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  • Roles of the actin cytoskeleton in aging and age-associated diseases
    Ageing Res. Rev. (IF 10.390) Pub Date : 2020-01-20
    Wing-Fu Lai; Wing-Tak Wong

    The integrity of the cytoskeleton is essential to diverse cellular processes such as phagocytosis and intracellular trafficking. Disruption in the organization and dynamics of the actin cytoskeleton leads to age-associated symptoms and diseases, ranging from cancer to neurodegeneration. In addition, changes in the integrity of the actin cytoskeleton disrupt the functioning of not only somatic and stem cells but also gametes, resulting in aberrant embryonic development. Strategies to preserve the integrity and dynamics of the cytoskeleton are, therefore, potentially therapeutic to age-related disorders. The objective of this article is to revisit the current understanding of the roles played by the actin cytoskeleton in aging, and to review the opportunities and challenges for transition of basic research to intervention development. It is hoped that, with the snapshot of evidence regarding changes in actin dynamics with advanced age, insights on anti-aging medicine can be attained for future research.

  • How age relates to spatial navigation performance: functional and methodological considerations
    Ageing Res. Rev. (IF 10.390) Pub Date : 2020-01-15
    Ineke J.M. van der Ham; Michiel H.G. Claessen

    Aging effects have often been reported for spatial navigation performance. Moreover, navigation performance is thought to be an early marker of pathological aging. Yet, the cognitive complexity of navigation and large individual variation in healthy population make it difficult to pinpoint the precise aging mechanisms involved. We performed a systematic literature review with specific attention to functional dissociation between the tasks used and methodological characteristics. The literature search resulted in 39 articles in which age comparisons were made for large-scale navigation measures. Outcomes were categorized into the domains of landmark, location (egocentric and allocentric), and path knowledge (route and survey). Results indicate that clear functional dissociation exists between these navigation knowledge domains. Aging effects are found for path knowledge most convincingly, while landmark and egocentric location knowledge are frequently omitted in assessment. The participant samples reported often neglect adult, middle aged participants, while this group could be highly informative to the aging process as well. Moreover, having a clear image of age-related performance across the lifespan could be a valuable addition towards the early detection of pathological aging through navigation performance.

  • HORMESIS AND GINKGO BILOBA (GB): Numerous Biological Effects of GB are Mediated via Hormesis
    Ageing Res. Rev. (IF 10.390) Pub Date : 2020-01-10
    Edward J. Calabrese; Vittorio Calabrese; Aristidis Tsatsakis; James J. Giordano

    Ginkgo biloba (GB) extracts have been shown to commonly induce biphasic dose responses in a range of cell types and endpoints (e.g., cochlea neural stem cells, cell viability, cell proliferation). The magnitude and width of the low dose stimulation of these biphasic dose responses are similar to those reported for hormetic dose responses. These hormetic dose responses occur within direct stimulatory responses as well as in preconditioning experimental protocols, displaying acquired resistance within an adaptive homeodynamic and temporal framework and repeated measurement protocols. The demonstrated GB dose responses further reflect the general occurrence of hormetic dose responses that consistently appear to be independent of the biological model, endpoint, inducing agent, and/or mechanism. These findings have important implications for consideration(s) of study designs involving dose selection, dose spacing, sample size, and statistical power. This illustrates and strengthens the need to characterize the low dose stimulatory response range and optimal dose in order to explore potential public health and clinical applications of plant-derived agents, such as GB.

  • Ribosomal DNA instability: an evolutionary conserved fuel for inflammaging
    Ageing Res. Rev. (IF 10.390) Pub Date : 2020-01-09
    Gianluca Storci; Maria Giulia Bacalini; Francesca Bonifazi; Paolo Garagnani; Sabrina De Carolis; Stefano Salvioli; Fabiola Olivieri; Massimiliano Bonafè

    Across eukaryotes, ribosomal DNA (rDNA) loci are characterized by intrinsic genomic instability due to their repetitive nature and their base composition that facilitate DNA double strand breaks and RNA:DNA hybrids formation. In the yeast, ribosomal DNA instability affects lifespan via the formation of extrachromosomal rDNA circles (ERC) that accrue into aged cells. In humans, rDNA instability has long been reported in a variety of progeric syndromes caused by the dysfunction of DNA helicases, but its role in physiological aging and longevity still needs to be clarified. Here we propose that rDNA instability leads to the activation of innate immunity and inflammation via the interaction with the cytoplasmic DNA sensing machinery. Owing to the recent clarified role of cytoplasmic DNA in the pro-inflammatory phenotype of senescent cells, we hypothesize that the accrual of rDNA derived molecules (i.e. ERC and RNA:DNA hybrids) may have a role in aging by contributing to inflammaging i.e. the systemic pro-inflammatory drift that associates with the onset of geriatric syndromes and age related dysfunctions in humans.

  • A third of community-dwelling elderly with intermediate and high level of Alzheimer’s neuropathologic changes are not demented: A meta-analysis
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-12-30
    Mahmoud Reza Azarpazhooh; Abolfazl Avan; Lauren E. Cipriano; David G. Munoz; Mahdiyeh Erfanian; Amin Amiri; Saverio Stranges; Vladimir Hachinski
  • Endosomal dysfunction impacts extracellular vesicle release: central role in Aβ pathology
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-12-28
    BD Arbo; LR Cechinel; RP Palazzo; IR Siqueira

    Alzheimer’s Disease (AD) is characterized by progressive loss of cognitive abilities; senile plaques represent the major histopathological findings. Amyloid precursor protein (APP) processing machinery, and its product amyloid-beta (Aβ) peptide, have been found in extracellular vesicles (EVs), specifically exosomes, which allows for Aβ peptide aggregation and subsequent senile plaques deposition. We review the APP processing imbalance in EVs, autophagic and endosomal pathways in AD. Increased intraluminal vesicle (ILV) production and exosome release appear to counteract the endosomal dysfunction of APP processing; however, this process results in elevated amyloidogenic processing of APP and augmented senile plaque deposition. Several players related to APP processing and dysfunctional endosomal-lysosomal-exosomal (and other EVs) pathway are described, and the interconnected systems are discussed. The components Arc, p75, Rab11 and retromer complex emerge as candidates for key convergent mechanisms that lead to increased EVs loaded with APP machinery and Aβ levels, in atrophy and damage of basal forebrain cholinergic neurons in AD.

  • Education and Age-related Decline in Cognitive Performance: Systematic Review and Meta-analysis of Longitudinal Cohort Studies
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-12-24
    D. Seblova; R. Berggren; M. Lövdén

    Central theories of cognitive aging propose that education is an important protective factor for decline in cognitive performance in older age. We conducted a systematic review and meta-analysis of reported estimates of an association between educational attainment and change in performance in six cognitive domains (episodic memory, processing speed, verbal fluency, crystallized intelligence, fluid intelligence, and global ability) in the general population of older individuals. The systematic search (11th of October 2019) identified 92 eligible articles. The episodic memory domain had the highest number of estimates (37 estimates from 18 articles, n = 109,281) included in the meta-analysis. The fewest estimates (6 estimates from 6 articles, n = 5,263) were included for fluid intelligence. Pooled mean estimates from an inverse-variance weighted random effects analysis were not statistically significant and indicated that any association between education and change in cognitive performance is likely of a negligible magnitude. The estimates for education’s role (one additional year) for change in cognitive performance ranged from -0.019 (95% confidence interval, CI = -0.047, 0.010) to 0.004SD (CI = -0.003, 0.012) per decade. Even if the larger positive point estimates (i.e., protective effects) are selectively considered, the influence of education on change is still at least 12 times less important for the cognitive functioning of an older individual than the association between education and level of cognitive performance. Sensitivity analyses did not substantially alter these results. However, heterogeneity was substantial, and remained largely unexplained by mean age, mean educational attainment, Gini coefficient, GDP per capita, maximum follow-up period, and publication year. Overall, education is an important factor in aging due to its robust association with level of performance, but the current base of empirical evidence is not revealing a consistent and substantial association between educational attainment and changes in cognitive performance in the general population. Theories of cognitive aging must be updated to incorporate this pattern of findings.

  • Does the neuropsychiatric inventory predict progression from mild cognitive impairment to dementia? A systematic review and meta-analysis
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-12-24
    Sabela C. Mallo; Scott B. Patten; Zahinoor Ismail; Arturo X. Pereiro; David Facal; Carlos Otero; Onésimo Juncos-Rabadán

    Background Neuropsychiatric Symptoms (NPS) are common in Mild Cognitive Impairment (MCI). The Neuropsychiatric Inventory (NPI) and its shorter version, the Neuropsychiatric Inventory Questionnaire (NPI-Q), are the most common measures to assess NPS. Our objective was to determine if NPI/NPI-Q ratings predict conversion from MCI to dementia. Methods Empirical longitudinal studies published in English or Spanish, concerned with the role of NPS as a risk factor for conversion from MCI to dementia, with a diagnosis of MCI following clinical criteria, that reported NPI/NPI-Q total score in converters versus non-converters, were included. Random effects models were used, and heterogeneity was explored with stratification and a random-effects meta-regression. The overall conversion rate and the standardized mean difference (SMD) for evolution, as a function of NPI/NPI-Q scores, were calculated. Results The overall conversion rate was 35%. Mean NPI/NPI-Q ratings were higher in converters versus in non-converters, with the overall SMD approaching significance. Heterogeneity was observed in studies of more than two years of follow-up and in a study with a mean age of more than 80 years. This heterogeneity concerned the size, not the direction of the difference. Conclusions Our results suggest that NPI/NPI-Q ratings are associated with conversion from MCI to dementia.

