Effect of age on caudate dopaminergic function in idiopathic Parkinsonism

Aging has long been implicated in the pathogenesis of Idiopathic Parkinsonism (IP). However, postmortem studies have demonstrated that the pathological changes in aging and IP affect the dopaminergic function in putamen and caudate nuclei differently. This has been considered by some authors as evidence against the role of aging in IP. We performed fluorodopa (FD) positron emission tomography (PET) in 36 patients with IP and 25 normal controls to test the hypothesis that the effect of aging on the striatal dopaminergic function in IP differs from the effect of aging in normal controls. We found that the FD uptake constant (Ki) in the caudate nucleus of patients with IP declines with both age (p = 0.002) and duration (p = 0.05) of symptoms. This effect was over and above that of normal aging (p = 0.007). We did not find a similar superimposed effect of age in the putamen. We conclude that the effect of aging on the dopaminergic function in the caudate nucleus in IP differs from that in normal aging. Whether this abnormal aging precedes and even predisposes to IP or is triggered by pathogenetic factors in IP is unclear.     

The frontal aging hypothesis evaluated.

That the human frontal lobes are particularly vulnerable to age-related deterioration has been frequently invoked as an explanation of functional decline in aging. This "frontal aging hypothesis" is evaluated in this review by examining evidence of selectively reduced frontal lobe function in aging. The frontal aging hypothesis predicts that functions largely dependent on frontal regions would decline in aging, while functions largely independent of frontal lobes would remain relatively spared. The hypothesis further predicts that age-related brain change would selectively impact frontal regions. The literatures on working memory, visuospatial attention, face recognition, and implicit memory were reviewed as exemplars of functions dependent on prefrontal, parietal, temporal and occipitotemporal cortices, respectively, with a view to establishing mediating structures and effects of aging. Age sensitivity was seen both in functions dependent on frontal integrity as well as in functions apparently independent of frontal integrity. Further, although prefrontal areas exhibit age-related decreases in regional volume, blood flow and metabolism, nonfrontal cortical regions undergo similar declines. It is concluded that while the frontal lobes are subject to age-related changes reflected in both behavior and pathology, there is only weak and conflicting evidence that frontal regions are selectively and differentially affected by aging. It is argued that a network-based theory of cognitive aging has advantages over the localizationist approach inherent in the frontal aging hypothesis.     

Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype

Cellular stress increases progressively with aging in mammalian tissues. Chronic stress triggers several signaling cascades that can induce a condition called cellular senescence. Recent studies have demonstrated that senescent cells express a senescence-associated secretory phenotype (SASP). Emerging evidence indicates that the number of cells expressing biomarkers of cellular senescence increases in tissues with aging, which implies that cellular senescence is an important player in organismal aging. In the brain, the aging process is associated with degenerative changes, e.g. synaptic loss and white matter atrophy, which lead to progressive cognitive impairment. There is substantial evidence for the presence of oxidative, proteotoxic and metabolic stresses in aging brain. A low-level, chronic inflammatory process is also present in brain during aging. Astrocytes demonstrate age-related changes that resemble those of the SASP: (i) increased level of intermediate glial fibrillary acidic protein and vimentin filaments, (ii) increased expression of several cytokines and (iii) increased accumulation of proteotoxic aggregates. In addition, in vitro stress evokes a typical senescent phenotype in cultured astrocytes and, moreover, isolated astrocytes from aged brain display the proinflammatory phenotype. All of these observations indicate that astrocytes are capable of triggering the SASP and the astrocytes in aging brain display typical characteristics of cellular senescence. Bearing in mind the many functions of astrocytes, it is evident that the age-related senescence of astrocytes enhances the decline in functional capacity of the brain. We will review the astroglial changes occurring during aging and emphasize that senescent astrocytes can have an important role in age-related neuroinflammation and neuronal degeneration.     

