Redox homeostasis and cellular stress response in aging and neurodegeneration.

Decreased expression and/or activity of antioxidant proteins leads to oxidative stress, accelerated aging, and neurodegeneration. While overwhelming levels and uncontrolled/dysregulated actions of reactive oxygen species (ROS) lead to deleterious effects, tighter regulation of those plays an important role in cell signaling. Mutations causing protein misfolding and the overload of toxic products derived from the free radical oxidation of polyunsaturated fatty acids, cholesterol, and glucose contribute to the disruption of the cellular redox homeostasis. Collectively or individually, these effects create pro-oxidant conditions in cells. Oxidative stress can induce neuronal damage, modulate intracellular signaling, and can ultimately lead to neuronal death by apoptosis or necrosis. Emerging evidence indicates that homocysteine (Hcy), a non-protein amino acid naturally present in the plasma, is implicated as a risk factor for numerous diseases. In particular, increased levels of circulating Hcy have been recognized as an independent risk factor for the development of vascular disease(s). Recent findings emphasize a relationship between elevated Hcy levels and neurodegeneration, which can be observed in Alzheimer's and Parkinson's diseases. An integrated response exists in the brain to detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are controlled by several genes termed "vitagenes." Among these, the heat-shock proteins (HSPs) form a highly conserved system that is responsible for the preservation and repair of the correct protein conformation. Recent studies have shown that the heat-shock response (HSR) contributes to cytoprotection in a number of human diseases including inflammation, cancer, aging, and neurodegenerative disorders. Given the broad cytoprotective properties of the HSR, interest mounts currently among investigators toward discovering and developing pharmacological agents capable of inducing HSR. L: -Acetylcarnitine (LAC) is proposed as a therapeutic agent for several neurodegenerative disorders and also current evidence suggests that the compound may play a critical role in the modulation of cellular stress response in health and disease conditions. Here, we review the emerging salient concepts highlighting the pathways of neurodegeneration and the role of LAC in modulating the redox-dependent mechanisms responsible for the upregulation of vitagenes in brain that leads to the enhancement of stress tolerance in brain.

Redox modulation of heat shock protein expression by acetylcarnitine in aging brain: relationship to antioxidant status and mitochondrial function.

There is significant evidence to show that aging is characterized by a stochastic accumulation of molecular damage and by a progressive failure of maintenance and repair processes. Protective mechanisms exist in the brain which are controlled by vitagenes and include members of the heat shock system, heme oxygenase-I, and Hsp70 as critical determinants of brain stress tolerance. Given the broad cytoprotective properties of the heat shock response, molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. Acetyl-L-carnitine is proposed as a therapeutic agent for several neurodegenerative disorders, and the present study reports that treatment for 4 months of senescent rats with acetyl-L-carnitine induces heme oxygenase-1 as well as Hsp70 and SOD-2. This effect was associated with upregulation of GSH levels, prevention of age-related changes in mitochondrial respiratory chain complex expression, and decrease in protein carbonyls and HNE formation. We hypothesize that maintenance or recovery of the activity of vitagenes may delay the aging process and decrease the risk of age-related diseases. Particularly, modulation of endogenous cellular defense mechanisms via acetyl-L-carnitine may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.

Redox regulation of heat shock protein expression by signaling involving nitric oxide and carbon monoxide: relevance to brain aging, neurodegenerative disorders, and longevity.

Increased free radical generation and decreased efficiency of the reparative/degradative mechanisms both primarily contribute to age-related elevation in the level of oxidative stress and brain damage. Excess formation of reactive oxygen and nitrogen species can cause proteasomal dysfunction and protein overloading. The major neurodegenerative diseases are all associated with the presence of abnormal proteins. Different integrated responses exist in the brain to detect oxidative stress which is controlled by several genes termed vitagenes, including the heat shock protein (HSP) system. Of the various HSPs, heme oxygenase-I (HO-1), by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. The HO-1 gene is redox regulated and its expression is modulated by redox active compounds, including nutritional antioxidants. Given the broad cytoprotective properties of the heat shock response, there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. These findings have opened up new neuroprotective strategies, as molecules inducing this defense mechanism can be a therapeutic target to minimize the deleterious consequences associated with accumulation of conformationally aberrant proteins to oxidative stress, such as in neurodegenerative disorders and brain aging, with resulting prolongation of a healthy life span.

