The effects of aging, injury and disease on microglial function: a case for cellular senescence

2007 ◽  
Vol 3 (3) ◽  
pp. 245-253 ◽  
Author(s):  
Kelly R. Miller ◽  
Wolfgang J. Streit
Keyword(s):  
Neurodegenerative Diseases ◽  
Cellular Senescence ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Aging Brain ◽  
Normal Brain ◽  
Age Related ◽  
Anti Inflammatory ◽  
Effects Of Aging ◽  
And Function

AbstractNeuroinflammation resulting from chronic reactive microgliosis is thought to contribute to age-related neurodegeneration, as well as age-related neurodegenerative diseases, specifically Alzheimer's disease (AD). Support of this theory comes from studies reporting a progressive, age-associated increase in microglia with an activated phenotype. Although the underlying cause(s) of this microglial reactivity is idiopathic, an accepted therapeutic strategy for the treatment of AD is inhibition of microglial activation using anti-inflammatory agents. Although the effectiveness of anti-inflammatory treatment for AD remains equivocal, microglial inhibition is being tested as a potential treatment for additional neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Given the important and necessary functions of microglia in normal brain, careful evaluation of microglial function in the aged brain is a necessary first step in targeting more precise treatment strategies for aging-related neurodegenerative diseases. Studies from our laboratory have shown multiple age-related changes in microglial morphology and function that are suggestive of cellular senescence. In this manuscript, we review current knowledge of microglia in the aging brain and present new, unpublished work that further supports the theory that microglia experience an age-related decline in proliferative function as a result of cellular senescence.

scholarly journals Novel Approaches for the Treatment of Alzheimer’s and Parkinson’s Disease

2019 ◽  
Vol 20 (3) ◽  
pp. 719 ◽  
Author(s):  
Michiel Van Bulck ◽  
Ana Sierra-Magro ◽  
Jesus Alarcon-Gil ◽  
Ana Perez-Castillo ◽  
Jose Morales-Garcia
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Current Knowledge ◽  
Chronic Illnesses ◽  
Aging Brain ◽  
Therapeutic Approaches ◽  
Neurodegenerative Process ◽  
Age Related ◽  
Parkinson’S Diseases ◽  
Current Therapies

Neurodegenerative disorders affect around one billion people worldwide. They can arise from a combination of genomic, epigenomic, metabolic, and environmental factors. Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer’s and Parkinson’s diseases. A progressive neurodegenerative process and neuroinflammation occur, and no current therapies can prevent, slow, or halt disease progression. To date, no novel disease-modifying therapies have been shown to provide significant benefit for patients who suffer from these devastating disorders. Therefore, early diagnosis and the discovery of new targets and novel therapies are of upmost importance. Neurodegenerative diseases, like in other age-related disorders, the progression of pathology begins many years before the onset of symptoms. Many efforts in this field have led to the conclusion that exits some similar events among these diseases that can explain why the aging brain is so vulnerable to suffer neurodegenerative diseases. This article reviews the current knowledge about these diseases by summarizing the most common features of major neurodegenerative disorders, their causes and consequences, and the proposed novel therapeutic approaches.

New Approaches to Profile the Microbiome for Treatment of Neurodegenerative Disease

2021 ◽  
pp. 1-29
Author(s):  
David R. Elmaleh ◽  
Matthew A. Downey ◽  
Ljiljana Kundakovic ◽  
Jeremy E. Wilkinson ◽  
Ziv Neeman ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Gut Microbiome ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Modern Society ◽  
Aging Brain ◽  
New Approaches ◽  
Microbiome Profile ◽  
Carry Over

Progressive neurodegenerative diseases represent some of the largest growing treatment challenges for public health in modern society. These diseases mainly progress due to aging and are driven by microglial surveillance and activation in response to changes occurring in the aging brain. The lack of efficacious treatment options for Alzheimer’s disease (AD), as the focus of this review, and other neurodegenerative disorders has encouraged new approaches to address neuroinflammation for potential treatments. Here we will focus on the increasing evidence that dysbiosis of the gut microbiome is characterized by inflammation that may carry over to the central nervous system and into the brain. Neuroinflammation is the common thread associated with neurodegenerative diseases, but it is yet unknown at what point and how innate immune function turns pathogenic for an individual. This review will address extensive efforts to identify constituents of the gut microbiome and their neuroactive metabolites as a peripheral path to treatment. This approach is still in its infancy in substantive clinical trials and requires thorough human studies to elucidate the metabolic microbiome profile to design appropriate treatment strategies for early stages of neurodegenerative disease. We view that in order to address neurodegenerative mechanisms of the gut, microbiome and metabolite profiles must be determined to pre-screen AD subjects prior to the design of specific, chronic titrations of gut microbiota with low-dose antibiotics. This represents an exciting treatment strategy designed to balance inflammatory microglial involvement in disease progression with an individual’s manifestation of AD as influenced by a coercive inflammatory gut.