Redox proteomics in aging rat brain: involvement of mitochondrial reduced glutathione status and mitochondrial protein oxidation in the aging process

Increasing evidence supports the notion that increased oxidative stress is a fundamental cause in the aging process and in neurodegenerative diseases. As a result, a decline in cognitive function is generally associated with brain aging. Reactive oxygen species (ROS) are highly reactive intermediates, which can modify proteins, nucleic acids, and polyunsaturated fatty acids, leading to neuronal damage. Because proteins are major components of biological systems and play key roles in a variety of cellular functions, oxidative damage to proteins represents a primary event observed in aging and age-related neurodegenerative disorders. In the present study, with a redox proteomics approach, we identified mitochondrial oxidatively modified proteins as a function of brain aging, specifically in those brain regions, such as cortex and hippocampus, that are commonly affected by the aging process. In all brain regions examined, many of the identified proteins were energy-related, such as pyruvate kinase, ATP synthase, aldolase, creatine kinase, and α-enolase. These alterations were associated with significant changes in both cytosolic and mitochondrial redox status in all brain regions analyzed. Our finding is in line with current literature postulating that free radical damage and decreased energy production are characteristic hallmarks of the aging process. In additon, our results further contribute to identifying common pathological pathways involved both in aging and in neurodegenerative disease development.     

骨骼肌衰老与MG29蛋白

目的：综述国内外有关MG29蛋白的研究进展及其与骨骼肌衰老的密切关系。 资料来源：应用计算机检索中文CNKI数据库、读秀学术搜索和超星数字图书,检索关键词为MG29,骨骼肌衰老等;英文数据库为Elsevier SD和Springer Link,检索关键词为MG29,aging skeletal muscle,sarcopenia等;此外还手工查阅多部相关专著。 资料选择：纳入标准：①有关MG29蛋白的位置、结构与功能。②有关MG29蛋白与骨骼肌衰老。③有关MG29蛋白与运动。④同领域内近期发表的针对性强、影响因子大的相关文章。排除标准：重复研究文章或是Meta分析类文章。 结局评价指标：MG29蛋白与骨骼肌衰老有密切关系。 结果：国内外许多专家学者近年来从组织学、生物化学和分子生物学等方面对骨骼肌衰老进行了深入的研究。目前普遍认为钙是调控骨骼肌兴奋收缩偶联的核心元素,其动态平衡,即钙稳态的变化和骨骼肌衰老密切相关。MG29蛋白是最新发现的一种位于横管膜上调控钙机制的类突触素族蛋白。研究发现,衰老大鼠骨骼肌内的MG29蛋白减少了大约50%,有人将青年大鼠的MG29蛋白基因敲除,MG29蛋白缺陷的青年大鼠也出现了类似衰老大鼠的特征,如肌力下降、易疲劳、肌浆网碎裂、横管系统肿胀、钙火花的动态活性发生变化以及隔离的钙池等,这说明MG29蛋白与骨骼肌衰老紧密相关。 结论：MG29蛋白与骨骼肌衰老密切相关,怎样通过改善MG29蛋白水平来延缓骨骼肌衰老将是后续研究的重点。     

A new glucocorticoid hypothesis of brain aging: implications for Alzheimer's disease

The original glucocorticoid (GC) hypothesis of brain aging and Alzheimer's disease proposed that chronic exposure to GCs promotes hippocampal aging and AD. This proposition arose from a study correlating increasing plasma corticosterone with hippocampal astrocyte reactivity in aging rats. Numerous subsequent studies have found evidence consistent with this hypothesis, in animal models and in humans. However, several results emerged that were inconsistent with the hypothesis, highlighting the need for a more definitive test with a broader panel of biomarkers. We used microarray analyses to identify a panel of hippocampal gene expression changes that were aging-dependent, and also corticosterone-dependent. These data enabled us to test a key prediction of the GC hypothesis, namely, that the expression of most target biomarkers of brain aging should be regulated in the same direction (increased or decreased) by both GCs and aging. This prediction was decisively contradicted, as a majority of biomarker genes were regulated in opposite directions by aging and GCs, particularly inflammatory and astrocyte-specific genes. Thus, the initial hypothesis of simple positive cooperativity between GCs and aging must be rejected. Instead, our microarray data suggest that in the brain GCs and aging interact in more complex ways that depend on the cell type. Therefore, we propose a new version of the GC-brain aging hypothesis; its main premise is that aging selectively increases GC efficacy in some cell types (e.g., neurons), enhancing catabolic processes, whereas aging selectively decreases GC efficacy in other cell types (e.g., astrocytes), weakening GC anti-inflammatory activity. We also propose that changes in GC efficacy might be mediated in part by cell type specific shifts in the antagonistic balance between GC and insulin actions, which may be of relevance for Alzheimer's disease pathogenesis.     

