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

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.

Redox regulation of cellular stress response in multiple sclerosis

“…HO is present in various tissues with the highest activity in the brain, liver, spleen, and testes. There are three isoforms of heme oxygenase, HO-1 or inducible isoform [13,16,22], HO-2 or constitutive isoform [49], and the recently discovered HO-3, cloned only in rat to date [50]. Elevation of HO-1 expression and activity in MS is probably due to elevated oxidative stress.…”

“…Members of the sirtuin family have since been found to function as deacetylases for numerous protein targets involved in many cellular pathways, including cellular stress responses, apoptosis, and axonal degeneration. The activity of sirtuins can be regulated by other compounds that can serve as activators (e.g., plant polyphenols) that increase enzyme activity by lowering the Km of its substrates or that can serve as inhibitors (e.g., sirtinol) [15,16]. Neuroprotection mediated by SIRT1 activation has been demonstrated in axotomized dorsal root ganglion neurons and in neurons containing the Huntingtin gene mutation responsible for neurodegeneration in Huntington disease.…”

Effect of black mulberry (Morus nigra) extract treatment on cognitive impairment and oxidative stress status of d-galactose-induced aging mice

“…As aging reduces mental, physical or social activities in human beings, anti-aging has become a major public issue (Bao et al 2014). Accumulated evidence suggests that oxidative stress is an essential source for the process of biological aging, and reactive oxygen species (ROS) and reactive nitrogen species (RNS) play an important role by oxidizing DNA, lipid and protein macromolecules (Calabrese et al 2010;Obrenovich et al 2011;Fransen et al 2013). There is a general reduction in different physiologic functions which lead to agerelated diseases during aging in most organs.…”

Carnitine-induced senescence in glioblastoma cells

“…Carnitine is an essential substance for the β-oxidation of fatty acids in mitochondria and is recognized as an antiaging nutrient (12,18). Several reports have shown that it Figure 2.…”