Redox proteomics, thiol homeostasis and neurophysiologicla correlations in aging and neurodegeneration

The terms "aging" and "neurodegeneration" are often used in a broad and generalized manner. Actually, they are particularly complex and multifaceted processes, involving different biochemical systems. Increasing evidence supports the notion that reduction of cellular expression and activity of antioxidant proteins and the resulting increase of oxidative stress are fundamental causes in the aging processes and neurodegenerative diseases. Within the frame of free radical hypothesis of aging, several lines of evidence suggest that accumulation of oxidative molecular damage is a causal factor in senescence. It is also increasingly evident that the mitochondrial genome may play a key role in aging and neurodegenerative diseases. Mitochondrial dysfunction is characteristic of several neurodegenerative disorders, and evidence for mitochondria being a site of damage in neurodegenerative disorders is partially based on decreases in respiratory chain complex activities in Parkinson s disease (PD), Alzheimer s disease (AD), and Huntington s disease (HD). Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant balance perturbation, are thought to underlie defects in energy metabolism and induce cellular degeneration. Efficient functioning of mantainance and repair process 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, heat shock proteins, also known as stress proteins and molecular chaperones, are highly conserved proteins for the preservation and repair of the correct conformation of cellular macromolecules, such as proteins, RNAs and DNA. Chaperone-buffered silent mutations may be activated during the aging process and lead to the phenotypic exposure of previously hidden features and contribute to the onset of multigenic diseases, such as age-related disorders, atherosclerosis and cancer. 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, metabolic disorders, cancer, infection, trauma, and aging. The major neurodegenerative diseases, Alzheimer s disease (AD), Parkinson s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington s disease (HD), and Friedreich s ataxia (FA), are all associated with the presence of abnormal. 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 perspectives in medicine and pharmacology, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. Particularly, modulation of endogenous cellular defense mechanisms such as the heat-shock response, and the proteasomal system, through nutritional antioxidants or pharmacological compounds may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. Moreover, by maintaining or recovering the activity of vitagenes, it would be possible to delay the aging process and decrease the occurrence of age-related diseases with resulting prolongation of a healthy life span