Determining the Causes and Consequences of Nicotine Dependence: Emerging Genetic Research Methods

Population aging is an enormous public health issue and there is clear need for strategies to maximize opportunities for successful aging. Many psychiatric illnesses are increasingly thought to be associated with accelerated aging, therefore emerging data on individual and policy level interventions that alter typical aging trajectories are relevant to mental health practitioners. Although the determinants and definition of successful aging remain controversial, increasing data indicate that psychiatric illnesses directly impact biological aging trajectories and diminish lifestyle, psychological, and socio-environmental factors that seem to reduce risk of morbidity and mortality. Many interventions designed to enhance the normal course of aging may be adjunctive approaches to management of psychiatric illnesses. We highlight recent data on interventions seeking to promote healthy aging, such as cognitive remediation, physical activity, nutrition, and complementary and alternative treatments for older people with and without psychiatric illnesses.     

Does the brain lead the metabolic decline in aging?: Lessons from animal models and human centenarians

We hypothesize that age-related metabolic alterations originate in the brain (studies in rodents), and that the functional decline of the brain may be protected by a favorable metabolic profile (studies in human centenarians). The metabolic decline with aging is associated with a progressive increase in fat mass in mammals and caloric restriction enhances life span in rodents. Here we show that a diminished biological response to leptin is a feature of aging. Leptin is a fat derived peptide that decreases body weight, fat mass, improves insulin sensitivity and energy expenditure through its receptors in the hypothalamus. We examined the effects of exogenous leptin on several metabolic parameters as a function of aging in rats. A prolonged elevation in plasma leptin levels in aging rats failed to decrease food intake, total fat mass, and intra-abdominal fat. Furthermore, the effects of leptin on liver triglyceride content, on insulin action and insulin secretion were markedly decreased in these animals compared to young controls. Leptin's failure in this aging model suggests its role in age-associated body fat accumulation, fat distribution and insulin resistance. We propose that a central nervous system resistance to leptin is probably a primary event that leads to the metabolic syndrome of aging, especially when availability of calories is unrestricted. Families of centenarians often have extremely high levels of high-density lipoprotein (HDL), which may have neurological as well as cardiovascular protective effects during aging. Because HDL level declines with aging, we tested if centenarians with higher HDL levels have greater cognitive protection. HDL levels correlated significantly with mini-mental state score (MMSE) of the centenarian, and each decrease in HDL tertile was associated with significant decrease in MMSE. These data suggests that the appearance of cognitive dysfunction in centenarians is associated with a decline in HDL cholesterol. This underscores the protective effects of increased HDL cholesterol, and its role in longevity. Taken together, these data suggest a determinant role for brain in the metabolic decline of aging, and highlight the advantage of favorable metabolic profile on the protection of brain from age-related cognitive decline.     

Aging in a dish: age-dependent changes of neuronal survival, protein oxidation, and creatine kinase BB expression in long-term hippocampal cell culture.