scholarly journals Anti-inflammatory Activity of Tocotrienols in Age-related Pathologies: A SASPected Involvement of Cellular Senescence

2018 ◽  
Vol 20 (1) ◽  
Author(s):  
Marco Malavolta ◽  
Elisa Pierpaoli ◽  
Robertina Giacconi ◽  
Andrea Basso ◽  
Maurizio Cardelli ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Inflammatory Activity ◽  
Age Related ◽  
Anti Inflammatory

scholarly journals A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Hongli Shi ◽  
Xing Ge ◽  
Xi Ma ◽  
Mingxuan Zheng ◽  
Xiaoying Cui ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Gut Microbiota ◽  
Neurodegenerative Diseases ◽  
Dietary Fiber ◽  
Brain Aging ◽  
Synaptic Proteins ◽  
Aging Brain ◽  
Normal Brain ◽  
Fiber Intake ◽  
Synaptic Ultrastructure

Abstract Background Cognitive impairment, an increasing mental health issue, is a core feature of the aging brain and neurodegenerative diseases. Industrialized nations especially, have experienced a marked decrease in dietary fiber intake, but the potential mechanism linking low fiber intake and cognitive impairment is poorly understood. Emerging research reported that the diversity of gut microbiota in Western populations is significantly reduced. However, it is unknown whether a fiber-deficient diet (which alters gut microbiota) could impair cognition and brain functional elements through the gut-brain axis. Results In this study, a mouse model of long-term (15 weeks) dietary fiber deficiency (FD) was used to mimic a sustained low fiber intake in humans. We found that FD mice showed impaired cognition, including deficits in object location memory, temporal order memory, and the ability to perform daily living activities. The hippocampal synaptic ultrastructure was damaged in FD mice, characterized by widened synaptic clefts and thinned postsynaptic densities. A hippocampal proteomic analysis further identified a deficit of CaMKIId and its associated synaptic proteins (including GAP43 and SV2C) in the FD mice, along with neuroinflammation and microglial engulfment of synapses. The FD mice also exhibited gut microbiota dysbiosis (decreased Bacteroidetes and increased Proteobacteria), which was significantly associated with the cognitive deficits. Of note, a rapid differentiating microbiota change was observed in the mice with a short-term FD diet (7 days) before cognitive impairment, highlighting a possible causal impact of the gut microbiota profile on cognitive outcomes. Moreover, the FD diet compromised the intestinal barrier and reduced short-chain fatty acid (SCFA) production. We exploit these findings for SCFA receptor knockout mice and oral SCFA supplementation that verified SCFA playing a critical role linking the altered gut microbiota and cognitive impairment. Conclusions This study, for the first time, reports that a fiber-deprived diet leads to cognitive impairment through altering the gut microbiota-hippocampal axis, which is pathologically distinct from normal brain aging. These findings alert the adverse impact of dietary fiber deficiency on brain function, and highlight an increase in fiber intake as a nutritional strategy to reduce the risk of developing diet-associated cognitive decline and neurodegenerative diseases.

Neuroimaging Approaches for Elderly Studies

2017 ◽  
pp. 1576-1617
Author(s):  
Charis Styliadis ◽  
Panagiotis Kartsidis ◽  
Evangelos Paraskevopoulos
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Structure And Function ◽  
Cognitive Capacity ◽  
Aging Brain ◽  
Cerebral Structure ◽  
Age Related ◽  
Elderly Populations ◽  
And Function ◽  
Age Related Changes

Advances in the field of neuroimaging have allowed for the examination of the effects of age-related changes on cognitive capacity in elderly populations. Structural techniques are now routinely used to report cortical atrophic rates in aging and particularly within the context of the Alzheimer's disease, and may be integrated with functional techniques which examine the functional characteristics of the cortex at rest and during the performance of a task. Despite advancing age cognitive function remains highly plastic, allowing for interventions that aim to maintain or even remediate its capacity and the mechanisms by which structure and function are altered among seniors. Overall, information on the integrity of the cerebral structure and function aid in the early detection and treatment of the Alzheimer's disease as well as the evaluation and track of the disease's progression. In this chapter, neuroimaging methods are presented along with findings that are particularly relevant for the study of neuroplasticity in the aging brain.

