The Good, the Bad, and the Ugly of ROS: New Insights on Aging and Aging-Related Diseases from Eukaryotic and Prokaryotic Model Organisms

Aging is associated with the accumulation of cellular damage over the course of a lifetime. This process is promoted in large part by reactive oxygen species (ROS) generated via cellular metabolic and respiratory pathways. Pharmacological, nonpharmacological, and genetic interventions have been used to target cellular and mitochondrial networks in an effort to decipher aging and age-related disorders. While ROS historically have been viewed as a detrimental byproduct of normal metabolism and associated with several pathologies, recent research has revealed a more complex and beneficial role of ROS in regulating metabolism, development, and lifespan. In this review, we summarize the recent advances in ROS research, focusing on both the beneficial and harmful roles of ROS, many of which are conserved across species from bacteria to humans, in various aspects of cellular physiology. These studies provide a new context for our understanding of the parts ROS play in health and disease. Moreover, we highlight the utility of bacterial models to elucidate the molecular pathways by which ROS mediate aging and aging-related diseases

Relationship between Pentosidine and Pyridinoline Levels in Human Diabetic Cataract Lenses

The relationship between the levels of two different crosslink compounds, pentosidine and pyridinoline, in human diabetic cataract lenses was investigated to elucidate the pathogenic mechanism of diabetic cataract. Subjects were classified into diabetes mellitus (DM) group and non-DM group according to the presence or absence of DM. The levels of the crosslink compounds were determined using high-performance liquid chromatography and spectrofluorometry after acid hydrolysis. In the non-DM group the pentosidine level was significantly and positively correlated with the pyridinoline level and age. In the DM group the pentosidine level was not significantly correlated with either pyridinoline level or age. Pyridinoline levels and age were not significantly correlated in either group. The increase in crosslink compounds due to glycation and the relationship between the compounds are changed in DM lenses

Trends in the Molecular Pathogenesis and Clinical Therapeutics of Common Neurodegenerative Disorders

The term neurodegenerative disorders, encompasses a variety of underlying conditions, sporadic and/or familial and are characterized by the persistent loss of neuronal subtypes. These disorders can disrupt molecular pathways, synapses, neuronal subpopulations and local circuits in specific brain regions, as well as higher-order neural networks. Abnormal network activities may result in a vicious cycle, further impairing the integrity and functions of neurons and synapses, for example, through aberrant excitation or inhibition. The most common neurodegenerative disorders are Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis and Huntington’s disease. The molecular features of these disorders have been extensively researched and various unique neurotherapeutic interventions have been developed. However, there is an enormous coercion to integrate the existing knowledge in order to intensify the reliability with which neurodegenerative disorders can be diagnosed and treated. The objective of this review article is therefore to assimilate these disorders’ in terms of their neuropathology, neurogenetics, etiology, trends in pharmacological treatment, clinical management, and the use of innovative neurotherapeutic interventions

The Relationship Between Circadian Rhythms and Neurodegenerative Disease

Neurodegenerative disease is a pervasive and insidious disease affecting a large proportion of the elderly population. Leading to the degeneration of neural tissue throughout the nervous system, it is a slow and progressive disorder. Because of its nature, it is possible that it has a connection to circadian rhythms. Circadian rhythms are the endogenous approximately 24-hour rhythms of the body commonly associated with the sleep-wake cycle, but they account for much more. This review aims to ascertain the relationship between the two by covering several facets of research pursued in the past five years. Beginning with establishing a basic understanding of neurodegenerative disease and circadian rhythms before moving on to the research. Genetic disruption accounts for the subtle yet most influential factor, affecting many systems later on. Next follows the best researched avenue of sleep followed by the immune response with neuroinflammation and apoptosis in neuronal tissue. Finally, is a brief overlook of avenues pursued outside of the brain investigating strong links to the kidneys and the bacteria of the intestines. With everything combined, it is clear that the relationship here is this positive-feedback loop of ever-worsening conditions in individuals with neurodegenerative disease. At the end, brief comments are noted on potential treatments mentioned throughout the review along with the continued progression and need for new potential avenues of research

Multiple system atrophy - a clinicopathological update

Multiple system atrophy (MSA) is a fatal, adult-onset neurodegenerative disorder of uncertain etiology, clinically characterized by various combinations of Levo-dopa-unresponsive parkinsonism, and cerebellar, motor, and autonomic dysfunctions. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, autonomic and peripheral nervous systems. The pathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein (αSyn) in both glia (mainly oligodendroglia) and neurons forming pathological inclusions that cause cell dysfunction and demise. The major variants are striatonigral degeneration (MSA with predominant parkinsonism / MSA-P) and olivopontocerebellar atrophy (MSA with prominent cerebellar ataxia / MSA-C). However, the clinical and pathological features of MSA are broader than previously considered. Studies in various mouse models and human patients have helped to better understand the molecular mechanisms that underlie the progression of the disease. The pathogenesis of MSA is characterized by propagation of disease-specific strains of αSyn from neurons to oligodendroglia and cell-to-cell spreading in a "prion-like" manner, oxidative stress, proteasomal and mitochondrial dysfunctions, myelin dysregulation, neuroinflammation, decreased neurotrophic factors, and energy failure. The combination of these mechanisms results in neurodegeneration with widespread demyelination and a multisystem involvement that is specific for MSA. Clinical diagnostic accuracy and differential diagnosis of MSA have improved by using combined biomarkers. Cognitive impairment, which has been a non-supporting feature of MSA, is not uncommon, while severe dementia is rare. Despite several pharmacological approaches in MSA models, no effective disease-modifying therapeutic strategies are currently available, although many clinical trials targeting disease modification, including immunotherapy and combined approaches, are under way. Multidisciplinary research to elucidate the genetic and molecular background of the noxious processes as the basis for development of an effective treatment of the hitherto incurable disorder are urgently needed

