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Cellular Stress Responses, Mitostress and Carnitine Insufficiencies as Critical Determinants in Aging and Neurodegenerative Disorders: Role of Hormesis and Vitagenes

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Abstract

The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. A prediction of this theory is that, among species, differential rates of aging may be apparent on the basis of intrinsic differences in oxidative damage accrual. Although widely accepted, there is a growing number of exceptions to this theory, most contingently related to genetic model organism investigations. Proteins are one of the prime targets for oxidative damage and cysteine residues are particularly sensitive to reversible and irreversible oxidation. The adaptation and survival of cells and organisms requires the ability to sense proteotoxic insults and to coordinate protective cellular stress response pathways and chaperone networks related to protein quality control and stability. The toxic effects that stem from the misassembly or aggregation of proteins or peptides, in any cell type, are collectively termed proteotoxicity. Despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress which increases in cancer, metabolic and neurodegenerative diseases. Pharmacological modulation of cellular stress response pathways has emerging implications for the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. A critical key to successful medical intervention is getting the dose right. Achieving this goal can be extremely challenging due to human inter-individual variation as affected by age, gender, diet, exercise, genetic factors and health status. The nature of the dose response in and adjacent to the therapeutic zones, over the past decade has received considerable advances. The hormetic dose–response, challenging long-standing beliefs about the nature of the dose–response in a lowdose zone, has the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses, including carnitines. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including the possible signaling mechanisms by which the carnitine system, by interplaying metabolism, mitochondrial energetics and activation of critical vitagenes, modulates signal transduction cascades that confer cytoprotection against chronic degenerative damage associated to aging and neurodegenerative disorders.

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Acknowledgments

Work from the authors’ laboratories was supported by grants from MIUR, FIRB RBRN07BMCT, I.N.B.B., and by ‘‘Fondi Ateneo’’ 2008 and 2009. We are very much honoured to contribute to this Special Issue in honour of Abel Lajtha. Everybody in the field of Neurochemistry knows Abel Lajtha and his great contribution to the advancement of research in Neurochemistry. He has been the Editor in Chief of the Journal “Neurochemical Research” for so many years holding very stimulating and interesting Meetings of the Editorial Board to which we are very proud to have participated. It is difficult to imagine future Editorial Board Meetings without him. We would like to thank him very much for his great contribution to the advancement and success of Neurochemical Research and ask him to continue helping us with its precious efforts and advices.

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Authors and Affiliations

  1. Department of Chemistry, University of Catania, Viale Andrea Doria, 95100, Catania, Italy

    Vittorio Calabrese, Carolin Cornelius & Anna Maria Giuffrida Stella

  2. Environmental Health Sciences Division, School of Public Health, University of Massachusetts, Amherst, MA, USA

    Edward J. Calabrese

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  1. Vittorio Calabrese
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  2. Carolin Cornelius
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  3. Anna Maria Giuffrida Stella
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  4. Edward J. Calabrese
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Correspondence to Vittorio Calabrese.

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Special issue article in honor of Dr. Abel Lajtha

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Calabrese, V., Cornelius, C., Stella, A.M.G. et al. Cellular Stress Responses, Mitostress and Carnitine Insufficiencies as Critical Determinants in Aging and Neurodegenerative Disorders: Role of Hormesis and Vitagenes. Neurochem Res 35, 1880–1915 (2010). https://doi.org/10.1007/s11064-010-0307-z

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