  • A viewpoint on change point modeling for cognitive aging research: Moving from description to intervention and practice
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-12-24
    Briana N. Sprague

    Chronological age is a commonly-used time metric, but there may be more relevant time measures in older adulthood. This paper reviews change point modeling, a type of analysis increasingly common in cognitive aging research but with limited application in applied research. Here, we propose a new application of such models for cognitive training studies. Change point models have the potential to assess intervention outcomes such as compression of morbidity or reduced decline after an event (e.g., reduced cognitive decline after a dementia diagnosis) as well as changes in outcome trajectories across different intervention dosages (e.g., initial vs. booster training). Through change point modeling, we can better understand how interventions impact cognitive aging trajectories.

  • Medium Chain Triglycerides induce mild ketosis and may improve cognition in Alzheimer’s disease. A systematic review and meta-analysis of human studies
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-12-20
    Konstantinos I. Avgerinos; Josephine M. Egan; Mark P. Mattson; Dimitrios Kapogiannis

    Introduction/Aim The brain in Alzheimer’s disease shows glucose hypometabolism but may utilize ketones for energy production. Ketone levels can potentially be boosted through oral intake of Medium Chain Triglycerides (MCTs). The aim of this meta-analysis is to investigate the effect of MCTs on peripheral ketone levels and cognitive performance in patients with mild cognitive impairment and Alzheimer’s disease. Methods Medline, Scopus and Web of Science were searched for literature up to March 1, 2019. Meta-analyses were performed by implementing continuous random-effects models and outcomes were reported as weighted Mean Differences (MDs) or Standardized Mean Differences (SMDs). Results Twelve records (422 participants) were included. Meta-analysis of RCTs showed that, compared with placebo, MCTs elevated beta-hydroxybutyrate (MD = 0.355; 95% CI, 0.286 - 0.424, I2 = 0%), showed a trend towards cognitive improvement on ADAS-Cog (MD = - 0.539; 95% CI, -1.239 - 0.161, I2 = 0%), and significantly improved cognition when combining ADAS-Cog with MMSE (SMD = - 0.289; 95% CI, −0.551 to −0.027, I2 = 0%). Conclusions In this meta-analysis, we demonstrated that MCTs can induce mild ketosis and may improve cognition in patients with mild cognitive impairment and Alzheimer’s disease. However, risk of bias of existing studies necessitates future trials.

  • Activation of immunosuppressive network in the aging process
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-12-12
    Antero Salminen

    Chronic low-grade inflammation has a key role in the aging process, a state called inflammaging. It is known that the chronic inflammatory condition generates counteracting immunosuppressive state in many diseases. Inflammaging is also associated with an immune deficiency; generally termed as immunosenescence, although it is not known whether it represents the senescence of immune cells or the active remodeling of immune system. Evidence has accumulated since the 1970’s indicating that immunosenescence might be caused by an increased activity of immunosuppressive cells rather than cellular senescence. Immune cells display remarkable plasticity; many of these cells can express both proinflammatory and immunosuppressive phenotypes in a context-dependent manner. The immunosuppressive network involves the regulatory subtypes of T (Treg) and B (Breg) cells as well as regulatory phenotypes of macrophages (Mreg), dendritic (DCreg), natural killer (NKreg), and type II natural killer T (NKT) cells. The immunosuppressive network also includes monocytic (M-MDSC) and polymorphonuclear (PMN-MDSC) myeloid-derived suppressor cells which are immature myeloid cells induced by inflammatory mediators. This co-operative network is stimulated in chronic inflammatory conditions preventing excessive inflammatory responses but at the same time they exert harmful effects on the immune system and tissue homeostasis. Recent studies have revealed that the aging process is associated with the activation of immunosuppressive network, especially the functions of MDSCs, Tregs, and Mregs are increased. I will briefly review the properties of the regulatory phenotypes of immune cells and examine in detail the evidences for an activation of immunosuppressive network with aging.

  • Comparative Effectiveness of Three Exercise Types to Treat Clinical Depression in Older Adults: A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-12-11
    Kyle J. Miller, Daniela C. Gonçalves-Bradley, Pinyadapat Areerob, Declan Hennessy, Christopher Mesagno, Fergal Grace
  • Does perturbation in the mitochondrial protein folding pave the way for neurodegeneration diseases?
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-12-06
    Ting Ji, Xiaolu Zhang, Zhenlong Xin, Baoping Xu, Zhenxiao Jin, Jiawei Wu, Wei Hu, Yang Yang

    Mitochondria, which are cell compartments that are widely present in eukaryotic cells, have been shown to be involved in a variety of synthetic, metabolic, and signaling processes, thereby playing a vital role in cells. The mitochondrial unfolded protein response (mtUPR) is a response in which mitochondria reverse the signal to the nucleus and maintain mitochondrial protein homeostasis when unfolded and misfolded proteins continue to accumulate. Multiple neurodegeneration diseases, including Alzheimer's disease (AD), Parkinson’s disease (PD), and familial amyotrophic lateral sclerosis (fALS), are public health challenges. Every year, countless efforts are expended trying to clarify the pathogenesis and treatment of neurological disorders, which are associated with mitochondrial dysfunction to some extent. Numerous studies have shown that mtUPR is involved in and plays an important role in the pathogenesis of neurological disorders, but the exact mechanism of the disorders is still unclear. Further study of the process of mtUPR in neurological disorders can help us more accurately understand their pathogenesis in order to provide new therapeutic targets. In this paper, we briefly review mtUPR signaling in Caenorhabditis elegans (C. elegans) and mammals and summarize the role of mtUPR in neurodegeneration diseases, including AD, PD and fALS.

  • The influence of vitamin D supplementation on IGF-1 levels in humans: A systematic review and meta-analysis
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-12-06
    Hamed Kord Varkaneh, Giulia Rinaldi, Azita Hekmatdoost, Somaye Fatahi, Shing Cheng Tan, Mahdi Shadnoush, Vahid Khni, Seyed Mohammad Mousavi, Meysam Zarezadeh, Shekoufeh Salamat, Hiba Bawadi, Jamal Rahmani

    Background Inconsistencies exist with regard to influence of vitamin D supplementation on IGF-1 levels. The inconsistencies could be attributed to several factors, such as dosage and duration of intervention, among others. To address these inconsistencies, this study was conducted to determine the impact of vitamin D supplementation on IGF-1 levels through a systematic review and meta-analysis of randomized controlled trials (RCTs). Methods A comprehensive systematic search was carried out in PubMed/MEDLINE, Web of Science, SCOPUS and Embase for RCTs that investigated the impact of vitamin D intake on circulating IGF-1 levels from inception until June 2019. Weighted mean difference (WMD) with the 95% CI were applied for estimating combined effect size. Subgroup analysis was performed to specify the source of heterogeneity among studies. Results Pooled results from eight studies demonstrated an overall non-significant increase in IGF-1 following vitamin D supplementation (WMD: 4 ng/ml, 95% CI: -4 to 11). However, a significant degree of heterogeneity among studies was observed (I2 = 66%). The subgroup analyses showed that vitamin D dosage of ≤1000 IU/day (WMD: 10 ng/ml) significantly increased IGF-1 compared to the vitamin D dosage of <1000 IU/day (WMD: -1 ng/ml). Moreover, intervention duration ≤12 weeks (WMD: 11 ng/ml) significantly increased IGF-1 compared to intervention duration <12 weeks (WMD: −3 ng/ml). In the epidemiological cohort study, participants under 60 years of age with a higher dietary vitamin D intake had significantly higher IGF-1 levels when compared to those with lower dietary vitamin D intake in second categories. Conclusion The main results indicate a non-significant increase in IGF-1 following vitamin D supplementation. Additionally, vitamin D dosages of <1000 IU/day and intervention durations of <12 weeks significantly raised IGF-1 levels.

  • The role of transposable elements activity in aging and their possible involvement in laminopathic diseases
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-11-28
    Davide Andrenacci, Valeria Cavaliere, Giovanna Lattanzi

    Eukaryotic genomes contain a large number of transposable elements, part of which are still active and able to transpose in the host genome. Mobile element activation is repressed to avoid deleterious effects, such as gene mutation or chromosome rearrangements. Control of transposable elements includes a variety of mechanisms comprising silencing pathways, which are based on the production of small non-coding RNAs. Silencing can occur either through transposable element RNA degradation or through the targeting of DNA sequences by heterochromatin formation and consequent transcriptional inhibition. Since the important role of the heterochromatin silencing, the gradual loss of heterochromatin marks in constitutive heterochromatin regions during the aging process promotes derepression of transposable elements, which is considered a cause of the progressive increase in genomic instability and of the activation of inflammatory responses. This review provides an overview of the effects of heterochromatin loss on the activity of transposable elements during the aging process and the possible impact on genome function. In this context, we discuss the possible role of the nuclear lamina, a major player in heterochromatin dynamics, in the regulation of transposable element activity and potential implications in laminopathic diseases.

  • Dopamine D3 receptor: a neglected participant in Parkinson Disease pathogenesis and treatment?
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-11-22
    Pengfei Yang, Joel S. Perlmutter, Tammie L.S. Benzinger, John C. Morris, Jinbin Xu

    Parkinson disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms which relentlessly and progressively lead to substantial disability and economic burden. Pathologically, these symptoms follow the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) associated with abnormal α-synuclein (α-Syn) deposition as cytoplasmic inclusions called Lewy bodies in pigmented brainstem nuclei, and in dystrophic neurons in striatal and cortical regions (Lewy neurites). Pharmacotherapy for PD focuses on improving quality of life and primarily targets dopaminergic pathways. Dopamine acts through two families of receptors, dopamine D1-like and dopamine D2-like; dopamine D3 receptors (D3R) belong to dopamine D2 receptor (D2R) family. Although D3R’s precise role in the pathophysiology and treatment of PD has not been determined, we present evidence suggesting an important role for D3R in the early development and occurrence of PD. Agonist activation of D3R increases dopamine concentration, decreases α-Syn accumulation, enhances secretion of brain derived neurotrophic factors (BDNF), ameliorates neuroinflammation, alleviates oxidative stress, promotes neurogenesis in the nigrostriatal pathway, interacts with D1R to reduce PD associated motor symptoms and ameliorates side effects of levodopa (L-DOPA) treatment. Furthermore, D3R mutations can predict PD age of onset and prognosis of PD treatment. The role of D3R in PD merits further research. This review elucidates the potential role of D3R in PD pathogenesis and therapy.

  • 更新日期:2019-11-18
  • The yin and yang faces of the mitochondrial deacetylase sirtuin 3 in age-related disorders
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-11-15
    Pedro Gomes, Sofia D. Viana, Sara Nunes, Anabela P. Rolo, Carlos M. Palmeira, Flávio Reis

    Aging, the most important risk factor for many of the chronic diseases affecting Western society, is associated with a decline in mitochondrial function and dynamics. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase that has emerged as a key regulator of fundamental processes which are frequently dysregulated in aging and related disorders. This review highlights recent advances and controversies regarding the roles of SIRT3 in metabolic, cardiovascular and neurodegenerative diseases, as well as the use of SIRT3 modulators as a therapeutic strategy against those disorders. Although most studies point to a protective role upon SIRT3 activation, there are conflicting findings that need a better elucidation. The discovery of novel SIRT3 modulators with higher selectivity together with the assessment of the relative importance of different SIRT3 enzymatic activities and the relevance of crosstalk between distinct sirtuin isoforms will be pivotal to validate SIRT3 as a useful drug target for the prevention and treatment of age-related diseases.

  • Premature cell senescence in human skin: dual face in chronic acquired pigmentary disorders
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-11-14
    Barbara Bellei, Mauro Picardo

    Although senescence was originally described as an in vitro acquired cellular characteristic, it was recently recognized that senescence is physiologically and pathologically involved in aging and age-related diseases in vivo. The definition of cellular senescence has expanded to include the growth arrest caused by various cellular stresses, including DNA damage, inadequate mitochondria function, activated oncogene or tumor suppressor genes and oxidative stress. While senescence in normal aging involves various tissues over time and contributes to a decline in tissue function even with healthy aging, disease-induced premature senescence may be restricted to one or a few organs triggering a prolonged and more intense rate of accumulation of senescent cells than in normal aging. Organ-specific high senescence rate could lead to chronic diseases, especially in post-mitotic rich tissue. Recently, two opposite acquired pathological conditions related to skin pigmentation were described to be associated with premature senescence: vitiligo and melasma. In both cases, it was demonstrated that pathological dysfunctions are not restricted to melanocytes, the cell type responsible for melanin production and transport to surrounding keratinocytes. Similar to physiological melanogenesis, dermal and epidermal cells contribute directly and indirectly to deregulate skin pigmentation as a result of complex intercellular communication. Thus, despite senescence usually being reported as a uniform phenotype sharing the expression of characteristic markers, skin senescence involving mainly the dermal compartment and its paracrine function could be associated with the disappearance of melanocytes in vitiligo lesions and with the exacerbated activity of melanocytes in the hyperpigmentation spots of melasma. This suggests that the difference may arise in melanocyte intrinsic differences and/or in highly defined microenvironment peculiarities poorly explored at the current state of the art. A similar dualistic phenotype has been attributed to intratumoral stromal cells as cancer-associated fibroblasts presenting a senescent-like phenotype which influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. Here, we present a framework dissecting senescent-related molecular alterations shared by vitiligo and melasma patients and we also discuss disease-specific differences representing new challenges for treatment.

  • Ageing, Age-related Diseases and Oxidative Stress: What to Do Next?
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-11-13
    Jiao Luo, Kevin Mills, Saskia le Cessie, Raymond Noordam, Diana van Heemst

    Among other mechanisms, oxidative stress has been postulated to play an important role in the rate of ageing. Oxidative damage contributes to the hallmarks of ageing and essential components in pathological pathways which are thought to drive multiple age-related diseases. Nonetheless, results from studies testing the hypothesis of oxidative stress in ageing and diseases showed controversial results. While observational studies mainly found detrimental effects of high oxidative stress levels on disease status, randomized clinical trials examining the effect of antioxidant supplementation on disease status generally showed null effects. However, re-evaluations of these counterinitiative observations are required considering the lack of reliability and specificity of traditionally used biomarkers for measuring oxidative stress. To facilitate these re-evaluations, this review summarizes the basic knowledge of oxidative stress and the present findings regarding oxidative damage and ageing and age-related diseases. Meanwhile, two approaches are highlighted, namely proper participants selection, together with the development of reliable biomarkers. We propose that oxidized vitamin E metabolites may be used to accurately monitor individual functional antioxidant level, which might serve as promising key solutions for future elucidating the impact of oxidative stress on ageing and age-related diseases.

  • Anti-ageing gene therapy: Not so far away?
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-11-05
    Alexander Vaiserman, Elena De Falco, Alexander Koliada, Olga Maslova, Carmela Rita Balistreri

    Improving healthspan is the main objective of anti-ageing research. Currently, innovative gene therapy-based approaches seem to be among the most promising for preventing and treating chronic polygenic pathologies, including age-related ones. The gene-based therapy allows to modulate the genome architecture using both direct (e.g., by gene editing) and indirect (e.g., by viral or non-viral vectors) approaches. Nevertheless, considering the extraordinary complexity of processes involved in ageing and ageing-related diseases, the effectiveness of these therapeutic options is often unsatisfactory and limited by their side-effects. Thus, clinical implementation of such applications is certainly a long-time process that will require many translation phases for addressing challenges. However, after overcoming these issues, their implementation in clinical practice may obviously provide new possibilities in anti-ageing medicine. Here, we review and discuss recent advances in this rapidly developing research field.

  • Emerging Role of Stem cell-derived Extravesicular MicroRNAs in Age-associated Human Diseases and in Different Therapies of Longevity
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-11-05
    Mujib Ullah, Nathan Norton Ng, Waldo Concepcion, Avnesh S Thakor

    Organismal aging involves the progressive decline in organ function and increased susceptibility to age-associated diseases. This has been associated with the aging of stem cell populations within the body that decreases the capacity of stem cells to self-renew, differentiate, and regenerate damaged tissues and organs. This review aims to explore how aging is associated with the dysregulation of stem cell-derived extracellular vesicles (SCEVs) and their corresponding miRNA cargo (SCEV-miRNAs), which are short non-coding RNAs involved in post-transcriptional regulation of target genes. Recent evidence has suggested that in aging stem cells, SCEV-miRNAs may play a vital role regulating various processes that contribute to aging: cellular senescence, stem cell exhaustion, telomere length, and circadian rhythm. Hence, further clarifying the age-dependent molecular mechanisms through which SCEV-miRNAs exert their downstream effects may inform a greater understanding of the biology of aging, elucidate their role in stem cell function, and identify important targets for future regenerative therapies. Additionally, current studies evaluating therapeutic role of SCEVs and SCEV-miRNAs in treating several age-associated diseases are also discussed.

  • Non-pharmacological therapeutic strategy options for patients with dementia based on cognitive function--A Bayesian network meta-analysis of randomized controlled trials
    Ageing Res. Rev. (IF 10.390) Pub Date : 2019-10-31
    Jing-hong Liang, Lu Lin, Ying-quan Wang, Rui-xia Jia, Xin-yuan Qu, Jing Li, Jia-yu Li, Sheng Qian, Yu-xi Qian, Shan Wang, Zhen Gao, Xing-xue Cheng, Yong Xu

    Dementia represents one of the most common neurodegenerative disorders in older adults. However, it is still unclear whether non-pharmacological therapies (NPTs) are effective or not and which treatment should be preferred. We applied a series of search strategies to identify eligible randomized controlled trials on 1st October, 2018, investigating the effects of NPTs of dementia in the older persons. Pairwise and network meta-analyses were sequentially performed. A total of 31 trials were included, which enrolled 1895 participants and 7 NPTs. Compared with control group, all the NPTs included were statistically beneficial to cognitive function, and our study indicated Comprehensive Therapy(CT) [the surface under the cumulative ranking curve(SUCRA=92.42%)] might be the best choice for dementia patients. Our study suggests CT might be the optimal NPT for improving the cognitive function of dementia patients. However, the above conclusions need to be further analyzed.

  • Non-apolipoprotein E and apolipoprotein E genetics of sporadic Alzheimer's disease.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2009-06-06
    Davide Seripa,Francesco Panza,Marilisa Franceschi,Grazia D'Onofrio,Vincenzo Solfrizzi,Bruno Dallapiccola,Alberto Pilotto

    The genetic epidemiology of sporadic Alzheimer's disease (SAD) remains a very active area of research,making it one of the most prolifically published areas in medicine and biology. Numerous putative candidate genes have been proposed. However, with the exception of apolipoprotein E (APOE), the only confirmed genetic risk factor for SAD, all the other data appear to be not consistent. Nevertheless, the genetic risk for SAD attributable to the APOE gene in the general population is 20-0%, providing a strong evidence for the existence of additional genetic risk factors. The first part of the present article was dedicated to non-APOE genetics of SAD, reviewing chromosomes-by-chromosomes the available data concerning the major candidate genes. The second part of this article focused on some recently discovered aspects of the APOE polymorphism and their implications for SAD. An attempt to identify the future directions for non-APOE genetic research in SAD was also discussed.

  • Biological changes associated with healthy versus pathological aging: a symposium review.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2009-03-12
    M N Rajah,S Bastianetto,K Bromley-Brits,R Cools,M D'Esposito,C L Grady,J Poirier,R Quirion,N Raz,E Rogaeva,W Song,J Pruessner

    The Douglas Mental Health University Institute, in collaboration with the McGill Centre for Studies in Aging, organized a 2-day symposium entitled "Biological Changes Associated with Healthy Versus Pathological Aging" that was held in 13 and 14 December 2007 on the Douglas campus. The symposium involved presentations on current trends in aging and dementia research across several sub-disciplines: genetics, neurochemistry, structural and functional neuroimaging and clinical treatment and rehabilitation. The goal of this symposium was to provide a forum for knowledge-transfer between scientists and clinicians with different specializations in order to promote cross-fertilization of research ideas that would lead to future collaborative neuroscience research in aging and dementia. In this review article, we summarize the presentations made by the 13 international scientists at the symposium and highlight: (i) past research, and future research trends in neuroscience of aging and dementia and (ii) links across levels of analysis that can lead to fruitful transdisciplinary research programs that will advance knowledge about the neurobiological changes associated with healthy aging and dementia.

  • Heat shock proteins as gatekeepers of proteolytic pathways-Implications for age-related macular degeneration (AMD).
    Ageing Res. Rev. (IF 10.390) Pub Date : 2009-03-12
    Kai Kaarniranta,Antero Salminen,Eeva-Liisa Eskelinen,Jürgen Kopitz

    Age-related macular degeneration (AMD) is the major diagnosis for severe and irreversible central loss of vision in elderly people in the developed countries. The loss of vision involves primarily a progressive degeneration and cell death of postmitotic retinal pigment epithelial cells (RPE), which secondarily evokes adverse effects on photoreceptor cells. The RPE cells are exposed to chronic oxidative stress from three sources: their high levels of oxygen consumption, their exposure to the high levels of lipid peroxidation derived from the photoreceptor outer segments and their exposure to constant light stimuli. Cells increase the expression of heat shock proteins (HSPs) in order to normalize their growth conditions in response to various environmental stress factors, e.g. oxidative stress. The HSPs function as molecular chaperones by preventing the accumulation of cellular cytotoxic protein aggregates and assisting in correct folding of both nascent and misfolded proteins. Increased HSPs levels are observed in the retina of AMD patients, evidence of stressed tissue. A hallmark of RPE cell aging is lysosomal lipofuscin accumulation reflecting a weakened capacity to degrade proteins in lysosomes. The presence of lipofuscin increases the misfolding of intracellular proteins, which evokes additional stress in the RPE cells. If the capacity of HSPs to repair protein damages is overwhelmed, then the proteins are mainly cleared in proteasomes or in lysosomes. In this review, we discuss the role of heat shock proteins, proteasomes, and lysosomes and autophagic processes in RPE cell proteolysis and how these might be involved in development of AMD. In addition to classical lysosomal proteolysis, we focus on the increasing evidence that, HSPs, proteasomes and autophagy regulate protein turnover in the RPE cells and thus have important roles in AMD disease.

  • Viewpoint: dried plum, an emerging functional food that may effectively improve bone health.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2009-03-12
    Shirin Hooshmand,Bahram H Arjmandi

    Osteoporosis is a debilitating disorder that affects both female and male, albeit to a greater extent in women than men. As the demographic shift to a more aged population continues, a growing number of men and women will be afflicted with osteoporosis and a search for potential non-pharmacological alternative therapies for osteoporosis is of prime interest. Aside from existing drug therapies, certain lifestyle and nutritional factors are known to reduce the risk of osteoporosis. Among nutritional factors, recent observations suggest that dried plum, or prunes (Prunus domestica L.) is the most effective fruit in both preventing and reversing bone loss. Animal studies and a 3-month clinical trial conducted in our laboratories have shown that dried plum has positive effects on bone indices. The animal data indicate that dried plum not only protects against but more importantly reverses bone loss in two separate models of osteopenia. Our initial animal study indicated that dried plum prevented the ovariectomy-induced reduction in bone mineral density (BMD) of the femur and lumbar vertebra. In another study, to mimic established osteoporosis, rats were ovariectomized and allowed to lose bone before the initiation of treatment. Dried plum as low as 5% (w/w) restored BMD to the level of intact rats. More importantly, dried plum reversed the loss of trabecular architectural properties such as trabecular number and connectivity density, and trabecular separation. We have also shown the effectiveness of dried plum in reversal of bone loss due to skeletal unloading. Analysis of BMD and trabecular bone structure by microcomputed tomography (microCT) revealed that dried plum enhanced bone recovery during reambulation following skeletal unloading and had comparable effects to parathyroid hormone. In addition to the animal studies, our 3-month clinical trial indicated that the consumption of dried plum daily by postmenopausal women significantly increased serum markers of bone formation, total alkaline phosphatase, bone-specific alkaline phosphatase and insulin-like growth factor-I by 12, 6, and 17%, respectively. This review summarizes the findings of studies published to date which examine the beneficial effects of dried plum on bone in both female and male animal models of osteoporosis as well as the only published clinical study.

  • Calcium-dependent and aspartyl proteases in neurodegeneration and ageing in C. elegans.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-10-03
    Chrysanthi Samara,Nektarios Tavernarakis

    Proteolytic mechanisms have been implicated in the process of ageing, and in many neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, which are most prevalent in old age. Simple model organisms such as the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster, which offer the prowess of sophisticated genetic approaches, have contributed to our understanding of ageing and neurodegeneration. Intensive research in these systems has resulted in detailed models of the ageing process, and also of several neurodegenerative diseases, which recapitulate same aspects of the human pathologies. Inappropriate cell death is a major component of these and other devastating conditions such as stroke. The dissection of the molecular mechanisms underlying the process of cell degeneration in ageing is of utmost importance. Evidence from investigations in C. elegans implicates deregulated proteolysis as one major determinant of cellular destruction in neurodegeneration and ageing, and suggests that the process depends critically on the activation of calcium-dependent, calpain proteases and lysosomal aspartyl proteases. Apart from shedding light on important but inadequately understood facets of such phenomena, these discoveries hold promise for developing novel, effective intervention strategies aiming to ameliorate or even counter inappropriate cell death.

  • Monitoring the ubiquitin/proteasome system in conformational diseases.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-10-03
    Kristina Lindsten,Nico P Dantuma

    Controlled proteolysis of regulatory or aberrant proteins by the ubiquitin/proteasome system is indispensable for cell viability. Conformational diseases such as Alzheimer's, Parkinson's and Huntington's disease are characterised by the accumulation of misfolded or aggregation-prone proteins. Since these proteins are typical substrates of the ubiquitin/proteasome system, it is not surprising that various models propose impairment of this system as a contributing factor to the pathology of conformational disorders. The complex nature of the ubiquitin/proteasome system and its universal role in cell physiology however turns evaluation of these attractive hypotheses into a major challenge. Several reporter substrates for the ubiquitin/proteasome system have recently been developed to facilitate functional studies of the system in living cells. In this review, we will discuss these new tools as well as the proteins associated with conformational disease that have been studied with these reporters.

  • Immunoproteasomes and immunosenescence.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-10-03
    Michele Mishto,Aurelia Santoro,Elena Bellavista,Massimiliano Bonafé,Daniela Monti,Claudio Franceschi

    Aging is a complex process which is accompanied with the decline and the reshaping of different functions of the body. In particular the immune system is characterized, during ageing (immunosenescence) by a remodeling of innate immunity (well preserved, up-regulated) and clonotypical immunity (severely altered) and by the occurrence of a chronic inflammatory process (inflammaging) which are, at least in part, genetically controlled. In this scenario, it can be anticipated that a crucial role is played by age-related structural and functional alterations and modifications of proteasomes and immunoproteasomes, the last being a key component of antigen processing and MHC class I antigen presentation. A variety of experimental data are available, suggesting that proteasomes are affected by age, and that in centenarians they are relatively preserved. On the contrary, few data are available on immunoproteasomes, likely as a consequence of the poverty of suitable cellular models. Lymphoblastoid cell lines from EBV immortalized B cells from old donors is envisaged as a possible model for the study of immunoproteasomes in humans and their changes with age. Thus, basic questions such as those related to possible consequences, for immune responses in infectious diseases and cancer, of age-related alterations of antigen processing and presenting, change with age of self-antigen repertoire, and the genetic basis of immunoproteasome activity and its change with age, remain largely unanswered.

  • The calpains in aging and aging-related diseases.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-10-03
    Ralph A Nixon

    Calpains are a family of calcium-dependent cysteine proteases under complex cellular regulation. By making selective limited proteolytic cleavages, they modulate the activity of enzymes, including key signaling molecules, and induce specific cytoskeletal rearrangements, accounting for their roles in cell motility, signal transduction, vesicular trafficking and structural stabilization. Calpain activation has been implicated in various aging phenomena and diseases of late life, including cataract formation, erythrocyte senescence, diabetes mellitus type 2, hypertension, arthritis, and neurodegenerative disorders. The early and pervasive involvement of calpains in Alzheimer's disease potentially influences the development of beta-amyloid and tau disturbances and their consequences for neurodegeneration and neuronal cell loss.

  • Aging, lipofuscin formation, and free radical-mediated inhibition of cellular proteolytic systems.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-10-03
    Pamela A Szweda,Melissa Camouse,Kathleen C Lundberg,Terry D Oberley,Luke I Szweda

    Alterations in a wide array of physiological functions are a normal consequence of aging. Importantly, aged individuals exhibit an enhanced susceptibility to various degenerative diseases and appear less able than their young and adult counterparts to withstand (patho)physiological stress. Elucidation of mechanisms at play in the aging process would benefit the development of effective strategies for enhancing the quality of life for the elderly. It is likely that decrements in cellular and physiological function that occur during aging are the net result of numerous interacting factors. The current review focuses on the potential contribution(s) of free radical-mediated modifications to protein structure/function and alterations in the activities of two major proteolytic systems within cells, lysosomes and the proteasome, to the age-dependent accumulation of fluorescent intracellular granules, termed lipofuscin. Specifically, aging appears to influence the interplay between the occurrences of free radical-derived modifications to protein and the ability of cells to carry out critical proteolytic functions. We present immunochemical and ultrastructural evidence demonstrating the occurrence of a fluorescent protein cross-link derived from free radical-mediated reaction(s) within lipofuscin granules of rat cerebral cortex neurons. In addition, we provide evidence that a fluorophore-modified protein present in lipofuscin granules is the alpha subunit of F1F0-ATP synthase, a mitochondrial protein. It has previously been shown that protein(s) bearing this particular fluorescent cross-link are resistant to proteolysis and can inhibit the proteasome in a non-competitive fashion (J. Biol. Chem. 269 (1994a) 21639; FEBS Lett. 405 (1997) 21). Therefore, the current findings demonstrate that free radical-mediated modifications to protein(s) that lead to the production of inhibitor(s) of cellular proteolytic systems are present on specific protein components of lipofuscin. In addition, the mitochondrial origin of one of these proteins indicates specific intracellular pathways likely to be influenced by free radical events and participate in the formation of lipofuscin. The results of these studies are related to previous in vitro and in vivo observations in the field, thus shedding light on potential consequences to cellular function. In addition, future research directions suggested by the available evidence are discussed.

  • Neuronal and microglial cathepsins in aging and age-related diseases.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-10-03
    Hiroshi Nakanishi

    It has been long believed that cathepsins compensate for each other because of their overlapping substrate specificities. However, there is increasing evidence that disturbance of the normal balance of their enzymatic activities is the first insult in brain aging and age-related diseases. The imbalance of cathepsins may further cause age-related neuropathological changes such as accumulation of autophagic vacuoles and the formation of ceroid-lipofuscin leading to neuronal dysfunction and damage. Leakage of cathepsins due to the fragility of lysosomal membranes during aging also contributes to neurodegeneration. Furthermore, the deficiency of cathepsin D has been recently revealed to provoke a novel type of lysosomal storage disease associated with massive neurodegeneration. In these animals, microglia are activated to initiate inflammatory and cytotoxic responses by binding and phagocytosis of storage neurons. Activated microglia also release some members of cathepsins to induce neuronal death by degrading extracellular matrix proteins. Thus the microglial activation possibly through sensing neuronal storage may also be an important causative factor for neurodegeneration in lysosomal storage diseases and age-related diseases such as Alzheimer's disease. This review describes the pathological roles of neuronal and microglial cathepsins in brain aging and age-related diseases.

  • Caspases, apoptosis and aging.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-10-03
    Jian-Hua Zhang,Yingpei Zhang,Brian Herman

    Caspases are a group of cysteine dependent aspartate-specific proteases. Originally found as the homolog of Ced-3 in C. elegans, 14 caspases have now been identified in mammals to date. Caspases play important roles in both the intrinsic and extrinsic apoptotic pathways and interact with the non-caspase apoptotic pathways. A number of recent published observations have suggested a strong association between apoptosis, age-related diseases and aging. Findings from our group and others reveal a strong correlation between alterations in caspase activity and aging. In this view point, we summarize current knowledge of the connection between caspases and aging observed in a variety of model systems from cultured cells in vitro to the in vivo models of rodents and humans.

  • Role of ubiquitin-mediated proteolysis in the pathogenesis of neurodegenerative disorders.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-10-03
    Robert Layfield,James R Cavey,James Lowe

    Intraneuronal inclusions containing ubiquitylated filamentous protein aggregates are a common feature of many of the major human neurodegenerative disorders, including Alzheimer's and Parkinson's disease. Loss of function mutations in enzymes of the ubiquitin conjugation/deconjugation pathway are sufficient to cause familial forms of neurodegenerative diseases, suggesting that failure of ubiquitin-mediated proteolysis could also be central to inclusion formation in the more common sporadic cases. Examination of ubiquitin-positive inclusions at the protein level provides evidence of attempted proteasomal proteolysis, however close inspection of the temporal aspects of inclusion formation indicates that ubiquitylation is probably a late event. In this regard, the presence of ubiquitin within inclusions of idiopathic neurodegenerative disorders may indicate not a primary dysfunction of ubiquitin-mediated proteolysis, but rather a secondary, presumably protective cellular response. Within this model, other factors are likely to be initiating in inclusion biogenesis. Consistent with these proposals, non-ubiquitylated forms of the principal ubiquitylated components of Alzheimer's disease neurofibrillary tangles and Parkinson's disease Lewy bodies, tau and alpha-synuclein proteins, respectively, can be degraded by proteasomes in a pathway which does not have an absolute requirement for ubiquitylation. Inhibition of proteasome function in the pathological state, as has been reported in both Alzheimer's and Parkinson's disease, could therefore contribute both to accumulation of non-ubiquitylated forms of aggregation-prone neuronal proteins, as well as impaired clearance of ubiquitylated aggregates.

  • Methylation and acetylation in nervous system development and neurodegenerative disorders.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-05-03
    Mark P Mattson

    The cytoarchitecture and cellular signaling mechanisms of the nervous system are complex, and this complexity is reflected at the molecular level with more genes being expressed in the nervous system than in any other tissue. Gene expression and protein function in neural cells can be regulated by methylation and acetylation. Studies of mice deficient in enzymes that control DNA methylation and of animals with a dietary deficiency of folate have established critical roles for methylation in development of the nervous system. Various neuronal proteins including histones and tubulin are regulated by acetylation which appears to serve important functions in the development, stability and plasticity of neuronal networks. Some inherited neurological disorders have recently been linked to mutations in genes that regulate DNA methylation, and alterations in DNA and protein methylation and/or acetylation have been documented in studies of age-related neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Manipulations of methylation and acetylation can affect the vulnerability of neurons to degeneration and apoptosis in experimental models of neurodegenerative disorders, suggesting a contribution to altered methylation and acetylation to the disease processes. Interestingly, dietary factors that influence DNA methylation may affect the risk of neurodegenerative disorders, for example, individuals with low dietary folate intake are at increased risk of Alzheimer's and Parkinson's diseases.

  • Targeting DNA methylation in cancer.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-05-03
    Moshe Szyf

    There is overwhelming evidence that DNA methylation patterns are altered in cancer. Methylation of CG-rich islands in regulatory regions of genes marks them for transcriptional silencing. Multiple genes, which confer selective advantage upon cancer cells such as tumor suppressors, adhesion molecules, inhibitors of angiogenesis and repair enzymes are silenced. In parallel, tumor cell genomes are globally less methylated than their normal counterparts. In contrast to regional hypermethylation, this loss of methylation in cancer cells occurs in sparsely distributed CG sequences. We now understand that DNA methylation machineries might include a number of DNA methyltransferases, proteins that direct DNA methyltransferases to specific promoters, chromatin modifying enzymes as well as demethylases. There is also data to suggest that pharmacological down regulation of some members of the DNA methylation machinery could inhibit cancer in vitro, in vivo and in clinical trials. Understanding which functions of DNA methylation machinery are critical for cancer is essential for the design of inhibitors of the DNA methylation machinery as anticancer agents. This review discusses the possible role of DNA methyltranferases and demethylases in tumorigenesis and the possible pharmacological and therapeutic implications of the DNA methylation machinery.

  • Hyper nuclear acetylation (HNA) in proliferation, differentiation and apoptosis.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-05-03
    Ko-ichi Kawahara,Hisashi Kawabata,Satoko Aratani,Toshihiro Nakajima

    Coactivators such as cyclic AMP-response-element binding protein (CREB)-binding protein (CBP) and p300/CBP associated factor (P/CAF) play a crucial role in coordinating and cointegrating eukaryotic transcription. One of the recent paradigms in the eukaryotic transcription field is the finding of molecular basis of coactivator function. The well characterized coactivators such as CBP and P/CAF have been proposed to coactivate/cointegrate gene expression with many transcription activators through two mechanisms. One is complex formation with the components with basal transcriptional machinery. Another is its intrinsic and associated enzymatic activity, which transfers an acetyl-base to the epsilon ( epsilon ) portion of lysine-residues in histones and certain nuclear proteins (factor acetyltransferases; FATs), such as p53, lymphoid enhancer-binding factor (LEF), and transcription factor IIE (TFIIE), which often results in increased transcriptional activity. Recently, the status of hyper nuclear acetylation (HNA) has been thought to influence proliferation, differentiation and apoptosis. Furthermore, recent reports showed that histone acetyltransferase (HAT) activity is increased in human disease, such as cancer and atherosclerosis, and studies have shown associations between nuclear acetylation/deacetylation and cell proliferation/differentiation.

  • Aging as war between chemical and biochemical processes: protein methylation and the recognition of age-damaged proteins for repair.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-05-03
    Steven Clarke

    Deamidated, isomerized, and racemized aspartyl and asparaginyl residues represent a significant part of the spontaneous damage to proteins that results from the aging process. The accumulation of these altered residues can lead to the loss of protein function and the consequent loss of cellular function. However, almost all cells in nature contain a methyltransferase that can recognize the major damaged form of the L-isoaspartyl residue, and some of these enzymes can also recognize the racemized D-aspartyl residue. The methyl esterification reaction can initiate the conversion of these altered residues to the normal L-aspartyl form, although there is no evidence yet that the L-asparaginyl form can be regenerated. This enzyme, the protein L-isoaspartate (D-aspartate) O-methyltransferase (EC, thus functions as a protein repair enzyme. The importance of this enzyme in attenuating age-related protein damage can be seen by the phenotypes of organisms where the gene encoding has been disrupted, or where its expression has been augmented.

  • Impact of aging on DNA methylation.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-05-03
    Bruce Richardson

    The biochemistry of aging is complex, with biologically significant changes occurring in proteins, lipids and nucleic acids. One of these changes is in the methylation of DNA. DNA methylation is a mechanism modifying gene expression. The methylation of sequences in or near regulatory elements can suppress gene expression through effects on DNA binding proteins and chromatin structure. Both increases and decreases in methylation occur with aging, depending on the tissue and the gene. These changes can have pathologic consequences, contributing to the development of malignancies and autoimmunity with aging, and possibly to other disorders as well. Thus, while aging can impact on DNA methylation, the changes in DNA methylation can also impact on aging. This review summarizes current evidence for changes in the methylation status of specific genes with aging, their impact on diseases that develop with aging, and mechanisms that may contribute to the altered DNA methylation patterns. As this field is still developing, it is anticipated that new knowledge will continue to accumulate rapidly.

  • Age-related trends in gene expression in the chemosensory-nasal mucosae of senescence-accelerated mice.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-02-28
    Thomas V Getchell,Xuejun Peng,Arnold J Stromberg,Kuey-Chu Chen,C Paul Green,Nishikant K Subhedar,Dharmen S Shah,Mark P Mattson,Marilyn L Getchell

    We have utilized high-density GeneChip oligonucleotide arrays to investigate the use of the senescence-accelerated mouse (SAM) as a biogerontological resource to identify patterns of gene expression in the chemosensory-nasal mucosa. Gene profiling in chronologically young and old mice of the senescence-resistant (SAMR) and senescence-prone (SAMP) strains revealed 133 known genes that were modulated by a three-fold or greater change either in one strain or the other or in both strains during aging. We also identified known genes in our study which based on their encoded proteins were identified as aging-related genes in the aging neocortex and cerebellum of mice as reported by Lee et al. (2000) [Nat. Genet. 25 (2000) 294]. Changes in gene profiles for chemosensory-related genes including olfactory and vomeronasal receptors, sensory transduction-associated proteins, and odor and pheromone transport molecules in the young SAMR and SAMP were compared with age-matched C57BL/6J mice. An analysis of known gene expression profiles suggests that changes in the expression of immune factor genes and genes associated with cell cycle progression and cell death were particularly prominent in the old SAM strains. A preliminary cellular validation study supported the dysregulation of cell cycle-related genes in the old SAM strains. The results of our initial study indicated that the use of the SAM models of aging could provide substantive information leading to a more fundamental understanding of the aging process in the chemosensory-nasal mucosa at the genomic, molecular, and cellular levels.

  • Aging, lipid modifications and phospholipases--new concepts.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-02-28
    Michael Balazy,Santosh Nigam

  • Age-related changes in vascular adrenergic signaling: clinical and mechanistic implications.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-02-28
    William E Schutzer,Scott L Mader

    A large and growing segment of the general population are age 65 or older, and this percentage will continue to rise. Primary care of this population has, and is becoming a priority for clinicians. Hypertension, orthostatic hypotension, arterial insufficiency, and atherosclerosis are common disorders in the elderly that lead to significant morbidity and mortality. One common factor to these conditions is an age-related decline in beta-adrenergic receptor (beta-AR)-mediated function and subsequent cAMP generation. Presently, there is no single cellular factor that can explain this age-related decline, and thus the primary cause of this homeostatic imbalance is yet to be identified. However, the etiology is clearly associated with an age-related change in the ability of beta-AR receptor to respond to agonist at the cellular level. This article will review what is presently understood regarding the molecular and biochemical basis of age-impaired beta-AR receptor-mediated signaling. A fundamental understanding of why beta-AR-mediated vasorelaxation is impaired with age will provide new insights and innovative strategies for the management of the multiple clinical disorders that effect older people.

  • Microvascular plasticity in aging.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-02-28
    David R Riddle,William E Sonntag,Robin J Lichtenwalner

    Understanding the bases of aging-related cognitive decline remains a central challenge in neurobiology. Quantitative studies reveal little change in the number of neurons or synapses in most of the brain but their ongoing replacement is reduced, resulting in a significant loss of neuronal plasticity with senescence. Aging also may alter neuronal function and plasticity in ways that are not evident from anatomical studies of neurons and their connections. Since the nervous system is dependent upon a consistent blood supply, any aging-related changes in the microvasculature could affect neuronal function. Several studies suggest that, as the nervous system ages, there is a rarefaction of the microvasculature in some regions of the brain, as well as changes in the structure of the remaining vessels. These changes contribute to a decline in cerebral blood flow (CBF) that reduces metabolic support for neural signaling, particularly when levels of neuronal activity are high. In addition to direct effects on the microvasculature, aging reduces microvascular plasticity and the ability of the vessels to respond appropriately to changes in metabolic demand. This loss of microvascular plasticity has significance beyond metabolic support for neuronal signaling, since neurogenesis in the adult brain is regulated coordinately with capillary growth.

