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.
Highlights
Mitochondrial dysfunction is inherent in a variety of human disorders from the classical mitochondrial diseases arising from mitochondrial DNA mutations to those involving mitochondrial signaling pathways to the rest of the cell, modulated by organellar dynamics and culminating in programmed cell death
The role of mitochondria in normal aging has been the focus of extensive research in the last decades and being complementary to and maturing from the free radical theory of aging, to the oxidative stress theory of aging, to the mitochondrial oxidative stress theory of aging, and today addressing the tight co-regulation of mitochondrial energy and redox signaling
Functions of carnitine and acylcarnitines in fatty acid metabolism, ketosis and buffering of the concentration ratio of acyl-CoA to free CoA, are significant in brain metabolism, under conditions associated with neurodegenerative damage
Summary
Whereas the acute induction of this enzyme in neural and other tissues is predominantly cytoprotective in nature, protracted or repeated up-regulation of the Hmox gene in astrocytes, oligodendroglia and possibly neurons may perpetuate cellular dysfunction and demise in many chronic degenerative and neuroinflammatory conditions long after provocative stimuli iniziation Within this context, heme-derived free ferrous iron, CO, and biliverdin/ bilirubin are all biologically active substances that can either ameliorate or exacerbate neural injury contingently to the specific disease conditions, such as intensity and duration of HO-1 expression and/or the nature of the resulting redox milieu [68,69,70,71]. Consistent with this notion, calorie restriction slows the progression of agerelated diseases, extending the lifespan of many species and, in addition, dietary supplementation with essential and/or branched chain amino acids (BCAAs) has been recently demonstrated to support cardiac and skeletal muscle mitochondrial biogenesis, thereby preventing oxidative damage and enhancing physical endurance in middle-aged mice, with resulting prolonged survival [73]
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