Brain aging and garbage cleaning : Modelling the role of sleep, glymphatic system, and microglia senescence in the propagation of inflammaging

Brain aging is a complex process involving many functions of our body and described by the interplay of a sleep pattern and changes in the metabolic waste concentration regulated by the microglial function and the glymphatic system. We review the existing modelling approaches to this topic and derive a novel mathematical model to describe the crosstalk between these components within the conceptual framework of inflammaging. Analysis of the model gives insight into the dynamics of garbage concentration and linked microglial senescence process resulting from a normal or disrupted sleep pattern, hence, explaining an underlying mechanism behind healthy or unhealthy brain aging. The model incorporates accumulation and elimination of garbage, induction of glial activation by garbage, and glial senescence by over-activation, as well as the production of pro-inflammatory molecules by their senescence-associated secretory phenotype (SASP). Assuming that insufficient sleep leads to the increase of garbage concentration and promotes senescence, the model predicts that if the accumulation of senescent glia overcomes an inflammaging threshold, further progression of senescence becomes unstoppable even if a normal sleep pattern is restored. Inverting this process by "rejuvenating the brain" is only possible via a reset of concentration of senescent glia below this threshold. Our model approach enables analysis of space-time dynamics of senescence, and in this way, we show that heterogeneous patterns of inflammation will accelerate the propagation of senescence profile through a network, confirming a negative effect of heterogeneity

Alzheimer’s Disease: From Immune Homeostasis to Neuroinflammatory Condition

Alzheimer’s Disease is the most common cause in the world of progressive cognitive decline. Although many modifiable and non-modifiable risk factors have been proposed, in recent years, neuroinflammation has been hypothesized to be an important contributing factor of Alzheimer’s Disease pathogenesis. Neuroinflammation can occur through the combined action of the Central Nervous System resident immune cells and adaptive peripheral immune system. In the past years, immunotherapies for neurodegenerative diseases have focused wrongly on targeting protein aggregates Aβ plaques and NFT treatment. The role of both innate and adaptive immune cells has not been fully clarified, but several data suggest that immune system dysregulation plays a key role in neuroinflammation. Recent studies have focused especially on the role of the adaptive immune system and have shown that inflammatory markers are characterized by increased CD4+ Teff cells’ activities and reduced circulating CD4+ Treg cells. In this review, we discuss the key role of both innate and adaptive immune systems in the degeneration and regeneration mechanisms in the pathogenesis of Alzheimer’s Disease, with a focus on how the crosstalk between these two systems is able to sustain brain homeostasis or shift it to a neurodegenerative condition

Changes in the Mitochondria in the Aging Process-Can α-Tocopherol Affect Them?

Aerobic organisms use molecular oxygen in several reactions, including those in which the oxidation of substrate molecules is coupled to oxygen reduction to produce large amounts of metabolic energy. The utilization of oxygen is associated with the production of ROS, which can damage biological macromolecules but also act as signaling molecules, regulating numerous cellular processes. Mitochondria are the cellular sites where most of the metabolic energy is produced and perform numerous physiological functions by acting as regulatory hubs of cellular metabolism. They retain the remnants of their bacterial ancestors, including an independent genome that encodes part of their protein equipment; they have an accurate quality control system; and control of cellular functions also depends on communication with the nucleus. During aging, mitochondria can undergo dysfunctions, some of which are mediated by ROS. In this review, after a description of how aging affects the mitochondrial quality and quality control system and the involvement of mitochondria in inflammation, we report information on how vitamin E, the main fat-soluble antioxidant, can protect mitochondria from age-related changes. The information in this regard is scarce and limited to some tissues and some aspects of mitochondrial alterations in aging. Improving knowledge of the effects of vitamin E on aging is essential to defining an optimal strategy for healthy aging

Understanding the gastrointestinal tract of the elderly to develop dietary solutions that prevent malnutrition

Although the prevalence of malnutrition in the old age is increasing worldwide a synthetic understanding of the impact of aging on the intake, digestion, and absorption of nutrients is still lacking. This review article aims at filling the gap in knowledge between the functional decline of the aging gastrointestinal tract (GIT) and the consequences of malnutrition on the health status of elderly. Changes in the aging GIT include the mechanical disintegration of food, gastrointestinal motor function, food transit, chemical food digestion, and functionality of the intestinal wall. These alterations progressively decrease the ability of the GIT to provide the aging organism with adequate levels of nutrients, what contributes to the development of malnutrition. Malnutrition, in turn, increases the risks for the development of a range of pathologies associated with most organ systems, in particular the nervous-, muscoskeletal-, cardiovascular-, immune-, and skin systems. In addition to psychological, economics, and societal factors, dietary solutions preventing malnutrition should thus propose dietary guidelines and food products that integrate knowledge on the functionality of the aging GIT and the nutritional status of the elderly. Achieving this goal will request the identification, validation, and correlative analysis of biomarkers of food intake, nutrient bioavailability, and malnutrition.info:eu-repo/semantics/publishedVersio