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  • Targeting NAD+ in translational research to relieve diseases and conditions of metabolic stress and ageing
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2020-01-15
    Brian C. Gilmour; Ruben Gudmundsrud; Johannes Frank; Amund Hov; Sofie Hindkjær Lautrup; Yahyah Aman; Helge Røsjø; Charles Brenner; Mathias Ziegler; Ole-Bjørn Tysnes; Charalampos Tzoulis; Torbjørn Omland; Arne Søraas; Trygve Holmøy; Linda H. Bergersen; Jon Storm-Mathisen; Hilde Nilsen; Evandro F. Fang

    Nicotinamide adenine dinucleotide (NAD+) plays a fundamental role in life and health through the regulation of energy biogenesis, redox homeostasis, cell metabolism, and the arbitration of cell survival via linkages to apoptosis and autophagic pathways. The importance of NAD+ in ageing and healthy longevity has been revealed from laboratory animal studies and early-stage clinical testing. While basic researchers and clinicians have investigated the molecular mechanisms and translation potential of NAD+, there are still major gaps in applying laboratory science to design the most effective trials. This mini-review was based on the programme and discussions of the 3rd NO-Age Symposium held at the Akershus University Hospital, Norway on the 28th October 2019. This symposium brought together leading basic researchers on NAD+, and clinicians who are leading or are going to perform NAD+ augmentation-related clinical studies. This meeting covered talks about NAD+ synthetic pathways, subcellular homeostasis of NAD+, benefits of NAD+ augmentation from maternal milk to offspring, current clinical trials of the NAD+ precursor nicotinamide riboside (NR) on Ataxia-Telangiectasia (A-T), Parkinson’s disease (PD), post sepsis fatigue, as well as other potential NR-based clinical trials. Importantly, a consensus is emerging with respect to the design of clinical trials in order to measure meaningful parameters and ensure safety.

  • Potential of coconut oil and medium chain triglycerides in the prevention and treatment of Alzheimer’s disease
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2020-01-15
    Pratishtha Chatterjee; Malika Fernando; Binosha Fenando; Cintia B Dias; Tejal Shah; Renuka Silva; Shehan Williams; Steve Pedrini; Heidi Hillebrandt; Kathryn Goozee; Edward Barin; Hamid R Sohrabi; Manohar Garg; Stephen Cunnane; Ralph N Martins

    Alzheimer’s disease (AD) is the most common form of dementia. Currently, there is no effective medication for the prevention or treatment of AD. This has led to the search for alternative therapeutic strategies. Coconut oil(CO) has a unique fatty acid composition that is rich in medium chain fatty acids(MCFA), a major portion of which directly reaches the liver via the portal vein, thereby bypassing the lymphatic system. Given that brain glucose hypometabolism is a major early hallmark of AD, detectable well before the onset of symptoms, ketone bodies from MCFA metabolism can potentially serve as an alternative energy source to compensate for lack of glucose utilisation in the brain. Additionally, neuroprotective antioxidant properties of CO have been attributed to its polyphenolic content. This review discusses how the metabolism of CO and MCFA may aid in compensating the glucose hypometabolism observed in the AD brain. Furthermore, we present the current evidence of the neuroprotective properties of CO on cognition, amyloid-β pathogenicity, inflammation and oxidative stress. The current review addresses the influence of CO/MCFA on other chronic disorders that are risk factors for AD, and addresses existing gaps in the literature regarding the use of CO/MCFA as a potential treatment for AD.

  • Mitophagy and DNA Damage Signaling in Human Aging
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2020-01-07
    Mansi Babbar; Sambuddha Basu; Beimeng Yang; Deborah L. Croteau; Vilhelm A. Bohr

    Aging is associated with multiple human pathologies. In the past few years mitochondrial homeostasis has been well corelated with age-related disorders and longevity. Mitochondrial homeostasis involves generation, biogenesis and removal of dysfunctional mitochondria via mitophagy. Mitophagy is regulated by various mitochondrial and extra-mitochondrial factors including morphology, oxidative stress and DNA damage. For decades, DNA damage and inefficient DNA repair have been considered major determinants for age-related disorders. Although defects in DNA damage recognition and repair and mitophagy are well documented to be major factors in age-associated diseases, interactivity between these is poorly understood. Mitophagy efficiency decreases with age leading to accumulation of dysfunctional mitochondria enhancing the severity of age-related disorders including neurodegenerative diseases, inflammatory diseases, cancer, diabetes and many more. Therefore, mitophagy is being targeted for intervention in age-associated disorders. NAD+ supplementation has emerged as one intervention to target both defective DNA repair and mitophagy. In this review, we discuss the molecular signaling pathways involved in regulation of DNA damage and repair and of mitophagy, and we highlight the opportunities for clinical interventions targeting these processes to improve the quality of life during aging.

  • Aging is associated with loss of beneficial effects of estrogen on leptin responsiveness in mice fed high fat diet: Role of estrogen receptor α and cytokines
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2020-01-02
    Zeinab Farhadi; Mohammad Khaksari; Hossein Azizian; Shahriar Dabiri; Hossein Fallah; Masoumeh Nozari

    Aging causes changes in body composition and energy balance. Estrogen plays an important role in body’s metabolism. The aim of this study was to determine whether estrogen has beneficial effects on leptin responsiveness in aged mice. Young 4 months and aged 19-21 female mice fed High Fat Diet (HFD) or Standard Diet (SD) for 12 weeks and following received estrogen for 4 weeks. Responsiveness to leptin was compared by measuring energy balance parameters. Results showed that HFD caused weight gain compared to SD in young, but had no effect on aged animals. Estrogen reduced body weight, energy intake and visceral fat in young, while none of these parameters was affected in aged animals. Although there was leptin sensitivity in aged compared to ovariectomized animals, estrogen only improved the sensitivity of young to leptin. Estrogen prevented increase in TNF-α and a decrease in IL-10 in HFD young and aged animals. Response to estrogen depended on age, and estrogen increased leptin sensitivity only in young animals. Determining the exact mechanism of this action is suggested in future studies.

  • AISA can control the inflammatory facet of SASP
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2020-01-02
    Patrizia A. d’Alessio; Marie C. Béné

    Senescent cells have been suspected, because of their secretory phenotype (SASP or senescence associated secretory profile), to contribute to the extension of the chronic inflammatory condition leading to unhealthy aging processes. AISA (Anti-Inflammatory Senescence Actives). AISA monoterpens have been characterized as possessing anti-inflammatory capacities in young cells submitted to pro-inflammatory cytokine stimulation. They have also been demonstrated to have the ability to act on senescent cells, reversing their characteristic pro-inflammatory phenotype. This is due to the fact that AISA act on the cytoskeleton scaffold of cells where actin polymerization induces the expression of adhesion molecules, fueling the infernal inflammatory loop. In comparison to other isoprenoid actives in degenerative diseases, the AISA monoterpene adds a mood-modulating capacity inducing the vagus nerve tone and its potent anti-inflammatory role.

  • Centenarians: An excellent example of resilience for successful ageing
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-12-31
    C. Borras; M. Ingles; C. Mas-Bargues; M. Dromant; J. Sanz-Ros; A. Román-Domínguez; L. Mallench-Gimeno; J. Gambini; J. Viña

    Centenarians are remarkable not only because of their prolonged life, but also because they compress morbidity until the very last moments of their lives, thus being proposed as a model of successful, extraordinary ageing. From the medical viewpoint, centenarians do not escape the physiological decline or the age-related diseases or syndromes (i.e. frailty), but the rate of such processes is slow enough to be counterbalanced by their increased intrinsic capacity to respond to minor stresses of daily life (i.e. resilience). These new concepts are reviewed in this paper. Allostatic stresses lead to a chronic low-grade inflammation that has led to the proposal of the “inflammaging” theory of ageing and frailty. The biology of centenarians, described in this review, provides us with clues for intervention to promote healthy ageing in the general population. One of the major reasons for this healthy ageing has to do with the genetic signature that is specific for centenarians and certainly different from octogenarians who do not enjoy the extraordinary qualities of centenarians.

