monitoring, while leaving reactive control mechanisms relatively spared.

Hepatitis A Virus and Hepatitis E Virus: Emerging and Re-Emerging Enterically Transmitted Hepatitis Viruses

Over the past two decades, progress in understanding human infections with hepatitis A virus (HAV) and hepatitis E virus (HEV) has been eclipsed by the priority of combating persistent hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. During that time, the global burden of liver disease caused by enteric hepatitis viruses has not abated. Because of vaccines, hepatitis A has become increasingly a disease of adults instead of early childhood in many regions of the world, resulting in an age-related shift toward more severe disease. HEV has remained endemic in many developing countries, and in well-developed, economically advanced countries it is now recognized as a cause of chronic, progressive liver disease in individuals with compromised immunity. The goal of this collection of articles is to review recent progress and to shine a bright light on gaps in our understanding of how these viruses replicate, cause disease, interact with the liver and host immune system, and are transmitted, along with prospects for improved control in human populations. Renewed efforts to study and compare HAV and HEV biology in humans and animal models have high potential to enhance our understanding of host-pathogen balance in the liver, and may contribute ultimately to the control of other infectious diseases of the liver.

Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria.

DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans, but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases.