Non-pathological Aging Research Articles

Serine racemase as a prime target for age‐related memory deficits

The learning and memory deficits associated with non-pathological ageing mainly result from alterations to the plasticity of neuronal network dynamics within the hippocampus. In addition to the broad spectrum of changes that affect the morphology and function of hippocampal excitatory circuits in the ageing brain, the impaired activation of the N-methyl-D-aspartate subtype of glutamate receptors (NMDA-R) is a typical feature, altering the induction and maintenance of long-term potentiation, a major form of synaptic plasticity. In addition to glutamate, the binding of a co-agonist at the strychnine-insensitive glycine-binding site is required for NMDA-R activation. This review presents recent evidence that: (i) the amino acid D-serine is an endogenous co-agonist of synaptic NMDA-R and necessary for long-term potentiation expression, (ii) reduced d-serine levels in the hippocampus contribute to synaptic plasticity and memory deficits in normal ageing, and (iii) age-related oxidative stress selectively targets hippocampal serine racemase to impact D-serine availability in neuronal networks. These results emphasize the critical role of the hippocampal d-serine-dependent pathway in changes affecting neuronal network dynamics in physiological ageing that underlie memory deficits. In addition, the central role of serine racemase in these changes opens new perspectives in the search for relevant therapeutic strategies aimed at reducing age-related memory defects.

The aging lung

There are many age-associated changes in the respiratory and pulmonary immune system. These changes include decreases in the volume of the thoracic cavity, reduced lung volumes, and alterations in the muscles that aid respiration. Muscle function on a cellular level in the aging population is less efficient. The elderly population has less pulmonary reserve, and cough strength is decreased in the elderly population due to anatomic changes and muscle atrophy. Clearance of particles from the lung through the mucociliary elevator is decreased and associated with ciliary dysfunction. Many complex changes in immunity with aging contribute to increased susceptibility to infections including a less robust immune response from both the innate and adaptive immune systems. Considering all of these age-related changes to the lungs, pulmonary disease has significant consequences for the aging population. Chronic lower respiratory tract disease is the third leading cause of death in people aged 65 years and older. With a large and growing aging population, it is critical to understand how the body changes with age and how this impacts the entire respiratory system. Understanding the aging process in the lung is necessary in order to provide optimal care to our aging population. This review focuses on the nonpathologic aging process in the lung, including structural changes, changes in muscle function, and pulmonary immunologic function, with special consideration of obstructive lung disease in the elderly.

Dynamic attentional modulation of vision across space and time after right hemisphere stroke and in ageing

IntroductionAttention modulates the availability of sensory information to conscious perception. In particular, there is evidence of pathological, spatial constriction of the effective field of vision in patients with right hemisphere damage when a central task exhausts available attentional capacity. In the current study we first examined whether this constriction might be modulated across both space and time in right hemisphere stroke patients without neglect. Then we tested healthy elderly people to determine whether non-pathological ageing also leads to spatiotemporal impairments of vision under conditions of high attention load. MethodsRight hemisphere stroke patients completed a task at fixation while attempting to discriminate letters appearing in the periphery. Attentional load of the central task was modulated by increasing task difficulty. Peripheral letters appeared simultaneously with the central task or at different times (stimulus onset asynchronies, SOAs) after it. In a second study healthy elderly volunteers were tested with a modified version of this paradigm. ResultsUnder conditions of high attention load right hemisphere stroke patients have a reduced effective visual field, over a significantly extended ‘attentional blink’, worse for items presented to their left. In the second study, older participants were unable to discriminate otherwise salient items across the visual field (left or right) when their attention capacity was loaded on the central task. This deficit extended temporally, with peripheral discrimination ability not returning to normal for up to 450 msec. ConclusionsDynamically tying up attention resources on a task at fixation can have profound effects in patient populations and in normal ageing. These results demonstrate that items can escape conscious detection across space and time, and can thereby impact significantly on visual perception in these groups.