  • Potassium channels in the neuronal homeostasis and neurodegenerative pathways underlying Alzheimer’s Disease: an update
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-12-17
    Chiara Villa; Huriye Suphesiz; Romina Combi; Enes Akyuz

    With more than 80 subunits, potassium (K+) channels represent a group of ion channels showing high degree of diversity and ubiquity. They play important role in the control of membrane depolarization and cell excitability in several tissues, including the brain. Controlling the intracellular and extracellular K+ flow in cells, they also modulate the hormone and neurotransmitter release, apoptosis and cell proliferation. It is therefore not surprising that an improper functioning of K+ channels in neurons has been associated with pathophysiology of a wide range of neurological disorders, especially Alzheimer’s disease (AD). This review aims to give a comprehensive overview of the basic properties and pathophysiological functions of the main classes of K+ channels in the context of disease processes, also discussing the progress, challenges and opportunities to develop drugs targeting these channels as potential pharmacological approach for AD treatment.

  • Frailty index and phenotype frailty score: sex- and age-related differences in 5XFAD transgenic mouse model of Alzheimer’s disease
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-12-16
    Smilja Todorovic; Natasa Loncarevic-Vasiljkovic; Milena Jovic; Srdjan Sokanovic; Selma Kanazir; Aleksandra Mladenovic Djordjevic

    Alzheimer’s disease patients (AD), as well as AD transgenic mice, are characterized by increased frailty. Furthermore, the assessment of frailty status represents a feasible approach for detecting individuals prone to develop more severe form of AD and for measuring the outcome of existing and putative AD therapeutics. The 5xFAD mouse is one of the widely used transgenic animal models of AD, but frailty in this model is scantly investigated. We used two validated mouse frailty assessment tools: phenotypic frailty score (FS) and clinical frailty index (FI) to investigate age- and sex- related differences in frailty status in 5xFAD mice. These tools measure different age-related deficits and do not necessarily identify the same subpopulations as frail. We detected a significant increase in frailty with age in both sexes, although females were surprisingly less frail than males. Depending on the tools used, a notable difference in frailty status was detected, with frailty index and frailty score identifying different mice as frail. These results warrant great caution when choosing the frailty tool and point to the need for further adaptation of frailty measurements in mouse models of AD.

  • Semi-automated quantitation of mitophagy in cells and tissues
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-12-13
    Lambert Montava-Garriga; François Singh; Graeme Ball; Ian G. Ganley

    Mitophagy is a natural phenomenon and entails the lysosomal degradation of mitochondria by the autophagy pathway. In recent years, the development of fluorescent pH-sensitive mitochondrial reporters has greatly facilitated the monitoring of mitophagy by distinguishing between cytosolic mitochondria or those delivered to acidic lysosomes. We recently published the mito-QC reporter, which consists of a mitochondrial outer membrane-localised tandem mCherry-GFP tag. This allows the quantification of mitophagy via the increase in red-only mCherry signal that arises when the GFP signal is quenched upon mitochondrial delivery to lysosomes. Here we develop a macro for FIJI, the mito-QC Counter, and describe its use to allow reliable and consistent semi-automated quantification of mitophagy. In this methods article we describe step-by-step how to detect and quantify mitophagy and show that mitophagy levels can be reliably calculated in different cell lines and under distinct stimuli. Finally, we show that the mito-QC Counter can be used to quantify mitophagy in tissues of mito-QC transgenic mice. We demonstrate that mitophagy levels in skeletal muscle correlates with glycolytic activity. Our present data show that the mito-QC Counter macro for FIJI enables the robust quantification of mitophagy both in vitro and in vivo.

  • The NAD+-mitophagy axis in healthy longevity and in artificial intelligence-based clinical applications
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-12-05
    Yahyah Aman, Johannes Frank, Sofie Hindkjær Lautrup, Adrian Matysek, Zhangming Niu, Guang Yang, Liu Shi, Linda H. Bergersen, Jon Storm-Mathisen, Lene J. Rasmussen, Vilhelm A. Bohr, Hilde Nilsen, Evandro F. Fang

    Nicotinamide adenine dinucleotide (NAD+) is an important natural molecule involved in fundamental biological processes, including the TCA cycle, OXPHOS, β-oxidation, and is a co-factor for proteins promoting healthy longevity. NAD+ depletion is associated with the hallmarks of ageing and may contribute to a wide range of age-related diseases including metabolic disorders, cancer, and neurodegenerative diseases. One of the central pathways by which NAD+ promotes healthy ageing is through regulation of mitochondrial homeostasis via mitochondrial biogenesis and the clearance of damaged mitochondria via mitophagy. Here, we highlight the contribution of the NAD+-mitophagy axis to ageing and age-related diseases, and evaluate how boosting NAD+ levels may emerge as a promising therapeutic strategy to counter ageing as well as neurodegenerative diseases including Alzheimer’s disease. The potential use of artificial intelligence to understand the roles and molecular mechanisms of the NAD+-mitophagy axis in ageing is discussed, including possible applications in drug target identification and validation, compound screening and lead compound discovery, biomarker development, as well as efficacy and safety assessment. Advances in our understanding of the molecular and cellular roles of NAD+ in mitophagy will lead to novel approaches for facilitating healthy mitochondrial homoeostasis that may serve as a promising therapeutic strategy to counter ageing-associated pathologies and/or accelerated ageing.

  • Revisiting the effects of menopause on the skin: functional changes, clinical studies, in vitro models and therapeutic alternatives
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-12-04
    Thamile Luciane Reus, Carla Abdo Brohem, Desiree Cigaran Schuck, Marcio Lorencini

    Menopause is a stage in a woman’s life characterized by twelve months of amenorrhoea. This transition happens due to changes in ovarian follicular activity, leading to endocrine, biological and clinical modifications. The main hormones related to these changes and symptoms are oestradiol, LH, FSH, AMH, Inhibin B and GnRH. It is important to point out that the skin is very affected by all these hormone changes, leading to a decrease in collagen content, water content, elasticity, thickness and impacting on all skin layers quality. Aiming to help women go through this period of their lifetimes with a better quality of life, cosmetic and pharmaceutical industries have studied formulations to improve skin quality. In order to study the safety and efficacy of these products, in vitro methods have been developed in order to mimic menopause and aged skin. In addition to that, many clinical methodologies for skin features assessment have also been improved and applied to evaluate the efficacy of treatments or compounds for menopause. Studying and improving skin models and skin evaluation methodologies may help in the identification of therapeutic targets, treatments, drugs and cosmetics along with new insights for future research in the dermatology field.

  • Multi-omics approaches to human biological age estimation
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-11-28
    Ilya Solovev, Mikhail Shaposhnikov, Alexey Moskalev

    Multi-omics approach nowadays increasingly applied to molecular research in many fields of life sciences. Biogerontology is not an exception; multi-omics gives possibility to evaluate complex biomarkers (or panels) which consist of quantitative as well as phenotypic ones. It is especially important because of weak understanding of the nature of aging. The difficulty now is distinguishing between causes and effects of aging. The application of the whole set of metabolome, methylome, transcriptome, proteome or metagenome data in aging biomarker design becomes the only way to create a holistic view of aging landscape without missing undiscovered mechanisms and levels of organization. We found patents, up-to-date multi-omics datasets and studies, which include bioinformatics innovations to predict biological age in humans. We hope that the review will be also useful for clinicians, because it follows majorly translational purposes.

  • Catalytic Antibody (Catabody) Platform for Age-Associated Amyloid Disease: From Heisenberg’s Uncertainty Principle to the Verge of Medical Interventions
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-11-26
    Stephanie A. Planque, Richard J. Massey, Sudhir Paul

    Quantum mechanics-based design of useful catalytic antibodies (catabodies) failed because of the uncertain structure of the dynamic catalyst-substrate complex. The Catabody Platform emerged from discovery of beneficial germline gene catabodies that hydrolyzed self-proteins by transient covalent pairing of the strong catabody nucleophile with a weak target protein electrophile. Catabodies have evolved by Darwinian natural selection for protection against misfolded self-proteins that threatened survival by causing amyloid disease. Ancient antibody scaffolds upregulate the catalytic activity of the antibody variable (V) domains. Healthy humans universally produce beneficial catabodies specific for at least 3 misfolded self-proteins, transthyretin, amyloid β peptide and tau protein. Catabody are superior to ordinary antibodies because of catalyst reuse for thousands of target destruction cycles with little or no risk of causing inflammation, a must for non-toxic removal of abundant targets such as amyloids. Library mining with electrophilic target analogs (ETAs) isolates therapy-grade catabodies (fast, specific). Ex vivo- and in vivo-verified catabodies specific for the misfolded protein are available to dissolve brain, cardiac and vertebral amyloids. Immunization with ETAs overcomes important ordinary vaccine limitations (no catabody induction, poor immunogenicity of key target epitopes). We conceive electrophilic longevity vaccines that can induce catabody synthesis for long-lasting protection against amyloid disease.

  • Increased Oxidative Stress, Inflammation, and Glutamate: Potential Preventive and Therapeutic Targets for Hearing Disorders
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-11-22
    Kadar N. Prasad, Stephen C. Bondy

    Hearing disorders constitute one of the major health concerns in the USA. Decades of basic and clinical studies have identified numerous ototoxic agents and investigated their modes of action on the inner ear, utilizing tissue culture as well as animal and human models. Current preventive and therapeutic approaches are considered unsatisfactory. Therefore, additional modalities should be developed. Many studies suggest that increased levels of oxidative stress, chronic inflammation, and glutamate play an important role in the initiation and progression of damage to the inner ear leading to hearing impairments. To prevent these cellular deficits, antioxidants, anti-inflammatory agents, and antagonists of glutamate receptor have been used individually or in combination with limited success. It is essential, therefore, to simultaneously enhance the levels of antioxidant enzymes by activating the Nrf2 (a nuclear transcriptional factor) pathway, dietary and endogenous antioxidant compounds, and B12-vitamins in order to reduce the levels of oxidative stress, chronic inflammation, and glutamate at the same time. This review presents evidence to show that increased levels of these cellular metabolites, biochemical or factors are involved in the pathogenesis of cochlea leading to hearing impairments. It presents scientific rationale for the use of a mixture of micronutrients that may decrease the levels of oxidative damage, chronic inflammation, and glutamate at the same time. The benefits for using oral administration of proposed micronutrient mixture in humans are presented. Animal and limited human studies indirectly suggest that orally administered micronutrients can accumulate in the inner ear. Therefore, this route of administration may be useful in prevention, and in combination with standard care, in improved management of hearing problems following exposure to well-recognized and studied ototoxic agents, such as noise, cisplatin, aminoglycoside antibiotics, and advanced age.

  • Endurance training improves plasma superoxide dismutase activity in healthy elderly
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-11-22
    Roberta Ceci, Guglielmo Duranti, Ester Sara Di Filippo, Danilo Bondi, Vittore Verratti, Christian Doria, Daniela Caporossi, Stefania Sabatini, Ivan Dimauro, Tiziana Pietrangelo
  • Telomere length analysis on leukocytes derived from patients with Huntington Disease
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-11-21
    Adriana PerezGrovas-Saltijeral, Adriana Ochoa-Morales, Antonio Miranda-Duarte, Leticia Martínez-Ruano, Aurelio Jara-Prado, Alejandra Camacho-Molina, Alberto Hidalgo-Bravo

    Introduction Huntington´s disease (HD) is a neurodegenerative disorder characterized by neuropsychiatric, motor and cognitive manifestations. It is caused by expansion of the trinucleotide CAG on HTT. The molecular bases are not completely understood, DNA damage, such as double and single strand breaks and oxidative stress (OS) have been implicated. At telomeres, DNA breaks are less efficiently repaired. Double strand breaks evoke the break induced replication (BIR) mechanism. BIR, plus inefficient repair can produce telomere shortening and cellular senescence. Our aim was to investigate the correlation between leukocyte relative telomeric length (RTL) and HD. Methods 206 samples were analyzed, 71 patients with molecular diagnosis and symptomatology (HD), 29 individuals with positive molecular test but asymptomatic (PP) and 106 healthy individuals (NP). Results We found a significant difference in RTL between HD patients compared with both, PP and NP, independently of subjects’ age. Discussion Here we present evidence supporting an association between telomere shortening and HD. Telomere shortening could be related to DNA damage caused by ROS and defective DNA repair mechanism. Both events have been probed to occur in the presence of a mutant Huntingtin. This study contributes with current evidence suggesting a potential role of telomere shortening as HD biomarker.

  • Changes of the coronary arteries and cardiac microvasculature with aging: Implications for translational research and clinical practice
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-10-21
    Francesco Piccirillo, Myriam Carpenito, Giuseppe Verolino, Camilla Chello, Annunziata Nusca, Mario Lusini, Cristiano Spadaccio, Francesco Nappi, Germano Di Sciascio, Antonio Nenna

    Aging results in functional and structural changes in the cardiovascular system, translating into a progressive increase of mechanical vessel stiffness, due to a combination of changes in micro-RNA expression patterns, autophagy, arterial calcification, smooth muscle cell migration and proliferation. The two pivotal mechanisms of aging-related endothelial dysfunction are oxidative stress and inflammation, even in the absence of clinical disease. A comprehensive understanding of the aging process is emerging as a primary concern in literature, as vascular aging has recently become a target for prevention and treatment of cardiovascular disease. Change of life-style, diet, antioxidant regimens, anti-inflammatory treatments, senolytic drugs counteract the pro-aging pathways or target senescent cells modulating their detrimental effects. Such therapies aim to reduce the ineluctable burden of age and contrast aging-associated cardiovascular dysfunction. This narrative review intends to summarize the macrovascular and microvascular changes related with aging, as a better understanding of the pathways leading to arterial aging may contribute to design new mechanism-based therapeutic approaches to attenuate the features of vascular senescence and its clinical impact on the cardiovascular system.

  • Ageing-associated changes in the expression of lncRNAs in human tissues reflect a transcriptional modulation in ageing pathways
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-11-09
    Saara Marttila, Kasit Chatsirisupachai, Daniel Palmer, João Pedro de Magalhães

    Ageing-associated changes in the protein coding transcriptome have been extensively characterised, but less attention has been paid to the non-coding portion of the human genome, especially to long non-coding RNAs (lncRNAs). Only a minority of known lncRNAs have been functionally characterised; however, a handful of these lncRNAs have already been linked to ageing-associated processes. To gain more information on the effects of ageing on lncRNAs, we identified from GTEx data lncRNAs that show ageing-associated expression patterns (age-lncRNAs) in 29 human tissues in 20-79-year-old individuals. The age-lncRNAs identified were highly tissue-specific, but the protein coding genes co-expressed with the age-lncRNAs and the functional categories associated with the age-lncRNAs showed significant overlap across tissues. Functions associated with the age-lncRNAs, including immune system processes and transcription, were similar to what has previously been reported for protein coding genes with ageing-associated expression pattern. As the tissue-specific age-lncRNAs were associated with shared functions across tissues, they may reflect the tissue-specific fine-tuning of the common ageing-associated processes. The present study can be utilised as a resource when selecting and prioritising lncRNAs for further functional analyses.

  • Neuroglial patterns are shared by cerebella from prion and prion-like disorder affected patients
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-11-02
    Moisés Garcés, M. Isabel Guijarro, Antonia Vargas, Juan J. Badiola, Marta Monzón

    Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, are considered prion-like disorders because they are all proteinopathies in which aberrant proteins spread throughout the brain during disease progression. The overall aim of this study is to determine how glial cells are commonly involved in the neurodegeneration progress observed in all these pathologies. The suggestion that they are cell types in which prion diseases and prion-like disorders have common behaviour is the hypothesis on which this study is based. Morphological and distribution differences in astroglial and microglial cells in the cerebellum from prion and prion-like disease-affected patients were assessed here by histopathological and immunochemical tools. To our knowledge, this is the first study to focus on the comparative assessment of glial profiles in these human brains. Activated microglial population was demonstrated in both, prion and prion-like disorders, although in higher extent in the first. In astroglial activation, specific patterns of alterations suggesting both degenerative and potentially neuroprotective or restorative stem cell response, were shown to be alternatively shared by cerebella from all disorders studied. Neuro-protective strategies for these disabling disorders are particularly desirable.

  • Extracellular vesicles as an emerging tool for the early detection of Alzheimer’s disease
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-11-01
    Tao-Ran Li, Xiao-Ni Wang, Can Sheng, Yu-Xia Li, Frederic Zhen-Tao Li, Yu Sun, Ying Han

    Alzheimer’s disease (AD) is characterized by a series of interacting pathophysiological cascades, including the aggregation of β-amyloid plaques and the formation of neurofibrillary tangles derived from hyperphosphorylated tau proteins. AD is the cause of approximately 70% of dementia, an irreversible and untreatable syndrome at its late stage. Hence, more efforts should be devoted to identifying at-risk or preclinical AD populations for early intervention and the improved design of drug trials. The exosome, a nanoscale subtype of extracellular vesicle that serves as a cell-to-cell communication messenger, is an emerging liquid biopsy tool for various diseases including AD. Recently, it has been discovered that brain-derived exosomes can flow through the blood-brain barrier to the peripheral blood, containing important protein and nucleic acid biomarkers that are associated with the pathogenesis and progression of AD. Other reports showed a strong involvement of exosomes in synaptic function, insulin resistance, and neuroinflammation, among others. Here, we summarize those studies and assess the value of exosomes as an emerging tool for the early detection of AD in conjunction with the current clinical diagnosis paradigm.