Results from different experimental systems demonstrate that increased oxidative damage plays a role in normal aging and age-associated pathology. In the current study, long-term cultures of hippocampal neurons were examined as a model system. It was established that neuronal survival in long-term culture decreases according to the Gompertz law and that neuronal "aging in the dish" is associated with increased oxidative damage of cell proteins. The increase of protein carbonyl formation in aged neurons was demonstrated both by Western blot analysis for oxidized proteins and by in situ immunocytochemical method, which was developed to analyze protein oxidation in fixed cells. In aging neuronal cultures, a gradual increase in creatine kinase (CK) content but decreased activity of enzyme per immunoreactive protein was found, suggesting the accumulation of inactive CK molecules. The increase in CK content was not a result of generalized protein elevation, since analysis of beta-actin content showed a time-dependent loss, probably reflecting decreased number of cellular processes with aging. These findings, showing "aging in a dish," consistent with the notion that aging is associated with increased protein oxidation, provide a system for study of age-related neurodegenerative disorders associated with oxidative stress.     

Aging impairs the late phase of long-term potentiation at the medial perforant path-CA3 synapse in awake rats

The effects of aging on long-term potentiation (LTP) in the dentate gyrus (DG) and CA1 are well documented, but LTP at the medial perforant path (MPP)-CA3 synapse of aged animals has remained unexplored. Because the MPP-DG and Schaffer-collateral-CA1 synapses account for only about 20% of total hippocampal synapses, global understanding of how aging affects hippocampal plasticity has remained limited. Much is known about LTP induction in the hippocampal formation, whereas the mechanisms that regulate LTP maintenance are less understood, especially during aging. We investigated the effects of aging on MPP-CA3 LTP induction and maintenance in awake rats. As is the case in the DG and CA1, high-frequency stimulation-induced LTP at the MPP-CA3 synapse is normal in aged rats. These data indicate that N-methyl-D-aspartate (NMDA) receptor-mediated processes are intact at the MPP-CA3 synapse in aged rats. In contrast, aging impaired the magnitude and duration of MPP-CA3 LTP over a period of days. Also, these data are consistent with reports that area CA3 is especially susceptible to age-related changes. Our data suggest that aging impairs mechanisms that regulate the late phase of MPP-CA3 LTP and contribute to a more global understanding of how aging affects hippocampal plasticity.     

Research and interpretation perspectives on aging related physical morbidity with spinal cord injury and brief review of systems

There are number of perspectives associated with the scientific study and interpretation of aging in the general population that also relate to the study of aging with spinal cord injury (SCI). These include era and survivor effects and have implications for design, analysis and interpretation of SCI aging research, which, in turn, have implications for planning, policy and clinical practice. Several factors specifically related to SCI also have implications for design, analysis and interpretation of SCI aging research. These include duration of injury, age at injury, neurological impairment (level and completeness of injury), and gender. Considering the skin, musculoskeletal, cardiovascular, respiratory, genitourinary, gastrointestinal, nervous, endocrine, and immune physiologic systems, appropriate research specific to a particular system and related morbidity in those aging with spinal cord injury is currently limited to the musculoskeletal, cardiovascular and respiratory systems. Research on certain aspects of aging with SCI is not currently feasible due to the rate and magnitude of historical changes in treatment and rehabilitation of SCI; and currently most research pertaining to aging with SCI will be highly subject to survivor effects. Nevertheless, there is a need for research on aging with SCI and many opportunities with regard to gaps in knowledge.     

Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging.

BACKGROUND: Little is known about the biological mechanisms underlying the excess medical morbidity and mortality associated with mood disorders. Substantial evidence supports abnormalities in stress-related biological systems in depression. Accelerated telomere shortening may reflect stress-related oxidative damage to cells and accelerated aging, and severe psychosocial stress has been linked to telomere shortening. We propose that chronic stress associated with mood disorders may contribute to excess vulnerability for diseases of aging such as cardiovascular disease and possibly some cancers through accelerated organismal aging. METHODS: Telomere length was measured by Southern Analysis in 44 individuals with chronic mood disorders and 44 nonpsychiatrically ill age-matched control subjects. RESULTS: Telomere length was significantly shorter in those with mood disorders, representing as much as 10 years of accelerated aging. CONCLUSIONS: These results provide preliminary evidence that mood disorders are associated with accelerated aging and may suggest a novel mechanism for mood disorder-associated morbidity and mortality.     