  • Mammalian longevity under the protection of PARP-1's multi-facets.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-02-28
    Marie-Laure Muiras

    Given the presence of continuous endogenous and exogenous sources of stress, mammalian species have evolved complex systems of protection, detoxification and repair, in order to maintain homeostasis during development and until reproductive maturity for the sake of the species. However, since no system is perfect, complete prevention of damage is unlikely to occur. Accumulation of macromolecular damage, including damage to DNA and genomic instability, is considered a driving force for the ageing process and age-related diseases. One of the immediate eukaryotic cellular responses to DNA breakage is the covalent post-translational modification of nuclear proteins with poly(ADP-ribose) from NAD+ as precursor, mostly catalysed by poly(ADP-ribose) polymerase-1 (PARP-1). Poly(ADP-ribosyl)ation is involved in DNA base-excision repair (BER), DNA-damage signalling and regulation of genomic stability. In recent years, many groups have become involved in PARP field, shedding light on new partners for PARP-1, new members of the PARP family and new physiological and pathophysiological properties for the founding member of the poly(ADP-ribose) polymerase super family. The present review focuses on PARP-1 and its role in the maintenance of genome stability and in mammalian longevity.

  • The search for type 2 diabetes genes.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2003-02-28
    Anna L Gloyn

    Type 2 diabetes (T2DM) is a serious disease with severe complications. Around one in 10 people alive today suffer from type 2 diabetes or are destined to develop it before they die. Inheritance plays an important role in the cause of type 2 diabetes. A considerable amount of research is devoted to defining the genes involved in the aetiology of this widespread disease. This information is crucial if we are to improve our methods of preventing and treating diabetes. Over the last 25 years there have been considerable advances in our understanding of the genetics of diabetes. Important discoveries have been made in dissecting the genes involved in rare monogenic forms of type 2 diabetes which has become a paradigm for genetic studies of type 2 diabetes. This review focuses on the main approaches currently adopted and our current understanding of the genes involved in susceptibility to type 2 diabetes.

  • PRELP, collagen, and a theory of Hutchinson-Gilford progeria.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-11-20
    Marc Lewis

    Proline/arginine-rich end leucine-rich repeat protein (PRELP) a small leucine-rich proteoglycan (SLRP), binds type I collagen to basement membranes and type II collagen to cartilage. Evidence for lack of binding of collagen in basement membranes and cartilage of Hutchinson-Gilford progeria (HGP) cases suggests PRELP involvement in that disease. PRELP deficiency is able to account for many symptoms of HGP. Moreover, PRELP also accounts for the fact that unlike many other collagen-related diseases, HGP symptoms are not congenital. The appearance of PRELP sometime after the third month of the birth, coincides with the appearance of HGP symptoms. Hutchinson-Gilford progeria has been diagnosed in twins with a chromosomal inversion at, or very near, the site of the PRELP gene.

  • Hip fractures among the elderly: causes, consequences and control.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-11-20
    Ray Marks,John P Allegrante,C Ronald MacKenzie,Joseph M Lane

    This review examines all pertinent literature sources published in the English language between 1966 to the present concerning hip fracture epidemiology, hip fracture injury mechanisms, and hip fracture management strategies. These data reveal hip fractures have several causes, but among these, the impact of falls and muscle weakness, along with low physical activity levels seems to be the most likely explanation for the rising incidence of hip fracture injuries. Related determinants of suboptimal nutrition, drugs that increase fall risk and lower the safety threshold and comorbid conditions of the neuromuscular system may also contribute to hip fracture disability. A number of interventions may help to prevent hip fracture injuries, including, interventions that optimize bone mass and quality, interventions that help prevent falls and falls dampening interventions. Rehabilitation outcomes may be improved by comprehensive interventions, prolonged follow-up strategies and ensuring that all aging adults enjoy optimal health.

  • Garlic and aging: new insights into an old remedy.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-11-20
    Khalid Rahman

    There has been an impressive gain in individual life expectancy with parallel increases in age-related chronic diseases of the cardiovascular, brain and immune systems. These can cause loss of autonomy, dependence and high social costs for individuals and society. It is now accepted that aging and age-related diseases are in part caused by free radical reactions. The arrest of aging and stimulation of rejuvenation of the human body is also being sought. Over the last 20 years the use of herbs and natural products has gained popularity and these are being consumed backed by epidemiological evidence. One such herb is garlic, which has been used throughout the history of civilization for treating a wide variety of ailments associated with aging. The role of garlic in preventing age-related diseases has been investigated extensively over the last 10-15 years. Garlic has strong antioxidant properties and it has been suggested that garlic can prevent cardiovascular disease, inhibit platelet aggregation, thrombus formation, prevent cancer, diseases associated with cerebral aging, arthritis, cataract formation, and rejuvenate skin, improve blood circulation and energy levels. This review provides an insight in to garlic's antioxidant properties and presents evidence that it may either prevent or delay chronic diseases associated with aging.

  • Iron as the malignant spirit in successful ageing.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-11-20
    Ada S Polla,Luigi L Polla,Barbara S Polla

    Iron enhances the production of the highly reactive and toxic hydroxyl radical, thus stimulating oxidative damage. Iron has been associated with a number of oxidative injury-dependent, age-related conditions and diseases. Indeed, oxidative injury is a major factor of (accelerated) ageing. This commentary reviews part of the existing literature on iron's deleterious effects, particularly in the context of ischemia-reperfusion injury and cardiovascular, brain and muscle diseases as well as skin ageing. Furthermore, the advantages of iron chelation are presented. Indeed, iron chelation or deprivation has been shown to act as a potent anti-oxidant in a variety of animal models of human diseases, preventing oxidative stress to tissues and organs. Iron chelators favor successful ageing in general, and when applied topically, successful skin ageing. It has also been proposed that gender-related differences in iron status are responsible for the increased longevity of women as compared to men. Despite this evidence, the role of iron in ageing and the possibilities of pharmacologically targeting iron have remained essentially unexplored. Iron thus appears as the "malignant spirit" in successful ageing.

  • Adenosine triphosphate-binding cassette transporter genes in ageing and age-related diseases.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-11-20
    Thomas Efferth

    The family of adenosine triphosphate (ATP)-binding cassette (ABC) transporters is the largest gene family known. While some ABC transporters translocate single substances across membranes with high specificity, others transport a wide variety of different lipophilic compounds. They are responsible for many physiological processes and are also implicated in a number of diseases. The present review focuses on ABC transporter genes which are involved in ageing and age-related diseases. Expression of ABCB1 (MDR1, P-glycoprotein) increases with age in CD4(+) and CD8(+) T-lymphocytes indicating that P-glycoprotein may be involved in the secretion of cytokines, growth factors, and cytotoxic molecules. As T cells in aged individuals are hyporesponsive leading to a reduced immunodefence capability, a role of ABCB1 in age-related immunological processes is presumed. The ABCA1 (ABC1) gene product translocates intracellular cholesterol and phospholipids out of macrophages. Genetic aberrations in ABCA1 cause perturbations in lipoprotein metabolism and contribute to atherosclerosis. ABCA4 (ABCR) represents a retina-specific ABC transporter expressed in rod photoreceptor cells. The ABCA4 gene product translocates retinyl-derivatives. Mutations in the ABCA4 gene contribute to age-related macular degeneration. Polymorphisms in the sulfonylurea receptor gene (ABCC8, SUR1) are associated with non-insulin-dependent diabetes mellitus (NIDDM). Sulfonylureas inhibit potassium conductance and are used to treat NIDDM by stimulation of insulin secretion across ATP-sensitive potassium channels in pancreatic beta-cell membranes. Possible diagnostic and therapeutic implications of ABC transporters for age-related diseases are discussed.

  • Can teatime increase one's lifetime?
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-11-20
    Kei Nakachi,Hidetaka Eguchi,Kazue Imai

    Lifestyle-related diseases, including cancer and cardiovascular disease, are also characterized as aging-related diseases, where aging may be the most potent causal factor. In light of this, prevention of lifestyle-related diseases will depend on slowing the aging process and avoiding the clinical appearance of the diseases. Green tea is now accepted as a cancer preventive on the basis of numerous in vitro, in vivo and epidemiological studies. In addition, green tea has also been reported to reduce the risk of cardiovascular disease. We found an apparent delay of cancer onset/death and all cause deaths associated with increased consumption of green tea, specifically in ages before 79 in a prospective cohort study of a Japanese population with 13-year follow-up data. This is consistent with analyses of age-specific cancer death rate and cumulative survival, indicating a significant slowing of the increase in cancer death and all cause death with aging. These results indicate that daily consumption of green tea in sufficient amounts will help to prolong life by avoiding pre-mature death, particularly death caused by cancer.