  • Desmoglein-3 acts as a pro-survival protein by suppressing reactive oxygen species and doming whilst augmenting the tight junctions in MDCK cells
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2019-10-31
    Xiao Li, Usama Sharif Ahmad, Yunying Huang, Jutamas Uttagomol, Ambreen Rehman, Ke Zhou, Gary Warnes, Simon McArthur, Eric Kenneth Parkinson, H Wan

    Kidney disease prevalence increases with age, with a common feature of the disease being defects in the epithelial tight junctions. Emerging evidence suggests that the desmosomal adhesion protein Desmoglein-3 (Dsg3) functions beyond the desmosomal adhesion and plays a role in regulating the fundamental pathways that govern cell fate decisions in response to environmental chemical and mechanical stresses. In this study, we explored the role of Dsg3 on dome formation, reactive oxygen species (ROS) production and transepithelial electrical resistance (TER) in MDCK cells, a kidney epithelial cell model widely used to study cell differentiation and tight junction formation and integrity. We show that overexpression of Dsg3 constrained nuclear ROS production and cellular doming in confluent cell cultures and these features coincided with augmented TER and enhanced tight junction integrity. Conversely, cells expressing dominant-negative Dsg3ΔC mutants exhibited heightened ROS production and accelerated doming, accompanied by increased apoptosis, as well as cell proliferation, with massive disruption in F-actin organization and accumulation and alterations in tight junctions. Inhibition of actin polymerization and protein synthesis was able to sufficiently block dome formation in mutant populations. Taken together, these findings underscore that Dsg3 has a role in controlling cellular viability and differentiation as well as the functional integrity of tight junctions in MDCK cells.

  • CARF: an emerging regulator of p53 tumor suppressor and senescence pathway.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2008-06-17
    Caroline T Y Cheung,Md Kamrul Hasan,Nashi Widodo,Sunil C Kaul,Renu Wadhwa

    Replicative senescence, a major outcome of normal cells with finite lifespan, is a widely accepted in vitro model for ageing studies. Limited repair and defense mechanisms of normal cells, in addition to DNA alterations and oncogene inductions under stress, are believed to result in senescence as a protective mechanism to prevent undesirable proliferation of cells. The ARF/p53/p21(cip1/waf1) tumor suppression pathway acts as a molecular sensor and regulator of cellular stress, senescence, and immortalization. Understanding the molecular regulation of this pathway by intrinsic and extrinsic signals is extremely important to address unsolved questions in senescence and cancer. CARF was first discovered as a binding partner of ARF and has since been shown to have both ARF-dependent and -independent functions that converge to regulate p53 pathway. CARF directly binds to p53 and HDM2, and functions in a negative feedback pathway. Whereas CARF transcriptionally represses HDM2 to increase p53 activity, HDM2 in return degrades CARF. Thus, CARF may act as a novel key regulator of the p53 pathway at multiple checkpoints. The aim of this article is to discuss the current knowledge about functions of CARF and its impact on p53 pathway in regulation of senescence and carcinogenesis.

  • Age-associated alterations in the levels of cytotoxic lipid molecular species and oxidative stress in the murine thymus are reduced by growth hormone treatment.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2017-09-04
    Valeria de Mello-Coelho,Roy G Cutler,Allyson Bunbury,Anita Tammara,Mark P Mattson,Dennis D Taub

    During age-associated thymic involution, thymocytes decrease and lipid-laden cells accumulate. However, if and how aging affects the thymic lipid profile is not well understood, nor is it known if the hormonal milieu modifies this process. Here we demonstrate a correlation between reduced thymocyte numbers and markers of inflammation and oxidative stress with age. Evaluating the lipidomics profile of the whole thymus, between the ages of 4 (young) and 18 months (old), we found increased amounts of triacylglycerides, free cholesterol, cholesterol ester and 4-hydroxynonenal (4-HNE) with age. Moreover, levels of C24:0 and C24:1 sphingomyelins and ceramide C16:0 were elevated in 12-14 month-old (middle-aged) mice while the levels of sulfatide ceramide and ganglioside GD1a increased in the old thymus. Evaluating isolated thymocytes, we found increased levels of cholesterol ester and 4-HNE adducts, as compared to young mice. Next, we treated middle-aged mice with growth hormone (GH), which has been considered a potent immunomodulator. GH reduced thymic levels of TNF-α and 4-HNE and increased the number of thymocytes as well as the thymic levels of dihydroceramide, a ceramide precursor and autophagic stimuli for cell survival. In conclusion, GH treatment attenuated inflammation and age-related increases in oxidative stress and lipotoxicity in the thymus.

  • Genome instability in Alzheimer disease.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2016-04-24
    Yujun Hou,Hyundong Song,Deborah L Croteau,Mansour Akbari,Vilhelm A Bohr

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Autosomal dominant, familial AD (fAD) is very rare and caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2) genes. The pathogenesis of sporadic AD (sAD) is more complex and variants of several genes are associated with an increased lifetime risk of AD. Nuclear and mitochondrial DNA integrity is pivotal during neuronal development, maintenance and function. DNA damage and alterations in cellular DNA repair capacity have been implicated in the aging process and in age-associated neurodegenerative diseases, including AD. These findings are supported by research using animal models of AD and in DNA repair deficient animal models. In recent years, novel mechanisms linking DNA damage to neuronal dysfunction have been identified and have led to the development of noninvasive treatment strategies. Further investigations into the molecular mechanisms connecting DNA damage to AD pathology may help to develop novel treatment strategies for this debilitating disease. Here we provide an overview of the role of genome instability and DNA repair deficiency in AD pathology and discuss research strategies that include genome instability as a component.

  • Longitudinal telomere length shortening and cognitive and physical decline in later life: The Lothian Birth Cohorts 1936 and 1921.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2016-02-16
    Sarah E Harris,Riccardo E Marioni,Carmen Martin-Ruiz,Alison Pattie,Alan J Gow,Simon R Cox,Janie Corley,Thomas von Zglinicki,John M Starr,Ian J Deary

    Telomere length is hypothesised to be a biological marker of both cognitive and physical ageing. Here we measure telomere length, and cognitive and physical abilities at mean ages 70, 73 and 76 years in the Lothian Birth Cohort 1936 (LBC1936), and at mean ages 79, 87, 90 and 92 years in the Lothian Birth Cohort 1921 (LBC1921). We investigate whether telomere length change predicts change in cognitive and physical abilities. In LBC1936 telomere length decreased by an average of 65 base pairs per year and in LBC1921 by 69 base pairs per year. However, change in telomere length did not predict change in cognitive or physical abilities. This study shows that, although cognitive ability, walking speed, lung function and grip strength all decline with age, they do so independently of telomere length shortening.

  • Editorial.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2015-09-09
    Alexander Bürkle,Tilman Grune,Efstathios S Gonos,Vilhelm A Bohr

  • Trajectories of physiological dysregulation predicts mortality and health outcomes in a consistent manner across three populations.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2014-12-03
    Emmanuel Milot,V Morissette-Thomas,Qing Li,Linda P Fried,Luigi Ferrucci,Alan A Cohen

    Mechanistic and evolutionary perspectives both agree that aging involves multiple integrated biochemical networks in the organism. In particular, the homeostatic physiological dysregulation (PD) hypothesis contends that aging is caused by the progressive breakdown of key regulatory processes. However, nothing is yet known about the specifics of how PD changes with age and affects health. Using a recently validated measure of PD involving the calculation of a multivariate distance (DM) from biomarker data, we show that PD trajectories predict mortality, frailty, and chronic diseases (cancer, cardiovascular diseases, and diabetes). Specifically, relative risks of outcomes associated with individual slopes in (i.e. rate of) dysregulation range 1.20-1.40 per unit slope. We confirm the results by replicating the analysis using two suites of biomarkers selected with markedly different criteria and, for mortality, in three longitudinal cohort-based studies. Overall, the consistence of effect sizes (direction and magnitude) across data sets, biomarker suites and outcomes suggests that the positive relationship between DM and health outcomes is a general phenomenon found across human populations. Therefore, the study of dysregulation trajectories should allow important insights into aging physiology and provide clinically meaningful predictors of outcomes.

