Stress responses, vitagenes and hormesis as critical determinants in aging and longevity: Mitochondria as a “chi”

Abstract

Understanding mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing reactive oxygen species (ROS)-mediated oxidative damage. But ROS 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 ROS produced in mitochondria, the longevity network regulates life span across species by coordinating information flow along its convergent, divergent and multiply branched signaling pathways, including vitagenes which are genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the 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 lowdose zone, having 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. Here we focus on possible signaling mechanisms involved in the activation of vitagenes resulting in enhanced defense against energy and stress resistance homeostasis dysiruption with consequent impact on longevity processes.

Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases

“…Vitagenes encode for heat shock proteins Hsp32 and Hsp70, the thioredoxin and the sirtuin protein systems (Calabrese et al, 2008). Dietary antioxidants have recently been demonstrated to be protective through the activation of hormetic pathways, including vitagenes (Cornelius et al, 2013), such as both melatonin and resveratrol that promote SIRT1 protein expression (Fig. 4) (Allard et al, 2009;Tajes et al, 2009).…”

“…However, recent findings have revealed that ROS formation is likely not the main cause of aging (Hekimi et al, 2011) and while chronic high levels of ROS can produce cellular damage, contributing to the aged phenotype, low levels are implicated in cellular stress responses and survival mechanisms, which are highly regulated processes controlled by a complex network of intracellular signaling pathways (López-Otín et al, 2013). By sensing the intracellular nutrient and energy status, the functional state of mitochondria, and the concentration of ROS produced in mitochondria, the longevity network regulates lifespan across species by coordinating information flow along multiply diverse signaling pathways, including vitagenes which are genes involved in preserving cellular homeostasis during stressful conditions (Cornelius et al, 2013). Vitagenes encode for heat shock proteins Hsp32 and Hsp70, the thioredoxin and the sirtuin protein systems (Calabrese et al, 2008).…”

Heat shock proteins in neurodegenerative disorders and aging

“…However, many nonthermal stimuli also denature proteins, such as oxidative stress, mitochondrial collapse, hypoxia, irradiation, endoplasmic reticulum stress, and physical trauma, and these stimuli often also induce heat shock protein synthesis (Aridon et al 2011;Lanneau et al 2010). Heat shock proteins are so essential for life and well conserved across species that the genes encoding some of these proteins have been termed "vitagenes" by Vittorio Calabrese and his colleagues (Calabrese et al , 2012Cornelius et al 2013). Despite the integrated network of chaperones and co-chaperones, proteins cannot always be folded back into their native shapes, especially when they are severely damaged.…”

Apurinic/Apyrimidinic Endonuclease 1 Upregulation Reduces Oxidative DNA Damage and Protects Hippocampal Neurons from Ischemic Injury

“…Hormesis is defined as favorable reactions to low-level stress and has been observed in the toxicological literature for many decades (4)(5)(6)(7)47). Hormesis elicits U-shaped or biphasic responses to stress and is mediated, at least in part, by the co-ordinated network of vitagenes (8)(9)(10)20). Preconditioning increases the expression of the vitagenes thioredoxin, sirtuin-1, Hsp32, and Hsp70 (1,2,16,59).…”

“…Mild cellular stress is known to engage the vitagene network of pro-survival proteins such as heat shock proteins 70 (Hsp70), Hsp32 (also known as heme oxygenase 1), thioredoxin, and sirtuin-1 (8,10,20). In order to examine whether PI also increased vitagenes, we probed for Hsp32, Hsp70, thioredoxin, and sirtuin-1 ( Supplementary Fig.…”