Neuropsychology and Cognitive Health in Healthy Older Adults: A Brief Overview for Psychiatric Nurses

This article contains a brief synopsis on nonpathological aspects of the neuropsychology of aging and cognitive health. In nonpathological aging, normal subtle decline occurs in a number of cognitive domains such as executive functioning, speed of processing, memory, language, and psychomotor ability; however, some domains of cognitive functioning appear to increase with age, such as vocabulary and crystallized intelligence. In the neuropsychology and the cognitive aging literatures, several hypotheses for such age-related declines are proposed, including the diminished speed-of-processing hypothesis, the common cause hypothesis, and the frontal aging hypothesis. As these age-related changes diminish cognitive reserve, the decline in the related cognitive domains emerges. Ways to protect and improve cognitive health are suggested to encourage positive neuroplasticity and discourage negative neuroplasticity. Implications for nursing practice are provided.

An overview of nonpathological geroneuropsychology: implications for nursing practice and research.

One aspect of successful aging is maintaining cognitive functioning, which includes both subjective cognitive functioning and objective cognitive functioning even in lieu of subtle cognitive deficits that occur with normal, nonpathological aging. Age-related cognitive deficits emerge across several domains including attention, memory, language, speed of processing, executive, and psychomotor, just to name a few. A primary theory explaining such cognitive deficits is cognitive reserve theory; it posits that biological factors such as demyelination and oxidative stress interfere with neuronal communication, which eventually produces observable deficits in cognitive functioning. Therefore, it is important to maintain or improve cognitive reserve to augment cognitive functioning in later life. This article provides a general overview of the principles of geroneuropsychology along with implications for nursing practice and research.

Hippocampal activity during the transverse patterning task declines with cognitive competence but not with age

BackgroundThe hippocampus is a brain region that is particularly affected by age-related morphological changes. It is generally assumed that a loss in hippocampal volume results in functional deficits that contribute to age-related cognitive decline. In a combined cross-sectional behavioural and magnetoencephalography (MEG) study we investigated whether hippocampal-associated neural current flow during a transverse patterning task - which requires learning relational associations between stimuli - correlates with age and whether it is modulated by cognitive competence.ResultsBetter performance in several tests of verbal memory, verbal fluency and executive function was indeed associated with higher hippocampal neural activity. Age, however, was not related to the strength of hippocampal neural activity: elderly participants responded slower than younger individuals but on average produced the same neural mass activity.ConclusionsOur results suggest that in non-pathological aging, hippocampal neural activity does not decrease with age but is rather related to cognitive competence.

Characterization of the 3xTg-AD mouse model of Alzheimer's disease: Part 1. Circadian changes

Circadian disturbances, including a fragmented sleep–wake pattern and sundowning, are commonly reported early in the progression of Alzheimer's disease (AD). These changes are distinctly different from those observed in non-pathological aging. Transgenic models of AD are a promising tool in understanding the underlying mechanisms and cause of disease. A novel triple-transgenic model of AD, 3xTg-AD, is the only model to exhibit both Aβ and tau pathology, and mimic human AD. The present study characterized changes pertaining to circadian rhythmicity that occur prior to and post-AD pathology. Both male and female 3xTg-AD mice demonstrated alterations to their circadian pacemaker with decreased nocturnal behavior when compared to controls. Specifically, males showed greater locomotor activity during the day and shorter freerunning periods prior to the onset of AD-pathology, and females had a decrease in activity levels during their typical active phase. Both sexes did not differ in terms of their freerunning periods or photic phase shifting ability. A decrease in vasoactive intestinal polypeptide-containing and vasopressin-containing cells was observed in the suprachiasmatic nucleus of 3xTg-AD mice relative to controls. This study demonstrates that abnormalities in circadian rhythmicity in 3xTg-AD mice precede expected AD pathology. This suggests that human studies may wish to determine if similar circadian dysfunction is predictive of early-onset AD.