  • Why do trees live so long?
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-10-05
    Robert M Lanner

    A long life multiplies a tree's reproductive opportunities, thus increasing its fitness. Therefore, characteristics that prolong life should be naturally selected. Longevity in trees is achieved by means of numerous behaviors and characteristics, some of which are unique to trees. These include the retention of stem-cell-like meristematic cells after each growth cycle; the ability to replace non-vigorous, lost, or damaged organs, both above and below ground, in the presence or absence of trauma; a sectored vascular system that allows part of a tree to survive where a whole one cannot; formation of clones; a mechanical structure that can react to forces tending to de-optimize it; a hormonal control system that coordinates the above behaviors; and synthesis of defensive compounds.

  • Transcriptional regulation of cellular ageing by the CCAAT box-binding factor CBF/NF-Y.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-10-05
    Koozi Matuoka,Kuang Yu Chen

    Cellular ageing is a systematic process affecting the entirety of cell structure and function. Since changes in gene expression are extensive and global during ageing, involvement of general transcription regulators in the phenomenon is likely. Here, we focus on NF-Y, the major CCAAT box-binding factor, which exerts differential regulation on a wide variety of genes through its interaction with the CCAAT box present in as many as 25% of the eukaryotic genes. When a cell ages, senescing signals arise, typically through DNA damage due to oxidative stress or telomere shortening, and are transduced to proteins such as p53, retinoblastoma protein, and phosphatidylinositol 3-kinase. Among them, activated p53 family proteins suppress the function of NF-Y and thereby downregulate a set of cell cycle-related genes, including E2F1, which further leads to downregulation of E2F-regulated genes and cell cycle arrest. The p53 family also induces other ageing phenotypes such as morphological alterations and senescence-associated beta-galactosidase (SA-gal) presumably by upregulation of some genes through NF-Y suppression. In fact, the activities of NF-Y and E2F decrease during ageing and a dominant negative NF-YA induces SA-gal. Based on these observations, NF-Y appears to play an important role in the process of cellular ageing.

  • Klotho: a fundamental regulator of aging.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-10-05
    Yo-ichi Nabeshima

    To escape aging and aging-related disorders has been one of mankind's biggest dreams from the beginning of history. However, our knowledge regarding the molecular mechanisms of aging has been limited. We recently developed a unique short lifespan mouse strain in which a single gene mutation caused multiple aging-related disorders and identified the responsible gene as klotho. The most characteristic phenotypes seem to be caused by abnormalities in calcium metabolism. Furthermore, the klotho gene is expressed principally in the important tissues for calcium homeostasis such as distal tubule cells of the kidney, choroid plexus in the brain, and the main cells of the parathyroid gland. Klotho plays a critical role for the regulation of calcium and phosphorus homeostasis by negatively regulating the synthesis of active Vitamin D. The deficiency of the klotho gene results in degradation of cells by the activation of calcium-dependent proteolysis in kidney, lung and heart. Importantly, the increased activation of calcium-dependent proteolysis occurs in the tissues of old mice together with the down regulation of klotho gene expression. What is Klotho protein required for and how does it act? In this review, I will discuss our working hypotheses on the biological roles and molecular functions of Klotho protein.

  • Circadian and age-related modulation of thermoreception and temperature regulation: mechanisms and functional implications.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-09-05
    Eus J W Van Someren,Roy J E M Raymann,Erik J A Scherder,Hein A M Daanen,Dick F Swaab

    At older ages, the circadian rhythm of body temperature shows a decreased amplitude, an advanced phase, and decreased stability. The present review evaluates to what extent these changes may result from age-related deficiencies at several levels of the thermoregulatory system, including thermoreception, thermogenesis and conservation, heat loss, and central regulation. Whereas some changes are related to the aging process per se, others appear to be secondary to other factors, for which the risk increases with aging, notably a decreased level of fitness and physical activity. Moreover, functional implications of the body temperature rhythm are discussed. For example, the relation between circadian rhythm and thermoregulation has hardly been investigated, while evidence showed that sleep quality is dependent on both aspects. It is proposed that the circadian rhythm in temperature in homeotherms should not be regarded as a leftover of ectothermy in early evolution, but appears to be of functional significance for physiology from the level of molecules to cognition. A new view on the functional significance of the circadian rhythm in peripheral vasodilation and the consequent out-of-phase rhythms in skin and core temperature is presented. It is unlikely that the strong, daily occurring, peripheral vasodilation primarily represents heat loss in response to a lowering of set point, since behavioral measures are simultaneously taken in order to prevent heat loss. Several indications rather point towards a supportive role in immunological host defense mechanisms. Given the functional significance of the temperature rhythm, research should focus on the feasibility and effectiveness of methods that can in principle be applied in order to enhance the weakened circadian temperature rhythm in the elderly.

  • UV-light-induced signal cascades and skin aging.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-09-05
    Laure Rittié,Gary J Fisher

    UV irradiation acts as a broad activator of cell surface growth factor and cytokine receptors. This ligand-independent receptor activation induces multiple downstream signaling pathways that regulate expression of multiple genes. These signaling pathways converge to stimulate transcription factor AP-1. Among genes whose expression is regulated by AP-1 are several matrix-metalloproteinase (MMP) family members and type I procollagen. UV-enhanced matrix degradation is accompanied with decreased collagen production mediated not only by activation of AP-1, but also by inhibition of transforming growth factor (TGF)-beta signaling. Several alterations to skin connective tissue that occur during aging are mediated by mechanisms that are similar to those that occur in response to UV irradiation. Thus, skin aging is associated with increased AP-1 activity, increased MMP expression, impaired TGF-beta signaling, enhanced collagen degradation, and decreased collagen synthesis. Knowledge gained from examining molecular responses of human skin to UV irradiation provides not only a framework for understanding mechanisms involved in skin aging, but also may help in development of new clinical strategies to impede chronological and UV-induced skin aging.

  • Translational fidelity, protein oxidation, and senescence: lessons from bacteria.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-09-05
    Thomas Nyström

    Senescence of growth-arrested Escherichia coli cells is like mandatory aging in higher eukaryotes, accompanied by increased oxidative modifications of macromolecules. Similar to aged flies, this senescence-related oxidation targets enzymes of the Krebs cycle. Additional targets include the universal stress protein A, the Hsp70 chaperone DnaK, translation elongation factors, and histone-like proteins. However, during the early stages of stasis, protein oxidation is more general and affects a large number of proteins. Attempts to correlate this protein oxidation with a reduced activity of the antioxidant defense systems or an increased tendency of the respiratory apparatus to produce reactive oxygen species (ROS) have generated conflicting results. Instead, recent data indicate that oxidation of proteins may occur in the absence of an increased oxidative stress and is rather caused by an increased production of substrates available for oxidative attack. Misfolded and aberrant proteins appear to be such substrates and the production of aberrant polypeptides surge during the early stages of stasis due to a reduced translational fidelity. The data point to a novel mechanism involved in protein oxidation that has not been considered previously in aging research.

  • Longevity, mortality and body weight.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-09-05
    Thomas T Samaras,Lowell H Storms,Harold Elrick

    The purpose of this study was to analyze the relation of total body weight to longevity and mortality. The MEDLINE database was searched for data that allow analysis of the relationship between absolute body weight and longevity or mortality. Additional data were used involving US veterans and baseball players. Trend lines of age at death versus body weight are presented. Findings show absolute body size is negatively related to longevity and life expectancy and positively to mortality. Trend lines show an average age at death versus weight slope of -0.4 years/kg. We also found that gender differences in longevity may be due to differences in body size. Animal research is consistent with the findings presented. Biological mechanisms are also presented to explain why increased body mass may reduce longevity. Life expectancy has increased dramatically through improved public health measures and medical care and reduced malnutrition. However, overnourishment and increased body size have promoted an epidemic of chronic disease and reduced our potential longevity. In addition, both excess lean body mass and fat mass may promote chronic disease.

  • Messenger RNA decay during aging and development.
    Ageing Res. Rev. (IF 10.390) Pub Date : 2002-09-05
    Gary Brewer

    Gene expression is a combination of many processes, including transcription, pre-mRNA processing, nucleocytoplasmic transport of mRNA, translation, mRNA decay, and protein modification and decay. Many changes in the programs of gene expression occur during development, differentiation, and aging. These alterations are reflected at both the mRNA and protein levels. While altered gene expression at the levels of transcription and protein turnover has been appreciated for some time, mRNA decay is now emerging as an important control point and a major contributor to gene expression as well. Continuing identification of the protein factors and cofactors, and mRNA instability elements, responsible for mRNA decay are allowing us to build a comprehensive picture of the highly orchestrated processes involved in mRNA decay and its regulation. Here, I survey mRNA decay processes in eukaryotes and describe some molecular mechanisms that alter the decay rates of specific mRNAs, leading to major changes in gene expression during development and aging.

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上海纽约大学William Glover