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.

Figure 1

Quantitative features of hormetic dose-response curve.

Figure 2

a,b. Vitagenes and the pathway of cellular stress response. Cumulating misfolded proteins in response to proteotoxic environmental stress conditions triggers the cellular stress response (Figure 2a). HSPs that are normally bound to HSF1, maintaining it in a repressed state before stress, are titrate away by damaged or misfolded proteins with resulting HSF-1 activation. Multi-step activation of HSF1 involves post-translational modifications, such as hyperphosphorylation and deacetylation, which allow HSF1 to trimerize, translocate into the nucleus, and bind to heat-shock elements (HSEs) in the promoter regions of its target hsp genes. Nutritional antioxidants, including carnosic acid, resveratrol, sulforaphane, dimethyl fumarate, acetyl-L-carnitine or carnosine are able to activate vitagenes, such as heme oxygenase, Hsp70, thioredoxin reductase and sirtuins which represent an integrated system for cellular stress tolerance. Phytochemicals and Acetyl-L-carnitine act through the activation of the vitagene system, with up-regulation of HO-1, Thioredoxin, the GSH and Sirtuin system, results in counteraction of pro-oxidant conditions (Figure 2b). During aging, a gradual decline in potency of the heat shock response occur and this may prevent repair of protein damage, leading to degeneration and cell death.