Cardiolipin biosynthesis and remodeling enzymes are altered during development of heart failure

Cardiolipin (CL) is responsible for modulation of activities of various enzymes involved in oxidative phosphorylation. Although energy production decreases in heart failure (HF), regulation of cardiolipin during HF development is unknown. Enzymes involved in cardiac cardiolipin synthesis and remodeling were studied in spontaneously hypertensive HF (SHHF) rats, explanted hearts from human HF patients, and nonfailing Sprague Dawley (SD) rats. The biosynthetic enzymes cytidinediphosphatediacylglycerol synthetase (CDS), phosphatidylglycerolphosphate synthase (PGPS) and cardiolipin synthase (CLS) were investigated. Mitochondrial CDS activity and CDS-1 mRNA increased in HF whereas CDS-2 mRNA in SHHF and humans, not in SD rats, decreased. PGPS activity, but not mRNA, increased in SHHF. CLS activity and mRNA decreased in SHHF, but mRNA was not significantly altered in humans. Cardiolipin remodeling enzymes, monolysocardiolipin acyltransferase (MLCL AT) and tafazzin, showed variable changes during HF. MLCL AT activity increased in SHHF. Tafazzin mRNA decreased in SHHF and human HF, but not in SD rats. The gene expression of acyl-CoA: lysocardiolipin acyltransferase-1, an endoplasmic reticulum MLCL AT, remained unaltered in SHHF rats. The results provide mechanisms whereby both cardiolipin biosynthesis and remodeling are altered during HF. Increases in CDS-1, PGPS, and MLCL AT suggest compensatory mechanisms during the development of HF. Human and SD data imply that similar trends may occur in human HF, but not during nonpathological aging, consistent with previous cardiolipin studies.

Altered gene expression of histone deacetylases in mood disorder patients

While the aging of the population is a sign of progress for societies, it also carries its load of negative aspects. Among them, cognitive decline and in particular memory loss is a common feature of non-pathological aging. Autobiographical memories, which rely on the hippocampus, are a primary target of age-related cognitive decline. Here, focusing on the neurobiological mechanisms of memory formation and storage, we describe how hippocampal functions are altered across time in non-pathological mammalian brains. Several hallmarks of aging have been well described over the last decades; among them, we consider altered synaptic communication and plasticity, reduction of adult neurogenesis and epigenetic alterations. Building on the neurobiological processes of cognitive aging that have been identified to date, we review some of the strategies based on lifestyle manupulation allowing to address age-related cognitive deficits.

Nonpathological Senescence Arises from Unsuitable External Influences

One of the most exciting events in current biogerontology is the elucidation of environmental control over the rate of aging. Many observations suggest that appropriate external stimuli can ameliorate the state of various biological entities and even rejuvenate them. Recent findings support the possibility that nonpathological aging of cells may be caused solely by external signals and moreover that this aging might be reversible. We have extended this principle to the level of the whole organism. We have suggested that a range of natural environmental conditions exists that corresponds to adequate vital activity within which an organism can maintain optimal functioning, renew itself, and remain ageless. But the environmental mortality of such organisms in natural niches is rather high. To reduce this mortality, the organism requires a milder but less stimulating environment in the presence of which (below some threshold level), the organism's renewal process becomes incomplete and the organism starts to age. Nevertheless, an age-dependent increase in the mortality rate due to senescence can be compensated for by a significant initial reduction in mortality due to environmental causes. The moderate present-day increase of life expectancy is the result of just such an initial mortality reduction. Living in a safe environment along with simulation of natural external positive influences or adequate responses to negative influences can decelerate, stop, and even reverse aging as well as considerably extend mean and extreme life span.

A common link between aging, schizophrenia, and autism?

Phillips & Silverstein (P&S, 2003) have proposed that NMDA-receptor hypofunction is the central reason for impaired cognitive coordination and abnormal gestalt-like perceptual processing in schizophrenia. We suggest that this model may also be applicable to non-pathological (or normal) aging given the compelling evidence of NMDA-receptor involvement during the aging process that results in age-related change in higher-level perceptual performance. Given that such deficits are present in other neurological disorders such as autism, an argument for a systematic assessment of perceptual functioning in these conditions may be posited.

