Reactive oxygen and nitrogen species (RONS) are produced by several endogenous and exogenous processes, and their negative effects are neutralized by antioxidant defenses. Oxidative stress occurs from the imbalance between RONS production and these antioxidant defenses. Aging is a process characterized by the progressive loss of tissue and organ function. The oxidative stress theory of aging is based on the hypothesis that age-associated functional losses are due to the accumulation of RONS-induced damages. At the same time, oxidative stress is involved in several age-related conditions (ie, cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases, and cancer), including sarcopenia and frailty. Different types of oxidative stress biomarkers have been identified and may provide important information about the efficacy of the treatment, guiding the selection of the most effective drugs/dose regimens for patients and, if particularly relevant from a pathophysiological point of view, acting on a specific therapeutic target. Given the important role of oxidative stress in the pathogenesis of many clinical conditions and aging, antioxidant therapy could positively affect the natural history of several diseases, but further investigation is needed to evaluate the real efficacy of these therapeutic interventions. The purpose of this paper is to provide a review of literature on this complex topic of ever increasing interest.

/pdf/oxidative-stress-aging-and-diseases-3hb33el5ni.pdf

Oxidative stress, aging, and diseases.

(Macro)autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Although the term autophagy was first used in 1963, the field has witnessed dramatic growth in the last 5 years, partly as a consequence of the discovery of key components of its cellular machinery. In this review we focus on mammalian autophagy, and we give an overview of the understanding of its machinery and the signaling cascades that regulate it. As recent studies have also shown that autophagy is critical in a range of normal human physiological processes, and defective autophagy is associated with diverse diseases, including neurodegeneration, lysosomal storage diseases, cancers, and Crohn's disease, we discuss the roles of autophagy in health and disease, while trying to critically evaluate if the coincidence between autophagy and these conditions is causal or an epiphenomenon. Finally, we consider the possibility of autophagy upregulation as a therapeutic approach for various conditions.

https://www.physiology.org/doi/pdf/10.1152/physrev.00030.2009

Regulation of Mammalian Autophagy in Physiology and Pathophysiology

Neurons are metabolically active cells with high energy demands at locations distant from the cell body. As a result, these cells are particularly dependent on mitochondrial function, as reflected by the observation that diseases of mitochondrial dysfunction often have a neurodegenerative component. Recent discoveries have highlighted that neurons are reliant particularly on the dynamic properties of mitochondria. Mitochondria are dynamic organelles by several criteria. They engage in repeated cycles of fusion and fission, which serve to intermix the lipids and contents of a population of mitochondria. In addition, mitochondria are actively recruited to subcellular sites, such as the axonal and dendritic processes of neurons. Finally, the quality of a mitochondrial population is maintained through mitophagy, a form of autophagy in which defective mitochondria are selectively degraded. We review the general features of mitochondrial dynamics, incorporating recent findings on mitochondrial fusion, fission, transport and mitophagy. Defects in these key features are associated with neurodegenerative disease. Charcot-Marie-Tooth type 2A, a peripheral neuropathy, and dominant optic atrophy, an inherited optic neuropathy, result from a primary deficiency of mitochondrial fusion. Moreover, several major neurodegenerative diseases—including Parkinson's, Alzheimer's and Huntington's disease—involve disruption of mitochondrial dynamics. Remarkably, in several disease models, the manipulation of mitochondrial fusion or fission can partially rescue disease phenotypes. We review how mitochondrial dynamics is altered in these neurodegenerative diseases and discuss the reciprocal interactions between mitochondrial fusion, fission, transport and mitophagy.

Mitochondrial dynamics–fusion, fission, movement, and mitophagy–in neurodegenerative diseases

During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

/pdf/preclinical-alzheimer-s-disease-definition-natural-history-1op128x94m.pdf

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

https://www.cell.com/neuron/pdf/S0896-6273(12)00756-8.pdf

Synaptic Energy Use and Supply

Background: Expression of the non-proline-dependent casein kinase 1 delta (CK1d) is highly elevated in Alzheimer’s disease (AD) brain tissue where it plays an important, early role in phosphorylation of the microtubule associate protein tau, and regulates aspects of the cell cycle which has recently been shown to reactivate in AD neurones leading to cell death. CK1d also regulates the levels of the period proteins Per1 and Per2 that control circadian rhythmwhich is often disturbed in AD. Thus, CK1d represents a potentially important target for drug development in AD and further analysis of the activity of different CK1d-mediated pathways is required. Methods: We have previously developed two selective CK1d inhibitors, PS110 & PS278-05 that are orally available and enter the brain at therapeutic levels with no overt signs of toxicity. Both compounds improved cognitive performance in the TMHT transgenic mouse model of tauopathy. Effects on tau phosphorylation were monitored using targeted mass spectrometry and western blotting with decreased phosphorylation at several sites including Threonine 231 and Serine 396, and a general reduction in level of total tau phosphorylation compared with vehicle-treated controls. Results: As expected, active CDK5 levels were substantially reduced, consistent with a significant reduction of total CK1d protein levels seen in treated animals. Finally, levels of Per1 and Per2 were reduced in treated animals although there was a marked difference between Per1 and Per2 suggesting different modes of action for PS110 and PS278-05. To further understand this we are applying a global phosphorylation workflow, SysQuant, to determine the cross-pathway effects of CK1d inhibition in mouse brain tissue. Results will be presented at the meeting.Conclusions: Ck1d appears to play a role in several aspects of AD pathology and clinical symptoms, and represents a tractable drug target. Inhibition of CK1d is likely to affect multiple cell signaling pathways and we will present data showing which pathways are most active in a mouse model of tauopathy and how these are modulated by CK1 inhibition

Restoration of axonal trafficking of mitochondria averts cognitive decline in mouse models of familial alzheimer's disease

Cytokine profile in the nasal secretion of children with allergic rhinitis and adenoid hypertrophy

Compounds and compositions that can modulate mitochondrial function in neuronal cells are provided herein, as are methods for using the compounds and compositions to treat or prevent conditions such as Alzheimer's disease. For example, compounds of Formula I, compositions containing the compounds, and methods for using the compounds and compositions are provided herein: 
wherein X is absent, CH 2 , or C(O); R 1 is H, OH, CN, NO 2 , halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-7 cycloalkyl, amino, C 1-3 alkylamino, or di(C 1-3 alkyl)amino; R 2 is H or C 1-6 alkyl; R 3 is H, C 1-6 alkyl, —C(O)(C 1-3 alkyl), or —C(O)O(C 1-3 alkyl); R 4 is C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R 5 groups; and R 5 is OH, CN, NO 2 , halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-7 cycloalkyl, amino, C 1-3 alkylamino, or di(C 1-3 alkyl)amino.

Compounds for modulating mitochondrial function

Autophagy is Required for the Maintenance of NAD

Consistent failure of clinical trials for Alzheimer Disease (AD) emphasizes the necessity to identify novel therapeutic targets for this debilitating condition. We recently identified the mitochondrial complex I (MCI) as a small molecule druggable therapeutic target for AD.

Eugenia Trushina

Papers

Restoration of axonal trafficking of mitochondria averts cognitive decline in mouse models of familial alzheimer's disease

Cytokine profile in the nasal secretion of children with allergic rhinitis and adenoid hypertrophy

Compounds for modulating mitochondrial function

Autophagy is Required for the Maintenance of NAD

Development of Novel Partial Mitochondrial Complex I Inhibitors as a Therapy for Alzheimer Disease.