The effects of aging on hippocampal and cortical projections of the forebrain cholinergic system

It has been proposed that disruption of cholinergic input to the hippocampus and cortex contributes to the learning and memory deficits associated with aging. The data reviewed here, however, suggest that the oft-stated generalization that normal aging is characterized by disruption of cholinergic input to the hippocampus and cortex is not entirely correct. Instead it appears that age-related changes are not consistently found on measures such as the activity of ChAT or the content of ACh in these regions, basal levels of ACh release in cortex, and the number of cholinergic neurons in the basal forebrain (source of cholinergic input to the hippocampus and cortex). These observations suggest that unlike Alzheimer's disease, normal aging does not reliably produce a degeneration of the cholinergic innervation of the hippocampus and cortex. The responsivity of the cholinergic system, however, is altered during normal aging. ACh synthesis and stimulation-induced release of ACh are diminished in aged animals. Further, the electrophysiological response of postsynaptic neurons to ACh is reduced during aging. Although some regional differences in these age-related changes may be present, the generalization that the functioning of the cholinergic system is impaired during aging is probably accurate. Thus, investigation of these changes in the dynamic properties of cholinergic input to the hippocampus and cortex during aging may provide clarification of the relationship between cholinergic dysfunction and age-related decline in learning and memory and may also provide a more reasonable rationale for treatment approaches.     

Lack of amyloid plaque formation in the central nervous system of a patient with Werner syndrome

Werner syndrome (WS) is an autosomal recessive disorder associated with accelerated aging. It is well documented on systemic aging but it is unclear whether the brain with WS shows accelerated aging. A 55‐year‐old patient with WS was studied and it was found that a deletion mutation of exon 26 of the WRN gene was not associated with CNS pathology, such as amyloid plaques or NFT. Furthermore, additional genetic analysis showed an apolipoprotein E genotype of ?3/?3 that did not play either an accelerating or inhibitory action on amyloid deposition. Therefore, based on the genetic and neuropathological analysis, it was observed that the WS‐associated aging seen in many organs did not extend to the CNS.     

Cu/Zn superoxide dismutase mRNA and enzyme activity, and susceptibility to lipid peroxidation, increases with aging in murine brains.

To protect against reactive oxygen species, prokaryotic and eukaryotic cells have developed an antioxidant defence mechanism where O2- is converted to H2O2 by superoxide dismutase (Sod), and in a second step, H2O2 is converted to H2O by catalase (Cat) and/or glutathione peroxidase (Gpx). If Sod levels are increased without a concomitant Gpx increase, then the intermediate H2O2 accumulates. This intermediate could undergo the Fenton's reaction, generating hydroxyl radicals which may lead to lipid peroxidation in cells. In this study, we investigate the expression of Sod1, Gpx1 and susceptibility to lipid peroxidation during the aging process in mouse brains. We demonstrate that the mRNA levels and enzyme activity of Sod1 are higher in brains from adult mice compared to neonatal mice. Furthermore, we show that a linear increase in Sod1 mRNA and enzyme activity occurs with aging (1-100 weeks). On the contrary, we find that the mRNA and enzyme activity for Gpx1 does not increase with aging in mouse brains. In addition, our results demonstrate that the susceptibility of murine brains to lipid peroxidation increases with aging. The data in this study are consistent with the notion that reactive oxygen species may contribute to the aging process in mammalian brains. These results are discussed in relation to the normal aging process in mammals, and to the premature aging and mental retardation in Down syndrome.     