Effect of antioxidant diets on mitochondrial gene expression in rat brain during aging.

Age-related increase of reactive oxygen species (ROS) is particularly detrimental in postmitotic tissues. Calorie restriction (CR) has been shown to exert beneficial effects, consistent with reduced ROS generation by mitochondria. Many antioxidant compounds also mimic such effects. N-acetyl cysteine (NAC) provides thiol groups to glutathione and to mitochondrial respiratory chain proteins; thus, it may counteract both ROS generation and effects. In the present study we investigated, in different rat brain areas during aging (6, 12, and 28 months), the effect of 1-year treatment with CR and dietary supplementation with NAC on the expression of subunit 39 kDa and ND-1 (mitochondrial respiratory complex I), subunit IV (complex IV), subunit alpha of F0F1-ATP synthase (complex V) and of adenine nucleotide translocator, isoform 1 (ANT-1). The observed age-related changes of expression were prevented by the dietary treatments. The present study provides further evidence for the critical role of mitochondria in the aging process.

Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia.

There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) associated with mitochondrial dysfunction. The mitochondrial genome may play an essential role in the pathogenesis of these diseases, and evidence for mitochondria being a site of damage in neurodegenerative disorders is based in part on observed decreases in the respiratory chain complex activities in Parkinson's, Alzheimer's, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant imbalance, are thought to underlie defects in energy metabolism and induce cellular degeneration. The precise sequence of events in FRDA pathogenesis is uncertain. The impaired intramitochondrial metabolism with increased free iron levels and a defective mitochondrial respiratory chain, associated with increased free radical generation and oxidative damage, may be considered possible mechanisms that compromise cell viability. Recent evidence suggests that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols, and in addition, that decreased expression of frataxin protein is associated with FRDA. Many approaches have been undertaken to understand FRDA, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to FRDA pathogenesis. Brains of FRDA patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress. In the central nervous system, heat shock protein (HSP) synthesis is induced not only after hyperthermia, but also following alterations in the intracellular redox environment. The major neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's disease (HD) and FRDA are all associated with the presence of abnormal proteins. Among the various HSPs, HSP32, also known as heme oxygenase I (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. This may open up new perspectives in medicine, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms, such as the heat shock response, through nutritional antioxidants, pharmacological compounds or gene transduction, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.

Redox regulation in neurodegeneration and longevity: role of the heme oxygenase and HSP70 systems in brain stress tolerance.

Efficient functioning of maintenance and repair processes seems to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed "vitagenes," among these, the heat shock system, a highly conserved mechanism responsible for the preservation and repair of cellular macromolecules, such as proteins, RNAs, and DNA. Recent studies have shown that the heat shock response contributes to establishing a cytoprotective state in a wide variety of human diseases, including ischemia and reperfusion damage, inflammation, cancer, as well as metabolic and neurodegenerative disorders. Recently, the involvement of the heme oxygenase (HO) pathway in antidegenerative mechanisms has received considerable attention, as it has been demonstrated that the expression of HO is closely related to that of amyloid precursor protein. HO induction occurs together with the induction of other heat shock proteins during various physiopathological conditions. The vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, products of HO-catalyzed reaction, represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response, molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. Particularly, manipulation of endogenous cellular defense mechanisms, via the heat shock response, through nutritional antioxidants or pharmacological compounds, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. Consistently, by maintaining or recovering the activity of vitagenes, it is feasible to delay the aging process and decrease the occurrence of age-related diseases with resulting prolongation of a healthy life span.