  • Sphingolipid metabolism regulates development and lifespan in Caenorhabditis elegans.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2014-12-02
    Roy G Cutler,Kenneth W Thompson,Simonetta Camandola,Kendra T Mack,Mark P Mattson

    Sphingolipids are a highly conserved lipid component of cell membranes involved in the formation of lipid raft domains that house many of the receptors and cell-to-cell signaling factors involved in regulating cell division, maturation, and terminal differentiation. By measuring and manipulating sphingolipid metabolism using pharmacological and genetic tools in Caenorhabditis elegans, we provide evidence that the synthesis and remodeling of specific ceramides (e.g., dC18:1-C24:1), gangliosides (e.g., GM1-C24:1), and sphingomyelins (e.g., dC18:1-C18:1) influence development rate and lifespan. We found that the levels of fatty acid chain desaturation and elongation in many sphingolipid species increased during development and aging, with no such changes in developmentally-arrested dauer larvae or normal adults after food withdrawal (an anti-aging intervention). Pharmacological inhibitors and small interfering RNAs directed against serine palmitoyl transferase and glucosylceramide synthase acted to slow development rate, extend the reproductive period, and increase lifespan. In contrast, worms fed an egg yolk diet rich in sphingolipids exhibited accelerated development and reduced lifespan. Our findings demonstrate that sphingolipid accumulation and remodeling are critical events that determine development rate and lifespan in the nematode model, with both development rate and aging being accelerated by the synthesis of sphingomyelin, and its metabolism to ceramides and gangliosides.

  • Inflamm-aging does not simply reflect increases in pro-inflammatory markers.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2014-07-11
    Vincent Morrisette-Thomas,Alan A Cohen,Tamàs Fülöp,Éléonor Riesco,Véronique Legault,Qing Li,Emmanuel Milot,Françis Dusseault-Bélanger,Luigi Ferrucci

    Many biodemographic studies use biomarkers of inflammation to understand or predict chronic disease and aging. Inflamm-aging, i.e. chronic low-grade inflammation during aging, is commonly characterized by pro-inflammatory biomarkers. However, most studies use just one marker at a time, sometimes leading to conflicting results due to complex interactions among the markers. A multidimensional approach allows a more robust interpretation of the various relationships between the markers. We applied principal component analysis (PCA) to 19 inflammatory biomarkers from the InCHIANTI study. We identified a clear, stable structure among the markers, with the first axis explaining inflammatory activation (both pro- and anti-inflammatory markers loaded strongly and positively) and the second axis innate immune response. The first but not the second axis was strongly correlated with age (r=0.56, p<0.0001, r=0.08 p=0.053), and both were strongly predictive of mortality (hazard ratios per PCA unit (95% CI): 1.33 (1.16-1.53) and 0.87 (0.76-0.98) respectively) and multiple chronic diseases, but in opposite directions. Both axes were more predictive than any individual markers for baseline chronic diseases and mortality. These results show that PCA can uncover a novel biological structure in the relationships among inflammatory markers, and that key axes of this structure play important roles in chronic disease.

  • Mediterranean diet and inflammaging in the elderly: the European project NU-AGE. Preface.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2014-01-30
    Aurelia Santoro,Patrizia Brigidi,Efstathios S Gonos,Vilhelm A Bohr,Claudio Franceschi

  • Splicing factor 3B1 hypomethylation is associated with altered SF3B1 transcript expression in older humans.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2014-01-28
    Alice C Holly,Luke C Pilling,Dena Hernandez,Benjamin P Lee,Andrew Singleton,Luigi Ferrucci,David Melzer,Lorna W Harries

    Ageing in man is associated with changes to the splicing factor pool. A proportion of splicing factors are regulated during ageing by mechanisms involving the Ataxia Telangiectasia Mutated (ATM) gene, but the factors that determine the remaining proportion have yet to be identified. DNA methylation is known to be an important regulatory mechanism of gene expression. We assessed age-associated methylation and expression levels for 27 splicing factor genes, in peripheral blood samples from the InCHIANTI study. Examination of splicing patterns at specific loci was examined in a second cohort, the Exeter 10000 study. 27/502 methylation probes in 17 different genes were associated with age. Most changes were not associated with transcript expression levels or splicing patterns, but hypomethylation of the SF3B1 promoter region was found to mediate 53% of the relationship between age and transcript expression at this locus (p=0.02). DNA methylation does not appear to play a major role in regulation of the splicing factors, but changes in SF3B1 expression may be attributable to promoter hypomethylation at this locus. SF3B1 encodes a critical component of the U2 snRNP; altered expression of this gene may therefore contribute to the loss of regulated mRNA splicing that occurs with age.

  • Cockayne Syndrome group B protein stimulates NEIL2 DNA glycosylase activity.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2014-01-11
    Maria D Aamann,Christina Hvitby,Venkateswarlu Popuri,Meltem Muftuoglu,Lasse Lemminger,Cecilie K Skeby,Guido Keijzers,Byungchan Ahn,Magnar Bjørås,Vilhelm A Bohr,Tinna Stevnsner

    Cockayne Syndrome is a segmental premature aging syndrome, which can be caused by loss of function of the CSB protein. CSB is essential for genome maintenance and has numerous interaction partners with established roles in different DNA repair pathways including transcription coupled nucleotide excision repair and base excision repair. Here, we describe a new interaction partner for CSB, the DNA glycosylase NEIL2. Using both cell extracts and recombinant proteins, CSB and NEIL2 were found to physically interact independently of DNA. We further found that CSB is able to stimulate NEIL2 glycosylase activity on a 5-hydroxyl uracil lesion in a DNA bubble structure substrate in vitro. A novel 4,6-diamino-5-formamidopyrimidine (FapyA) specific incision activity of NEIL2 was also stimulated by CSB. To further elucidate the biological role of the interaction, immunofluorescence studies were performed, showing an increase in cytoplasmic CSB and NEIL2 co-localization after oxidative stress. Additionally, stalling of the progression of the transcription bubble with α-amanitin resulted in increased co-localization of CSB and NEIL2. Finally, CSB knockdown resulted in reduced incision of 8-hydroxyguanine in a DNA bubble structure using whole cell extracts. Taken together, our data supports a biological role for CSB and NEIL2 in transcription associated base excision repair.

  • Changes in splicing factor expression are associated with advancing age in man.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2013-06-12
    Alice C Holly,David Melzer,Luke C Pilling,Alexander C Fellows,Toshiko Tanaka,Luigi Ferrucci,Lorna W Harries

    Human ageing is associated with decreased cellular plasticity and adaptability. Changes in alternative splicing with advancing age have been reported in man, which may arise from age-related alterations in splicing factor expression. We determined whether the mRNA expression of key splicing factors differed with age, by microarray analysis in blood from two human populations and by qRT-PCR in senescent primary fibroblasts and endothelial cells. Potential regulators of splicing factor expression were investigated by siRNA analysis. Approximately one third of splicing factors demonstrated age-related transcript expression changes in two human populations. Ataxia Telangiectasia Mutated (ATM) transcript expression correlated with splicing factor expression in human microarray data. Senescent primary fibroblasts and endothelial cells also demonstrated alterations in splicing factor expression, and changes in alternative splicing. Targeted knockdown of the ATM gene in primary fibroblasts resulted in up-regulation of some age-responsive splicing factor transcripts. We conclude that isoform ratios and splicing factor expression alters with age in vivo and in vitro, and that ATM may have an inhibitory role on the expression of some splicing factors. These findings suggest for the first time that ATM, a core element in the DNA damage response, is a key regulator of the splicing machinery in man.

  • Base excision repair in the mammalian brain: implication for age related neurodegeneration.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2013-05-07
    Peter Sykora,David M Wilson,Vilhelm A Bohr

    The repair of damaged DNA is essential to maintain longevity of an organism. The brain is a matrix of different neural cell types including proliferative astrocytes and post-mitotic neurons. Post-mitotic DNA repair is a version of proliferative DNA repair, with a reduced number of available pathways and most of these attenuated. Base excision repair (BER) is one pathway that remains robust in neurons; it is this pathway that resolves the damage due to oxidative stress. This oxidative damage is an unavoidable byproduct of respiration, and considering the high metabolic activity of neurons this type of damage is particularly pertinent in the brain. The accumulation of oxidative DNA damage over time is a central aspect of the theory of aging and repair of such chronic damage is of the highest importance. We review research conducted in BER mouse models to clarify the role of this pathway in the neural system. The requirement for BER in proliferating cells also correlates with high levels of many of the BER enzymes in neurogenesis after DNA damage. However, the pathway is also necessary for normal neural maintenance as larger infarct volumes after ischemic stroke are seen in some glycosylase deficient animals. Further, the requirement for DNA polymerase β in post-mitotic BER is potentially more important than in proliferating cells due to reduced levels of replicative polymerases. The BER response may have particular relevance for the onset and progression of many neurodegenerative diseases associated with an increase in oxidative stress including Alzheimer's.