Early onset ageing and service preparation in people with intellectual disabilities: institutional managers' perspective

Although longevity among older adults with intellectual disabilities is increasing, there is limited information on their premature aging related health characteristics and how it may change with increasing age. The present paper provides information of the institutional manager's perception on early onset aging and service preparation for this population. We used purposive sampling to recruit 54 institutional managers who care for people with intellectual disabilities in Taiwan. The present study employed a cross-sectional design using a self-administrative structured questionnaire that was completed by the respondents in November 2009. The results showed that more than 90% of the respondents agreed with earlier onset aging characteristics of people with ID. However, nearly all of the respondents expressed that the government policies were inadequate and the institution is not capable of caring for aging people with ID, and more than half of them did not satisfy to their provisional care for this group of people. With regard to the service priority of government aging policy for people with ID, the respondent expressed that medical care, financial support, daily living care were the main areas in the future policy development for them. The factors of institutional type, expressed adequacy of government's service, respondent's job position, age, and working years in disability service were variables that can significantly predict the positive perceptions toward future governmental aging services for people with ID (adjusted R² = 0.563). We suggest that the future study strategy should underpin the aging characteristics of people with intellectual disabilities and its differences with general population to provide the useful information for the institutional caregivers.     

Aging and Apolipoprotein E in HIV Infection

With the implementation of increasingly effective antiretroviral therapy (ART) over the past three decades, individuals infected with HIV live a much longer life. HIV infection is no longer a terminal but rather a chronic disease. However, the lifespan of infected individuals remains shorter than that of their uninfected peers. Even with ART, HIV infection may potentiate “premature” aging. Organ-associated disease and systemic syndromes that occur in treated HIV-infection are like that of older, uninfected individuals. Brain aging may manifest as structural changes or neurocognitive impairment that are beyond the chronological age. The spectrum of neurological, cognitive, and motor deficiencies, currently described as HIV-associated neurocognitive disorders (HAND), may reflect earlier onset of mechanisms common to HIV infection and aging (accelerated aging). HAND could also reflect the neurological impact of HIV infection superimposed on comorbidities linked to age and chronic inflammation, leading to a higher prevalence of neurocognitive impairment across the age span (accentuated aging). In addition, apolipoprotein E (ApoE), one of the most influential host risk factors for developing Alzheimer’s disease, has been implicated in the development of HAND. But studies differ as to whether ApoE is relevant, and whether age and ApoE interact to impair brain function in the HIV-infected patient. What is clear is that HIV-infected individuals are living longer with HIV, and therefore factors related to aging and health need to be examined in the context of current, effective ART. This review addresses the recent evidence for the influence of aging and ApoE on HIV-associated neurocognitive impairment.     

Adult hippocampal neurogenesis and aging

The demographic changes in the foreseeable future stress the need for research on successful cognitive aging. Advancing age constitutes a primary risk factor for disease of the central nervous system most notably neurodegenerative disorders. The hippocampus is one of the brain regions that is prominently affected by neurodegeneration and functional decline even in what is still considered “normal aging”. Plasticity is the basis for how the brain adapts to changes over time. The discovery of adult hippocampal neurogenesis has added a whole new dimension to research on structural plasticity in the adult and aging hippocampus. In this article, we briefly summarize and discuss recent findings on the regulation of adult neurogenesis with relevance to aging. Aging is an important co-variable for many regulatory mechanisms affecting adult neurogenesis but so far, only few studies have specifically addressed this interaction. We hypothesize that adult neurogenesis contributes to a neural reserve, i.e. the maintained potential for structural plasticity that allows compensation in situations of functional losses with aging. As such we propose that adult neurogenesis might contribute to the structural correlates of successful aging.     

Free radicals and aging

Aging is characterized by decrements in maximum function and accumulation of mitochondrial DNA mutations, which are best observed in organs such as the brain that contain post-mitotic cells. Oxygen radicals are increasingly considered responsible for part of these aging changes. Comparative studies of animals with different aging rates have shown that the rate of mitochondrial oxygen radical generation is directly related to the steady-state level of oxidative damage to mitochondrial DNA and is inversely correlated with maximum longevity in higher vertebrates. The degree of unsaturation of tissue fatty acids also correlates inversely with maximum longevity. These are the two known traits connecting oxidative stress with aging. Furthermore, caloric restriction, which decreases the rate of aging, proportionately decreases mitochondrial oxygen radical generation, especially at complex I. These findings are reviewed, highlighting the results obtained in the brain.