On the Involvement of Prefrontal Networks in Cognitive Ageing

Normal ageing is associated with a wide variety of disturbances in the structure and function of the human brain. Recent neuroimaging studies suggest that the prefrontal cortex (PFC) is particularly vulnerable to the effects of ageing. These findings are compatible with the so-called ‘frontal ageing hypothesis' which has been formulated on the basis of neuropsychological research on non-pathological ageing. We will argue on the basis of recent structural and functional neuroimaging studies that this hypothesis needs to be refined, especially to acknowledge the possible relevance of a distinction between subregions within the PFC. In addition, findings with regard to a differential involvement of grey versus white matter suggest that both have to be considered in relation to age- related cognitive decline. Hence, neural networks and larger systems of interconnected brain regions and the functional activity in these circuits may be more important than specific cortical regions to explain age effects on cognitive functioning. Finally, it is important to consider individual variability due to sex differences and age-extrinsic biomedical factors in research which examines the relationship between brain structure or function and cognitive ageing.

Aging and bilateral symmetry detection.

The salience of bilateral symmetry varies as a function of the orientation of the symmetry axis. Vertical symmetry is most salient, followed by horizontal and then oblique orientations. We tested symmetry detection in different age groups to determine whether performance of this intermediate-level visual task is affected by normal, nonpathological aging. We tested forty participants and analyzed the results with respect to age group and symmetry orientation (vertical, horizontal, and 45 degree oblique). There was a vertical symmetry detection advantage for all participants, where sensitivity was highest for vertical symmetry, followed by horizontal symmetry, and then the oblique symmetry. Sensitivity to symmetry did not differ for the two younger age groups (aged 19-39 and 40-60), but declined significantly for the group aged 61-70, and declined again for the oldest group aged 71-80. This age-related difference in sensitivity to symmetry was not reflected in a measure of bias, where there were no differences as a function of age.

The dopamine and serotonin systems during aging in human and rodent brain. A brief review

]During nonpathological aging, quantitative changes occur in the pre- and post-synaptic elements of both the dopamine and serotonin systems. The level of dopamine in the human striatum declines up to 50% with age, while smaller and more variable changes are found in rodent brain (0–30%). Postsynaptically, the density of D-2 dopamine receptors also declines by 25–50% in both human and rodent striata. Conversely, D-1 receptors have been reported to increase with age in human, and to remain stable in rodent brain. In the serotonin system, the concentration of serotonin remains stable during nonpathological aging in both rodents and humans. The density of S-2 serotonin receptors declines 20–50% with age in human frontal cortex and hippocampus, and by 30% in mouse cortex. The density of S-l serotonin receptors is unchanged throughout the mouse lifespan, but declines by 30–50% in human frontal cortex. In rodents, the up-regulation of D-2 receptors in response to antagonist (neuroleptic) treatment is impaired in old animals. Conversely, the down-regulation of D-2 receptors in response to chronic agonist (bromocriptine) treatment is equivalent at all ages. Similarly, the down-regulation of S-2 receptors to antidepressant (amitriptyline) treatment in mice is constant over the lifespan. Attempts to up-regulate serotonin receptors with antagonists have, thus far, been unsuccessful.

The Normative Aging Study: An Interdisciplinary and Longitudinal Study of Health and Aging

The Normative Aging Study is a comprehensive interdisciplinary longitudinal study located in the VA Outpatient Clinic in Boston, Mass. The study was inaugurated in 1963 by the VA because of its statutory responsibility for the medical care of 25 million war veterans of whom 2 million are now 65 years of age and over, a figure which will rise to over 7 million in the next 20 years. Approximately 2,000 male veterans are enrolled for their lifetime as research subjects and undergo recurrent examinations administered on an outpatient basis. The focus of the study is on non-pathological aging, so that the subjects were carefully screened in advance to satisfy rigid health criteria regardless of age. The study is distinctive because of its large N and the socioeconomic diversity of its population. Parameters include clinical medicine, biochemistry, special senses, oral medicine, anthropometry and behavior. The study is designed to investigate the relationship between normal aging and the natural history of chronic diseases. The investigation of environmental correlates of age change throughout the logitudinal design will also suggest the intrinsic or extrinsic nature of the aging process. The hybrid cross-sectional-longitudinal design will also enable the partialing of secular from true aging effects. Functional ages pertaining to various aspects of aging are being developed as a tool for assessing relative aging rates and the relationship among such differences in aging.