  • Special issue on the segmental progeria Cockayne syndrome.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2013-04-16
    David M Wilson,Vilhelm A Bohr

  • Multiple interaction partners for Cockayne syndrome proteins: implications for genome and transcriptome maintenance.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2013-04-16
    Maria D Aamann,Meltem Muftuoglu,Vilhelm A Bohr,Tinna Stevnsner

    Cockayne syndrome (CS) is characterized by progressive multisystem degeneration and is classified as a segmental premature aging syndrome. The majority of CS cases are caused by defects in the CS complementation group B (CSB) protein and the rest are mainly caused by defects in the CS complementation group A (CSA) protein. Cells from CS patients are sensitive to UV light and a number of other DNA damaging agents including various types of oxidative stress. The cells also display transcription deficiencies, abnormal apoptotic response to DNA damage, and DNA repair deficiencies. Herein we have critically reviewed the current knowledge about known protein interactions of the CS proteins. The review focuses on the participation of the CSB and CSA proteins in many different protein interactions and complexes, and how these interactions inform us about pathways that are defective in the disease.

  • Mitochondrial deficiency in Cockayne syndrome.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2013-02-26
    Morten Scheibye-Knudsen,Deborah L Croteau,Vilhelm A Bohr

    Cockayne syndrome is a rare inherited disorder characterized by accelerated aging, cachectic dwarfism and many other features. Recent work has implicated mitochondrial dysfunction in the pathogenesis of this disease. This is particularly interesting since mitochondrial deficiencies are believed to be important in the aging process. In this review, we discuss recent findings of mitochondrial pathology in Cockayne syndrome and suggest possible mechanisms for the mitochondrial dysfunction.

  • Markers of oxidant stress that are clinically relevant in aging and age-related disease.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2013-02-23
    Kimberly D Jacob,Nicole Noren Hooten,Andrzej R Trzeciak,Michele K Evans

    Despite the long held hypothesis that oxidant stress results in accumulated oxidative damage to cellular macromolecules and subsequently to aging and age-related chronic disease, it has been difficult to consistently define and specifically identify markers of oxidant stress that are consistently and directly linked to age and disease status. Inflammation because it is also linked to oxidant stress, aging, and chronic disease also plays an important role in understanding the clinical implications of oxidant stress and relevant markers. Much attention has focused on identifying specific markers of oxidative stress and inflammation that could be measured in easily accessible tissues and fluids (lymphocytes, plasma, serum). The purpose of this review is to discuss markers of oxidant stress used in the field as biomarkers of aging and age-related diseases, highlighting differences observed by race when data is available. We highlight DNA, RNA, protein, and lipid oxidation as measures of oxidative stress, as well as other well-characterized markers of oxidative damage and inflammation and discuss their strengths and limitations. We present the current state of the literature reporting use of these markers in studies of human cohorts in relation to age and age-related disease and also with a special emphasis on differences observed by race when relevant.

  • Quantitative analysis of WRN exonuclease activity by isotope dilution mass spectrometry.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2012-07-07
    Aswin Mangerich,Sebastian Veith,Oliver Popp,Jörg Fahrer,Rita Martello,Vilhelm A Bohr,Alexander Bürkle

    Werner syndrome is a disorder characterized by a premature aging phenotype. The disease is caused by mutations in the WRN gene which encodes a DNA helicase/exonuclease which is involved in multiple aspects of DNA metabolism. Current methods mostly rely on radiometric techniques to assess WRN exonuclease activity. Here we present an alternative, quantitative approach based on non-radioactive isotope dilution mass spectrometry (LC-MS/MS). A oligoduplex substrate mimicking the telomeric sequence was used for method development. Released nucleotides, which correlate with the degree of oligoduplex degradation, were dephosphorylated, purified, and quantified by LC-MS/MS. Heavy-isotope-labeled internal standards were used to account for technical variability. The method was validated in terms of reproducibility, time-course and concentration-dependency of the reaction. As shown in this study, the LC-MS/MS method can assess exonuclease activity of WRN mutants, WRN's substrate and strand specificity, and modulatory effects of WRN interaction partners and posttranslational modifications. Moreover, it can be used to analyze the selectivity and processivity of WRN exonuclease and allows the screening of small molecules for WRN exonuclease inhibitors. Importantly, this approach can easily be adapted to study nucleases other than WRN. This is of general interest, because exonucleases are key players in DNA metabolism and aging mechanisms.

  • Indo-US workshop on base excision DNA repair, brain function and aging.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2012-05-15
    Bruce Demple,Kalluri S Rao,Vilhelm A Bohr

  • Repair of persistent strand breaks in the mitochondrial genome.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2011-12-06
    Peter Sykora,David M Wilson,Vilhelm A Bohr

    Oxidative DNA damage has been attributed to increased cancer incidence and premature aging phenotypes. Reactive oxygen species (ROS) are unavoidable byproducts of oxidative phosphorylation and are the major contributors of endogenous oxidative damage. To prevent the negative effects of ROS, cells have developed DNA repair mechanisms designed to specifically combat endogenous DNA modifications. The base excision repair (BER) pathway is primarily responsible for the repair of small non-helix distorting lesions and DNA single strand breaks. This repair pathway is found in all organisms, and in mammalian cells, consists of three related sub-pathways: short patch (SP-BER), long patch (LP-BER) and single strand break repair (SSBR). While much is known about nuclear BER, comparatively little is known about this pathway in the mitochondria, particularly the LP-BER and SSBR sub-pathways. There are a number of proteins that have recently been found to be involved in mitochondrial BER, including Cockayne syndrome proteins A and B (CSA and CSB), aprataxin (APTX), tryosyl-DNA phosphodiesterase 1 (TDP1), flap endonuclease 1 (FEN-1) and exonuclease G (EXOG). These significant advances in mitochondrial DNA repair may open new avenues in the management and treatment of a number of neurological disorders associated with mitochondrial dysfunction, and will be reviewed in further detail herein.

  • Aging-kb: a knowledge base for the study of the aging process.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2011-11-22
    Kevin G Becker,Karen A Holmes,Yongqing Zhang

    As the science of the aging process moves forward, a recurring challenge is the integration of multiple types of data and information with classical aging theory while disseminating that information to the scientific community. Here we present AGING-kb, a public knowledge base with the goal of conceptualizing and presenting fundamental aspects of the study of the aging process. Aging-kb has two interconnected parts, the Aging-kb tree and the Aging Wiki. The Aging-kb tree is a simple intuitive dynamic tree hierarchy of terms describing the field of aging from the general to the specific. This enables the user to see relationships between areas of aging research in a logical comparative fashion. The second part is a specialized Aging Wiki which allows expert definition, description, supporting information, and documentation of each aging keyword term found in the Aging-kb tree. The Aging Wiki allows community participation in describing and defining concepts and terms in the Wiki format. This aging knowledge base provides a simple intuitive interface to the complexities of aging.

  • Differences in the accumulation of mitochondrial defects with age in mice and humans.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2011-10-22
    Laura C Greaves,Martin J Barron,George Campbell-Shiel,Thomas B L Kirkwood,Douglass M Turnbull

    Mitochondrial DNA mutations and associated defects in cytochrome c oxidase (COX) are proposed to play an important role in human ageing; however there have been limited studies on the frequency of these defects in normal mouse ageing. Here we compare COX-deficiency in two epithelial tissues; the colon and the ciliary epithelium, from human and mouse. The pattern of accumulation of COX-deficiency is similar in both tissues in the two species; however the frequency of colonic crypts with COX-deficiency in aged humans is significantly higher than in aged mice, whereas the levels of COX-deficiency in the ciliary epithelium are higher in the mouse than in humans. This suggests the impact of mitochondrial defects on normal ageing may differ significantly between species.

