INFLAMMATION, ADVANCING AGE AND NUTRITION Chapter 26 - Cellular Stress Response, Hormesis, and Vitagens in Aging and Longevity: Role of mitochondrial “Chi”

Abstract Understanding the mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. The average life span has increased over the few last centuries as a consequence of medical and environmental factors, but the maximal life span remains unchanged. Extension of the maximal life span is currently possible in animal models following measures such as genetic manipulations and caloric restriction. Caloric restriction appears to prolong life by reducing reactive oxygen species-mediated oxidative damage. But reactive oxygen species formation, which is positively implicated in cellular stress response mechanisms, is a highly regulated process controlled by a complex network of intracellular signaling pathways. By sensing the intracellular nutrient and energy status, the functional state of mitochondria, and the concentration of reactive oxygen species produced in mitochondria, the longevity network regulates life span across species by coordinating information flow along its convergent, divergent, and multiply branched signaling pathways; these involve vitagenes, which are genes involved in preserving cellular homeostasis during stress conditions. Vitagenes encode components of the heat shock protein (HSP32 and HSP70), thioredoxin, and sirtuin protein systems. Dietary antioxidants have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose-response challenges long-standing beliefs about the nature of the dose-response in a low-dose zone, and thus has the potential to significantly affect the design of preclinical 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. In this chapter, we focus on possible signaling mechanisms involved in the activation of vitagenes, resulting in enhanced defense against energy and stress resistance, as well as homeostasis disruption, which consequent affects longevity processes. Keywords Free radicals; Redox balance; mitochondrial medicine; Vitagens; Heme oxygenas; Hormesis Acknowledgments Work from the authors’ laboratories was supported by grants from MIUR, FIRB RBRN07BMCT, I.N.B.B., and by the “Fondi Ateneo” 2008 and 2009. Copyright © 2014 Elsevier Inc. All rights reserved.