scholarly journals Role of Age-Related Mitochondrial Dysfunction in Sarcopenia

2020 ◽  
Vol 21 (15) ◽  
pp. 5236 ◽  
Author(s):  
Evelyn Ferri ◽  
Emanuele Marzetti ◽  
Riccardo Calvani ◽  
Anna Picca ◽  
Matteo Cesari ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cellular Senescence ◽  
Significant Loss ◽  
Muscle Aging ◽  
Age Related ◽  
Mitochondrial Functions ◽  
Health Quality ◽  
Skeletal Muscle Aging ◽  
And Function

Skeletal muscle aging is associated with a significant loss of skeletal muscle strength and power (i.e., dynapenia), muscle mass and quality of life, a phenomenon known as sarcopenia. This condition affects nearly one-third of the older population and is one of the main factors leading to negative health outcomes in geriatric patients. Notwithstanding the exact mechanisms responsible for sarcopenia are not fully understood, mitochondria have emerged as one of the central regulators of sarcopenia. In fact, there is a wide consensus on the assumption that the loss of mitochondrial integrity in myocytes is the main factor leading to muscle degeneration. Mitochondria are also key players in senescence. It has been largely proven that the modulation of mitochondrial functions can induce the death of senescent cells and that removal of senescent cells improves musculoskeletal health, quality, and function. In this review, the crosstalk among mitochondria, cellular senescence, and sarcopenia will be discussed with the aim to elucidate the role that the musculoskeletal cellular senescence may play in the onset of sarcopenia through the mediation of mitochondria.

scholarly journals The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases

2020 ◽  
Vol 21 (6) ◽  
pp. 2108 ◽  
Author(s):  
Wioletta Rozpędek-Kamińska ◽  
Natalia Siwecka ◽  
Adam Wawrzynkiewicz ◽  
Radosław Wojtczak ◽  
Dariusz Pytel ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Stress Conditions ◽  
World Population ◽  
Dependent Manner ◽  
Age Related ◽  
The Unfolded Protein Response

Higher prevalence of neurodegenerative diseases is strictly connected with progressive aging of the world population. Interestingly, a broad range of age-related, neurodegenerative diseases is characterized by a common pathological mechanism—accumulation of misfolded and unfolded proteins within the cells. Under certain circumstances, such protein aggregates may evoke endoplasmic reticulum (ER) stress conditions and subsequent activation of the unfolded protein response (UPR) signaling pathways via the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent manner. Under mild to moderate ER stress, UPR has a pro-adaptive role. However, severe or long-termed ER stress conditions directly evoke shift of the UPR toward its pro-apoptotic branch, which is considered to be a possible cause of neurodegeneration. To this day, there is no effective cure for Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), or prion disease. Currently available treatment approaches for these diseases are only symptomatic and cannot affect the disease progression. Treatment strategies, currently under detailed research, include inhibition of the PERK-dependent UPR signaling branches. The newest data have reported that the use of small-molecule inhibitors of the PERK-mediated signaling branches may contribute to the development of a novel, ground-breaking therapeutic approach for neurodegeneration. In this review, we critically describe all the aspects associated with such targeted therapy against neurodegenerative proteopathies.

scholarly journals Cellular Aging Characteristics and Their Association with Age-Related Disorders

Antioxidants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 94 ◽  
Author(s):  
Magdalena Rudzińska ◽  
Alessandro Parodi ◽  
Anastasia V. Balakireva ◽  
Olga E. Chepikova ◽  
Franco M. Venanzi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cellular Senescence ◽  
Current Knowledge ◽  
Cell Metabolism ◽  
Critical Role ◽  
Cellular Aging ◽  
Molecular Signaling ◽  
Age Related ◽  
Organelle Communication ◽  
Metabolic Dysfunctions