  • Aging, longevity and health.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2011-08-09
    Lene Juel Rasmussen,Miriam Sander,Ulla M Wewer,Vilhelm A Bohr

    The IARU Congress on Aging, Longevity and Health, held on 5-7 October 2010 in Copenhagen, Denmark, was hosted by Rector Ralf Hemmingsen, University of Copenhagen and Dean Ulla Wewer, Faculty of Health Sciences, University of Copenhagen and was organized by Center for Healthy Aging (CEHA) under the leadership of CEHA Managing Director Lene Juel Rasmussen and Prof. Vilhelm Bohr, National Institute on Aging, NIH, Baltimore, USA (associated to CEHA). The Congress was attended by approximately 125 researchers interested in and/or conducting research on aging and aging-related topics. The opening Congress Session included speeches by Ralf Hemmingsen, Ulla Wewer, and Lene Juel Rasmussen and Keynote Addresses by four world renowned aging researchers: Povl Riis (The Age Forum), Bernard Jeune (University of Southern Denmark), George Martin (University of Washington, USA) and Jan Vijg (Albert Einstein School of Medicine, USA) as well as a lecture discussing the art-science interface by Thomas Söderqvist (Director, Medical Museion, University of Copenhagen). The topics of the first six Sessions of the Congress were: Neuroscience and DNA damage, Aging and Stress, Life Course, Environmental Factors and Neuroscience, Muscle and Life Span and Life Span and Mechanisms. Two additional Sessions highlighted ongoing research in the recently established Center for Healthy Aging at the University of Copenhagen. This report highlights outcomes of recent research on aging-related topics, as described at the IARU Congress on Aging, Longevity and Health.

  • 3rd International Genome Dynamics in Neuroscience Conference: "DNA repair and neurological disease".
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2011-08-09
    Keith W Caldecott,Vilhelm A Bohr,Peter J McKinnon

  • The excitatory neurotransmitter glutamate stimulates DNA repair to increase neuronal resiliency.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2011-07-07
    Jenq-Lin Yang,Peter Sykora,David M Wilson,Mark P Mattson,Vilhelm A Bohr

    Glutamate is the most abundant excitatory neurotransmitter in the vertebrate central nervous system and plays an important role in synaptic plasticity required for learning and memory. Activation of glutamate ionotropic receptors promptly triggers membrane depolarization and Ca(2+) influx, resulting in the activation of several different protein kinases and transcription factors. For example, glutamate-mediated Ca(2+) influx activates Ca(2+)/calmodulin-dependent kinase, protein kinase C, and mitogen activated protein kinases resulting in activation of transcription factors such as cyclic AMP response element binding protein (CREB). Abnormally prolonged exposure to glutamate causes neuronal injury, and such "excitotoxicity" has been implicated in many acute and chronic diseases including ischemic stroke, epilepsy, amyotrophic lateral sclerosis, Alzheimer's, Huntington's and Parkinson's diseases. Interestingly, although glutamate-induced Ca(2+) influx can cause DNA damage by a mitochondrial reactive oxygen species-mediated mechanism, the Ca(2+) simultaneously activates CREB, resulting in up-regulation of the DNA repair and redox protein apurinic/apyrimidinic endonuclease 1. Here, we review connections between physiological or aberrant glutamate receptor activation, Ca(2+)-mediated signaling, oxidative DNA damage and repair efficiency, and neuronal vulnerability. We conclude that glutamate signaling involves an adaptive cellular stress response pathway that enhances DNA repair capability, thereby protecting neurons against injury and disease.

  • Xeroderma pigmentosum and other diseases of human premature aging and DNA repair: molecules to patients.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2011-06-29
    Laura J Niedernhofer,Vilhelm A Bohr,Miriam Sander,Kenneth H Kraemer

    A workshop(1) to share, consider and discuss the latest developments in understanding xeroderma pigmentosum and other human diseases caused by defects in nucleotide excision repair (NER) of DNA damage was held on September 21-24, 2010 in Virginia. It was attended by approximately 100 researchers and clinicians, as well as several patients and representatives of patient support groups. This was the third in a series of workshops with similar design and goals: to emphasize discussion and interaction among participants as well as open exchange of information and ideas. The participation of patients, their parents and physicians was an important feature of this and the preceding two workshops. Topics discussed included the natural history and clinical features of the diseases, clinical and laboratory diagnosis of these rare diseases, therapeutic strategies, mouse models of neurodegeneration, molecular analysis of accelerated aging, impact of transcriptional defects and mitochondrial dysfunction on neurodegeneration, and biochemical insights into mechanisms of NER and base excision repair.

  • Gross energy metabolism in mice under late onset, short term caloric restriction.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2011-04-22
    Kerry M Cameron,Andrew Golightly,Satomi Miwa,John Speakman,Richard Boys,Thomas von Zglinicki

    Late onset, short-term moderate caloric restriction (CR) may have beneficial health effects. A 26% CR regime induced at 14 months of age for 70 days in male C57Bl/6 (ICRFa) mice resulted in a reduction in body mass of 17%. A decrease in daily energy expenditure was associated with decreased body mass in CR mice. There was no difference in total levels of physical activity between the CR and ad libitum (AL) groups; however, activity patterns were different. We developed a Bayesian model to dissect the impact of food anticipation activity (FAA) and feeding on physical activity. FAA was stronger in CR mice and remaining basal activity was higher in AL mice, but CR mice displayed larger diurnal variations as well as a phase shift in their diurnal activity. CR mice displayed lower body temperature, especially late during the dark phase. This was due to lower basal (activity-independent) temperature at all times of the day, coupled to a phase shift in the diurnal rhythm. The correlation between body temperature and physical activity was independent of feeding regimen and light/dark cycles. Reduction of body mass and basal temperature were major compensatory mechanisms to reduced food availability during late-onset, short-term CR.

  • CUL4B-deficiency in humans: understanding the clinical consequences of impaired Cullin 4-RING E3 ubiquitin ligase function.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2011-03-01
    Claudia Kerzendorfer,Lesley Hart,Rita Colnaghi,Gillian Carpenter,Diana Alcantara,Emily Outwin,Antony M Carr,Mark O'Driscoll

    Cullin's encode the structural components for one of the most abundant E3 ubiquitin ligase families in eukaryotes accounting for as many as 400 distinct E3 ubiquitin ligases. Because of their modular assembly involving combinations of multiple distinct adaptor and substrate receptor proteins, it comes as no surprise that these E3's are implicated in a plethora of fundamental biochemical processes ranging from DNA replication and repair to transcription and development. Herein, we focus on one member of the cullin family, namely the Cullin 4-RING E3 ligases (CRL4's). More specifically, we overview what has been learned about some of the functions of CRL4's from various model systems. We discuss the unexpected association of defective CUL4B with syndromal X-linked mental retardation in humans and speculate on the biochemical consequences and clinical implications of defective CRL4 function. In particular, mutations in CUL4B highlight a previously unappreciated role for CRL4's in neuronal function and cognition in humans.

  • Mitochondrial helicases and mitochondrial genome maintenance.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2010-06-26
    Nadja C de Souza-Pinto,Maria D Aamann,Tomasz Kulikowicz,Tinna V Stevnsner,Vilhelm A Bohr

    Helicases are essential enzymes that utilize the energy of nucleotide hydrolysis to drive unwinding of nucleic acid duplexes. Helicases play roles in all aspects of DNA metabolism including DNA repair, DNA replication and transcription. The subcellular locations and functions of several helicases have been studied in detail; however, the roles of specific helicases in mitochondrial biology remain poorly characterized. This review presents important recent advances in identifying and characterizing mitochondrial helicases, some of which also operate in the nucleus.

  • Nutrition and aging.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2010-04-07
    Wen-Hsing Cheng,Vilhelm A Bohr,Rafael de Cabo

  • Effect of progerin on the accumulation of oxidized proteins in fibroblasts from Hutchinson Gilford progeria patients.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2009-12-05
    Gabriela Viteri,Youn Wook Chung,Earl R Stadtman

    The mutation responsible for Hutchinson Gilford Progeria Syndrome (HGPS) causes abnormal nuclear morphology. Previous studies show that free radicals and reactive oxygen species play major roles in the etiology and/or progression of neurodegenerative diseases and aging. This study compares oxidative stress responses between progeric and normal fibroblasts. Our data revealed higher ROS levels in HGPS cells compared to age-matched controls. In response to oxidative challenge, progeric cells showed increased mRNA levels for mitochondrial superoxide dismutase (SOD) and SOD protein content. However, this did not prevent a drop in the ATP content of progeria fibroblasts. Previous studies have shown that declines in human fibroblast ATP levels interfere with programmed cell death and promote necrotic inflammation. Notably, in our investigations the ATP content of progeria fibroblasts was only approximately 50% of that found in healthy controls. Furthermore, HGPS fibroblast analysis revealed a decrease in total caspase-like proteasome activity and in the levels of two active proteolytic complex subunits (beta(5) and beta(7)). A number of studies indicate that the molecular mechanisms causing accelerated aging in progeric patients also occur in healthy cells of older individuals. Thus, the results of this study may also help explain some of the cellular changes that accompany normal aging.