Different molecular signaling pathways, biological processes, and intercellular communication mechanisms control longevity and are affected during cellular senescence. Recent data have suggested that organelle communication, as well as genomic and metabolic dysfunctions, contribute to this phenomenon. Oxidative stress plays a critical role by inducing structural modifications to biological molecules while affecting their function and catabolism and eventually contributing to the onset of age-related dysfunctions. In this scenario, proteins are not adequately degraded and accumulate in the cell cytoplasm as toxic aggregates, increasing cell senescence progression. In particular, carbonylation, defined as a chemical reaction that covalently and irreversibly modifies proteins with carbonyl groups, is considered to be a significant indicator of protein oxidative stress and aging. Here, we emphasize the role and dysregulation of the molecular pathways controlling cell metabolism and proteostasis, the complexity of the mechanisms that occur during aging, and their association with various age-related disorders. The last segment of the review details current knowledge on protein carbonylation as a biomarker of cellular senescence in the development of diagnostics and therapeutics for age-related dysfunctions.

Aging affects vascular structure and function in a limb-specific manner

2008 ◽  
Vol 105 (5) ◽  
pp. 1661-1670 ◽  
Author(s):  
Steven K. Nishiyama ◽  
D. Walter Wray ◽  
Russell S. Richardson
Keyword(s):  
Shear Rate ◽  
Intima Media Thickness ◽  
Structure And Function ◽  
Vascular Pathology ◽  
Ischemic Reperfusion ◽  
Age Related ◽  
Vessel Structure ◽  
Healthy Young People ◽  
Effects Of Aging ◽  
And Function

The limb-specific effects of aging upon vessel structure and function are not well understood. Consequently, in 12 young (26 ± 2 yr) and 12 old (72 ± 1 yr) healthy subjects, we utilized ultrasound Doppler to evaluate intima-media thickness (IMT), ischemic reperfusion, and flow-mediated dilation (FMD) following (5 min) suprasystolic cuff occlusion in both the arm [brachial artery (BA)] and the leg [popliteal artery (PA)]. Structural measurements, whether normalized for vessel size or not, revealed a greater IMT in both the BA and PA with age (young: BA 0.028 ± 0.001 and PA 0.046 ± 0.003 cm, old: BA 0.039 ± 0.002 and PA 0.073 ± 0.005 cm; P < 0.05). Ischemic reperfusion revealed a similar pattern as IMT in terms of limb and age-related differences. There was an age-related attenuation in both BA FMD (old: 38% smaller BA FMD compared with young) and PA FMD (old: 71% smaller PA FMD compared with young). However, when this percent change was normalized for shear rate, only the PA FMD of the old group was still significantly attenuated (old: 41% smaller PA FMD/shear rate compared with young). Together, the finding of differential structural and functional parameters in the arms and legs of healthy young people, and the somewhat negative findings that are specific to the legs of otherwise healthy older people (greater IMT and attenuated FMD), support and may help to better understand the increased propensity to develop a vascular pathology in the legs with age.

scholarly journals Inefficiency in Self-organized Attentional Switching in the Normal Aging Population is Associated with Decreased Activity in the Ventrolateral Prefrontal Cortex

2008 ◽  
Vol 20 (9) ◽  
pp. 1670-1686 ◽  
Author(s):  
Adam Hampshire ◽  
Aleksandra Gruszka ◽  
Sean J. Fallon ◽  
Adrian M. Owen
Keyword(s):  
Prefrontal Cortex ◽  
Problem Solving ◽  
Frontal Cortex ◽  
Posterior Parietal Cortex ◽  
Reward Processing ◽  
Aging Brain ◽  
Ventrolateral Prefrontal Cortex ◽  
Age Related ◽  
Dorsolateral Prefrontal ◽  
Effects Of Aging

Studies of the aging brain have demonstrated that areas of the frontal cortex, along with their associated top-down executive control processes, are particularly prone to the neurodegenerative effects of age. Here, we investigate the effects of aging on brain and behavior using a novel task, which allows us to examine separate components of an individual's chosen strategy during routine problem solving. Our findings reveal that, contrary to previous suggestions of a specific decrease in cognitive flexibility, older participants show no increased level of perseveration to either the recently rewarded object or the recently relevant object category. In line with this lack of perseveration, lateral and medial regions of the orbito-frontal cortex, which are associated with inhibitory control and reward processing, appear to be functionally intact. Instead, a general loss of efficient problem-solving strategy is apparent with a concomitant decrease in neural activity in the ventrolateral prefrontal cortex and the posterior parietal cortex. The dorsolateral prefrontal cortex is also affected during problem solving, but age-related decline within this region appears to occur at a later stage.

Sign in / Sign up

Export Citation Format

Share Document