  • A potential impact of DNA repair on ageing and lifespan in the ageing model organism Podospora anserina: decrease in mitochondrial DNA repair activity during ageing.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2009-06-03
    Mette Soerensen,Ricardo Gredilla,Mathis Müller-Ohldach,Alexandra Werner,Vilhelm A Bohr,Heinz D Osiewacz,Tinna Stevnsner

    The free radical theory of ageing states that ROS play a key role in age-related decrease in mitochondrial function via the damage of mitochondrial DNA (mtDNA), proteins and lipids. In the sexually reproducing ascomycete Podospora anserina ageing is, as in other eukaryotes, associated with mtDNA instability and mitochondrial dysfunction. Part of the mtDNA instabilities may arise due to accumulation of ROS induced mtDNA lesions, which, as previously suggested for mammals, may be caused by an age-related decrease in base excision repair (BER). Alignments of known BER protein sequences with the P. anserina genome revealed high homology. We report for the first time the presence of BER activities in P. anserina mitochondrial extracts. DNA glycosylase activities decrease with age, suggesting that the increased mtDNA instability with age may be caused by decreased ability to repair mtDNA damage and hence contribute to ageing and lifespan control in this ageing model. Additionally, we find low DNA glycosylase activities in the long-lived mutants grisea and DeltaPaCox17::ble, which are characterized by low mitochondrial ROS generation. Overall, our data identify a potential role of mtDNA repair in controlling ageing and life span in P. anserina, a mechanism possibly regulated in response to ROS levels.

  • Metabolic evolution suggests an explanation for the weakness of antioxidant defences in beta-cells.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2009-04-29
    Armin Rashidi,Thomas B L Kirkwood,Daryl P Shanley

    The lack of an effective antioxidant system in beta-cells, which renders them susceptible to oxidative stress, is to date without explanation. The particular weakness of beta-cells in females, in both humans and mice, is another unexplained observation. We hypothesise that reactive oxygen species (ROS) in beta-cells, by their negative effect on insulin synthesis/secretion, play a fitness-enhancing role for the whole organism. Under stress conditions, the release of stress hormones produces insulin resistance and, owing to ROS preventing beta-cells from secreting insulin at the level required to maintain homeostasis, diverts glucose to insulin-independent tissues such as the brain and the foetus. We suggest that pancreatic beta-cells lost part of their antioxidant defence in association with brain evolution, and lost even more in females when placental mammals evolved. The unusual antioxidant status of beta-cells may thus be explained as an instance of co-evolution of the brain, cortisol and corticosteroid receptors, and beta-cells in the endocrine pancreas.

  • Oxidative stress, telomere length and biomarkers of physical aging in a cohort aged 79 years from the 1932 Scottish Mental Survey.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2008-11-04
    John M Starr,Paul G Shiels,Sarah E Harris,Alison Pattie,Mark S Pearce,Caroline L Relton,Ian J Deary

    Telomere shortening is a biomarker of cellular senescence and is associated with a wide range of age-related disease. Oxidative stress is also associated with physiological aging and several age-related diseases. Non-human studies suggest that variants in oxidative stress genes may contribute to both telomere shortening and biological aging. We sought to test whether oxidative stress-related gene polymorphisms contribute to variance in both telomere length and physical biomarkers of aging in humans. Telomere lengths were calculated for 190 (82 men, 108 women) participants aged 79 years and associations with 384 SNPs, from 141 oxidative stress genes, identified 9 significant SNPS, of which those from 5 genes (GSTZ1, MSRA, NDUFA3, NDUFA8, VIM) had robust associations with physical aging biomarkers, respiratory function or grip strength. Replication of associations in a sample of 318 (120 males, 198 females) participants aged 50 years confirmed significant associations for two of the five SNPs (MSRA rs4841322, p=0.008; NDUFA8 rs6822, p=0.048) on telomere length. These data indicate that oxidative stress genes may be involved in pathways that lead to both telomere shortening and physiological aging in humans. Oxidative stress may explain, at least in part, associations between telomere shortening and physiological aging.

  • Dyskeratosis Congenita: a historical perspective.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2007-12-07
    Amanda J Walne,Inderjeet Dokal

    "Dyskeratosis Congenita (DC) also known as Zinsser-Engman-Cole syndrome is a rare multi-system bone marrow failure syndrome characterised by mucocutaneous abnormalities and an increased predisposition to cancer". This is a common definition of DC but how did this definition arise? The aim of this review is to follow the development of DC and associated diseases from its first reported description in the early 20th century to the current understanding of the genes involved and its pathophysiology in 2007 in a chronological order. Although this review is not intended to be an exhaustive citation of the literature available it does provide a summary of the key developments, citing particularly the earlier reports of each development.

  • Special issue on cancer and ageing.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2008-12-09
    G Pawelec,V Bohr,J Campisi

  • Upregulated ex vivo expression of stress-responsive inflammatory pathway genes by LPS-challenged CD14(+) monocytes in frail older adults.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2008-11-26
    Tao Qu,Jeremy D Walston,Huanle Yang,Neal S Fedarko,Qian-Li Xue,Brock A Beamer,Luigi Ferrucci,Noel R Rose,Sean X Leng

    Frailty has been increasingly recognized as an important clinical syndrome in old age. The frailty syndrome is characterized by chronic inflammation, decreased functional and physiologic reserve, and increased vulnerability to stressors, leading to disability and mortality. However, molecular mechanisms that contribute to inflammation activation and regulation in frail older adults have not been investigated. To begin to address this, we conducted a pathway-specific gene array analysis of 367 inflammatory pathway genes by lipopolysaccharide (LPS)-challenged CD14(+) monocytes from 32 community-dwelling frail and age-, race-, and sex-paired nonfrail older adults (mean age 83 years, range 72-94). The results showed that ex vivo LPS-challenge induced average 2.0-fold or higher upregulated expression of 116 genes in frail participants and 85 genes in paired nonfrail controls. In addition, frail participants had 2-fold or higher upregulation in LPS-induced expression of 7 stress-responsive genes than nonfrail controls with validation by quantitative real time RT-PCR. These findings suggest upregulated expression of specific stress-responsive genes in monocyte-mediated inflammatory pathway in the syndrome of frailty with potential mechanistic and interventional implications.

  • Opinion section on frailty.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2008-10-28
    Linda P Fried,Ravi Varadhan,Vilhelm A Bohr

  • Aging-from molecules to populations.
    Mech. Ageing Dev. (IF 3.603) Pub Date : 2008-09-16
    Miriam Sander,Kirsten Avlund,Martin Lauritzen,Tina Gottlieb,Barry Halliwell,Tinna Stevnsner,Ulla Wewer,Vilhelm A Bohr

    The mean age of the human population is steadily increasing in many areas around the globe, a phenomenon with large social, political, economic and biological/medical implications. Inevitably, this phenomenon is stimulating great interest in understanding and potentially modulating the process of human aging. To foster interactions and collaboration between diverse scientists interested in the biochemical, physiological, epidemiological and psychosocial aspects of aging, The University of Copenhagen Faculty of Health Sciences recently organized and co-sponsored a workshop entitled Aging-From Molecules to Populations. The following questions about human aging were discussed at the workshop: What is the limit of human life expectancy? What are the key indicators of human aging? What are the key drivers of human aging? Which genes have the greatest impact on human aging? How similar is aging-related cognitive decline to pathological cognitive decline associated with neurological disease? Are human progeriod diseases, characterized by premature aging, good models for "normal" human aging? Is delayed or "elite" aging informative about "normal" human aging? To what extent and by what mechanisms do early life environmental factors influence aging-associated physical and cognitive decline? To what extent and by what mechanism does the social environment influence life course outcomes? What physiological factors underlie the timing and extent of aging-associated physical and cognitive decline? How do cultural stereotypes and perceptions of aging influence the process and experience of aging? One of the primary outcomes of the workshop was a recognition that cross-disciplinary studies and "out-of-the-box" approaches, especially those that adopt an integrated life course perspective on human health status, are needed to expedite advances in aging research. This and other outcomes of the workshop are summarized and discussed in this report.

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